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THECELL'S 
DESIGN 

How CHEMISTRY REVEALS 
THE CREATOR'S ARTISTRY 



FAZALE RANA, PHD 



BakerBooks 

division of Bal<er Publishing Group 
Grand Rapids, Michigan 



CONTENTS 



List of Illustrations 9 
Acknowledgments 13 
Introduction: A Rare Find 15 

1. Masterpiece or Forgery? 23 

2. Mapping the Territory 35 

3. The Bare Essentials 53 

4. Such a Clean Machine 69 

5. Which Came First? 97 

6. Inordinate Attention to Detail 109 

7. The Proper Arrangement ofElements 

8. The Artist s Handwriting 141 

9. Cellular Symbolism 169 

10. Total Quality 183 

11. A Style All His Own 203 

12. An Elaborate Mosaic 225 

13. Coloring Outside the Lines 245 

14. The Masterpiece Authenticated 269 

Epilogue 285 
Notes 287 
Glossary 314 
Index 327 



ILLUSTRATIONS 



Figures 

1.1 The Explanatory Filter 25 

2.1 The Cell (with inset) 37 

2.2 Protein Structure 44 

2.3 Phospholipid Structure 46 

2.4 Phospholipid Bilayer Structure 47 

2.5 Membrane Proteins 47 

2.6 Fluid Mosaic Model 48 

2.7 DNA Structure 49 

2.8 Chromosome Structure 51 

2.9 Central Dogma of Molecular Biology 52 

4.1 The Bacterial Flagellum 71 

4.2 F.-F.ATPase 72 

4.3 Assembly of the Bacterial Flagellum 75 

4.4 The AcrA/AcrB/TolC Complex 76 

4.5 Virus Structure and Life Cycle 79 

4.6 Viral DNA Packaging Motor 80 

4.7 The Myosin Linear Motor 82 

4.8 Dynein 83 

4.9 Brownian Motion and Brownian Ratchets 92 

4.10 The BiP Brownian Ratchet 94 



5.1 DNA Replication and Cell Division 100 

5.2 mRNA Splicing 103 

5.3 Ribosome Structure 104 

5.4 Chaperone Activity 106 

6.1 Aquaporin Structure 113 

6.2 Amino Acid Side Groups 114 

6.3 Proton Wire 116 

6.4 Collagen 117 

7.1 Nucleotide Structure 131 

7.2 DNA Backbone and Side Chains 132 

7.3 The Phosphodiester Bonds of RNA 133 

7.4 Differences between Deoxyribose and Ribose 133 

7.5 Gene Structure 135 

7.6 High-Energy Bonds of ATP 138 

8.1 Carbohydrate Structures 147 

8.2 The Lac Operon 149 

8.3 Base-Pairing Rules and the Even Parity Code ofDNA 161 

9.1 Prior Minimization Capacity of the Genetic Code 176 

9.2 The HistoncOctamcr 179 

10.1 tRNA Structure 188 

10.2 Protein Synthesis at the Ribosome 190 

10.3 RNA Polymerase Production ofmRNA 194 

11.1 LUCA and the Tree of Life 217 

11.2 Semiconservative DNA Replication 219 

11.3 DNA Replication Bubble 220 

11.4 The Proteins ofDNA Replication 222 

12.1 Bilayer Assemblies 230 

12.2 Fatty Acids and Micelles 239 

13.1 The Futile Cycle ofGlycolysis 252 

13.2 Pseudogenes 257 

13.3 Two Metabolic Fates ofProteins 263 



11 

Tables 

3.1 Genome size of Life's Simplest Organisms 56 

3.2 Minimum Genome Size for Photoautotrophs 57 

3.3 Estimates of the Essential Genome Size 59 

8.1 Cellular Sentences 143 

8.2 Parity Bit Assignment 159 
9.1 The Genetic Code 172 

11.1 Examples of Molecular Convergence 207 



ACKNOWLEDGMENTS 



This book represents the sacrifice and hard work of many people, not just the 
author s. I want to thank my wife, Amy Rana, and my children — Amanda, 
Whitney, and Mackenzie — for their love, encouragement, and understand- 
ing when this book project took "priority" over family matters. 

Each member of the Reasons To Believe team has supported me with 
their friendship and encouragement in this endeavor and I am grateful. 
Kathy and Hugh Ross deserve a special mention for their inspiration and 
the opportunities they have given me. 

I especially want to acknowledge the editorial department (staff and 
volunteers) who dedicated themselves to this book as if it was their own 
labor of love. Thank you Patti Townley-Covert, Sandra Dimas, Marj Har- 
man, Linda Kloth, Kristi Sandberg, and Colleen Wingenbach for your 
expert editorial guidance and help with all the little chores that must be 
done during a book project. Thank you Jonathan Price and Phillip Chien 
for designing the many figures found in this book. 

The critical peer-review of scholars Dr. Matt Carlson, Dr. Russell Carlson, 
Richard Deem, Dr. Lyle McCurdy, Amy Rana, Kenneth Samples, and Dr. 
Jeff Zweerink was invaluable, and this book is better for it. Still, I assume 
all responsibility for any errors found herein. I'm indebted to Joe Aguirre, 
Ken Hultgren, Dr. Dave Rogstad, Dr. Hugh Ross, Kenneth Samples, and 
Dr. Jeff Zweerink for our many stimulating conversations in the hallway 
and during lunch. These discussions helped to directly and indirectly shape 
the contents ofthis book. 

I also want to thank my friends at Baker Books, especially Bob Hosack 
and Paul Brinkerhoff, for their efforts on this project and for their belief 
in our work at Reasons To Believe. 



13 



INTRODUCTION 

A Rare Find 



"What would you like to be when you grow up?" As a child, I usually 
answered, "I don't know." 

Yet deep down inside I knew exactly what I wanted to be — an explorer. I 
never told anyone my desire though, because I was convinced there weren't 
any new territories left to discover and explore. 

By the time I entered college and was ready to choose a career path, I 
decided (at my father's urging) to enroll in a premed program. Not long 
afterwards, I began taking courses in chemistry and biology. That's when I 
realized I'd been wrong as a youngster. An abundance of scientific "lands" 
remained to investigate! For me, the most exciting of all was the molecular 
world inside the cell. 

My fascination with life's chemical systems prompted me to change my 
course of study and launched my career as a biochemist. I joined a band 
of scientific explorers who — with the aid of electron microscopes, spec- 
trometers, chromatographs, ultracentrifuges (and an assortment of other 
laboratory techniques) — made available new vistas on the inner workings 
ofthe cell. 



The Most Fascinating Discovery of All 

The forays made by biochemical adventurers into the cell's molecular 
environs have opened up windows on life at its most fundamental level. 

15 



16 Introduction 

Scientists have fairly complete knowledge about the chemical composi- 
tion of the cell's structures and contents. We know, for the most part, 
how living systems extract energy from the environment and convert it 
into a form that the cell can use for its operations. We are beginning to 
grasp the relationship between the structure of biomolecules and their 
function. And, we understand how the cell stores and manages the in- 
formation needed to carry out life's activities. The molecular basis for 
inheritance and the chemical processes responsible for cell division stand 
in full view. 

As amazing as these insights are, for me, the most fascinating discovery 
made by scientific pioneers has little to do with the cell's structures or activi- 
ties. Rather, it is the sheer beauty and artistry of the biochemical realm. 



Biochemistry as Art 

So far, only a small portion of the splendor of life's chemistry has been 
captured in scientists' attempts to represent the structures, chemical in- 
teractions, and operational mechanisms of biochemical systems. Still, the 
magnificence of the cell's inner workings is evident even in the "crude" 
images produced by biomolecular explorers. 

In some ways, biochemists who attempt to depict what they've "seen" 
on the molecular frontiers inside the cell are like the cowboy artists of the 
past. Artists like Charles M. Russell (1864-19 26) sought to convey the 
adventure and majesty of the Old West on canvas for those who would 
never get a chance to experience it firsthand. Still, the best artist could never 
fully capture the actual splendor of a sunset over the western horizon or 
the panoramic sweep of the snow-covered Rocky Mountains. 

Though the remarkable depictions "painted" by biochemists are available 
for people to ponder, those who have never worked directly on biochemical 
problems can't fully appreciate the grandeur of the cell's molecular domain. 
Too much of the beauty is lost in the scientific translations. 



Biochemistry's Impact 

Unlike art, which some argue should be done strictly for its own sake,, 
the last half-century of biochemical advance has been more than "science 

for science's sake." The ever increasing understanding of the cell's chemistry 



17 

has revolutionized our day-to-day lives. Biochemistry drives many of the 
technological advances in biomedicine, agriculture, and even industry. 

But as important as these biochemical applications are, perhaps the 
most significant outcome of the so-called molecular biology revolution is 
universal recognition that biochemical systems appear to be designed. 

This elegance, evident in virtually all aspects of the cell's chemistry, car- 
ries profound philosophical and theological significance that prompts 
questions about the origin, purpose, and meaning of life. Though I once 
embraced the evolutionary paradigm, its inadequate explanations for the 
origin of life coupled with the sophistication and complexity of the cell's 
chemical systems convinced me as a biochemistry graduate student that a 
Creator must exist. = 



A Controversial Beginning 

Theists and atheists alike can see design in biological and biochemical 
systems. Even the well-known evolutionary biologist Richard Dawkins, an 
outspoken atheist, acknowledges that "biology is the study of complicated 
things that give the appearance of having been designed for a purpose." 

While the indicators of design in biological and biochemical systems are 
not controversial, their source is. For me, and many others, biochemical 
design is best explained as the handiwork of a Creator.: Yet, the majority in 
the scientific community maintains that the design found in the biological 
and biochemical realms is the product of a naturalistic evolutionary process. 
According to this view, natural selection operates on random variation 
again and again to yield structures and systems chat appear intentional 
but, in fact, are not. 

The late Francis Crick, who shared the Nobel Prize for discovering the 
structure of DNA, cautioned, "Biologists must constantly keep in mind 
that what they see was not designed, but rather evolved.". So even though 
life's chemistry looks as if it s the product of a Creator, many in the scientific 
community suppress this obvious intuition. 

Recent advances in biochemistry, however, make this resistance harder 
and harder to accept. Life scientists now have research tools they only 
dreamed about a few years ago. Researchers routinely isolate the fragile, 
complex molecular assemblies that constitute the cell's chemical systems. 
New techniques allow biochemists to manipulate the cell's structures and 



18 Introduction 

processes at a molecular level and visualize its chemical constituents at an 
atomic level. All this progress has led to remarkable insight into the cell s 
chemistry. This detail reveals biochemical systems that seem far more pur- 
poseful, intricate, and sophisticated than ever imagined. 

As biochemists learn more about the details of the cell's chemical systems, 
the appearance of design becomes increasingly pervasive and profound. 
Currently, hundreds of scientists who represent a range of scientific disci- 
plines express skepticism about "the ability of random mutation and natural 
selection to account for the complexity of life.". This skepticism largely 
fuels the recent resurgence of the creation (intelligent design)/evolution 
controversy in America. 



Darwin's Black Box 

In spite of the mind-boggling evidence for biochemical design, most 
works that explore the creation/evolution controversy give life's chemical 
systems cursory attention, typically confined to a chapter or two. As far as 
I know, few, if any, provide a book-length treatment. The chief exception is 
Michael Behe s Darwin's Black Box, a seminal work (originally published in 
1996) that presents a potent case for intelligent design from a biochemical 
perspective. In this book, Behe argues that biochemical systems, by their 
very nature, are irreducibly complex. 

According to Behe, irreducible complexity describes "a single system 
composed of several well-matched interacting parts that contribute to 
basic function, wherein removal of any one of the parts causes the system 
to effectively cease functioning." 

Behe makes the case that irreducibly complex systems cannot be pro- 
duced from protosystems by the Darwinian process of slight incremental 
changes that inch towards the finished product. Anyprotosystem that lacks 
even one of the parts that contributes to "basic function" is nonfunctional. 
Even if all the essential components are present, they too must interact with 
one another in a "just-so" fashion, or that system will not function. If the 
protosystem doesn't have function, then natural selection can't operate on 
it to produce an improved form. Without function, natural selection has 
nothing to select. 

Irreducibly complex systems, and hence biochemical systems, must be 
produced all at once. Therefore, it's completely within the bounds of rational 



thought to conclude that irreducibly complex biochemical systems came 
inio existence through intelligent agency. 

The case for intelligent design made in Darwin's Black Box is compel- 
ling. Still, Bche's explanation rises and falls on the perceived validity of the 
concept of irreducible complexity. Several scientists have leveled significant 
challenges against this argument. < And, even though Behe has responded 
to these critics, many skeptics remain unconvinced. 

Darwin's Black Box primarily argues for intelligent design by empha- 
sizing the inability of natural selection to generate irreducibly complex 
systems in a gradual stepwise evolutionary process. And because natu- 
ral processes can't explain irreducibly complex biochemical systems, they 
must be designed. Critics generally view this approach as agod-of-the-gaps 
argument — illegitimately evoking God as the explanation whenever science 
cannot account for some feature or process in nature. Critics maintain that 
the case for intelligent design rests on a lack of understanding and reject 
Behe's argument on this basis alone. 

These objections motivated me to write this book. 

An Increasing Weight of Evidence 

Irreducible complexity is but one of a vivid ensemble of biochemical 
features that individually and collectively point to intelligent design. The 
Cell's Design goes beyond irreducible complexity and communicates avast 
range of amazing properties that characterize life's chemistry. 

The never before compiled evidence shows that the cell displays far 
more than a single feature that reflects intelligent design at the biochemi- 
cal level. Rather, a magnificent gallery of awe-inspiring characteristics sig- 
nify a Masters brilliance at work. While skeptics may not be impressed 
by the irreducible complexity of biochemical systems, perhaps they will 
respond differently to a growing collection of evidence that leads to one 
conclusion — a supernatural basis for life. 

The hallmark indicators of design displayed in the cell's chemistry make 
a case for a Creator based on what scientists know, not on what we don't 
understand. Instead of arguing for creation by relying on the perceived in- 
ability of natural processes to generate life's chemical systems, this approach 
frames the support for intelligent design in positive terms by highlighting 
biochemical features that reflect the Creator's signature. 



20 .— - 

The Lay of the Land 

In many respects, Behe pioneered the biochemical case for intelligent 
design in Darwin's Black Box. The Cell's Design continues this explora- 
tion and strives to make the biochemical case for a Creator much more 
compelling. 

Chapter 1 describes and justifies the approach used to argue for intel- 
ligent design in biochemical systems — one that relies upon the weight of 
interrelated evidence. Chapter 2 consists of a brief overview of cell biol- 
ogy and biochemistry. This section provides the necessary background to 
appreciate the elegant and powerful design that can only be seen in the 
details of the cell's chemical systems. 

The next ten chapters describe separate biochemical arguments for de- 
sign. Each one indicates the work of an intelligent and creative mind. Col- 
lectively, these arguments constitute a compelling weight of evidence for 
a supernatural basis for life. 

Chapter 13 responds to one of the most common challenges leveled 
against arguments for intelligent design: imperfections found in nature. 
Chapter 14 unveils the biomolecular masterpiece found in the cell and, in 
doing so, authenticates the biochemical intelligent design argument. 

In most works of this nature, the authors are quick — perhaps too quick — 
to declare the inability of evolutionary processes to produce certain features 
of the biological realm. Their argument goes something like this: "If evolu- 
tion can't produce it, then a Creator must have." The Cell's Design avoids 
this negative approach. Instead of focusing on what evolution can or cannot 
do, this book emphasizes the aspects of biochemical systems that make a 
positive case for intelligent design. 

Biochemical systems are complex and in nearly every case incompletely 
understood. Scientists are still working out what they believe to be the pos- 
sible mechanisms for evolutionary change. Often there simply isn't enough 
understanding to say for certain if evolutionary processes can or cannot 
generate specific biochemical characteristics. Of course, the burden of proof 
should be on evolutionary biologists to explain in detail how biochemical 
systems originated all on their own. 

In a few cases though, enough understanding already exists to criti- 
cally evaluate the likelihood of evolutionary mechanisms generating spe- 
cific properties of life's chemistry. This is true for the origin of the genetic 
code (chapter 9), the convergent beginnings of many biochemical systems 



(Chapter 11), and the emergence of cell membranes (chapter 12). In these 
cases, a detailed critique of the evolutionary paradigm accompanies the 
positive case for intelligent design. 

I invite you to come and explore the molecular world of the cell and 
perhaps you'll be as captivated by the beauty and artistry of the molecular 
landscape as I am. As we look at the systems that constitute life at its most 
fundamental level, it is my hope that the weight of the evidence will con- 
vince you that biochemical design results from a Creator's hand, a Divine 
Artist. 

The technical terminology that is so much apart of cell biology and 
biochemistry can feel overwhelming for many people. So, the details have 
been limited to those necessary to show the Creator's fingerprints. However, 
the Creator s signature style is ultimately most evident in the finer points of 
the cell's chemistry. Please keep in mind, that for an Artist's work to be fully 
appreciated, one must take the time to study its subtleties and nuances. 

Unfamiliar terrain never guarantees a simple path. But struggling over, 
around, and through the obstacles can lead to vistas of unimagined beauty 
and splendor as nature's art comes into view. It's definitely worth every 
effort to get there. 

But, before unfolding the map that supplies the necessary directions, 
its important to come up with a strategy to determine whether the cell is 
actually a masterpiece of a Divine Artist or only appears that way. 




The Unknown Masterpiece (Reproduced by permission from © Mark Harris) 



1 



MASTERPIECE OR FORGERY? 



Sometime in the early 1970s, a junk dealer came across five ink drawings 
while clearing out a deceased woman's apartment in London. He hung 
onto them for several years, after which time one of them wound up in the 
hands of a Brighton art dealer. Eventually, that dealer showed the mysterious 
drawing to Mark Harris, an art aficionado, who concluded that the piece 
might well be an unknown work by Picasso., 

This drawing, referred to as Picasso's The Unknown Masterpiece, has 
provoked a heated controversy between his estate and Harris. The estate 
and its beneficiaries deny the drawing's authenticity. 

In the face of this rejection, Harris and his collaborators began amass- 
ing a large body of evidence to support their claim that Picasso, indeed, 
painted the masterpiece. 

To make the case, Harris points to hallmark features of Picasso's work. 
For example, a fingerprint rolled into the wet ink at the time the drawing 
was made, appears near the bottom of the piece. Many artists in the early 
1900s, including Picasso, began fingerprinting artwork to stave off fraud. 
This mark could conclusively identify the work as a Picasso if compared 
with his known fingerprint. However, the estate refuses to comply, officially 
insisting that Picasso did not fingerprint his work during the 1930s. 

23 



Ihc Cell's Design 

While photographing the painting, Harris also discovered what seems to 
be Picasso's dated signature. A Scotland Yard handwriting expert identified 
features in the signature consistent with those from other Picasso works. 

The drawing also contains a number of features characteristic of other 
Picasso works and appears to have connections to several specific pieces. 
Both Mark Harris and Melvin Becraft (author oi Picasso's Guernica: Images 
within Images) place Picasso's The Unknown Masterpiece between his 1925 
work. The Three Dancers, and his 1937 work, Guernica. Picasso was known 
to carry ideas and themes from work to work. The Unknown Masterpiece 
links themes, symbolisms, and hidden imagery in The Three Dancers v^ith 
those found in Guernica — connections not previously apparent. 

Harris also recognized themes that reflect the events of Picasso's life at 
the time The Unknown Masterpiece was created. The year 1934 was a time 
of intense crisis for Picasso. The tragedies he experienced appear in the 
imagery of the mysterious drawing. Related symbolism depicting these 
circumstances also occurs in other Picasso pieces of the same period. 

It remains to be seen if Harris's case for authenticity convinces the Pi- 
casso estate and the art world. Still, he has assembled what appears to be a 
compelling argument on the painting's behalf. 

The approach used by Harris to argue for the authenticity of The Un- 
known Masterpiece can also be used to make the case that life's chemistry 
has been created by a Divine Artist. Before articulating and defending this 
approach, a discussion on methods to detect intelligent design reveals how 
difficult this undertaking can be. 

Detecting a Master at Work 

Most people are pretty good at distinguishing between the work of an 
intelligent agent and the outworking of natural processes. It's usually not 
that difficult, for example, to discriminate between an unusually shaped 
rock and an arrowhead intentionally made out of stone. Philosopher Jay 
Richards and astronomer Guillermo Gonzalez point out in their book The 
Privileged Planet that most individuals have no idea how they make the 
distinction between an intelligently designed object and one generated by 
natural processes. They just intuitively do.: 

Usually people can trust their intuition. Still, as Richards and Gonzalez 
discuss, subjective bias and the capacity of natural processes to yield objects 



tint mimic design nuke the possibility oi false positives (i.e., mistaking the 
product of blind processes for intelligent design) a troubling reality. 

To avoid false positives, arigorous and formalized scheme to reliably detect 
the activity of an intelligent agent is necessary. In The Design Inference, William 
Dembski pioneers and proposes such a methodology — something he calls an 
"explanatory filter."., This filter consists of a sequence of three yes/no questions 
that guide the decision process of determining whether an intelligent mind 
has been at work (see figure 1.1). Based on this filter — if an event, system, or 
object is intentionally produced by a designer, then it will (1) be contingent, 
(2) be complex, and (3) display an independendy specifiedpattern. According 
to the filter, to be confident that an event, system, or object has been produced 
by an intelligent designer it can't be a regularity that necessarily stems from 
the laws of nature, and it can't be the result of chance. According to Dembski, 
the explanatory filter highlights the most important quality of intelligendy 
designed systems, namely, specified complexity. In other words, complexity 
alone is not enough to indicate the work of an intelligent agent; it must con- 
form to a pattern. And, that pattern must be independendy specified. 

If an event, system, or object successfully passes through the filter, then, 
Dembski argues, it must emanate from the activity of an intelligent agent. The 
filter ensures that the product of natural processes is not mistaken for deliber- 
ate design. And yet, while this approach avoids false positives, it is plagued 



Um 




Specification 



Nsssssity 



*- Chance 



Design 



Figure 1.1. The Explanatory Filter 

Three questions are used to determine if an event, system, or object stems from the activity of an 
intelligent agent. Can it be explained as a consequence of the laws of nature (necessity)? If yes, 
then it is not designed. If no, then can it be explained as a consequence of chance (contingent)? 
If yes, then it is not designed. If no, then does it display a specified pattern (specification)? If no, 
then it is not designed. If yes, then it must be the product of an intelligent designer. 



26 

by false negatives. For example, the filter will fail to register intelligent design 
if the agent operates in away that mimics natural processes or in a manner 
that simulates chance. = In other words, if God created life using evolutionary 
processes, the filter may not be able to detect his involvement. 

Filtering Out Forgeries 

Can the explanatory filter be used to detect intelligent design in bio- 
chemical systems? Dembski says "yes." In Intelligent Design, he describes 
the relationship between specified and irreducible complexity. Biochem- 
ist Michael Behe argues that irreducible complexity is an indicator of 
biochemical intelligent design; but according to Dembski, irreducible 
complexity is a type of specified complexity. The specified pattern is the 
simultaneous co-occurrence of components required for the system to 
have minimal function. 

Behe argues, and Dembski agrees, that Darwinian evolutionary mecha- 
nisms cannot generate irreducibly complex biochemical systems. In terms 
of formally applying the explanatory filter, this limitation means that bio- 
chemical systems are not a regularity produced by the outworking of na- 
ture s laws. Biochemical systems are contingent, complex, and conform to 
an independently specified pattern (irreducibility). 

The explanatory filter seems to effortlessly identify irreducibly complex 
biochemical systems as the product of an intelligent agent. Careful consider- 
ation of the questions posed at the first and second decision points, however, 
exposes potential problems that could clog the filter. The first decision node 
seeks to determine if an event, system, or object is contingent or a necessary 
consequence of the laws of nature. While it certainly seems as if irreducibly 
complex biochemical systems are contingent, there are biochemists who 
disagree. Some scientists maintain that life's origin (and hence the origin of 
biochemical systems) is a cosmic imperative built into the laws of nature. 

The notion that biochemical systems are a necessity can be questioned on 
numerous grounds. Still, given the current state of scientific knowledge, 
it can't be ruled out with absolute certainty. Nobody really knows if life is 
a cosmic imperative or not. The question posed at the first decision point 
in the explanatory filter can't be answered with a simple "yes" or "no." 

Further complicating the first decision is the view held by many origin- 
of-life researchers that the origin of biochemical systems stems from both 



necessity and chance. In other words, the answer to the question posed at 
the filter's first stage is not either "yes or no" hut both "yes and no." Again, 
scientific challenges to this view can be raised, but the current state of sci- 
entific knowledge makes it impossible to decisively rule out an evolutionary 
explanation for life's origin that appeals to both necessity and chance. 

Potential problems confront the second decision point in the filter as 
well. Simple visual inspection of most biochemical systems reveals their 
complexity. Yet, are biochemical systems so complex they can't be explained 
by chance alone or more appropriately by chance operated on by some 
selection process? Intuitively, it does indeed seem as if this is the case. But 
biochemists lack the knowledge to substantiate this conclusion. 

In many respects, biochemical knowledge is still in its infancy. For ex- 
ample, biochemists still don't understand the relationship between amino 
acid sequence and protein structure, let alone function (see page 42). To 
rigorously demonstrate that biochemical systems are so complex that they 
defy a naturalistic explanation, biochemists need this basic understanding. 
Establishing the relationship between amino acid sequence and protein 
function is no trivial exercise and will take decades of concerted effort by the 
biochemical research community. So, there is no way to answer the second 
question posed by the explanatory filter with any level of certainty. 

The point is not to debate the validity of the explanatory filter as a de- 
sign detection methodology. Rather, it is to describe a suitable, practical 
approach that can demonstrate whether or not the cell's chemical systems 
are the work of a Creator. In principle, the filter seems capable of detect- 
ing intelligent design. But in practice, at least with respect to biochemical 
design, it can't be used to establish intelligent causation — until much more 
is learned about biochemical systems and the potential of naturalistic pro- 
cesses to generate them. 

So what would constitute a workable approach for detecting intelligent 
design in biochemical systems ? 

Predictable Patterns 

In spite of the potential problems associated with the explanatory filter, 
Dembski appears to be onto something really important with his concept 
of specified complexity as a marker for intelligent design. Systems inten- 
tionally produced by human designers typically display certain hallmark 



2g The-Cell'sDeslgn 

characteristics. That is, these types of systems conform to a pattern or speci- 
fication that exists independent of the system. These patterns are strong 
indicators that an intelligent human agent has been involved. 

Pattern (or specification in Dembski s words), and not necessarily com- 
plexity, appears to be the most important property when it comes to rec- 
ognizing the work of human intelligence. In defining what he means by 
design, Dembski notes that 

when intelligent agents act, they leave behind a characteristic trademark 
or signature. ..It is design in this sense — as a trademark, signature, vestige 
or fingerprint — that this criterion for discriminating intelligently from 
unintelligently caused objects is meant to identify." 

In the quest to detect deliberate mindful design, the only thing needed is 
to identify a pattern that reflects the work of an intelligent agent. Once es- 
tablished, this pattern can be used as the standard and compared with events, 
systems, or objects suspected to be the work of an intelligent agent. 

When people distinguish between the work of an intelligent agent and 
the outworking of natural processes, it's not intuition they use. Rather, 
whether they realize it or not, they are using pattern recognition. 

Though simple, this approach is profoundly powerful. For example, art 
aficionado Mark Harris is using pattern recognition in his quest to dem- 
onstrate that The Unknown Masterpiece is authentic. Harris has identified 
a set of features that characterize Picasso's work. This set of features consti- 
tutes the pattern Harris uses as a reference or standard against which The 
Unknown Masterpiece is compared. 

Pattern matching is quite common in science as well. For example, analytical 
chemists routinely use pattern recognition as a way to determine the identity 
of an unknown chemical compound by comparing the physical, chemical, and 
spectral properties for a series of known standards with those possessed by the 
unknown substance. The identity of the unknown compound is revealed when 
its characteristics closely match those possessed by a known chemical entity. 

Identifying an Original 

While it's relatively straightforward to establish a pattern that reflects 
Picasso's work or one that helps determine the identity of an unknown ma- 
terial, how could it be possible to specify a pattern that reflects the activity 



of a creator? How could he Creator's fingerprint possibly be 
recognized in nature? 

In the quest to identify the Divine Artists signature in nature, two things would 
be useful: (1) a set of criteria that universally describes the behavior of an intelligent 
designer and(2)some understanding of theCreators properties and capabilities. 

I in fortunately, no universal criteria for the behavior of an intelligent agent ex- 
ists. The only example available to base the pattern on is the behavior of human 
designers. Is it legitimate to generalize human behavior to form aset of criteria 
that universally describes the activity of any intelligent agent ? Could it be that, in 
general, other intelligent creators behave in ways distinct from human designers? 
Do human creators function in a way that deviates from the norm? This problem 
threatens to frustrate the use of pattern recognition to detect a Creator at work in 
the natural realm, unless the behavior of human designers can somehow be connected 
to this Divine Artist s work. 

To maintain that the Creator is an unidentified Genius is not sufficient. In order 
to gain insight into his or her or its characteristics and ability, an identity must be 
specified. Assuming the intelligent designer is the God described in the Old and 
New Testaments, the Bible reveals information that offers a limited but useful 
perspective on how he operates. 

The biblical account of humanity's origin establishes the link between human 
designers and the Creator. The Genesis 1 creation account and Genesis 5:1-2 teach 
that God created human beings (male and female) in his image)^ This declaration 
implies that humans bear a similarity to their Maker, at least in some ways. 

Scripture doesn't explicitly define what is meant by the image of God. Over the 
centuries, theologians have discussed and debated this topic. Some believe the image 
describes humanity's resemblance to God, while others think the image of God 
allows humans to function as his representatives or viceroys on Earth.,., A consensus 
of ideas identifies four characteristics:, - 

• Human beings possess a moral component. They inherently un- 
derstand right and wrong and have a strong innate sense of justice. 

• Humans, though physical, are also spiritual beings who recognize a reality 

beyond this universe and physical life. Mankind intuitively acknowledges 
the existence of God and has a propensity towards worship and prayer. 



30 

• Human beings relate to God, to themselves, to other people, and to 
other creatures. There is a relational aspect to God's image. 

• Humanity's mental capacity reflects God's image. Human beings 
possess the ability to reason and think logically. They can engage in 
symbolic thought. People express themselves with complex abstract 
language. They are aware of the past, present, and future. Human be- 
ings display intense creativity through art, music, literature, science, 
and technical inventions. 

The intellectual component of God's image holds the greatest relevance for 
pattern recognition as evidenced in human beings. This mental likeness reveals 
itself in human creativity (art, music, literature, and technical inventiveness). 
As God is a Creator, so too are human beings — they are minicreators. Being a 
reflection of their Maker implies that the hallmark characteristics of humanly 
designed systems will mirror those that were divinely designed. 

The expectation, however, is that humanly produced systems would, at best, 
be an imperfect reflection. If biochemical systems are indeed the product of 
a Master Creator who made man in his image, then the defining character- 
istics of those systems should be analogous to the hallmark characteristics of 
humanly crafted systems. At the same time, the cell's chemical systems should 
be clearly superior to anything produced by the best human minds. 

Much like Dembski's explanatory filter, any design detection protocol that 
relies on pattern recognition is bedeviled by false negatives. Consequently, 
this approach underdetermines intelligent design. Pattern recognition will 
not detect the Creator's activity if he works in a way that mimics natural 
processes or simulates chance. Additionally, there are many technologies 
that humans have yet to discover. If the Creator employed any of these as- 
yet-unknown technologies in the design of biochemical systems, they will 
remain unrecognized as part of the pattern that reflects his artistry. 



Investigating the Claim 

Pattern recognition represents a form of analogical reasoning. One of 
the most common forms of reasoning, analogical thinking is not only an 
integral part of day-to-day decision making, but also factors significantly 
into legal and scientific reasoning. The proper way to reason using analo- 
gies must be kept in mind to effectively employ pattern recognition while 
searching for the Creator s signature within biochemical systems. i. 



Analogical thinking employs inductive reasoning. As such, it is not neat 
and tidy. Conclusions are not certain but probabilistic. 

This type of reasoning involves comparing events, systems, or objects. If 
they are highly similar, then it can be concluded they are the same in 
some way. It, however, they are significantly dissimilar, such a conclusion 
would be unwarranted. 

For example, when two systems labeled A and B are compared, if A 
possesses properties a, b, c, d, e.. . and z — and B possesses proper- 
ties a, b, c, d, e... — it is reasonable to conclude that B possesses property 
z as well. This conclusion becomes even more likely if the property z 
somehow relates to properties a, b, c, d, e . . . . 

To properly reason from analogy, several factors must be considered: 

• The relevance of similarities is critical. The properties being compared 
must be relevant to the conclusion. 

• The number of similarities that are part of the analogy impacts the likeliness 

of the conclusion.The greater the number of similarities the greater the validity 
of the conclusion. 

• The number of events, objects, or systems that enter into the comparison 

influences the conclusion. The greater the number of separate comparisons, 
the more probable the conclusion. 

• The diversity of the events, objects, or systems compared has bearing on the 

conclusion. Greater diversity translates into greater confidence about the 
conclusion reached through comparison. 

• Disanalogy is important. In addition to shared similarities — the ways 
in which the events, objects, or systems differ must be considered. 

Mark Harris's case for the authenticity of Picasso's The Unknown Masterpiece 
illustrates the principles that constitute effective analogical reasoning. Harris 
hasn't relied on a single piece of evidence but rather on a weight of evidence — a 
number of similarities. These similaritiesarerelevant to Picasso's authorship. They 
are also quite diverse in nature. 

Any one of the individual pieces of evidence cited by Harris points to Picasso 
as the painting's creator. Still, in isolation, each piece of evidence can be dismissed 
by plausible counter-explanations. Someone might have forged Picasso's sig- 
nature or perhaps a kindred spirit memorialized his tragic circumstances. Yet, all 
the evidence combined points to the same conclusion — Picasso drew The Unknown 



32 

supports this conclusion, it becomes more difficult to defend alternative 
explanations and the less likely it becomes that the painting is fraudulent. 
In addition, the case for authenticity doesn't rest simply on the weight of 
evidence amassed by Harris but on how some pieces of evidence interrelate. 
For example, the themes in The Unknown Masterpiece not only explain those 
in The Three Dancers and Guernica but also depict the timely events that 
bridge gaps between the appropriate dates. The way these pieces of evidence 
nicely "dovetail" with one another makes for a compelling claim. 

Finding God's Fingerprints 

Various lines of evidence can also make a powerful case that life's molecular 
artistry stems from the Creator described in the Bible. To be convincing, this 
position must be built upon a weight of evidence. For an idea to gain credibility 
in the scientific arena, it must find support from a collective body of data that 
works in concert to support one conclusion. Skeptics are within their rights 
to regard a single piece of evidence or a single line of reasoning as marginal in 
support of intelligent design. However, if a litany of diverse evidence exists, it 
becomes less tenable to reject a supernatural basis for life, even if naturalistic 
explanations for the emergence of biochemical systems have been advanced. 

Instead of making the argument that evolutionary processes cannot generate 
irreducibly complex biochemical systems, the approach used here maintains 
that irreducible complexity — a property that frequendy characterizes humanly 
designed systems — is one of the indicators of intelligent design because such 
specified complexity results from forethought and planning. Now, Behes 
concept of irreducible complexity (delineated in Darwin's Black Box) con- 
tributes to an overall pattern that points to the Creator's work in biochemical 
systems. Some of the details of this template — like molecular motors, chicken- 
and-egg relationships, fine-tuning and optimization, molecular convergence, 
pre-planning, quality control, biochemical information, the genetic code, and 
the fine-tuning of the genetic code — are discussed in chapters 3-12. 



God of the Gaps 

Unfortunately, too often Christian apologists or intelligent design advo- 
cates who argue for the work of a Creator focus on the perceived inability 
of natural processes to explain life's chemistry. By default, they conclude 



that the cell's biochemical systems must be designed. And as skeptics rightly 
point out, this conclusion doesn't necessarily follow. For these critics, the 
case for biochemical intelligent design, and hence biblical creation, rests 
on faulty "god-of-the-gaps" reasoning. 

Scientists admit they still have an incomplete understanding of many as- 
pects of life's chemistry, and many Christians and design theorists exploit this 
lack of knowledge. Skeptics rightly maintain that the evidence for intelligent 
design often rests merely on what science doesn't know, not on what has been 
discovered. Because science operates with partial knowledge, new discoveries 
and new insights always hold the potential to fill in the gaps and explain what 
the laws of chemistry and physics can accomplish. According to this critique, 
once science fills in the gaps, the evidence for a Creator will vanish. 



Compiling the Evidence 

Rather than use a negative approach that relies on gaps in understanding, 
the subsequent chapters make use of pattern recognition to identify the God 
of the Bible's involvement in bringing life into being. Such a method makes it 
possible to build ^positive case for biochemical intelligent design. This approach 
inherently depends on what science currently knows about life's chemistry and 
how the organization of biochemical systems relates to the characteristics of 
humanly designed systems — not on what science doesn't know. 

To demonstrate purposeful design, the cell's biochemical systems will be 
probed for the hallmark features of intelligent creativity in the same way 
that Mark Harris uncovered Picasso's telltale signatures in The Unknown 
Masterpiece. 

This strategy anticipates scientific advance and looks for future studies to 
uncover additional characteristics that reflect intelligent design as knowl- 
edge gaps become filled. From a theological standpoint, it is reasonable to 
expect that the cell's chemical systems should reflect the Creator's "signa- 
ture," if life's origin has a supernatural basis (Rom. 1 :20).i. This "signature" 
manifests itself as evidence for deliberate design. 

Is the artistry found in biochemical systems the authentic work of a Di- 
vine Artist, or is it a forgery produced by natural processes? The following 
chapters seek to answer this question. But first, to guide this exploration 
the next chapter provides a description — a map of sorts — of the cell and 
its molecular constituents. 




Jan Vermeer, The Artist's Studio (Reproduced by permission from Kunsthistorisches Museum, Vienna, 
Austria/The Bridgeman Art Library) 



MAPPING THE TERRITORY 



One of the best known works by Dutch painter Jan Vermeer (1632-1675) 
is The Artist's Studio. This baroque piece depicts an artist in a brightly lit 
studio painting a carefully posed subject. On the wall behind the young 
woman hangs a large map., 

Speculation abounds as to the meaning of the map. Some think it makes 
political commentary; others maintain the map is an allegory for the spread 
of the artist's reputation.: 

Maps frequently find their way into works of art. Artists often use them 
as a device to critique a specific culture. A map can also signify power and 
sovereignty over a particular territory. 

Biologists also use maps. Over the last half-century, researchers have 
used light and electron microscopes to systematically map the cell's in- 
terior. Application of biochemical techniques has increased knowledge 
about the structural and compositional makeup of the subcellular world. 
These biological and biochemical depictions of the cell's interior become 
the maps that represent science's growing control over life at its most fun- 
damental level. 

Studying the biological map that hangs in the Divine Artist's studio 
supplies the background necessary to appreciate the elegant sophistica- 

35 



tion of the cell's chemical systems. This exploration also sets the stage for 
understanding biochemical design as the Creators craftsmanship. 

Sighting the New World 

The same year that Jan Vermeer painted The Artist's Studio (1665), Robert 
Hooke discovered cells. 4 Following his initial work, a number of biologists 
reported the existence of cells in plants and animals. These discoveries cul- 
minated in the cell theory developed independently by Matthias Schleiden 
in 1838 and Theodor Schwann in 1839. 

This theory states that cells are the fundamental units of life and the 
smallest entities that can be considered "life." As a corollary, all organisms 
consist of one or more cells. Most life-forms on Earth are single-celled 
(bacteria, archaea, and protozoans). Multicellular organisms (plants, ani- 
mals, and fungi) are made up of specialized cells that carry out the many 
activities necessary for life. 

Most cells are between 5 and 40 microns in size. (A micron is one- 
millionth of a meter.) The average width of a human hair ranges between 
20 and 180 microns. An idealized cell is defined by a cell boundary or 
membrane. This structure separates the cell's interior from the exterior sur- 
roundings. The cytoplasm (made up of water, salts, and organic molecules) 
forms the cell's internal matrix. Organelles are large structures embedded 
within the cytoplasm. These compartments carry out specific functions 
for the cell. A membrane, similar to the cell membrane, surrounds most 
organelles. The nucleus houses the cell's genetic material (DNA). Like other 
organelles, a membrane also surrounds the nucleus (see figure 2.1). 

Two Different Worlds 

By the mid-1950s, biologists recognized two fundamentally distinct 
cell types: eukaryotic and prokaryotic. Eukaryotic cells contain a nucleus, 
organelles, and internal membrane systems. Unicellular protists and multi- 
cellular fungi, plants, and animals are examples of eukaryotic organisms. 

Prokaryotic cells are typically about one micron in diameter. These cells 
appear to be much simpler than eukaryotic cells. Apart from a cell boundary, 
prokaryotes lack any visible defining features. They don't have a nucleus, 
organelles, or internal membranes. Their genetic material consists of "naked" 



Rough Animal Cell 

endoplasmic 

reticulum Cell membrane 



Hdidsonne 
I yio-ikeleton 



Mitochondrion 



Nuclear envelope 

Nucleus 

Nucleolus 



Centrioles 
Vesicle 




Smooth 

endoplasmic 

reticulum 



Lysosome 



Ribosome 
Golgi apparatus 
Mitochondrion 



- Outer membrane 
-Cell wall 

- Inner (plasma) 
membrane 



Figure 2.1. The Cell (with inset) 

A schematic of a typical animal cell. A representation of a bacterial cell is found in the inset 



TO The Cell's Design 

highly coiled DN A that resides in the cytoplasm. Bacteria and archaea are 
prokaryotic organisms. Archaea are similar to bacteria in appearance, but 
fundamentally differ in their biochemical makeup. 

Zooming In 

In many ways the Internet has made life much easier. Its now common- 
place to go to a website, click a computer mouse a few times, and pull up 
a map of nearly any location in the world. Perhaps most useful of all is the 
capability to zoom in to get a more detailed view of a specific area or to 
zoom out for a better perspective on the surrounding region. 

The previous section took a quick look at the downloaded map of the 
cell. The next two sections progressively zoom in to view the eukaryotic 
cell s territory in greater detail. First, the internal biological features within 
a typical eukaryotic cell are explored. Then, the focus moves in even tighter 
on the biochemical makeup of these subcellular structures. 

Cell Membranes 

Cell membranes are thin and cannot be seen with a light microscope. 
They are only 7.5 to 10 nanometers thick. (A nanometer is one-billionth 
of a meter.) Electron micrographs show cell membranes to resemble a 
sandwich cookie. The inner and outer surfaces appear dark (due to high 
electron density), whereas the membrane's interior looks like vanilla cream 
(due to low electron density). 

The cell membrane (also called the plasma membrane) creates a protected 
environment within the cell. Isolation from the cell's surroundings makes it 
possible for life's activities to occur in an efficient manner. Cell membranes 
are like plastic sandwich bags that hold the cell s contents and regulate the 
flow ofmaterials into and out of the cell. (The molecular makeup of cell 
membranes is described in the next section, p. 45.) 

Cytoplasm 

Generally, biologists refer to all the material inside the plasma membrane, 
excluding the nucleus, as the cytoplasm. Specifically, cytoplasm (or more 
precisely the cytosol) is the liquid suspension composed of water, salts, 
molecules, and molecular aggregates that surrounds the organelles and 
other structures inside the cell. 



Mapping the Territory QQ 

Cytoskeleton 

A network of filaments extends throughout the cytoplasm and attaches 
to the plasma membrane and organelles. Biologists refer to this filamentous 
network as the cytoskeleton. It imparts structural integrity to the cell and 
forms the framework for the cell's shape and movement. 

The cytoskeleton is not permanent. It assembles and disassembles in 
various locales within the cytoplasm as needed. This threadlike structure 
functions as a "railway system" that the cell's machinery uses to ferry organ- 
elles and other cellular cargo from place to place within the cell. 

Three types of filaments make up the cytoskeleton: microtubules, in- 
termediate filaments, and microfilaments. These filaments are made up of 
proteins. (Proteins are discussed in more detail in the next section, p. 42.) 
Microtubules are long slender tubes 20 to 25 nanometers in diameter and 
are composed of the protein tubulin. Intermediate filaments are about 8 to 
10 nanometers in diameter. They consist of ropelike assemblies of protein 
fibers that intertwine. Microfilaments, which consist of the protein actin, 
are only 6 nanometers in diameter. 

Nucleus 

The mostprominent feature and control center inside eukaryotic cells is 
the nucleus. This large organelle houses DN A (deoxyribonucleic acid), the 
cell's genetic material. (DNA's molecular structure is described in the next 
section, p. 48.) The DN A in the cell's nucleus interacts with proteins to form 
chromosomes. Within the nucleus is a dense area called the nucleolus. 

A double membrane system surrounds the nucleus. The inner and outer 
membranes connect at various points to form nuclear pores. These pores 
control the passage of materials in and out of the nucleus. The outer mem- 
brane is continuous with a network of membranes in the cytoplasm called 
the endoplasmic reticulum. 

Ribosomes 

Within the nucleolus, ribosomes (see p. 102) are assembled. Once put 
together, ribosomes are exported from the nucleus to the cytoplasm and 
endoplasmic reticulum. These subcellular particles measure about 23 nano- 
meters in diameter and consist of two subunits, one large and the other 



40 The Cell's Design 

small. Ribosomes are made up ofproteins and RNA (ribonucleic acid) 
molecules. 

The cell may contain up to a half-million ribosomes. These indispensable 
particles play the central role in protein synthesis. Ribosomes are distributed 
throughout the cell in the cytoplasm. Some are attached to the cytoskeleton 
and some are embedded in the endoplasmic reticulum membranes. 

Endoplasmic Reticulum 

A complex system of membrane tunnels and sacs, the endoplasmic reticu- 
lum concentrates near the cell's nucleus and accounts for over 50 percent of 
the cell's membranes. It is a continuous tubelike structure with a single inter- 
nal space, the lumen. This space acts as a compartment that keeps materials 
separated from the rest of the cell. The endoplasmic reticulum connects the 
outer membrane of the nucleus's envelope to the plasma membrane. 

Two regions constitute the endoplasmic reticulum. One region, the rough 
endoplasmic reticulum, has ribosomes associated with the outer surface of 
the endoplasmic reticulum membrane. Proteins made by these ribosomes 
are deposited into the lumen for further biochemical processing. The en- 
doplasmic reticulum functions like an assembly line with a conveyor belt 
that prepares and processes proteins for export. Proteins transported into 
the lumen eventually (1) make their way into lysosomes and peroxisomes, 
(2) become incorporated into the plasma membrane, or (3) are secreted 
out ofthe cell. 

No ribosomes are associated with the smooth endoplasmic reticulum. This 
area produces small round membrane-bound sacs (vesicles) that contain 
the proteins processed in the lumen. These vesicles typically make their 
way to the Golgi apparatus. 

Golgi Apparatus 

Stacks of flattened membrane-bound sacs that look like a pile of pita 
bread make up the Golgi apparatus. Numerous small vesicles surround 
these membrane stacks. This organelle makes biochemical modifications 
to the contents of vesicles that originate from the endoplasmic reticulum 
and then distributes these vesicles to different locations throughout the 
cell. Materials due to be secreted into the cell's exterior also pass through 
the Golgi apparatus. 



Mapping the Territory A^ 

Lysosomes 

Membrane-bound vesicles, lysosomes pinch off from the Golgi appara- 
tus and vary in size. They contain about forty different types of digestive 
enzymes and break down food, unneeded molecules, and damaged cell 
components. This action allows the components that make up these struc- 
tures to be reused by the cell. Lysosomes are like the cell's recycling bins. 

Peroxisomes 

Similar in appearance to lysosomes, peroxisomes also bud off from the 
Golgi apparatus. However, they contain oxidative enzymes instead of diges- 
tive enzymes. A peroxisome's enzymes detoxify materials harmful to the cell 
by oxidizing them, much in the same way that liquid bleach sanitizes. 

Mitochondria 

Roughly the size of bacteria, mitochondria possess their own genetic 
material in the form of a small circular piece of DNA. Two membranes 
surround these large organelles: an outer membrane and a highly folded 
inner membrane. Unlike other organelles in the cytoplasm, cells cannot 
make mitochondria from scratch. Mitochondria come from preexisting 
mitochondria through a replication and division process. The cell's nucleus 
controls this replication. 

Acting as the cell's power plant, mitochondria carry out biochemical 
reactions that extract energy from organic materials. This energy is stored 
in the form of high-energy chemical compounds used by the cell to power 
its processes. 

The number of mitochondria per cell varies depending on the cell's en- 
ergy requirements. Cells that utilize a significant amount of energy, like 
those found in muscle and the liver, require several thousand copies of 
this organelle. 

Chloroplasts 

Double-membrane organelles, chloroplasts are found only in plant cells. 
Like mitochondria, they have their own DNA and replicate themselves. 
Additionally they contain stacks of internal membrane sacs. Pigments in 
the membranes of the sacs absorb light energy so the chloroplasts can carry 



42 The Cell's Design 

out photosynthesis. Chloroplasts are like solar cells converting sunlight 
into useable energy. 

The Cell Wall 

Plant cells have a porous cell wall that lies on the outside surface of the 
plasma membrane. This porosity allows water and nutrients to pass through 
the cell wall to the plant cell surface. In contrast to cell membranes, the wall 
that surrounds plant cells is visible with a light microscope. Composed of 
primarily cellulose (a large sugar molecule that consists of glucose subunits), 
the cell wall gives the plant cell its shape. The wall also cements adjacent 
plant cells together. 

Extracellular Matrix 

In all multicellular organisms, the space surrounding the cells consists 
of a fluid and an irregular network of fibers. The cells often help create 
the extracellular environment by secreting materials produced inside the 
cell. This extracellular matrix holds cells together to form tissues. Cells 
migrate through this matrix and interact with one another in the extracel- 
lular environs. 



Enlarging the Molecular Domain 

Taking a close look at the internal biological features of the cell gives 
a broad overview of the layout of the land. Even with this level of detail, 
however, much of the cell's landscape remains hidden from view. The only 
way to get a thorough picture of the cell's inner works is to zoom in even 
further on the cell's membranes, cytoplasm, and organelles. These structures 
are ultimately composed of molecules. This section describes the biochemi- 
cal makeup of the cell and discusses how its molecular constituents interact 
to form its subcellular features. 

Proteins 

These "workhorse" molecules of life take part in essentially every cellular 
and extracellular structure and activity. Some proteins help form structures 
inside the cell and in the cell's surrounding matrix. They are dissolved in 



Mapping the Territory A^ 

the cytosol and the lumen of organelles or they aggregate to form larger 
structures like the cytoskeleton. Structural proteins also associate with the 
cell membrane in a variety of ways (see p. 46). Proteins called enzymes cata- 
lyze chemical reactions. Enzymes are perhaps the most important type of 
protein. These biomolecules speed up the rate of chemical transformations 
by bringing the molecules together so they can react more readily. Other 
proteins harvest chemical energy, serve in the cell's defense systems, and 
store and transport molecules — and that's only a few of their roles. 

Proteins are made up of one or more polypeptides. These chainlike mol- 
ecules fold into precise three-dimensional structures. This architecture 
determines the way the polypeptides interact with each other and conse- 
quently determines the protein's function (see figure 2.2). 

Polypeptides form when the cellular machinery links smaller subunit 
molecules called amino acids together in a head-to-tail fashion like beads 
on a string. Each amino acid possesses a specific set of chemical and physical 
properties. Cells employ twenty different amino acids, which (in principle) 
can link up in any possible order to form a polypeptide. 

Each amino acid sequence imparts a unique chemical and physical profile 
along the polypeptide's chain. This profile determines how the polypeptide 
chain folds and, therefore, how it interacts with other polypeptide chains to 
form a functional protein. The amino acid sequence ultimately determines 
a polypeptide's function because a specific sequence will fold into a specific 
structure, and structure dictates function (see figure 2.2). 

Because proteins are such large complex molecules, biochemists catego- 
rize protein structure into four different levels: primary, secondary, tertiary, 
and quaternary structures (see figure 2.2). 

A protein's primary structure is the linear sequence of amino acids that 
make up each of its polypeptide chains. The secondary structure refers to 
short-range, three-dimensional arrangements of the polypeptide chain's 
backbone arising from the interactions between chemical groups that make 
up its backbone. Three of the most common secondary structures are the 
random coil, alpha (a) helix, and beta ((3) pleated sheet (see figure 2.2). 
Tertiary structure describes the overall shape of the entire polypeptide 
chain and the location of each of its atoms in three-dimensional space. The 
structure and spatial orientation of the chemical groups that extend from 
the polypeptide backbone are also part of the tertiary structure. Quaternary 
structure arises when several individual polypeptide chains interact to form 
a functional protein structure. 



Secondary 

structure 

a-helix / 



Primary structure 
Polypeptide chain 



Amino acids 







\ 




f" Val ^. 



^^^ c^ 



Secondary structure 
P-pleated slieet 




Tertiary structure 
Folded polypeptide chain 



Quaternary structure 
Assembled subunits 



Mapping the Territory AZ 

Enzymes have special regions on their surfaces called active sites. These 
locations can be either pockets or crevices. Chemical reactants bind to 
the active site. The binding of these molecules is highly specific. Once 
bound, the reactants are held in the just-right orientation in space so that 
the reaction between them readily takes place. By facilitating the interac- 
tions between chemical reactants, enzymes speed up the rate of chemical 
reactions. Other proteins, like receptors, have binding sites on their surfaces 
as well. These regions are similar to active sites. 

Cell Membranes 

Two classes of biomolecules interact to form cell membranes: lipids 
and proteins. Lipids, a structurally heterogeneous group of compounds, 
share water insolubility as a defining property. They also readily dissolve 
in organic solvents. Cholesterol, triglycerides, saturated and unsaturated 
fats, oils, and lecithin are familiar examples of lipids. 

Phospholipids are the cell membrane s major lipid component. A phos- 
pholipid's molecular shape roughly resembles a distorted balloon with two 
ropes tied to it (see figure 2.3). Biochemists divide phospholipids into 
two regions that possess markedly different physical properties. The head 
region, corresponding to the "balloon," is soluble in water or hydrophilic 
(water-loving). The phospholipid tails, corresponding to the "ropes" tied 
to the balloon, are insoluble in water or hydrophobic (water-hating). 

Chemists refer to molecules, like phospholipids, that possess molecular 
regions with distinct solubility characteristics, as amphiphilic (ambivalent 
in its likes). Soaps and detergents are amphiphilic compounds known to 
virtually everyone. 

Amphiphilicity has great biological importance. Phospholipids' schizo- 
phrenic solubility properties play a key role in cell membrane structure. 
When added to water, phospholipids spontaneously organize into sheets 
that are two molecules thick called bilayers. When organized into a bilayer, 
phospholipid molecules align into two monolayers with the phospholipid 
head groups adjacent to one another and the phospholipid tails packed 

Figure 2.2. Protein Structure 

Biochemists categorize protein structure into four different levels. Primary structure is the linear 
sequence of amino acids that make up the polypeptide chains. Secondary structure refers to the 
three-dimensional arrangement of the polypeptide chains backbone. The a helix and (5 pleated 
sheet are the two most common types of secondary structures. Tertiary structure describes the 
overall shape of a polypeptide chain. Quaternary structure arises when individual polypeptide 
chains interact to form a functional protein. 



46 



The Cell's Design 




Hydrocarbon 
chains 



together closely. The mono- 
layers, in turn, come together 
so that the phospholipid tails 
of one monolayer contact the 
phospholipid tails of its com- 
panion monolayer. This tail- 
to-tail arrangement ensures 
that the water-soluble head 
groups contact water and the 
water-insoluble tails sequester 
from water (see figure 2.4). 

This arrangement of phos- 
pholipids into a bilayer struc- 
ture gives cell membranes their 
sandwich-cookie appearance 
in electron micrographs. The 
head groups that form the 
cell membrane's inner and 
outer surfaces are electron 
dense, rendering them dark. 
The phospholipid tails are less 
electron dense and, therefore, 
appear light. 

Proteins associate with the 
cell membrane in a variety 
of ways. Peripheral proteins 
bind to the inner or outer 
membrane surfaces. Integral 
proteins embed into the cell 
membrane. Some integral pro- 
teins insert only slightly into 
the membrane interior, while 
others penetrate nearly half- 



Figure 2.3. Phospholipid Structure 

Schematic representation of a typical pliosphiolipid superimposed on its molecular structure. 
The phosphate head group region (circle) is soluble in water while the hydrocarbon tails are 
insoluble. 



Mapping the Territory 



47 



Bi layer 




Head group 



Tails 



Figure 2.4. Phospholipid Bilayer Structure 

A small segment of a bilayer. This structure spontaneously forms when phospholipids are 
added to water. Note the tail-to-tail arrangement. 



way into the membrane s core, and still others span the entire membrane 
(see figure 2.5). 

Membrane proteins serve the cell in numerous capacities. Some proteins 
function as receptors, binding compounds that allow the cell to communi- 
cate with its external environment. Some catalyze chemical reactions at the 
cell's interior and exterior surfaces. Some shuttle molecules across the cell 



Integral protein 

r c . , \ f ^^ 



Peripheral 
protein 



Peripheral 
protein 



Integral protein 




Figure 2.5. Membrane Proteins 

A small segment ofa typical cell membrane. Proteins associate with the cell 
membrane in a variety of ways. Peripheral proteins bind to the inner or outer 
membrane surfaces. Integral proteins embed into the ceil membrane. 



48 



The Cell's Design 



Glycolipid 




Phospholipid Globular protein 



Helical protein 



Figure 2.6. Fluid Mosaic Model 

A segment ofthe cell membrane illustrates the fluid mosaic model. The phospholipid bilayer 
functions as a two-dimensional fluid that serves as both a cellular barrier and a solvent for 
integral membrane proteins. The membrane proteins and lipids freely diffuse throughout the 
cell membrane. 



membrane; others form pores and channels through the membrane. Some 
membrane proteins impart structural integrity to the cell membrane. 

Since the early 1970s, the fluid mosaic model has provided the frame- 
work to understand membrane structure and function. This model views 
the phospholipid bilayer as a two-dimensional fluid that serves as both a 
cellular barrier and a solvent for integral membrane proteins. The fluid 
mosaic model allows the membrane proteins and lipids to freely diffuse 
laterally throughout the cell membrane. Beyond the bilayer structure and 
asymmetry, the fluid mosaic model fails to attribute structural and func- 
tional organization to cell membranes (see figure 2.6). 



DNA 



DNA consists of chainlike molecules known as polynucleotides. Two 
polynucleotide chains align in an antiparallel fashion to form a DNA mol- 
ecule. The two strands are arranged parallel to one another with the starting 
point of one strand, the 5' end (reads "five prime"), in the polynucleotide 
duplex located next to the ending point of the other strand, the 3' end (reads 
"three prime"), and vice versa. The paired polynucleotide chains resemble a 



Mapping the Territory 



49 



End 



Start 




Fused ring 



Twisting 



Six-membered ring 



Start 



"Rungs' 



Polynucleotide 
"ladder" 



Double 
helix 



Figure 2.7. DN A Structure 

DNA consists of chainlike molecules that Iwisl around each other forming the well-known DNA 
double helix. The polynucleotide chains of DNA are formed from four different nucleotides — 
adenosine (A), guanosine (G), cytidine (C), and thymidine (T). 



ladder with the side groups extending from the backbone interacting with 
each other to form rungs. The coupled polynucleotide chains twist around 
each other forming the well-known DNA double helix. 

The cell's machinery forms polynucleotide chains by linking together four 
different subunit molecules called nucleotides. The four nucleotides used 
to build DNA chains are adenosine, guanosine, cytidine, and thymidine — 
famously abbreviated A, G, C, and T, respectively (see figure 2.7). 

DNA stores the information necessary to make all the polypeptides 
used by the cell. The sequence of nucleotides in DNA strands specifies the 
sequence of amino acids in polypeptide chains. The nucleotide sequence 
that codes the amino acid sequence of a particular polypeptide (or other 



5Q The Cell's Design 

functional products) is known as a gene. Through the use of genes, DNA 
stores the information functionally expressed in the amino acid sequences 
of polypeptide chains. 

Proteins interact with DNA to make chromosomes. These structures only 
become visible in the cell nucleus when the cell divides. Each chromosome 
consists of a single DNA molecule that wraps around a series of globular 
protein complexes. The globular proteins are called histones. These struc- 
tures repeat to form a supramolecular structure that resembles a string of 
beads (see figure 2.8). Biochemists refer to the "beads" as nucleosomes. 

The nucleosomes coil to form a structure called a solenoid. The sole- 
noid further condenses to form higher order structures that comprise the 
chromosome proper. Between cell division events, the chromosome exists 
in an extended diffuse form that is not detectable. Prior to and during 
cell division, the chromosome condenses to form its readily recognizable 
compact structures. 

Central Dogma of Molecular Biology 

The central dogma ofmolecular biology describes how information 
stored in DNA becomes functionally expressed through the amino acid 
sequence and activity of polypeptide chains (see figure 2.9). DNA does 
not leave the nucleus to direct the synthesis of polypeptide chains. Rather 
the cellular machinery copies the gene s sequence by assembling another 
polynucleotide, messenger RNA (mRNA). Scientists refer to the process 
of copying mRNA from DNA as transcription. 

A single-stranded molecule, mRNA is similar, but not identical, in com- 
position to DNA. One ofthe most important differences between DNA 
and mRNA is the use of uridine (U) in place of thymidine (T) to form 
the mRNA chain. 

Once transcribed from the DNA, mRNA migrates from the nucleus of 
the cell into the cytoplasm. At the ribosome, mRNA directs the synthesis 
of polypeptide chains. The information content ofthe polynucleotide 
sequence is then translated into the polypeptide amino acid sequence. The 
polypeptide chain then folds to form a fully functional protein. 

Much more about the cell's biochemical and biological systems could be 
discussed. More details appear in subsequent chapters as the need arises. For 
now, this brief introduction offers a sufficient view of the cell's landscape to 



DNA 
double helix 




2 nm 



700 nm 




Colled 

chromosome 

arm 



1400 nm 



Centromere Chromatids 



Figure 2.8. Chromosome Structure 

DNA and proteins interact to make chromosomes. Their fundamental structural elements are 
nucleosomes. Each nucleosome consists of a single DNA molecule that wraps around a series of 
'^lobular protein conglomerates made up of histones. The nucleosomes further coil and condense to 
:orm the chromosome proper. 



52 



The Cell's Design 



DNA 



mRNA 




Polypeptide 
Output 



Reader and 
Assembler 



Translation 



Transcription 



Figure 2.9. Central Dogma of Molecular Biology 

This concept describes hiow information stored in DNA becomes functionally expressed 
through the amino acid sequence of polypeptide chains. The cellular machinery copies the 
gene's sequence by assembling another polynucleotide, messenger RNA (mRNA). Once 
assembled, mRNA migrates from the nucleus of the cell into the cytoplasm. At the ribosome, 
mRNA directs the synthesis of polypeptide chains. 



appreciate its organization, complexity, and elegant design. (For access to 
a list of animations of biochemical activities in the cell, see reference.,) 

Is it possible to substantiate this molecular design as a masterpiece on 
prominent display in the Divine Artist's studio? The next chapter begins 
to develop the case for biochemical intelligent design by examining the 
minimum complexity of the simplest life-forms. 



THE BARE ESSENTIALS 



Pablo Picasso and Georges Braque revolted against the artistic tradition 
of the early 1900s by refusing to imitate nature. They rejected the visual 
appeal of paint texture and color and abandoned the play of light on form 
and movement. Instead, Picasso and Braque established the Cubist school 
of art. This approach fragmented three-dimensional objects and redefined 
them as a series ofinterlocking planes.. 

However, Cubism was short-lived. The movement dispersed shortly after 
World War I. Still, its reach extended throughout the twentieth century. 

Influenced by Cubism, minimalism began in the late 1950s with the exhibi- 
tion of Frank Stellas Black Paintings at the Museum of Modern Art in New 
York.. Like Cubists, minimalists reacted against what they saw as the pre- 
tentiousness of more expressive and traditional art movements. They sought 
to reduce art to the smallest number of colors, shapes, lines, and textures. 
These artists wanted their viewers to experience art without the distraction 
of composition, themes, and the elements of more traditional work. 

Not confined exclusively to the art world, minimalism has also impacted 
music, architecture, and philosophy. Recently, a type of minimalism has 
even found its way into biochemistry. 

It's becoming fashionable for biochemists to strip away all the excesses 
of the cell's chemical systems. The scientific community thinks that by 

53 



54 The Cell's Design 

eliminating the distraction of superfluous biochemical systems, they'll gain 
fundamental insight into life's indispensable chemical processes. Reducing 
life to its bare essentials will help scientists achieve a better definition of 
life and provide insight into its origin. 

Complexity is often considered an indicator of design. But as Dembski s 
explanatory filter highlights, complexity, in and of itself, does not necessarily 
indicate the work of a Creator. Only complexity that conforms to a speci- 
fied pattern does. The immense complexity of the cell's chemical systems 
obscures these hallmark characteristics of design. To see those intricate 
details, the cell's biochemical excesses must be eliminated. 

So, scientists have focused attention on the simplest known life-forms, 
prokaryotes. These microbes come close to the minimal requirements for 
life. Biochemists find genome size a convenient measure of complexity. 
(The term "genome" refers to an organism's entire hereditary informa- 
tion stored in the nucleotide sequences of DNA.) The chief information 
housed in an organisms genome is the instructions the cells machinery 
uses to make proteins. 

Proteins take part in virtually every biochemical process and play critical 
roles in nearly every cell structure (see chapter 2, p. 42). Cataloging the 
number and types ofproteins present in an organism gives biochemists 
important insight into its structures and operations, and hence, biological 
complexity. 

The cell's machinery uses the information encoded in the nucleotide 
sequences of genes to manufacture proteins. The genome of eukaryotic 
organisms consists of both genes that encode proteins (and other use- 
ful products) and noncoding DNA sequences. The genome structure of 
prokaryotes, however, is far simpler. For the most part, only protein-coding 
DNA sequences make up their genomes. In prokaryotes, generally one 
gene corresponds to one protein. Therefore, knowledge about the number 
and types of genes present in a prokaryote s genome yields insight into the 
number and type of proteins present in the organism. And this relationship 
makes genome size a good initial measure of biological complexity. 



Biochemical Minimalism 

One of the most important advances in biochemistry over the last decade 
has been the emergence of techniques to sequence, analyze, and manipulate 



Ti; Bare Essentials 

genomes. These methodologies, still in their infancy, fall within the scope of 
the new scientific discipline of genomics and pave the way for biochemists to 
define life's minimal complexity. Genomics cross-sects genetics, molecular 
biology, biochemistry, and computer science. 

In 1995 The Institute for Genomic Research (TIGR) reported the 
first-ever genome sequence. TIGR scientists tried out their new "shotgun" 
sequencing strategy and determined the DNA sequence of the Hemophilus 
influenzae genome., (This bacterium has been implicated in bronchitis, 
meningitis, and pneumonia.) Since this time, scientific reports of fully 
sequenced genomes have poured forth. 

A fairly large database of microbial genomes now exists. Biochemists 
easily add several genomes to this database per month. 

Less Is More 

Biochemists have gained insight into life's minimum complexity by 
surveying the microbial database of sequenced genomes to identify the sim- 
plest. Table 3.1 samples the results., To date, Pelagibacter ubique holds the 
record for having the most streamlined genome — at least for a free-living, 
self-sufficient prokaryote. This microbe, which accounts for 25 percent of 
microbial cells in the open ocean, possesses 1,354 gene products. (A gene 
product refers to both proteins and functional RNAs like ribosomal and 
transfer RNA.) 

Based on the P. ubique genome, it appears that the least complicated 
(for independently existing life) contains about 1,350 genes. Given the 
relatively small number of sequenced genomes currently available to as- 
sess life's complexity, it may well be that the minimum requirement for 
independent life extends below that number. To date, however, all genomes 
smaller than 1,350 gene products belong to parasitic microbes, organisms 
that aren't self-sufficient and must rely on the biochemistry of the host 
organism they invade., 

P. ubique gets by with a reduced genome because it feeds on the abun- 
dance of organic debris in the oceans. These organisms, which belong to 
a group called heterotrophs, don't require the proteins that produce the 
organic food stuff needed to support their activities. Heterotrophs get their 
nutrients from organic materials they eat. 



56 



The Cell's Design 



Table 3.1 
Genome Sizes of Life's Simplest Organisms 







Approximate 


Organism 


Domain 


Genome Size 


Pelagibacter ubique 


Bacteria 


1,354 


Thermoplasma acidophilum 


ArcJiaea 


1,509 


Aquifex aeolicus 


Bacteria 


1,512 


Picrophilus torridus 


Ardhaea 


1,535 


Helicobacter pylori 


Bacteria 


1,591 


Methanopyrus kandlerikM^ 9 


Anchaea 


1,692 


Methanococcus jannaschii 


ArcJiaea 


1,738 


Streptococcus pyogenes 


Bacteria 


1,752 


Methanobacterium 


Anchaea 


1,855 


thermoautotrophicum 






Thermotoga maritima 


Bacteria 


1,877 


Thiomicrospira crunogena X C L - 2 


Ardhaea 


1,922 



In contrast, autotrophs survive by generating the organic materials they 
need using inorganic compounds and energy sources found in the environ- 
ment. Two types of autotrophs exist: chemoautotrophs and photoauto- 
trophs. Chemoautotrophs use chemical energy extracted from the environ- 
ment as an energy source to produce organic materials. Photoautotrophs 
produce food stuff by using light energy. It's quite likely the minimum 
genome size for autotrophs is somewhat larger than the minimum het- 
erotrophic genome because of the additional metabolic systems required 
to harvest energy from the environment and to produce organic materials 
from inorganic compounds. 

Table 3.1 suggests that chemoautotrophs require a minimum genome 
size in the range of about 1,500 to 1,900 gene products to exist indepen- 
dently. Even in 1999, when the first microbial genome sequences were 
becoming available, evolutionary biologist Colin Patterson recognized 
that the 1,700 genes of Methanococcus are "perhaps close to the minimum 
necessary for independent life.". 

Table 3.2 provides a list of minimum genome sizes for photoauto- 
trophs. Based on limited data, it appears as if that minimum falls roughly 
between 1,700 and 2,300 gene products — larger than required for 
chemoautotrophs. 



The Bare Essentials 



57 



Table 3.2 
Minimum Genome Sizes for Pliotoautotrophs 









Approximate 


Organism 




Domain 


Genome Size 


Prochlorococcus marinus MED4 




Bacteria 


1,716 


Prochlorococcus marinus SS1 20 




Bacteria 


I4884 


Chlorobium tepidum JLS 




Bacteria 


?,?RR 


Thermosynechococcus elongatus 


BP-1 


Bacteria 


2,475 



This sampling of microbial genomes indicates that the simplest life- 
forms capable of independent living require roughly between 1,300 and 
2,300 gene products depending on the organisms specific lifestyle (het- 
erotrophic, chemoau to trophic, or photo auto trophic). Each gene product 
represents one of the cell's molecular parts. Even with unnecessary bio- 
chemical systems stripped away, the simplest life-forms appear remarkably 
complex. 



Down to the Nitty Gritty 

The discovery of parasitic microbes with reduced genome sizes (like 
Mycoplasma pneumonia and Borrelia burgdorferi with 677 and 863 gene 
products respectively) indicates that life exists, though not independently, 
with genome sizes less than 1,350 genes., Because they are parasites, these 
microbes must exploit the host cell's metabolism to exist. (In general, para- 
sitic microbes can get by with reduced genome sizes because of their reliance 
on host cell biochemistry.) 

Two of the most extreme examples of parasitic genomes belong to Myco- 
plasma genitalium and Nanoarchaeum equitans.m M. genitalium parasitizes 
the human genital and respiratory tract. A'^. equitans lives as a parasite 
attached to the surface of an independently existing hyperthermophilic 
host (Ignicoccus). The M. genitalium genome possesses about 480 gene 
products, whereas the genome of A', equitans consists of about 550. 

Because these genomes are so extensively pared down, they help de- 
termine the bare minimal requirements for life (assuming building block 
molecules such as amino acids, nucleotides, sugars, and fatty acids are read- 
ily available). Researchers find these parasites useful for identifying the 



so The Cell's Design 

"nonnegotiable" biochemical systems that must be present for an entity 
to be recognized as a form of life. 

A significant percentage of parasitic genomes are dedicated to mediat- 
ing interactions between the parasite and its host and, therefore, can be 
considered as nonessential to a strictly minimal life-form. So the bare es- 
sential genome is quite likely much smaller than 480 to 550 gene products. 
Researchers have employed both theoretical and experimental approaches 
to identify the essential gene set that defines "life.",! 

In Theory 

To theoretically construct the minimum gene set, biochemists compare 
genomes looking for commonly shared genes. Researchers reason that these 
common genes constitute the minimum gene products necessary for life. 
The first study of this type was conducted in 1996 by scientists from the 
National Institutes of Health. This seminal work compared the genomes 
of the two parasites, M. genitalium and H. influenzae, and estimated the 
size of a minimum genome to be about 256 genes. : 

In 1999, an international team of scientists estimated the minimum 
number of genes for life to be about 246. These investigators developed 
a universal minimal gene set by comparing the genomes of representatives 
from life's three domains — Eubacteria, Archaea, and Eukarya. 

Since then, biochemists have conducted more sophisticated theoretical 
studies using an expanded database and have determined that the number 
of shared genes found among representatives of all life-forms falls between 
60 and 80. Still, due to horizontal gene transfer, these researchers con- 
clude that the Last Universal Common Ancestor (LUCA) — evolution's 
hypothetical organism from which all life derives — must have possessed 
500 to 600 genes. These most recent studies, however, have uncovered 
inherent problems with theoretical genome comparisons. Researchers now 
question if these types of comparative analyses are the best way to identify 
the minimal gene set. 

In the Lab 

Experimental strategies to ascertain the minimum number of genes 
needed for life are also being pursued. These protocols ("knock-out ex- 
periments") involve either the random or systematic mutation of genes to 



The Bare Essentials 



59 



determine those indispensable for life. If researchers can grow the microbe 
after a gene has been disabled, then the gene is deemed nonessential. While 
some of the first studies were done with parasitic microbes (because of their 
reduced genome sizes), biochemists are now applying these techniques to 
a wide range ofprokaryotes. Table 3.3 summarizes the results of some of 
these studies.,! 

Table 3.3 
Estimates of the Essential Genome Size 



Organism 
Bacillus subtilis 
Bacillus subtilis 
Mycoplasma genitallum 
Mycoplasma genitallum 
Hemophilus Influenzae 
Staphylococcus aureus 
Escherichia coli 
Pseudomonas aeruginosa 
Pseudomonas aeruginosa 
Mycobacterium tuberculosis 



Essential Gene 

Technique Products 

Site-specific Mutagenesis 254-450 

Systematic inactivation of genes 192 

Gbbal transposon mutagenesis I 265-350 

Gbbal transposon mutagenesis II 382 

High-density transposon mutagenesis 478 

Rapid shotgun antisense method 168 

Genetic ftxjtprindng technique 620 

Library of transposon inserdon mutants I 300-400 

Library of transposon insertion mutants II 335 

SubsaturaBon mutagenesis postgenomb analysis 1 ,490 



The methods used to determine the essential gene set for minimal life 
are in their infancy. Still, these initial experimental studies collectively indi- 
cate that life in its most stripped-down form requires somewhere between 
200 and 500 genes. Even though some biochemists think that theoretical 
estimates of minimal genome size are flawed, those measurements come 
fairly close to those obtained experimentally. 

In the Cell 



The genome of bacterial intracellular symbionts (endosymbionts) pro- 
vides another means to determine the size of the minimal gene set. These 
parasites permanently reside inside the cells of the host and possess dramati- 
cally reduced genomes. Scientists believe that the gene sets of intracellular 
symbionts are close to what is fundamentally essential for life. In contrast, 
the genomes of extracellular parasites (like M. genitalium) consist of both 
genes essential for life and those that mediate host-parasite interactions. 



gQ The Cell's Design 

One of the smallest endosymbiont genomes is possessed by species of 
Buchnera. These microbes make their living inside the cells of aphids. While 
the genome size of the different Buchnera species varies, the smallest ones 
are estimated to contain between 350 and 400 gene products. i6 

In 2003, a research team compared the five completely sequenced ge- 
nomes of insect endosymbionts and discovered they shared 313 genes. n 
The scientists concluded that this number is close to the minimum amount 

needed to sustain an intracellular symbiont. In 2006, a team of molecular 
biologists determined that the genome of the extreme endosymbiont, Car- 
sonella ruddii, consisted of only 182 gene products, is This quantity is likely 
to be a good measure of the bare essential requirements for life. Again, this 
insight into the minimum gene set from endosymbionts coincides with 
values obtained from theoretical and experimental estimates. is 

In the Future 

Though the genomic tools to assess life's minimum complexity are 
powerful, they are still crude. In years to come, biochemists will undoubt- 
edly develop more sophisticated ways to identify life's bare essentials. 

One exciting plan involves synthetically reconstructing the presumed 
minimum genome (based on the M. genitalium knock-out experiments) 
and inserting it into a M. genitalium cell with its DNA removed. 20 By sys- 
tematically exploring synthetic variants of the minimum genome, it should 
be possible to rigorously establish the essential gene set. 

This approach faces a number ofsignificant technical hurdles, however. 

The chief difficulty is synthesizing a DNA molecule hundreds of thousands 

of nucleotides long. (On average, a gene product is about 1,000 nucleotides 

in length.) Some progress towards this goal has been made. Independent 

research teams have synthesized from scratch the genomes ofthe poliovirus 

(7,000 nucleotides long), the bacteriophage cp/)jr7 74 (5,400 nucleotides long), 

and the E. co// polyketide synthase gene cluster (32,000 nucleotides long). 21 
As remarkable as these advances are, a DNA segment 32,000 nucleotides in 

length is a long way from one hundreds ofthousands ofnucleotides long. 
While much ofthe focus has been on genomics with its top-down approach 
to life's minimum complexity, other researchers are using a different strategy, 
one that starts at the bottom and works its way up. This bottom -up approach 
generally entails producing artificial cell membranes and using them to encap- 
sulate some ofthe basic components ofthe cell's molecular machinery. 22 



The Bare Essentials g ]^ 

Though just getting started, this research effort is making some remark- 
able progress. Scientists from Rockefeller University in New York have 
successfully produced a membrane-encapsulated artificial cell about the 
size of a bacterium. And, it is capable of generating proteins.:, The research- 
ers extracted the biochemical machinery responsible for protein synthesis 
from E. coli and encapsulated it within a phospholipid bilayer system. They 
also introduced DNA molecules containing the genes that code for pore- 
forming proteins. These proteins associate with the cell membrane and 
form pores that serve as conduits for amino acids to enter the artificial cell. 
The influx of amino acids provides an ongoing supply of the raw materials 
needed to make proteins. Though far from a living entity (because it can't 
replicate itself), this artificial cell helps define life's essential systems. 

In the Divine Artist's Studio 

To create a masterpiece, an artist typically performs one process after 
another — sketching, refining, adding color, shading, intensifying, and 
perfecting. Much like art, biochemists have discovered that life also requires 
a series of steps.: These steps include: 

assembly ofboundary membranes 

formation of energy capturing capabilities by the boundary 
membrane 

encapsulation of macromolecules (like proteins, RNA, and DNA) 
within the boundary membrane 

introduction of pores into the boundary membrane that can funnel 
raw materials into the interior space 

production of systems that allow the macromolecules to grow 
generation of catalysts that speed up the growth of the encapsulated 
macromolecules 

provision for the macromolecules to replicate 

introduction of information into one set of macromolecules that 
directs the production of other macromolecules 
development ofmechanisms to cause the boundary membrane to 
subdivide into two smaller systems that can grow 
production of the means to pass information-containing macromol- 
ecules to the daughter products of the subdivision process 



g2 The Cell's Design 

Origin-of-life researcher David Deamer stated, "Looking down this list, 
one is struck by the complexity of even the simplest form oflife.":., 

The bottom-up method involved with identifying the process lends 
itself more readily to identifying life's essential biochemical operations 
than genomics' top-down strategy. Still, key insight into life's essential 
features has come from knock-out experiments and theoretical studies. 
These two complementary approaches both indicate that life in its bare 
minimal form requires genes that control DNA replication, cell division, 
protein synthesis, and assembly of the cell membrane. Minimal life also 
depends upon genes that specify at least one biochemical pathway that can 
extract energy from the environment. 



Internal Composition 

As biochemists labor to determine the minimum number of gene products 
needed for life, microbiologists are making discoveries that revolutionized 
the scientific community's understanding ofprokaryotes. These advances 
indicate that life's bare essentials extend far beyond the number of proteins 
that must simultaneously occur for life to exist. Life's minimum complexity 
also requires organization of these gene products within the cell. 

Prior to the mid-1990s, microbiologists had a simple view ofprokaryotes 
as "vessels" that contained a jumbled assortment of life molecules randomly 
dispersed inside the cell. In short, microbiologists did not think these 
organisms possessed any type of internal organization. 

This perception stood in sharp contrast to the remarkable internal orga- 
nization displayed by the complex cells (eukaryotes) that make up the 
multicellular fungi, plant, and animal kingdoms as well as single-celled 
protozoans. Eukaryotic cells possess numerous internal compartments — 
membrane systems, a nucleus, organelles, acytoskeleton, and other compo- 
nents that organize the cell contents at the subcellular and even molecular 
level (see chapter 2). 

Now the traditional view ofprokaryotes is changing. Microbiologists 
have begun recognizing that these microbes display a remarkable degree of 
internal organization. This ordering, however, does not involve subcellular 
structures. Rather the arrangement occurs at the molecular level — both 
spatially and temporally.: Microbiologists Lucy Shapiro (Stanford) and 
Richard Losick (Harvard) said: 



The Bare Essentials 



63 



The use of immunogold electron microscopy and fluorescence microscopy to 
study the subcellular organization of bacterial cells has revealed a surprising 
extent of protein compartmentalization and localization.!, 

Shapiro and Losick point out that in some cases, this internal ordering of 
proteins appears nonessential for cell survival. In other instances, however, 
the organization clearly involves essential cell activities. A few examples 
of extraordinary internal organization in prokaryotes include a bacterial 
chromosome(s), DNA polymerase, cell-division proteins, the bacterial 
cytoskeleton, and bacterial internal compartmentalization. 

Bacterial Chromosomes 

Unlike eukaryotic cells (which have DNA and proteins associated to 
form chromosomes inside the cell nucleus), bacteria and archaea possess 
one or more small naked pieces of DNA that loop to form a twisted circle. 
Microbiologists long thought that this bacterial DNA diffused freely and 
randomly throughout the cell and that when the cell divided, the segrega- 
tion of the two duplicated DNA molecules between the daughter cells 
was a passive process. 

It turns out, however, this view is incorrect. Microbiologists now know 
that the bacterial DNA has to have a specific orientation within the cell. 
Moreover, during cell division, a complex ensemble of proteins must not 
only segregate the two newly reproduced DNA circles, but also must 
maintain the chromosomes in the correct orientation — if not, cell death 
results.;. 

Bacteria also contain plasmids, extremely small extrachromosomal pieces 
of circular DNA. Once again it was long regarded that these plasmids were 
randomly dispersed and free to migrate throughout the cell. As with the 
bacterial chromosome, though, scientists have now determined that even 
plasmids cluster and localize inside the cell.. 

DNA Polymerase 

DNA polymerases duplicate DNA molecules during cell replication. 
Instead of moving along the DNA double strand, like a "train on a track," 
to produce two copies of DNA from the parent DNA molecule, microbi- 
ologists have determined that DNA polymerase must be localized near the 
middle of the cell. In other words, instead of being randomly distributed 



g4 The Cell's Design 

throughout the cell, these enzymes must be situated in a specific region. 
Microbiologists now view bacterial DN A polymerases as "replication fac- 
tories" anchored precisely in the cell. Their activity during cell replication 
seems to be intimately connected to the machinery that orients and segre- 
gates the bacterial chromosome. 

Recent work also indicates that DN A topoisomerases also must be pre- 
cisely situated in the bacterial cell. These enzymes control the topology 
of the DNA molecule by introducing and relaxing the supercoiling of 
DNA molecules. If DNA topoisomerases don't localize with the replica- 
tion origin, the bacterial chromosome will not become properly oriented 
within the cell.,, 

Cell-Division Proteins 

Bacterial cell division, in which the mother cell divides near its midplane 
to produce two daughter cells, requires dynamic spatial and temporal local- 
ization of several proteins. The FtsZ protein is key in this process. Several 
copies of FtsZ accumulate at the middle of the cell and aggregate to form 
a ring that extends around the inner surface of the cell wall. : During cell 
division, the FtsZ ring contracts to pinch the mother cell into two daugh- 
ters. Disruption ofthis ring assembly results in cell death. 

An ensemble of proteins regulates the way FtsZ binds to the inner cell 
wall and ensures that the FtsZ ring forms at the proper location. For ex- 
ample, the Min C and Min D proteins keep the FtsZ proteins from binding 
to the wrong place in the cell wall. The Min E protein interacts with Min 
C and Min D proteins to promote FtsZ binding at the cell's midplane. Any 
disruption of FtsZ, Min C, Min D, or Min E function and interactions 
compromises cell replication. 

Recent work indicates that the Min C, Min D, and Min E proteins rapidly 
oscillate inside the bacterial cell from pole to pole in a spiral fashion. This 
back and forth movement plays a critical role in establishing the FtsZ ring 
at the cell's midplane.- 

Bacterial Cytoskeleton 

Microbiologists traditionally thought that bacteria lacked a cytoskel- 
eton. In fact, the absence of a cytoskeleton was considered a defining fea- 
ture of prokaryotic cells, one that distinguished them from eukaryotic 



The Bare Essentials 



65 



cells. According to tradition, only complex eukaryotic cells possessed a 
cytoskeleton. 

Recent advances completely overturn this long-standing view of bac- 
teria. Research revealed that these microbes possess complex cytoskeletal 
structures with components that correspond to the cytoskeletal elements 
found in eukaryotic cells... The FtsZ ring, which locates to the cell's mid- 
plane and plays a central role in cell division, is properly understood as 
a cytoskeletal component corresponding to tubulin in eukaryotic cells. 
The MreB protein, which corresponds to actin in eukaryotic cells, forms 
a helical structure that spans the length of nonspherical bacterial species. 
The MreB complex helps establish cell shape and serves as a "track" to ferry 
molecules around inside the bacterial cell. 

Another bacterial cytoskeletal component that corresponds to interme- 
diate filaments in eukaryotic cells is crescentin. This protein plays a role in 
determining cell shape. It even appears that the spiraling action of the Min 
proteins — C, D, and E — form an additional helical cytoskeletal structure 
independent of the one formed by the MreB protein. , 

Bacterial Internal Compartmentalization 

Traditionally, microbiologists considered the lack of internal compart- 
mentalization and the absence of organelles to be the defining features of 
prokaryotic cells. According to tradition, only complex eukaryotic cells 
possessed organelles and displayed subcellular compartmentalization. But 
this conventional view of prokaryotes is incorrect. Recent advances have 
uncovered examples of compartmentalization within bacteria and have 
even identified the existence of bacterial organelles. 

One example of a bacterial organelle is the carboxysome. This organelle 
consists of a protein shell that houses the enzymes involved in carbon fixa- 
tion reactions. The carboxysome sequesters these enzymes from the rest 
of the cell. Carbon fixation reactions are sensitive to the environment and 
could not proceed unprotected in the cytoplasm. Carboxysomes even have 
pores that allow influx of the raw materials needed to carry out the carbon 
fixation reactions and the outgo ofreaction products. 

When initially detected in bacterial cytoplasm, microbiologists thought 
carboxysomes were viral particles that had invaded the cell. The paradigm 
that prokaryotes lacked internal compartmentalization was so pervasive 
that no one could envision these inclusions actually being organelles. It was 



g/C The Cell's Design 

only after carbon fixation enzymes were found associated with carboxy- 
somes that this deeply entrenched paradigm was abandoned. Organelles, 
like carboxysomes, are widespread among bacteria. 

The last decade of research has overturned the traditional view of bacteria. 
These litde "bags of molecules" actually display an incredible degree of internal 
organization. They also possess exquisite composition of biochemical activity 
in spatial and temporal terms. As microbiologists continue to probe, more ex- 
amples of structural and functional organization are sure to be discovered. 

Bacterial internal organization seems to be universal among microorgan- 
isms and seems to be a property necessary for life. It adds another dimension 
to life's minimal complexity. In other words, minimal life not only requires 
the simultaneous occurrence of a relatively large number of gene products, 
but also their spatial and temporal organization. 

A Complex and Well-Organized Masterpiece 

When minimalists created a piece of art, they wanted the viewer to 
experience it without the distractions that can come from the composi- 
tion, theme, and other devices of more traditional works. Similarly, over 
the past several years, biochemical minimalists have attempted to strip life 
of its superfluous systems so scientific viewers can contemplate life in its 
bare essence. 

Though still very much in formative stages, these efforts have been quite 
successful. Scientists are honing in on the minimum number of genes and 
essential biochemical systems necessary for life in its various forms (parasitic, 
heterotrophic, chemoautotrophic, and photoautotrophic). Most striking 
in these preliminary results is their remarkable complexity. 

It appears as if a lower bound of several hundred genes exists, below which 
life cannot be pushed and still recognized as "life." In Darwin's Black Box, 
biochemist Michael Behe argues that individual biochemical systems are 
irreducibly complex..,. The initial insight into life's minimal complexity 
indicates that its notjust individual biochemical systems that are irreducibly 
complex; so is life itself. Systems produced by human designers are often 
irreducibly complex. This feature is a hallmark characteristic of intelligent 
design. 

Behe makes the powerful case that irreducibly complex systems cannot 
emerge through an undirected stepwise process. The incredible complex 



The Bare Essentials 



67 



nature of minimal life, likewise, makes it difficult to envision how natural 
evolutionary processes could have produced even the simplest life-forms — 
whether parasitic, heterotrophic, or autotrophic. 

In Origins of Life, Hugh Ross (an astronomer) and I reach the identical 
conclusion by considering the probability of the essential gene set coming 
into existence simultaneously. According to this analysis, it is superastro- 
nomically improbable for the essential gene set to emerge simultaneously 
through natural means alone. 4,, If left up to an evolutionary process, not 
enough resources or time exist throughout the universe s history to generate 
life in its simplest form. 

The overthrow of the traditional view of prokaryotes — as little bags of 
assorted molecules haphazardly arranged inside the cell — also substanti- 
ates the case for life being a divinely created masterpiece. Microbiologists 
now understand that these microbes display exquisite spatial and tempo- 
ral organization at the molecular level. This organization adds an extra 
dimension of complexity that has yet to be explained away by naturalistic 
evolutionary processes. 

Common experience teaches that it takes thought and intentional effort 
to carefully organize a space for functional use. By analogy, the surprising 
internal composition of prokaryotic cells bespeaks of intelligent design. 
Instead of resembling a preschooler's messy fingerpainting, the interior of 
the simplest cell is best described as a carefully planned and marvelously 
executed work of art — one that masterfully carries out life's most basic 
processes in living color. Disrupting this arrangement is often lethal. 

This chapter focused on the general biochemical features of the simplest 
life-form — the essential gene set and internal molecular organization — 
which indicate that life's chemistry is the work of a Creator. Instead of 
being restricted to the minimal biochemical requirements for life, the next 
several chapters reveal the rich and full artistry of life's chemical systems. 
Chapter 4 shows the profound intricacy ofmolecular motors. 



SUCH A CLEAN MACHINE 



For some, automobiles are works of art. For a few, like Ken Eberts, auto- 
mobiles are the subject of art. Perhaps it's no accident that Eberts became 
one of the world's most preeminent automotive fine artists., He began his 
career as an automotive designer for the Ford Motor Company, creating 
the very concepts that eventually fueled his passion for painting. Now his 
artwork conveys the excitement that's very much a part of car history. 

Automobiles make fascinating subjects because they cultivate a sense of 
exhilaration and nostalgia. Their form, color, and gloss, plus the way light 
plays on their surface, make them aesthetically enticing. 

While its generally the automobile s exterior that inspires art, that's not 
the only part of a vehicle considered a thing of beauty. Ask any racecar 
mechanic who marvels at a gleaming engine under the hood — the motor 
of a mean machine can be even more awe-inspiring than the exterior. Teams 
of engineers often labor long and hard to create the elegant engines that 
power automotive "works of art." 

Such a motor makes for a quintessential example of a humanly designed 
system. Every feature stems from forethought and careful planning. These 
engineering masterpieces consist of numerous components that precisely 
and necessarily interact to achieve power. Machines operate according to 
the laws of physics and chemistry, but cannot be reduced to them.; 

69 



TQ The Cell's Design 

Nature's laws cannot explain an automobile engine s origin. A mechanical 
wonder like a motor is irreducibly complex, and this characteristic indicates 
that the engine was intelligently designed. 

Motors and machines are found not only under the hoods of automobiles. 
They are also found inside of cells. One of the most remarkable advances 
in biochemistry during the last part of the twentieth century has been the 
recognition that many biochemical systems function as molecular-level 
machines. Remarkably, some of these biomolecular motors bear an eerie 
resemblance to humanly designed engines. Yet, these biomachines are far su- 
perior in construction and operation than their man-made counterparts. 

Biomachines make a powerful case for biochemical intelligent design 
and reinvigorate one of history's most well-known arguments for a Cre- 
ator's existence: the Watchmaker argument popularized in the eighteenth 
century by William Paley, a British theologian. 

A Gallery of Molecular Motors 

For an artist, there may be no greater form of recognition than to have his 
work featured and displayed for the general public to appreciate. Since 1968, 
Eberts has produced over one thousand original paintings that are part of 
collections all over the world. His works have been exhibited throughout 
the United States, and over twenty-five art galleries have honored him 
with one-artist shows. 

The biomolecular art show that follows honors its Creator no less. Thanks 
to a decade or so of biochemical advance,justafew of the Divine Artist smany 
biomolecular machines are now on display for people to contemplate. 

As in any exhibit, not every piece may be equally stimulating. Often 
observers stroll through the displays until something of interest catches 
their eye. Then its easy to get caught up in every fascinating nuance. 

A Magnificent Motor 

The bacterial flagellum has become the "poster child" for Intelligent De- 
sign., The flagellum looks like a whip and extends from the bacterial cell 
surface. Some bacteria have only a single flagellum, others possess several. 
Rotation of the flagellum(a) allows the bacterial cell to navigate its environ- 
ment in response to various chemical signals (see figure 4.1). 



Such a Clean Machine 



"1 



Bushing, 



Universal joint 



Propeller 




Stator 



Rotor 



Figure 4.1. The Bacterial Flagelluni 

The proteins of the bacterial flagellum form a literal rotary motor. 



An ensemble of over forty different kinds of proteins makes up the typical 
bacterial flagellum. These proteins function in concert as a literal rotary 
motor. The bacterial flagellums components stand as direct analogs to the 
parts of a man-made motor, including a rotor, stator, drive shaft, bushing, 
universal joint, and propeller. 4 

The bacterial flagellum is essentially a molecular-sized electrical motor. 
The flow of positively charged hydrogen ions through the bacterial inner 
membrane powers the flagellums rotation.. As research continues on the bac- 
terial flagellum, its machinelike character becomes increasingly evident.. 



Cruising throughout Nature 

The rotary motor, F -F ATPase, plays a central role in harvesting en- 
ergy for cellular use. F -F ATPase associates with cell membranes. The 
mushroom-shaped Fj portion of the complex extends above the membrane s 
surface. The "button of the mushroom" literally corresponds to an engine 
turbine (see figure 4.2). 



72 



The Cell's Design 



Stator 



Turbine 



Rotor 



Cam 




F. Channel 

Figure 4.2. F,F ATPase 

The rotary motor F,-F ATPase consists ofa rotor, cam, turbine, and stator. 



The F,-F ATPase turbine interacts with the part of the complex 
that looks like a "mushroom stalk." This stalklike component functions 
as a rotor. The flow of positively charged hydrogen ions (or in some 
instances sodium ions) through the F component embedded in the 
cell membrane drives the rotation of the rotor. A rod-shaped protein 
structure that also extends above the membrane surface performs as a 
stator. This protein rod interacts with the turbine holding it stationary 
as the rotor rotates. 

The electrical current that flows through the channels of the F complex 
is transformed into mechanical energy that drives the rotor's movement. A 



Such a Clean Machine 



73 



cam that extends at a right angle from the rotor's surface causes displace- 
ments of the turbine. These back-and-forth motions are used to produce 
ATP (adenosine triphosphate). The cell uses this compound as a source of 
chemical energy to drive the operation of cellular processes. 

Back It Up 

V-type ATPases bear a strong structural resemblance to F,-F ATPases. 
Like their counterparts, V-type ATPases are rotary motors replete with a 
turbine, rotor, cam, and stator. They pump hydrogen, sodium, andpotas- 
sium ions establishing electrical potentials across cell membranes. Roughly 
speaking, the V-type ATPases operate in a reverse mode compared to the 
F-F ATPases. For V-type ATPases, the breakdown of ATP, mediated 
via the turbine, drives the rotation of its rotor. This rotation forces posi- 
tively charged protons, sodium, or potassium ions across the cell membrane 
through the channel ofthe V-type ATPase., 

For the Long Haul 

Bacterial conjugation refers to the transmission of DN A between bacte- 
rial cells. The protein complex responsible for transporting DNA across the 
cell envelope associates with the cell membrane. This DNA-transporting 
complex consists of multiple copies of the protein TrwB. Recent structural 
studies ofthe TrwB protein complex indicate that its architecture closely 
resembles the turbine of the F -F and V-type ATPases. The TrwB com- 
plex pumps DNA across the cell membrane through a channel that forms 
when the TrwB subunits interact. The DNA molecule corresponds to 
the protein rotor in the F-F and V-type ATPases. 

Expelling the Exhaust 

Recently, two independent teams of biochemists characterized the struc- 
ture of the AcrA/AcrB/TolC complex isolated from the bacterium Escheri- 
chia coli (E. coli). Their work uncovered another type of rotary motor that 
functions as an integral part of a literal molecular-level peristaltic pump 
(see figure 4.4). , 

These devices push fluids through a tube using positive displacement. . 
A flexible tube carefully positioned within a circular pump casing contains 



74 The Cell's Design 

An Efficient Assembly Line 

The production of the bacterial flagellum resembles a well-orchestrated manufacturing 
process. Its assembly pathway displays an exquisite molecular logic that results in the 
orderly production of this particular motor. Each step in the process seems to have been 
planned with subsequent steps in mind. 

The information required to produce the more than forty proteins that make up the 
bacterial flagellum resides with the bacteria's EN\ (see chapter 2, p. 48). In bacteria, genes 
specifying proteins involved in the same cellular process often lie next to one another along 
the EN\ molecule. Biochemists use the term operon to describe a grouping of these jux- 
taposed genes. The flagellar genes, organized into over fourteen different operons, cluster 
into three operon classes: Class 1, Class 2, and Class 3 (see figure 4.3). 

The flagellar operons are typically "tumed off" making no proteins until the bacterial 
cell "senses" that the time has arrived to produce flagella. When this happens, the Class 1 
operons "turn on" directing the production of two proteins. The two Class 1 proteins, in 
tum, activate Class 2 operon genes. The Class 2 operons turn on one at a time according 
to the spatial positioning of the proteins within the flagellum. 

Proteins forming the innermost structures of the flagellum, such as the rotor and stator, 
are produced first followed by the proteins forming the drive shaft and bushings. Once 
the stator, rotor, drive shaft, and bushing (called the basal body) have been assembled, 
the Class 3 operons tum on and the Class 2 operons shut down. The genes of the Class 3 
operons produce the proteins that form the universal joint and whiplike flagellum. 

This well-orchestrated process of gene expression ensures that the proper proteins 
are present at the proper time during the assembly of the flagellum. The cell avoids 
wasting precious resources by making proteins only when needed. Additionally, improper 
assembly of the flagellum will result if proteins are made ahead of time. Rsr example, if 
the cell makes the protein forming the whipHke flagellum before the basal body comes 
together, this protein will assemble into a whipUke structure inside the cell. 

Watching almost any manufacturing process evokes appreciation for the efficient and 
orderly production that depends on careful planning, design, and engineering. Witness- 
ing the assembly of bacterial flagella elicits the same type of response. The biochemical 
pathway to their structure and assembly evokes a sense of awe at the engineering bril- 
liance involved.. 



the fluid. A rotor fitted with rollers, shoes, or wipers compresses part of the 
fluid-filled tube as it rotates. This compression causes the part ofthe tube 
in contact with the rotor to collapse, forcing the fluid through the tube. 
In turn, the tube opens up as the rotor continues to turn allowing fluid to 
flow from a reservoir into the pump in a process known as restitution. 

AcrA/AcrB/TolC is found in numerous types ofbacteria (including 
several pathogenic microbes). It imparts resistance to noxious chemicals 



Such a Clean Machine 



75 



Class 1 
flhDC 



I Activates genes 



Class 2 
fllFGHIJK, fllMNOPQR, fllE, fllBAE, fIgBCDEFGHIJ, fllAZY, figAMN 




Turns off genes 

Turns o-ii ' 



e n e s 

"^ .feMitf 5 -^-Eg^lip 5 



Activates genes 
Class 3 I 



Class 3 
fIgKL, fllDST, fIgMN, fliC, tar, tap, cheRBY: 







Figure 4.3. Assembly of the Bacterial Flagellum 

Flagellum assembly proceeds through a well-orchestrated process that ensures the right 
proteins are produced at the proper time. Class 1 operons direct the production of two 
proteins. The two Class 1 proteins, in turn, activate Class 2 operon genes (fliFGHlJK, 
fliMNOPQR, fliE, etc.). The Class 2 operons turn on, one at a time according to the spatial 
positioning of the proteins within the flagellum. Once the Class 2 operons shut down, the 
Class 3 operons direct the production ofproteins to complete the assembly ofthe flagellum. 



Nccess 




la ^fding 




^•^trusio/, 




Substrate 



Drug-binding 



Vestibule y^ 




IVIedium 



Outer 
membrane 



Periplasm 



AcrB 



membrane 



Cytoplasm 



Such a Clean Machine 

in the environment. Tiiis protein ensemble spans tiie bacterial inner and 
outer membranes and pumps structurally diverse compounds from the 
cell's interior to the external environment. Such a process minimizes the 
level of harmful materials in the cell, dramatically limiting their deleteri- 
ous effects. 

As part of its action, the AcrA/AcrB/TolC complex also recognizes 
and removes a wide range of antibiotics from the cell. This activity confers 
pathogenic bacteria with multidrug resistance. Biochemists refer to AcrA/ 
AcrB/TolC as a multidrug transporter (MDT) and expend considerable 
effort to understand its structure and function to more effectively combat 
antibiotic resistance. 

The primary component of AcrA/AcrB/TolC MDT is AcrB, which 
consists of three identical protein subunits that span the bacteria's inner 
membrane. The AcrB ensemble functions like a rotary motor. In response to 
the flow of positively charged hydrogen ions through the inner membrane 
(an electrical current), each subunit alternately binds antibiotics (or other 
offending materials) in the cell's interior and, through a three-step rotation, 
transports these materials by a peristaltic mechanism into a compartment 
formed by the AcrA. 

The enclosure formed by this accessory protein bridges the space between 
the inner and outer membranes. Once in the AcrA porter, the noxious 
materials are collected by a funnellike structure that's part ofTolC. This 
accessory protein spans the outer membrane. Once undesirable materials 
pass through the TolC channel, they are expelled into the cell's exterior. 

A Spinning Spindle 

Based on recent structural studies, biochemists have proposed that a 
protein complex isolated from a virus operates as a molecular rotary motor. 
If their proposal is correct, this viral motor will be the first of its type to be 
identified in biological systems.,, This viral motor, a DNA translocator, 
generates the mechanical force needed to (1) transport viral DNA into 
newly formed viral capsules (capsids) during viral assembly and (2) inject 
viral DNA into the host cell during infection. 

Viruses are subcellular particles composed of a protein capsid that houses 
viral genetic material (either DNA or RNA). The capsid forms as a result 

Figure 4.4. The AcrA/AcrB/TolC Complex 

The AcrA/AcrB/TolC complex is a rotary motor that operates as a literal molecular-level 
peristaltic pump. 



-yg The Cell's Design 

of the interaction of multiple copies of identical protein subunits. Some 
viruses also have a protein tail that extends from the base of the viral capsid. 
Like the capsid, this viral tail consists of several protein subunits (see figure 
4.5). 

When present, the viral tail plays an important role in the infection 
process. The tail binds the virus to the target cell's surface and injects the 
viral genetic material into the host cell. 

Once inside the cell, the viral genetic material uses the host cell's enzy- 
matic machinery to make copies of the virus's components. Viral proteins 
and genetic material then assemble forming multiple copies of the virus. 
Over time, the newly produced virus particles cause the host cell to rupture. 
When it bursts, the newly formed viral particles are released to repeat the 
infectious cycle. 

The DNA translocator motor resides in the tail region near the base 
of the viral capsid. The "heart" ofthe motor is the head-to-tail connector. 
This cone-shaped structure forms through the interaction of twelve protein 
subunits (see figure 4.6). 

The wide end of the connector fits into the opening found at the base of 
the viral capsid. The narrow end serves as the point of DNA entry during 
the viral assembly process. Six separate viral RNA molecules encircle the 
connector at the base of the viral capsid to form scaffolding. This structure 
acts as a binding site for five ATPase molecules. (ATPases are a class of 
proteins that break down ATP [adenosine triphosphate], an energy-storing 
molecule.) 

ATP breakdown causes energy to be released, making it available to 
power cellular processes. According to one model, the activity ofthe viral 
ATPases drives the rotation of the connector. This rotation causes the viral 
DNA double helix, which interacts with the narrow end of the connector, 
to spiral into the viral capsid. In other words, due to the helical character 
of the DNA molecule, it becomes a spindle, the connector serves as a ball 
race, and collectively the capsid base, RNA scaffold, and viral ATPases 
form a stator. 

Interestingly, the chemical groups that form the external surface ofthe 
connector in contact with the rotary motor's "stator" have "oily" proper- 
ties. The "oily" surface functions as a lubricant allowing the connector to 
rotate with relative ease during DNA translocation. 

Recent experimental work, however, raises questions about the rotary 
mechanism ofthe viral DNA packaging motor.,, Researchers failed to 




Tail fibers 



Figure 4.5. Virus Structure and Life Cycle 



Viral DNA Packaging Motor 



Ball race 




Stator 



DNA spindle 



Figure 4.6. Viral DNA Packaging Motor 

This motor consists ofa spindle, ball race, and stator. The viral DNA double helix 
corresponds to a spindle. The connector serves as a ball race. Collectively the capsid base, 
RNA scaffold, and viral ATPases form a stator. 



Such a Clean Machine 



81 



detect rotation of the connector during tlie DNA packaging operation. 
Instead, it appears that the connector may act as a valve to prevent DNA 
from "leaking out" of the capsid once driven into the head by the viral 
motor. They note that, "the spring-like shape of the connector suggests, 
indeed, that through compression and expansion, the connector may act 
as a 'Chinese finger trap' allowing the passage of the DNA in one direction 
during packaging but preventing its exit in the reverse."!. 

Even though it's not clear to biochemists how the DNA viral packaging 
motor operates, its machinelike character is not in doubt. 

A Sniveling Motor 

The molecular motor myosin generates the force that produces muscle 
contraction and transports organelles throughout the cell. In contrast to 
the biomotors just discussed, myosin is not a rotary motor. Rather, it's 
a linear motor with a rigid lever arm. Myosin also possesses a molecular 
hinge that functions as a pivot point for the swinging lever arm (see figure 

4.7).: 

Through genetic engineering and biophysical studies, researchers 
have directly (and indirectly) observed the swing of myosin's lever arm 
and the swiveling of the myosin hinge. ; These measurements of the 
myosin motor in operation provide convincing proof of the swinging 
lever arm model for myosin motor function and myosin's machinelike 
character. 

Riding the Rails 

Dynein is a massive molecular motor that plays a role in generating a 
wavelike motion in eukaryotic flagella (which possess a fundamentally 
different structure than bacterial flagella). These motors also move cargo 
throughout the cell along microtubule tracks that are part of the cell's cy- 
toskeleton (chapter 2, p. 39). In addition, dynein helps maintain the Golgi 
apparatus (chapter 2, p. 40) and plays a role in cell division (mitosis).: (See 
figure 4.8.) 

Three domains make up dynein. The microtubule binding domain con- 
nects to the AAA-ring domain through a stalklike structure. The AAA ring 
consists of six identical protein subunits that form a hexameric ring with a 
central opening. Another stalklike structure extends from the AAA ring. 



82 



The Cell's Design 



Two Positions of tiie iVIyosin Lever Arm 




Figure 4.7. The Myosin Linear Motor 

A linear motor, myosin possesses a molecular hinge that functions as a pivot point for the 
swiveling of a rigid lever arm. 



This domain binds the cargo that dynein transports around the cell along 
microtubules. =4 

The dynein motor changes chemical energy into mechanical motion. 
At the release of chemical energy, the motor's power stroke alters the angle 
between the cargo-binding stalk and the stalk that connects the AAA 



Such a Clean Machine 



83 



Cell Cargo 



AAA ring 



"■.:.: .:i|!Wl|| 

i, %. . :N..i«i:iiiiiyi^ 
■V#;;.;^^». ' 




Figure 4.8. Dynein 

Dynein is a massive molecular motor that moves cargo throughout the cell along microtubule 
tracks. Dynein's power stroke alters the angle between the cargo-binding stalk and the stalk 
that connects the AAA ring to the microtubule. 



ring to the microtubule. It also increases the size of the AAA ring's central 
opening. The structural change in the AAA ring drives the angle change 
between the two stalks. This angle change leads to the movement of dynein 
along the microtubule. 

Remarkably, the distance that dynein moves along the microtubule for 
each power stroke varies with the size of the cargo attached to this molecular 
motor. As the load increases, the distance that dynein moves per power 
stroke decreases. It appears that the dynein motor literally shifts gears in 
response to the load. =3 



QA The Cell's Design 

Other Biomechanical Marvels 

Recent structural studies also indicate that a number of protein complexes, 
though not molecular motors, possess components that resemble parts of 
man-made devices. One remarkable example is RNA polymerase II. 

RNA polymerase II. In 2000, researchers from Stanford University 
reported the structure of the RNA polymerase II backbone at 3.5 A resolu- 
tion.!. This complex consists of twelve protein subunits that work together 
to synthesize messenger RNA using DN A as a template. Produced this way, 
messenger RNA contains the information necessary to direct the synthesis 
ofproteins at ribosomes. 

Because of the large size, fragility, complexity, and low abundance of 
RNA polymerase II in the cell, its structural analysis took nearly twenty 
years to complete.: The results, however, were well worth waiting for — 
they led to a Nobel Prize.: 

RNA polymerase II has a remarkable machinelike character. Its subunits 
form a channel that houses the chainlike DN A template. "Jaws" help grip 
the DNA template to hold it in place during RNA synthesis. The newly 
formed RNA chain locks a hinge clamp into place as the chain exits the 
channel. A funnellike pore then delivers the small subunit molecules to the 
channel where they are added to the growing end of the RNA chain. 

DNA replication. A number of protein complexes that participate in 
DNA replication possess a clamp that holds onto DNA strands.:. Because 
of DN As helical structure and other torsional stresses on the molecule, the 
proteins that replicate DNA encounter considerable torque. The clamp 
helps these proteins grip the DNA molecule while maintaining their pre- 
cise position along the DNA double helix. As replication takes place the 
proteins involved in DNA replication move along that spiral. The clamps 
allow these proteins to rapidly slide along the DNA during the replication 
process. 

Thioredoxin reductase. Structural characterization at 3.0 A resolution 
reveals that thioredoxin reductase function is built around a ball-and- 
socket joint. This protein, isolated from the E. coli bacterium, assists in 
the transfer of electrons between molecules. During the catalytic cycle, the 
enzyme undergoes a conformational rearrangement that involves the 67° 
rotation of one of its domains around a clearly defined swivel surface. 

RNA polymerase II, DNA sliding clamp proteins, and E. coli thioredoxin 
reductase represent just a few of the many protein complexes that possess 



Such a Clean Machine 



85 



components qualitatively identical to certain parts of man-made devices. 
The origin of these biomolecular motors and machines can be explained 
by a new version of an old argument. 

The Watchmaker Argument Updated 

Experience teaches that machines and motors don't just happen. Even 
the simplest require thoughtful design and manufacture. This common 
understanding undergirds one of history's best known arguments for God's 
existence. 

The Watchmaker line of reasoning was best articulated by Anglican 
natural theologian William Paley (1743-1805). In the opening pages ofhis 
1802 work Natural Theology; or. Evidences of the Existence and Attributes 
of the Deity Collectedfrom the Appearances of Nature, Paley sets forth his 
famous analogy. 

In crossing a heath, suppose I pitched my foot against a stone, and were 
asked how the stone came to be there; I might possibly answer, that, for any 
thing I knew to the contrary, it had lain there for ever.... But suppose I had 
found a watch upon the ground, and it should be inquired how the watch 
happened to be in that place; I should hardly think of the answer which I 
had before given, that, for any thing I knew, the watch might have always 
been there. Yet why should not this answer serve for the watch as well as for 
the stone? Why is it not as admissible in the second case, as in the first? For 
this reason, and for no other, viz. that, when we come to inspect the watch, 
we perceive (what we could not discover in the stone) that its several parts 
are framed and put together for a purpose, e.g. that they are so formed and 
adjusted as to produce motion, and that motion so regulated as to point 
out the hour of the day; that, if the different parts had been differently 
shaped from what they are, of a different size from what they are, or placed 
after any other manner, or in any other order, than that in which they are 
placed, either no motion at all would have been carried on in the machine, 
or none which would have answered the use that is now served by it. ... 
This mechanism being observed . . . , the inference, we think, is inevitable, 
that the watch must have had a maker: that there must have existed, at some 
time, and at some place or other, an artificer or artificers who formed it for 
the purpose which we find it actually to answer; who comprehended its 
construction, and designed its use. 3, 



Og The Cell's Design 

For Paley, the characteristics of a watch and the complex interaction of 
its precision parts for the purpose of telling time implied the work of an 
intelligent designer. Paley asserted that, by analogy, just as a watch requires 
a watchmaker so too life requires a Creator. He reasoned that, like a watch, 
organisms display a wide range of features characterized by the precise 
interplay of complex parts for specific purposes. 

According to the Watchmaker analogy: 

Watches display design. 

Watches are the product of a watchmaker. 

Similarly: 

Organisms display design. 

Therefore, organisms are the product of a Creator. 

Facing the Critics 

Over the centuries the Watchmaker argument hasn't fared well. Skeptics 
often point to David Hume's 1779 work Dialogues Concerning Natural 
Religion. This critical analysis of design arguments is considered devastat- 
ing to Paley's case for the Creator. Hume leveled several criticisms; the 
foremost centered on the nature of analogical reasoning. 

Based on Hume's arguments, skeptics curtly dismissed the Watchmaker 
argument, maintaining that the two things compared — organisms and 
watches — were too dissimilar for a good analogy (see chapter 1, p. 30). 
Hume asserted that the strength of an analogical argument depends on 
the similarity of the two things compared. He wrote that "whenever you 
depart, in the least, from the similarity of the cases, you diminish propor- 
tionably the evidence; and may at last bring it to a very weakanalogy, which 
is confessedly liable to error and uncertainty.".,! 

Atheist B. C. Johnson underscored Hume's case by arguing that Paley 
did not use a strict enough criterion for identifying intelligent design. Paley 
argued that design is evident when a system contains several parts that work 
together for apurpose. Johnson, in contrast, says, "We can identify a thing 
as designed, even when we do not know its purpose, only if it resembles the 
things we make to express our purposes.";, 



Such a Clean Machine 



87 



Others argued that organisms are not machines, and those who saw them 
as such took the analogy too far. According to these skeptics, the analogy 
between machines and living systems was simply an explanatory analogy, 
an illustration that provided a framework to guide understanding. ,4 

The merit of the Watchmaker argument then rests on the questions: 
Do living systems resemble man-made machines enough to warrant the 
analogy? And, if so, how strong is this analogy, and can a conclusion rea- 
sonably be drawn from it ? 

Risingjrom the Dead 

The discovery of biomolecular motors and machines inside the cell gives 
new life to the Watchmaker argument. In many instances, molecular-level 
biomachinery stands as a strict analog to man-made machinery and rep- 
resents a potent response to the legitimate criticism leveled by Hume and 
others, given the state of knowledge at the time. Biomachines found in the 
cell s interior reveal a diversity of form and function that mirrors the diver- 
sity of designs produced by human engineers. The one-to-one relationship 
between the parts of man-made machines and the molecular components of 
biomachines is startling. And each new example of a biomotor strengthens 
Paley's case for the Creator. 

Biomotors and machines are not explanatory analogies. The motors 
and machines described in this chapter are motors and machines by defi- 
nition. And, because machines stem from the work of a designer, these 
molecular-level machines must emanate from the work of an Intelligent 
Designer. The strong, close, and numerous analogies between biologi- 
cal motors and man-made devices logically compel the conclusion that 
these biomotors, and consequently life's chemistry, are the product of 
intelligent design. 

Nanotechnology's Acclaim 

The analogy between molecular motors and man-made machinery 
finds additional strength in cutting-edge work conducted by researchers 
developing nanodevices.^ These molecular-level devices are comprised of 
precisely arranged atoms and molecules. With dimensions less than 1,000 
nanometers (one-billionth of a meter), nanostructures have applications 



gg The Cell's Design 

in manufacturing, electronics, medicine, biotechnology, and agricul- 
ture among others. But one of the key hurdles preventing nanodevices 
from becoming a truly viable technology was their inability to power 
movement. 

An important breakthrough was announced at the Sixth Foresight 
Conf er ence on Molecular Nano techno logy (November 1998). Scientists, 

Paley's Biochemical Watch 

William Paley "pitched his foot against a watch" while "crossing a heath." Yale bio- 
chemist Jimin Wang stumbled onto a mechanical molecular clock inside cyanobacteria 
{photosynthetic blue-green algae) while performing a structural analysis of the Kai 
proteins. is The KaiA, KaiB, and KaiC proteins play an integral role in the circadian 
oscillation that regulates the metabolic processes of cyanobacteria. 

The biochemical activity of this blue-green algae varies periodically in response to 
the light-dark cycle. When it is dark, certain metabolic activities shut down. 

The KaiC protein is key to this cyanobacterial circadian rhythm. When its levels 
are high inside the cell, the protein represses gene expression. Low levels stimulate 
gene expression. At night, the KaiC protein forms complexes with the KaiA and KaiB 
proteins. During the daylight hours, the KaiABC complexes dissociate. 

The molecular architecture of the KaiABC complex bears striking similarity to the 
F , - '^ ATPase rotary motor. Six KaiC proteins interact to form a structure similar to the 
turbine of the F F ATPase rotary motor. Two copies of the KaiA protein interact to 
form a structure that resembles the rotor of the F,-F ATPase motor. A spring-loaded 
mechanism causes the KaiA protein duplex to alternate between two forms (like the 
opening and closing of a pair of scissors), one that interacts with the KaiC complex 
channel and one that does not. The KaiB protein functions like a wing nut fastening 
the KaiA duplex to the bottom of the KaiC complex. 

The KaiA duplex rotates within the channel, with the KaiB wing nut controlling the rotation 
rate of the KaiA rotor. As the KaiA rotor steps through the KaiC channel, a cam sequentially 
causes changes to each of the KaiC proteins. This mechanical action causes phosphate 
chemical groups to attach to those proteins. WTien fiiUy phosphorylated, the KaiC complex 
dissociates. The formation and dissociation of the KaiABC complex regulates the KaiC levels 
inside the cell, which in turn controls the cyanobacterial circadian oscillation. 

Once the KaiABC complex is assembled, the mechanical clocklike rotary action of 
the KaiA duplex within the KaiC channel controls its stability through the phosphorylation 
of the individual KaiC proteins. According to Wang, "The Kai complexes are a rotary 
clock for phosphorylation, which sets up the destruction pace of the night-dominant 
Kai complexes and the timely releases of KaiA." 

In Paley's words, "This mechanism being observed..., the inference, we think, is 
inevitable, that the watch must have had a maker." 



Such a Clean Machine 



89 



working separately at Cornell University and at the University of Washing- 
ton in Seattle, "like molecular mechanics ...[,] have unbolted the motors 
from their cellular moorings, remounted them on engineered surfaces and 
demonstrated that they can perform work.",. 

Advancing these earlier feasibility studies, scientists from Cornell 
University produced a hybrid nanomechanical device powered by the 
F,-F ATPase biological molecular motor.. The researchers connected 
F,-F ATPase to an engineered surface via the enzyme's turbine. They 
then attached nickel nanopropellers to the motors rotor. Upon adding 
ATP — a chemical compound that powers the F -F ATPase rotor — 
the nanopropellers rotated at a velocity of 0.74 to 8.3 revolutions per 
second. 

Sodium azide — an inhibitor of the F -F ATPase rotor — halted the 
nanopropellers' rotation. In the absence of an inhibitor, this rotation typi- 
cally lasted for at least 2.5 hours before the nanopropellers broke away 
from the F,-F ATPase rotor. These molecular motors, co-opted from 
cells, operated at near 80 percent efficiency in this particular system — far 
better than humans can achieve with man-made devices. 

F-F ATPase is not the only molecular motor used by scientists to 
power nanodevices. Researchers are exploring the feasibility of using the 
viral DNA packaging motor in gene therapy as a device to deliver DNA 
to cells with defective genes. Proof-of-principle studies indicate that it 
is possible to assemble a DNA packaging motor from the components 
of the viral DNA packaging motor that can drive the translocation of 
DNA like "driving a bolt with a hex nut.",: Addition ofmagnesium ions 
and ATP caused the imitation motor to rotate, and addition of either the 
chemical compound EDTA or S-ATP (inhibitors of the motor) halted 
its rotation. 

These two studies powerfully demonstrate that the molecular motors 
in the cell are literal motors in every sense. Any perceived differences 
between man-made motors and biomotors evaporate in light ofthese 
advances. 

This work is just the beginning. Even greater support for the 
Watchmaker argument will likely accrue with future advances in nan- 
otechnology — particularly as researchers continue to borrow from 
the superior designs found inside the cell to drive developments in 
nanotechnology.. 



gQ The Cell's Design 

The Artist's Expertise 

Recent work, described as "science at its very best," provides insight into 
the superior intelligence of the Designer responsible for the molecular 
motors found in nature. 44 In the quest to build nanodevices, synthetic 
chemists have produced molecular switches, gears, valves, shuttles, ratchets, 
turnstiles, and elevators.: These molecular-level devices have obvious utility 
in nanodevices, but their construction holds additional significance. They 
represent a significant step towards the "holy grail" of nanotechnology: 
single-molecule rotary motors capable of rotating in a single direction that 
can power movement in nanodevices... 

Significant steps toward this goal were achieved in 1999 when a team of 
researchers from Boston College and a collaborative team from the Uni- 
versity ofGroningen in the Netherlands and Tohuku University in Japan 
independently designed and synthesized the first single-molecule rotary 
motors with the capability of spinning in one direction. The rotation of the 
motors is driven by UV radiation and heat or through chemical energy. 

These synthetic molecular motors are the product of careful design and 
planning. The light- and heat-driven molecular motor made by the team 
from the universities of Groningen and Tohuku depends upon the "unique 
combination of axial chirality and the two chiral centers in the molecule" 
positionedjust right in three-dimensional space.. Likewise, the molecular 
motor developed by the team from Boston College is dependent upon 
molecular chirality, as well as fine-tuning ofthe molecular substituents... 

It is clear these molecular motors did not happen by accident or as the 
natural outworking of the laws of chemistry and physics. In fact, the chemi- 
cally driven molecular motor — comprised of only seventy-eight atoms — 
took over four years to build.. In spite of all the effort that went into the 
preparation of these synthetic molecular motors, both rotary motors rotate 
in a cumbersome and stepwise fashion. Recently, chemists have prepared 
even more sophisticated synthetic single-molecule rotary motors capable 
of changing their direction of rotation in response to chemical cues. Still, 
these motors are qualitatively no less crude in their operation than the 
first-generation motors.. 

The contrast between these synthetic molecular motors designed by 
some ofthe finest and most creative organic chemists in the world and 
the elegance and complexity of molecular motors found in cells is striking. 
Considering the efforts of scientists working to develop nanoscale devices. 



Such a Clean Machine 



91 



the elegance of God's creation on display shows just how superior the bril- 
liance of the Divine Artist and Grand Designer must be. 

A Watchmaker Prediction 

Many of the cell's molecular devices that should, in principle, be included 
in the Watchmaker analogy remain unrecognized because the corresponding 
technology has yet to be developed by human designers. The possibility that 
advances in human technology will mirror the cell's existing technology 
leads to the Watchmaker prediction. 

If the Watchmaker analogy truly supports design, then it's reasonable 
to expect that life's biochemical machinery anticipates human technology 
advances. Recent progress made in nanotechnology already makes signifi- 
cant strides towards making that prediction a reality. 

Brownian Ratchets 

One of the chief technical hurdles that stands in the path of viable nano - 
devices is the inability to generate directional movement within nano- 
machinery. Some researchers have proposed Brownian ratchets as a way 
around this barrier. s. 

These theoretical devices make use of Brownian motion (see figure 4.9). 
This phenomenon describes the random zigzag movement of microscopic 
objects suspended in a liquid or gas. When the sum of forces exerted on 
a suspended object by the gas or liquid molecules generates a directional 
force, it causes the particle to move. The forces are short-lived and randomly 
directed. This causes the particle to move in a zigzag fashion. 

Brownian ratchets exploit Brownian motion but use barriers to restrict 
the motion in a specified direction. These ratchets require energy input to 
erect and maintain the barriers that prevent motion in unwanted directions. 
In response to this energy input, Brownian ratchets produce directional 
movement of microscopic materials — making the ratchets a new genera- 
tion ofpotential motors. In short, the components of Brownian ratchets 
try to wander in every direction. But carefully placed barriers prevent them 
from going the wrong way. 

Recent proof-of-principle experiments demonstrate that devices built 
around Brownian ratchets may well be possible. This proof-of-principle 



Brownian Motion 




Brownian Ratchet 



Barrier ■ 




Figure 4.9. Brownian Motion and Brownian Ratchets 

This phenomenon describes the random, zigzag movement of microscopic objects 
suspended in a liquid or gas. Brownian ratchets rely on barriers to restrict the motion to 
specified direction. 



Such a Clean Machine 



93 



took a significant step toward reality in 1999 when a research team built a 
device that transports DNA molecules using a Brownian ratchet.,. These 
scientists think this DNA transport device can be used to separate DNA 
fragments, a process required to sequence DNA. 

Brownian ratchets are rapidly moving from the theoretical realm to real- 
ity. While nanotechnologists strive to develop and implement Brownian 
ratchet technology in nanodevices, biochemists have already discovered 
several Brownian ratchets inside the cell. Three examples of these motors 
are kinesin, BiP, and collagenase. 

Kinesin 

This molecular motor transports cellular cargo along microtubules that 
form part of the cell's cytoskeleton. : Kinesin's structure resembles two golf 
clubs with their shafts intertwined around one another in a helical fashion. 
Attached to kinesin's rodlike region are two lobe-shaped structures that 
resemble the heads ofgolf clubs. 

The kinesin heads interact with microtubules. The rodlike shaft binds the 
cellular cargo that kinesin will transport along the microtubules. Kinesin 
then "walks" along the microtubule with the heads attaching and detach- 
ing to the microtubule in an alternating fashion. This motor moves in 
only one direction. 

Biochemists are still attempting to understand how kinesin operates. 
Recently two biophysicists proposed that the kinesin motor functions as 
a Brownian ratchet.. According to this idea, the kinesin heads randomly 
diffuse. But once the head binds to the microtubule, it restricts the move- 
ment and binding of the other head. This restriction causes kinesin to move 
in a single direction along the microtubule. 

BiP 

The BiP protein (also referred to as the Kar2p protein) associated with 
the endoplasmic reticulum (see chapter 2, p. 40) represents another example 
of a biochemical Brownian ratchet. BiP plays a role in moving proteins 
across the endoplasmic reticulum (ER) into its internal space (lumen) for 
processing and preparation for secretion from the cell (see figure 4.10). 

Once produced at the ribosomes associated with the ER, proteins 
travel through channels in the ER membrane. These channels consist of a 



94 



The Cell's Design 



Brownian Ratchet 



Lumen 



BiP 
Translocator 




Figure 4.10. Hie BiP 
Brownian Ratchet 

The BiP protein associated 
with the endoplasmic 
reticulum (ER) is a 
biochemical Brownian 
ratchet. BiP binds proteins 
in the lumen of the ER 
and prevents them from 
diffusing back into the 
channel. 

diffusing back into the 
channel. 

conglomeration of several proteins (Sec61p and Sec62/63p). In addition 
to the channel proteins, BiP is required for protein transport through the 
ER channels. BiP resides in the ER lumen. Initially, biochemists thought 
that BiP pulled the proteins through the channel using chemical energy. 
But, an elegant study published in 1999 demonstrated that BiP operates 
as a Brownian ratchet.,, 

Instead of pulling proteins through the ER channels, BiP uses chemi- 
cal energy to bind the protein chains as they passively diffuse through the 



Such a Clean Machine 



95 



channel. When BiP binds proteins, it prevents them from diffusing back 
into the channel. This restricts the proteins' movement to a single direction 
through the channel. 

Collagenase 

Biochemists recently identified the protein collagenase MMP-1 as a 
specialized type of Brownian ratchet. This protein — called a "burnt bridge" 
Brownian ratchet.,, — breaks down the collagen fibers found in the extracel- 
lular space of connective tissues. 

The extracellular matrix (ECM) is the region between cells in biological 
tissues. A complex network of fibers forms scaffolding in the ECM that 
imparts shape and mechanical resistance to the tissue. Fibers made from the 
protein collagen are among the most abundant components of the ECM 
scaffolding. The collagen consists of three elongated protein chains that 
intertwine to form what biochemists call a triple helix. 

From time to time, the scaffolding of the extracellular matrix is remodeled. 
Existing fibers are broken apart, and new fibers are laid down. Certain disease 
processes result from improper remodeling of the ECM scaffolding. 

Special proteins called matrix metalloproteinases (MM?) break down 
the ECM collagens. MMP-1 collagenase moves along collagen in a single 
direction as it degrades the fiber, looking for specific cleavage sites. Diffu- 
sion in the reverse direction along the collagen fiber is prevented because 
cleavage of the fiber destroys the "tracks" (or burns the bridge behind it), 
preventing reverse migration. MMP-1 collagenase functions as a Brown- 
ian ratchet in which directional movement is coupled to the breakdown 
(proteolysis) of the collagen fiber. 

The discovery of biochemical Brownian ratchets strengthens the Watch- 
maker analogy in two ways. First, it adds to the number of biomolecular 
machines that are strict analogs to man-made devices. Second, it satisfies the 
Watchmaker prediction. In other words, life's Brownian ratchets precede 
and pave the way for the development of man-made Brownian ratchets 
that could one day become part of nanodevices. 



Molecular Motors and the Pattern of Intelligent Design 

Chapter 3 described the remarkable overall complexity and organization 
of the simplest life-forms. Even in its most minimal form, life displays an 



96 



The Cell's Design 



inherent irreducible complexity. Simplest life also displays a remarkable 
organization at the molecular level. 

This chapter elaborated on some of the details of this molecular complex- 
ity and organization — details that reveal the operation of molecular-level 
machines inside the cell. The cell's machinery logically indicates that life's 
chemistry stems from intelligent agency. An eerie resemblance between the 
cell's molecular motors and humanly designed machinery, both in form and 
function, revitalizes William Paley's Watchmaker argument in a way that 
addresses the legitimate concerns raised by skeptics over the centuries. 

These molecular motors are irreducibly complex, an independent indi- 
cator of intelligent design. They would suffer from the same problem as 
Paley's watch 

if the different parts had been differently shaped from what they are, of a 
different size from what they are, or placed after any other manner, or in 
any other order, than that in which they are placed, either no motion at 
all would have been carried on in the machine, or none which would have 
answered the use that is now served by it... 

Work done in the burgeoning arena of nanoscience and nanotechnol- 
ogy not only highlights the machinelike character of these biomotors, it 
exposes the elegance and sophistication of their design. The cell's machinery 
is vastly superior to anything that the best human designers can conceive 
or accomplish. As a case in point, bacterial flagella operate near 100 per- 
cent efficiency... This capability stands in sharp distinction to man-made 
machines. Electric motors only function at 65 percent efficiency and the 
best combustion engines only attain a 30 percent efficiency. 

The superiority of the cell's molecular machines is consistent with the no- 
tion that the intelligent designer is the Creator described in the Bible. It also 
prompts the question: Is it really reasonable to conclude that these biomo- 
tors are the products of blind, undirected physical and chemical processes, 
when they are far beyond what the best human minds can achieve ? 

Life's biomolecular motors not only bring to light one of the most remark- 
able design features inside the cell, they also highlight the Creator's artistry. 
The elegance and beauty of the cell's machinery cannot be overlooked in the 
midst of making the case for intelligent design. Its grandeur is even more 
captivating than the automobile designs that inspire Ken Ebertss fine art. 

The next chapter examines another aspect of the cell's biochemical sys- 
tems that raises some provocative questions about life's origin. 



WHICH CAME FIRST? 



M. C. Escher's woodcuts, lithographs, and mezzotints almost always require 
a second look. These pieces explore spatial illusions, impossible construc- 
tions, and repeating geometric patterns. 

Escher's designs contain strong mathematical components. Its no surprise 
that mathematicians and scientists are drawn to him. Ironically, Escher 
had no formal training in either discipline. He even failed his high school 
exams. 1 

Some of this Dutch graphic artist's most well-known works include Sky 
and Water, which plays with shadows and light to transform fish in the 
water into birds in the sky, and Ascending and Descending, in which aline 
of people simultaneously ascend and descend staircases in a never-ending 
loop. One of Escher's most fascinating pieces. Drawing Hands, depicts 
a sheet ofpaper with two "sketched" wrists flat on the page. The two- 
dimensional wrists transition into three-dimensional hands that appear 
to be drawing one another. 

Drawing Hands exposes a fascinating paradox that plays on the concept 
of an infinite loop. The two hands appear strictly interdependent — one 
cant exist without the other. The only way the two hands could arise is if 
an artist, like Escher, sketches them. 

Over the last few decades, biochemists have discovered several chemi- 
cal operations in the cell that, like Drawing Hands, consist of components 
strictly interdependent on one another. These "chicken-and-egg" systems 

97 



gg The Cell's Design 

raise questions about how life's chiemistry came about. The molecules that 
comprise these works of art can't exist apart from each other — unless a 
Divine Artist sketched them. 



A Simultaneous Situation 

Human engineers frequently encounter which-comes-first issues when 
designing systems and processes. The radio frequency identification (RFID) 
industry illustrates this problem. A chicken-and-egg dilemma confronts 
manufacturers who consider adopting this technology. 

RFID systems employ tags or transponders that emit radio waves. This 
signal allows the tagged items to be identified automatically. Ideally, this 
methodology will one day replace bar codes and universal product codes 
(UPC). The new tags can store much more data and have a diverse range 
of potential applications from identifying pets to tracking cases and pallets 
of product in the supply chain.. 

But many manufacturers resist RFID systems in spite of their potential 
benefits because of the cost. They won't use the technology until its price 
drops. And, the price won't drop until RFID technology is widely adopted. 
In addition, companies that represent one part of the supply chain won't 
accept the technology until it's widely used by other companies in the rest 
ofthe chain. 

Resolution to these chicken-and-egg problems for the RFID indus- 
try will come only when all parties agree to simultaneously switch to the 
technology or if they are forced to implement these systems. For example, 
a mandate from the FDA could require the pharmaceutical industry to 
employ RFID technology. 

Everyday experience teaches that chicken-and-egg systems can come to 
fruition only through intentional planning and implementation. These 
systems, therefore, are a potent indicator of intelligent design. Several ex- 
amples of biochemical chicken-and-egg systems demonstrate why. 

Does DNA Draw Proteins or Do Proteins Draw DNA? 

DN A houses the information the cell needs to make proteins, which play 
a role in virtually every cell function. Proteins also help build practically 
every cellular and extracellular structure (see chapter 2, p. 42). Given this 



Which Came First? 



99 



importance, the information housed in DNA defines life's most funda- 
mental operations and structures. 

When cells divide and organisms reproduce, DNA and the information 
it stores is passed on to the daughter cells and their offspring. Biochemical 
blueprints are conveyed to the next generation through DNA replication. 
This process generates two "daughter" molecules identical to the "parent" 
DNA molecule. Once replication occurs, a complex system distributes the 
two DNA molecules generated by replication between the daughter cells 
produced during cell division (see figure 5.1). 

Biochemists commonly refer to DNA as a self-replicating molecule 
because its structural properties make itpossible to generate two identical 
daughter molecules from the original parent. In reality, however, DNA 
cannot replicate on its own. 

A Naturalistic Descent 

Mutual interdependence of DNA and proteins stands as a major stumbling block 
for evolutionary explanations of life's origin. + Origins-of-life researchers even refer 
to this conundrum as the chicken-and-egg paradox. Because these two molecules 
are so complex, scientists don't think DNA and proteins could simultaneously arise 
from a primordial soup. The existence of DNA apart from proteins and proteins apart 
from DNA is like a column of people trying to simultaneously ascend and descend 
a staircase. 

The RNA-world hypothesis has been proposed as a resolution to this paradox. This 
model maintains that RNA preceded DNA and proteins. RNA can simultaneously store 
information (like DNA) and catalyze chemical reactions (like proteins). So, it's thought that 
the RNA world eventually evolved into the DNA-protein world of contemporary biochem- 
istry, with RNA currently functioning as an intermediary between DNA and proteins. 

While the RNA-world hypothesis rescues the origin- of- life paradigm from the 
chicken-and-egg paradox on paper, in practical terms it appears largely untenable. 
Numerous problems abound for the RNA-world hypothesis. For example, it's unlikely 
that the prebiotic chemical reactions identified in the laboratory for the production 
of ribose and the nucleobases could take place on early Earth. And, even if these 
compounds did form, it's unlikely they could assemble into functional RNA molecules. 
In fact, Leslie Orgel, one of the world's leading origin-of-life researchers, has said, "It 
would be a miracle if a strand of RNA ever appeared on the primitive Earth." 

Even in the face of these serious problems, most origin-of-life scientists are con- 
vinced that the RNA world must have existed and paved the way for the DNA-protein 
world. If it didn't, the chicken-and-egg paradox — from an evolutionary standpoint — 
cannot be resolved. 



Parental DNA 



Mother cell 



Daughter cell 




Daughter cell 



Replicated DNA 
after one generation 



Figure 5.1. DNA Replication and Cell Division 

When cells divide, DNA is passed on to the daughter cells. DNA replication generates two 
"daughter" molecules identical to the "mother" DNA molecule. 



Which Came First? 



101 



DN A replication requires a myriad of proteins. (Chapter 1 1 details DNA 
replication and the role that proteins play in this process.) The synthesis of 
proteins and the replication of DNA are mutually interdependent. Proteins 
cannot be produced without DNA, and DNA cannot be produced without 
proteins— both hands draw each other. 



Proteins Make Proteins 

When the cell's machinery copies the genetic information stored in 
the DNA molecule, it sets the stage for protein synthesis (see chapter 2, 
p. 50). First, a single-stranded polynucleotide messenger RNA (mRNA) 
molecule (transcription) is assembled using DNA as a template. After 
processing, mRNA migrates from the nucleus ofthe cell into the cyto- 
plasm. At the ribosome, mRNA directs the synthesis of protein molecules 
(translation). 

While the details of transcription (taking DNA to mRNA) and transla- 
tion (taking mRNA to proteins) differ in prokaryotes and eukaryotes, both 
processes heavily depend upon proteins. In bacteria, mRNA production 
requires RNA polymerase, a complex protein made from six polypeptide 
subunits.7 Biochemists have labeled these subunits: alpha (a), beta (|3), beta 
prime (|3'), omega (co), and sigma (o). RNA polymerase consists of two a 
subunits and one each ofthe (3, |3', cd, and a subunits. It takes five subunits 
(a, a, |3, |3' and co) to form the core protein. 

The RNA polymerase core is capable of synthesizing mRNA on its own 
but can't recognize the location along the DNA strand where the gene be- 
gins. This role is performed by the o subunit. In fact, several different types 
of o subunits exist. Each one recognizes the start site for genes involved in 
different cellular processes. 

In eukaryotic organisms, three different types of RNA polymerase tran- 
scribe genes (RNA polymerase I, RNA polymerase II, and RNA poly- 
merase III). Like the bacterial form, eukaryotic RNApolymerases are com- 
posed of numerous subunits. However, in eukaryotes, RNApolymerases 
need transcription factors— proteins that recognize genes and initiate the 
gene-copying process. 

Once mRNA is produced in eukaryotes, it undergoes extensive modi- 
fication before heading to the ribosome. s These modification reactions all 
involve proteins. 



1 Q2 The Cell's Design 

The first set of reactions "caps" one end of mRNA. This capping process 
begins when an enzyme called guanylyl transferase attaches a chemically 
modified guanine (called 7-methylguanine) to the first nucleotide in the 
mRNA strand. After the 7-methylguanine is attached, another enzyme 
guanine 7-methyl transferase adds methyl groups to the nucleotides in the 
second and third positions of the mRNA chain. 

The next set of reactions modifies the opposite end of the mRNA strand. 
The poly (A) polymerase protein adds about two hundred adenine nucle- 
otides to the last position of the mRNA molecule to form the poly (A) 
tail. This tail imparts stability to the mRNA molecule. 

The final modification to mRNA, the splicing reactions, also requires pro- 
teins. In eukaryotes, the sequences that make up genes consist of stretches 
of nucleotides that code for the amino acid sequence of polypeptide chains 
(exons). These exons are interrupted by nucleotide sequences that don't code 
for anything (introns). After the gene is transcribed, the intron sequences are 
excised from the mRNA and the exons are spliced together. This process is 
mediated by an RNA-protein complex called a spliceosome (see figure 5.2). 

Once synthesized and processed, mRNA migrates to the ribosome where 
it directs protein synthesis. Ribosomes are massive complexes composed 
of proteins and RNA molecules (ribosomal RNA or rRNA)., 

Though ribosomes of prokaryotes and eukaryotes have the same general 
structure, they differ in size. Ribosomes consist of two major subunits. The 
508 and 30S subunits in prokaryotes combine to form a 70S ribosome. 
The 60S and 40S subunits in eukaryotes form an SOS ribosome (see figure 
5.3). 

In prokaryotes, the large subunit contains two rRNA molecules and 
about thirty different protein molecules. The small subunit consists of a 
single rRNA molecule and about twenty proteins. The large subunit in 
eukaryotes is formed by three rRNA molecules that combine with about 
fifty distinct proteins. Their small subunit consists of a single rRNA mol- 
ecule and over thirty different proteins. 

Researchers have focused extensive effort on understanding the struc- 
ture of ribosomes and the role of proteins and rRNA in protein synthesis. 
Amazing progress has been made. The latest work indicates that the pro- 
duction ofproteins is ultimately mediated by rRNA. Still, a myriad of 
proteins that make up ribosomes play an integral structural and functional 
role, helping mRNA bind to the ribosome and causing the newly formed 
protein chain to properly fold.,. 



5 31 32 



Exon Intron Exon 



Start site for RNA synthesis 



105 106 147 

Intron Exon 



iiitt»iililft*|ii|lii<«l^fta!3-»|i||| 



Primary 
RNA 5'G- 
transcript 



Poly (A) 
site 



'm'Gppp 



3' cleavage and addition 
of poly (A) tail 




3' poly (A) tail 



31 



105 147 



■(A)„ 



Figure 5.2. mRNA Splicing 

In eukaryotes, the DNA sequences that make up genes consist ofstretches of nucleotides that 
code for the amino acid sequence of polypeptide chains (exons) interrupted by nucleotide 
sequences that don't code for anything (introns). After the gene is copied by assembling the 
mRNA, a 7-methylguanine (mVGppp) cap and a poly (A) tail are added. Next, the intron 
sequences are excised from the mRNA and the exons spliced together by the spliceosome 
(not shown). 




Prokaryotic 



165(1,500 bases) 



O® ® ® Q^ 



® 



(SI' 



(Total: 21) 




235 (2,900 bases) 



rRNA 



55(120 bases) 

+ 



(Totalis 1) 




Subunits 



Assembled ribosomes 



Ribosome 



Which Came First? 



105 



Proteins also play a critical role in the initiation of translation. In both 
prokaryotes and eukaryotes, proteins called initiation factors help ready 
the ribosome for protein synthesis by binding to the small subunit.,, The 
small subunit and the initiation factors form the pre-initiation complex, 
which binds mRNA. Once it's bound, the initiation factors dissociate from 
the small subunit. The initiation complex, in turn, binds the large subunit 
to form the ribosome. Protein synthesis is now ready to begin. 

For protein production to proceed, RNA molecules called transfer RNAs 
(tRNAs) must bind amino acids, then ferry them to the ribosome. Each 
of the twenty amino acids used by the cell to form proteins has at least one 
corresponding tRNA molecule. An activating enzyme (aminoacyl-tRNA 
synthetase) links each amino acid to its specific tRNA carrier. Each tRNA 
and amino acid partnership has a corresponding activating enzyme specific 
to that pair. 

Another set of proteins (elongation factors) help usher the amino acid- 
tRNA pairs to the ribosome and properly position them for protein syn- 
thesis.: (The role of aminoacyl-tRNA synthetases and elongation factors 
in protein synthesis is expounded on further in chapter 10.) 

This brief and simplified survey of the process of protein production 
makes clear that proteins cannot be made without proteins. The very pro- 
teins that make proteins are made by the processes described — so what 
came first? 



The Art of Protein Folding 

Many proteins need the assistance of other proteins to fold into the 
proper three-dimensional shape after they've been produced at the ribo- 
some. The physicochemical properties of amino acid sequences determine 
the way that the polypeptide chain folds into its complex three-dimensional 
shape (see chapter 2, p. 42). In a few cases, polypeptide chains will fold into 
the proper three-dimensional structure on their own. But, most proteins 
can't, or if they can, the process is slow and inefficient. 

In the cell's environment, improperly folded proteins or proteins that fold 
slowly and inefficiently represent a potential catastrophe. In the crowded 

Figure 5.3. Ribosome Structure 

Ribosomes are massive complexes formed from proteins and RNA molecules. The ribosomes of 
prokaryotes and eukaryotes have the same general structure but differ in size. Ribosomes consist 
oftwo major subunits: the 50S and 30S subunits in prokaryotes that combine to form a 70S 
ribosome and the 60S and 40S subunits in eukaryotes that combine to form an SOS ribosome. 



106 



The Cell's Design 



cell, improperly folded proteins tend to aggregate and form massive clumps 
that gunk up the cells operations. 

To sidestep this potential disaster, virtually every cell throughout 
the biological realm, from bacteria to humans, relies on a family of 
proteins called chaperones to encourage efficient and accurate protein 
folding. 

Two types of chaperones exist in most organisms: molecular chaperones 
and chaperonins.i. Each category consists of numerous proteins that work 
cooperatively to assist folding (see figure 5.4). Recent work indicates that 
parts of the ribosome have chaperone activity helping the newly formed 
polypeptide chain begin folding. 

Once released from the ribosome, some proteins adopt their native 
three-dimensional structure. Others need more help. Several different 



Ribosome 




(GroEL) 
Chaperonin 



Figure 5.4. Chaperone Activity 

Chaperones and chaperonins help polypeptide chains fold once they are released 
from the ribosome. 



Which Came First? 



107 



chaperones will bind to these polypeptides. They help stabilize the partially 
folded protein, preventing it from aggregating with other proteins in the 
cell. When these chaperones debind from the polypeptide chain, it folds 
into its intended three-dimensional shape. 

Other proteins need more help to fold than chaperones can provide. 
Once the chaperones disassociate from the partially folded polypeptide 
chain, these proteins are ushered to chaperonins. These large complexes 
consist of several polypeptide subunits. Perhaps the best understood chap- 
eronin is GroEL-GroES, found in the haclerium Escherichia coli. 

The GroEL component of the E. coli chaperonin consists of fourteen 

subunits that organize into two ringlike structures that stack on top of one 

another. The stacked rings form a barrellike ensemble with a large open 

cavity. A partially folded polypeptide is ushered into the GroEL cavity. 

Another protein complex, GroES, serves as a cap that covers the GroEL 

cavity. This cavity provides the optimal environment for protein folding.,. 
Once properly folded, the polypeptide chain is released from the GroEL 

cavity after the GroES lid disassociates from the barrel. 

This overview of protein folding highlights the fact that many proteins 
cannot fold without proteins. Even chaperones and chaperonins require 
ribosomes, chaperones, and chaperonins to fold. 

A Never-Ending Loop 

Over the last half-century biochemists have discovered several chemi- 
cal systems in the cell that, like Escher's Drawing Hands, consist of com- 
ponents strictly interdependent on one another. The few examples cited 
in this chapter represent three of the most central and fundamental 
activities for life. The "chicken-and-egg" systems of DNA replication, 
protein synthesis, and protein folding raise questions about how life's 
chemistry came into existence. Molecules that comprise these operations 
can't exist apart from one another — unless a Divine Artist created them 
at the same time. 

Human designers and engineers frequently face these kinds of problems. 
They can be resolved only by the strategic and simultaneous implementation 
of interdependent components. In like manner, the biochemical chicken- 
and-egg systems add strength to the biochemical intelligent design analogy. 
Only the work of a Creator could have put them in place. 



1AQ The Cell's Design 

Biochemical chicken-and-egg systems represent a special type of irre- 
ducible complexity in which the system depends on the system to exist. 
Like all irreducibly complex systems, significant questions abound about 
the ability — or inability — of stepwise evolutionary processes to produce 
them. 

The next chapter explores another feature of life's chemistry that points 
to divine design: the structural and functional fine-tuning and precision 
of biochemical systems. 



INORDINATE ATTENTION 
TO DETAIL 



Sir John Everett Millais (1829-1896) was a childhood prodigy. His im- 
mense artistic talent earned him a place in the Royal Academy schools of 
Great Britain at the extraordinary age of eleven., 

As a student at the academy, Millais met William Holman Hunt and 
Dante Gabriel Rossetti. In 1848, these three men formed the Pre-Raphaelite 
Brotherhood, which rejected Mannerism. Initially influenced by Raphael, 
Mannerism dominated art instruction in the academic world during that 
time. This artistic style created dramatic effects by depicting figures with 
elongated forms in exaggerated unbalanced poses illuminated by unrealistic 
lighting. 

However, the Pre-Raphaelites desired a return to the abundant details, 
intense colors, and complex compositions produced before Raphael. They 
believed that the central purpose of art was to imitate nature and wanted 
to portray objects with photographic precision. In fact, critics of the Pre- 
Raphaelites condemned their excessive attention to detail as ugly and eye- 
jarring. Other reviewers supported their devotion to nature and rejection 
of contemporary conventions. 

109 



220 The Cell's Design 

Millais paid unusual attention to detail in his paintings, focusing on the 
beauty and complexity of natural settings. He achieved his first popular 
success in 1852 with The Huguenot and Ophelia. The latter work portrays 
a drowned Ophelia, partially submerged in a gently flowing stream in the 
midst of idyllic surroundings. Millias's depiction of the natural setting is 
so dense and elaborate that it inaugurated a new style sometimes described 
as a type of pictorial ecosystem. 

The Pre-Raphaelite movement and Millais have little influence on today s 
art, which often abandons any attempt to depict reality. Still, the amazing 
precision and attention to every detail make these works worth seeing. 

Meticulous accuracy and the explicit refinement of details also evoke a 
sense of wonder at life's chemistry. Over the last half-century, scientists have 
discovered time and again that molecular precision defines biochemical 
systems. But biochemical fine-tuning far exceeds the best efforts of Millais 
and the Pre-Raphaelites, highlighting the Creator's exceptional care. 

Precision and fine-tuning — hallmark features of intelligent design — 
dominate the best human design and are often synonymous with excep- 
tional quality. The exacting attention to detail in biochemical systems dem- 
onstrates the abilities of a Divine Artist and through analogy strengthens 
the biochemical intelligent design argument. 



A Meticulous Exactness 

For the most part, biochemical systems consist of an extensive ensemble 
of large complex molecules (e.g., proteins, DNA, and RNA). An intimate 
relationship exists between a biomolecule's structure and its functional role 
in the cell. Much like an artist uses an assortment of brushes to complete 
a painting, proteins, DNA, and RNA possess a wide range of molecular 
architectures that permit them to work in concert with one another to 
form the cell's structures and carry out all of its biochemical operations 
(see chapter 2, p. 42). The biochemist's mantra is "structure determines 
function." 

The last half-century of research into the structure-function relationships 
of biochemical systems has consistently demonstrated that the function of 
biomolecules critically depends on the exact location and spatial orientation 
of its chemical constituents. In many instances, function is controlled by 
just a few chemical groups. For example, substituting a single amino acid in 



Inordinate Attention to Detail 



111 



some proteins can have dramatic effects on their function. In other cases, 
the strict spatial arrangement of a suite of amino acids controls the protein's 
function. (See the discussion of aquaporins below.) 

In addition, the interactions between biomolecules often depend on 
the exacting placement of chemical groups. For example, in many bio- 
chemical pathways, proteins bind with each other. These protein-protein 
interactions are highly specific, occurring only between particular proteins. 
Recent work, for example, indicates that the specificity of protein binding 
depends on the exact placement of only a few amino acids located on the 
three-dimensional surface of the folded protein. 4 

The number of high-precision biochemical systems is far too numer- 
ous to detail. As each week passes, biochemists report on more and more 
examples of biochemical fine-tuning in the scientific literature. Looking 
at a few examples conveys a sense of the remarkable exactness of biochemi- 
cal systems. 

Artistically Detailed Aquaporins 

Aquaporins illustrate how advances in biochemical and biophysical 
methodologies increasingly reveal mounting evidence for design. These 
integral proteins and the closely related aquaglyceroporins form channels 
in cell membranes (see chapter 2, p. 45). The channels provide conduits for 
water — and glycerol and related materials in the case of aquaglyceroporins — 
to flow in and out of the cell. Aquaporin and aquaglyceroporin channels 
are unusually selective, transporting only water and glycerol, respectively, 
across the cell membrane. These protein channels exclude all other materials, 
even hydrogen ions (protons). This amazing property has, in large mea- 
sure, motivated biochemists to study the structure-function relationships 
of aquaporins and aquaglyceroporins over the last decade or so. 

For years, several observations suggested that water-conducting pores 
must exist in cell membranes. But biochemists didn't have the methods to 
isolate water channels until the early 1990s. The first aquaporin (designated 
AQPl) was discovered in the cell membrane of red blood cells. 

Methods developed to isolate AQPl and advances in molecular biol- 
ogy opened up the floodgates of scientific investigation. In short order, 
biochemists demonstrated that AQPl was broadly distributed in a wide 
range of tissues in mammals. Defects in these aquaporins were linked to 
several diseases. 



I 22 The Cell's Design 

Researchers also discovered that several distinct aquaporins exist (des- 
ignated AQPO, AQP2, AQP4, AQP5, AQP6, and AQP8). They iden- 
tified aquaglyceroporins — the proteins that conduct glycerol and other 
related compounds — and labeled specific ones (AQP3, AQP7, and AQP9). 
Aquaporins and aquaglyceroporins have a complex distribution pattern 
in mammalian tissues, with each tissue type displaying a characteristic set 
and abundance.. 

Since then, biochemists have discovered aquaporins in amphibians, 
insects, plants, and an assortment of microbes. These protein channels 
appear to be ubiquitous throughout nature, signifying their physiological 
importance. 

Aquaporins reside within the phospholipid bilayer of the cell membrane 
(see chapter 2, p. 45). Their protein chain folds to form six bilayer-spanning 
segments. These regions organize within the cell membrane to form an 
hourglass-like structure. The bilayer-spanning segments form two groups, 
each containing three membrane-spanning regions, separated by a narrowly 
constricted area within the membrane. The water channel is housed within 
this narrow constriction (see figure 6.1). 

High resolution X-ray diffraction studies on a variety of aquaporins 
indicate that the selectivity of these channels depends on (1) the pore size 
of the channel, (2) the specific identity and precise location of amino acids 
that line the channel, and (3) the exact orientation of water molecules 
within the channel. 

Biochemists have recently turned their attention to AQPZ, the aqua- 
porin found in the bacterium E. coli. This aquaporin proves interesting 
because it displays an unusually specific and rapid rate of water movement 
through its channel. Researchers hope that explaining the high selectivity 
of the AQPZ channel will yield key insights into the structure-function 
relationships of other aquaporins. Scientists have already discovered that 
the pore size of the AQPZ channel contributes to its selectivity. A precise 
diameter allows water to pass through the channel while excluding larger 
molecular species. 

The transport specificity of the AQPZ conduit also stems from pre- 
cisely balancing the hydrophilic (water-loving) and hydrophobic (water- 
hating) character of the channel. This balance excludes materials with 
different physical properties than the channel's. Its hydrophilic character is 
established by the precise arrangement of the carbonyl chemical groups of 
eight amino acids (glycine-59, glycine-60, histidine-61, phenylalanine-62. 



Inordinate Attention to Derail 



113 



Helical 
segment 




Extra- 
cellular 



Lipid 
bilayer 



Intra- 
cellular 



COOH 



HjN 




HOOC 



Figure 6.1. Aquaporin Structure 

The aquaporin protein cliain folds to form six bilayer-spanning segments represented 
as cylinders in the diagram. The six segments form two groups, each containing three 
membrane-spanning regions, separated by a narrowly constricted region within the 
membrane, where the water channel resides. 



glutamine-182, glutaric acid- 183, serine- 184, and valine- 185) that line the 
channels interior (see figure 6.2 for the chemical structure of amino acid 
side chains). 

These amino acids are brought into proper alignment through the fold- 
ing of the aquaporin protein chain into an exacting three-dimensional 
architecture. 



I Glycine 



Serine 



Threonine 



HO CH, 



CH,-CH 



OH 

I 

Cysteine | 

HS CHi^ 



Tyrosine 



HO<f > CH, 



Asparagine 



NH, 



X CH, 



Glutamine 



Alanine 



Valine 



Leucine 



NH, 



H 

I 
C-COQ- 

+ 

H 

1 

c-coo~ 

+ 
H 

c coo- 

NH, 

+ 

H 

C-COO" 

NH, 
+ 

H 

-C-COO" 

NH, 

+ 

H 

C COO" 

NH, 

+ 

H 



,C CH; CH3I C C00~ 

I ^H, 
+ 



CH, 



CH, 



CH 



CH, 



CH, 



CH CH, 



CH, 



H 

I 

C COO" 

NH, 
+ 

H 

C COO" 

NH, 

+ 

H 
' C COO" 

NH3 

+ 



Isoleucine 



In 
If 



CHj-CHj-CH^C-COO 

CH,' NH, 



Proline 



H,C C: 



C COO" 



H,C- 



Ki" 



Phenylalanine I H 

/ VcHjIc-coo" 



Tryptophan 



NH, 

1 + 

JH "" 
I 



,'",,- C- CHjfC-COO' 

II ^1 

'■-,, NCH NH, 
H _ _ 1+ 

Methionine H 

CHj-S-CHj CH^^C COO' 



NH, 
+ 

H 

'C CH^pC COO' 

NH, 

+ 

H 

C COO" 



Aspartic 
Acid 



Glutamic 
Acid 



Lysine 



C-CH, CH, 



O 



H,N"CH, CH,-CH, CH; 



Arginine 



NH, 

+ 

H 

I 

C-COO" 

NH, 
+ 

H 



H,N- C NH CH, CH, CH,| C COO" 



NH, 



NH, 

+ 



I + 

Histidine H 

(atpH6.0) ^^__^ chJc-COO- 



HN^ NH 



NH, 
+ 



Inordinate Attention to Detail 



115 



Hydrophobic amino acids (valine, phenylalanine, and isoluecine), which 
line the channel wall, establish the channel's hydrophobicity.. Other re- 
search teams have likewise noted that the composition, location, and spa- 
tial orientation of amino acids forming the channel determine aquaporin 
specificity for water transport. 

Other studies point to the importance of amino acids at the mouth of 
aquaporin and aquaglyceroporin pores. For example, work on an aqua- 
glyceroporin from the malaria parasite, Plasmodium falciparum, pinpointed 
the importance of interaction between a positively charged amino acid 
(arginine-196) and a negatively charged one (glutamate-125). Precise bond- 
ing of these two amino acid residues enables the pore to transport water 
along with glycerol through its channel. Replacing glutamate-125 with the 
amino acid serine all but abolished the permeability of water through the 
channel of this aquaglyceroporin. 

The relationship between aquaporins structure and function appears to 
be extremely sensitive. Recent work indicates that the difference between 
the selectivity of aquaporins and aquaglyceroporins stems from a single 
amino acid difference in the channel's interior. Aquaglyceroporins have a 
smaller glycine in place of a larger histidine in the aquaporin pore. : 

Glycine's smaller size allows larger glycerol molecules to make their way 
through the channel. Histidine's larger size blocks the movement of glycerol 
through the pore, yet allows water to freely permeate through aquaporin 
openings. Substitution of isoleucine for histidine (or glycine) accounts for 
the unique water conductance profile of the aquaporin AQJPM from the 
archaea, Methanothermobacter marburgensisP 

Other researchers have noted the importance a single amino acid can 
play in establishing aquaporin selectivity. For example, a team of United 
States and Japanese scientists noted that use of an asparagine in place of 
glycine-57 in the membrane-spanning regions of aquaporins causes AOJP6 
to function as a conduit for negatively charged chemical species (anions) 
instead of water or glycerol. 

One magnificent property of aquaporins is their ability to conduct 
water while preventing the flow of hydrogen ions through the channel. 

Figure 6.2. Amino Acid Side Groups 

The twenty amino acids are used by the cell's machinery to construct proteins. The shaded region 
of the diagram corresponds to the parts ofthe molecules that are identical for all amino acids. 
These parts ofthe molecules form the backbone ofthe protein chain. The nonshaded region 
ofthe diagram describes the part ofthe molecules unique to each amino acid. These so-called 
R groups form the side chains extending from the backbone ofthe protein molecule. 



2 25 The Cell's Design 



0-H— ■ 0-H'— O-H-" 0-H--- 0-H— O-H-— O-H"- 
I I I t I I I 

H H H H H H H 



/ 



0-H"" 0-H"" 0-H"" 0-H"" 0-H"" 0-H"" 0-H- 
I I I I I I I 

H H H H H H H 



H" 



Hydrogen O-H"" 0-H"" O-H"" 0-H"" 0-H"" 0-H"" 0-H> 

'O" H H H H H H H 

(proton) i j ; ; ; : : 

0-H"" 6-H"" 6-H"" 6-H"" 6-H"" 6-H"" 6-H- 
I I I I I I I 

H H H H H H H 



Figure 6.3. Proton Wire 

In water, hydrogen ions (or protons) make their way rapidly through water by moving along 
a "proton wire" formed by a linear arrangement ofwater molecules. The proton wire pathway 
is depicted by arrows. 



Hydrogen ions are highly mobile in water. But they don't physically migrate 
through water as other ions do. Instead, hydrogen ions make their way 
rapidly through water by moving along a "proton wire" formed by a linear 
arrangement of water molecules (see figure 6.3). is In effect, they are passed 
through water by binding to a water molecule at one end of the wire. That 
forces a hydrogen ion off of a water molecule at the opposite end of the 
wire. This movement results from quantum tunneling between the water 
molecules that constitute the proton wire. 

A column ofwater molecules fills the membrane pores of aquaporins 
and aquaglyceroporins. In principle, this column should function as a 
proton wire conducting hydrogen ions. However, recent work explains 
how aquaporins and aquaglyceroporins keep hydrogen ions from moving 
through their channels. 

An exacting arrangement of water molecules within the channel actually 
blocks the hydrogen ion flow. Instead of water molecules forming a linear 
procession with the same orientation throughout the channel — setting 
up a proton wire — approximately halfway through the channel, the water 
molecules change orientation breaking the wire. Two asparagines in the 
middle of the channel mediate the change in orientation of the column 
of water molecules. This exacting arrangement allows water molecules to 



Inordinate Attention to Detail 



117 



freely pass through the aquaporin and aquaglyceroporin channels while 
hindering the flow of hydrogen ions. 

The biochemical fine-tuning of aquaporins appears to exceed the best 
precision attained by human engineers and designers. Yet, the molecular 
precision necessary for aquaporins to selectively transport water and glyc- 
erin through cell membranes is not unique to these pore-forming proteins. 
Other membrane channels display the same type of biochemical fine-tuning 
relying on the precise positioning and spatial orientation of amino acid 
residues to attain transport specificity.,. 

Carefully Composed Collagen 

The structural precision that characterizes proteins is not confined to the 
exact arrangements and spatial orientation of amino acids. In some proteins, 
amino acid composition is also fine-tuned. Among these are collagens — 
the most abundant proteins in the animal kingdom. They are found in the 
matrix of bone, connective tissue, and skin. 

The collagen fibers located in the matrices of tissues are formed from 
smaller fibrils (see figure 6.4). In turn, these fibrils consist of laterally 



Triple helix 




a chain 



n. 



Ii; 



Collagen fibril 



1 



K 



1 




Figure 6.4. Collagen 

Collagen molecules are fibrous proteins that consist ofthree polypeptide chains intertwined 
around one another to form the collagen triple helix. The triple helices, in turn, associate to 
form fibrils. These fibrils associate to form much larger collagen fibers. 



2 2§ The Cell's Design 

associated collagen molecules. These molecules are made up of three poly- 
peptide chains intertwined to form the collagen triple helix.,. The helix 
requires a highly specific amino acid composition in order to form. In 
essence, the single polypeptides of collagen are polyproline chains with 
glycine amino acids interspersed every third position. Because of their 
small size, the glycine residues allow the polyproline chains to twist into 
a helical conformation. 

Collagen molecules will spontaneously aggregate into fibrils, so they are 
produced inside the cell in a form that will not self-assemble. This form, 
pro-collagen, has large globular ends that prevent association of collagen 
chains. Once produced, the collagen is secreted to the cell's exterior. Then, 
an enzyme called collagenase cleaves the globular ends from the pro-collagen 
to form protein chains that can readily aggregate. 

Because of collagen's key structural role in animal tissues, biochemists 
long thought this biomolecule was stable at body temperatures for warm- 
blooded creatures and at environmental temperatures for cold-blooded 
animals. To nearly everyone's surprise, however, recent work indicates that 
the collagen triple helix and fibrils are unstable at body temperatures with 
the chains spontaneously unfolding from the triple helix arrangement into 
random coils. Even more surprising is the fact that this instability seems 
carefully orchestrated by precise adjustments to the collagen amino acid 
composition. 

Biochemists think the instability of the collagen triple helix plays an 
important role in the assembly of fibrils. The unfolded regions of the 
collagen triple helix promote the lateral association of the collagen triple 
helices into the higher order structure of the fibrils. If the triple helix 
was stable, these associations could not occur. Once the fibrils form, the 
mutual interaction among the collagen molecules stabilizes the triple 
helix conformation. The tendency of the collagen helices to unfold also 
imparts collagen fibrils with elasticity. This property makes the tissues 
that form tendons and ligaments flexible and able to withstand stresses 
and strains. 

Finally, the unfolded regions are also sites where collagenase enzymes 
can breakdown collagen molecules and hence, collagen fibrils. This break- 
down allows tissues to undergo dynamic restructuring as animals face ever- 
changing demands (e.g., due to growth). The exacting amino acid composi- 
tion imparts collagen with strength and elasticity and allows biochemical 
machinery to resculpture it as needed. 



Inordinate Attention to Detail 1 1 Q 

Perfect Timing 

Exact fine-tuning is not limited to the structure of biomolecules. Some- 
times the rate of biochemical processes is also meticulously refined. Recent 
studies indicate that the rate of messenger RNA and protein breakdown, 
two processes central to the cell's activity, are exquisitely regulated by the 
cell's machinery. 

Shutting Down Production 

Messenger RNA (mRNA) plays a central role in protein production 
(see chapter 2, p. 50, and chapter 5, p. 101). These molecules mediate the 
transfer of information from the nucleotide sequences ofDNA to the 
amino acid sequences of proteins. 

The cell's machinery copies mRNA from DN A only when the cell needs 
the protein encoded by aparticular gene housed in the DNA. When that 
protein is not needed, the cell shuts down production. This practice is a 
matter of efficiency. In this way, the cell makes only the mRNAs and con- 
sequently the proteins it needs. 

Once produced, mRNAs continue to direct the production of proteins 
at the ribosome. Fortunately, mRNA molecules have limited stability 
and only exist intact for a brief period of time before they break down. 
This short lifetime benefits the cell. If mRNA molecules unduly per- 
sisted, then they would direct the production of proteins at the ribosome 
beyond the point the cell needs (see chapter 2, p. 50). Overproduction 
would not only be wasteful, it would also lead to the coexistence of 
proteins that carry out opposed functions within the cell. The care- 
ful control of mRNA levels is necessary for the cell to have the right 
amounts of proteins at the right time. Unregulated protein levels would 
compromise life. 

Until recently, biochemists thought regulation of mRNA levels (and 
hence protein levels) occurred when the cell's transcriptional machinery 
carefully controlled mRNA production. New research, however, indicates 
that mRNA breakdown also helps regulate its level.,, 

Prior to this work, biochemists thought that the degradation of mRNA 
was influenced only by abundance, size, nucleotide sequence, and so forth. 
However, this perspective was incorrect. The breakdown ofmRNA mol- 
ecules is not random but precisely orchestrated. 



220 The Cell's Design 

Remarkably, messenger RN A molecules, which correspond to proteins that 
are part of the same metabolic pathways, have virtually identical decay rates. The 
researchers also found that mRN A molecules, which specify proteins involved 
in the cell's central activities, have relatively slow breakdown rates. Proteins only 
needed for transient cell processes are encoded by mRNAs with rapid rates of 
degradation. The decay of mRNA molecules is not only fine-tuned but also 
displays an elegant biochemical logic that bespeaks of intelligence. 

Tagged for Destruction 

Proteins, which play a role in virtually every cell structure and activity, 
are constantly made — and destroyed — by the cell. Those that take part in 
highly specialized activities within the cell are manufactured only when 
needed. Once these proteins have outlived their usefulness, the cell breaks 
them down into their constitutive amino acids. The removal of unnecessary 
proteins helps keep the cell's interior free of clutter. 

On the other hand, proteins that play a central role in the cell's opera- 
tion are produced on a continual basis. After a period of time, however, 
these proteins inevitably suffer damage from wear and tear and must be 
destroyed and replaced with newly made proteins. Its dangerous for the 
cell to let damaged proteins linger. 

Once a protein is damaged, it's prone to aggregate with other proteins. 
These aggregates disrupt cellular activities. Protein degradation and turn- 
over, in many respects, are just as vital to the cell's operation as protein 
production. And, as is the case for mRNAs, protein degradation is an ex- 
acting, delicately balanced process. =<, 

This complex undertaking begins with ubiquitination. When damaged, 
proteins misfold, adopting an unnatural three-dimensional shape. Misfolding 
exposes amino acids in the damaged protein's interior. These exposed amino 
acids are recognized by E3 ubiquitin ligase, an enzyme that attaches a small 
protein molecule (ubiquitin) to the damaged protein.:, Ubiquitin functions 
as a molecular tag, informing the cell's machinery that the damaged protein 
is to be destroyed. Severely damaged proteins receive multiple tags. 

To the Rescue 

Ubiquitination is a reversible process with de-ubiquitinating enzymes 
removing inappropriate ubiquitin labels. This activity prevents the cells 



Inordinate Attention to Detail 



121 



machinery from breaking down fully functional proteins that may have 
been accidentally tagged for destruction because E3 ubiquitin ligase oc- 
casionally makes mistakes. 

A massive protein complex, a proteasome, destroys damaged ubiq- 
uitinated proteins, functioning like the cell's garbage can. The overall 
molecular architecture of the proteasome consists of a hollow cylinder 
topped with a lid that can exist in either an opened or closed conforma- 
tion. Protein breakdown takes place within the cylinder's interior. The lid 
portion of the proteasome controls the entry of ubiquitinated proteins 
into the cylinder. 

The proteasome lid contains de-ubiquitinating activity. If a protein has 
only one or two ubiquitin tags, it's likely not damaged and the lid will re- 
move the tags rescuing the protein from destruction. The cell's machinery 
then recycles the rescued protein. If, on the other hand, the protein has 
several ubiquitin tags, the lid cannot remove them all and shuttles the 
damaged protein entry into the proteasome cylinder. 

The proteasome lid regulates a delicate balance between destruction and 
rescue, ensuring that truly damaged proteins are destroyed and proteins 
that can be salvaged escape unnecessary degradation. The cell's protein 
degradation system, like messenger RNA breakdown, displays fine-tuning 
and elegant biochemical logic that points to a Creator's handiwork. 

Regulating Production 

Not only is the breakdown of proteins and messenger RNAs exquisitely 
fine-tuned, but so is the timing of their production throughout the cell cycle. 
All cells go through a cycle of activity that begins and ends with mitosis 
(the process of cell division that yields two daughter cells identical to the 
mother cell). Once mitosis is completed, cells go through distinct phases 
of growth and preparation for the next round of cell division. 

Biochemists estimate that about 20 percent of genes are turned on (or 
expressed) only during specific points in the cell cycle. At other times, these 
genes are turned off This regulation occurs because the proteins (and other 
products) encoded by these genes are useful to the cell only at particular 
intervals during the cell cycle. At other times, they serve no purpose. By 
producing biomolecules only when they're required, the cell avoids need- 
less waste of resources. This careful control of gene expression and protein 
production also serves another important function. 



222 The Cell's Design 

Recent work indicates that the regulation in gene expression throughout 
the cell cycle closely resembles "just-in-time" production and delivery used 
by manufacturers and builders. != When building a home, for example, the 
construction materials are not all delivered to the job site at once. They are 
delivered only as needed. This schedule ensures efficient management of 
resources. It avoids waste and makes things easier to find, keeping the job 
site uncluttered. Breakage is reduced and errors eliminated that would occur 
if the wrong materials were inadvertently used because of excess supplies. 

The regulation of gene expression occurs in such away that messenger 
RNA is continuously produced for those proteins needed at every stage 
in the cell cycle. Other proteins with transient use to the cell are produced 
just-in-time and no sooner. As soon as they're no longer needed, production 
shuts down. This schedule keeps the cell from becoming cluttered with 
unnecessary proteins and eliminates errors that could occur if proteins are 
engaged in activities at the inappropriate time by mistake (see chapter 4, 
p. 74.) 

Throughout the course of the cell cycle, gene expression takes place in 
interdependent waves. Genes coding for proteins needed at the same point 
in the cell cycle are turned on all together atjust the right time and turned 
off when the cell no longer needs them. When a wave of gene expression 
is initiated, it produces proteins called transcription factors whose sole 
function is to turn on or activate genes needed in the ensuing surge of gene 
expression (see chapter 7, p. 135). It also produces transcription factors 
whose only role is to turn off genes that code for proteins that were part 
of the previous wave. 

As with messenger RNA and protein degradation, the precision and 
elegant biochemical logic of messenger RNA and protein production 
throughout the cell cycle (resembling the best practices of manufacturers 
and builders) are the types of biochemical features that show the Creator's 
artistry. 



The Painstaking Results 

The photographic precision of the Pre-Raphaelite works of art evokes 
tremendous admiration. This type of concentrated effort also equates with 
the best possible quality in engineered systems. Exact fine-tuning does 
not arise by happenstance in either art or engineering. Rather, it results 



Inordinate Attention to Detail 



123 



from careful planning and a commitment to execute designs using the best 
craftsmanship possible. 

Such deliberate calibration is a clear indicator of human intelligent de- 
sign. By analogy the molecular precision and fine-tuning that pervades the 
design of biochemical systems are potent markers for the work of a Divine 
Engineer and Artist. No detail is too small to escape the Creator's atten- 
tion. This fine-tuning defines the structure and compositional makeup of 
proteins and is very much a key feature of biochemical processes. In fact, 
the cell cycle, itself, actually depends on the precise timing of biochemical 
events. 

Most remarkable is the apparently extreme nature of this biochemical 
fine-tuning. It is comparable to the inordinate attention to detail achieved 
by the Pre-Raphaelite artists and the impressive fine-tuning achieved by 
top human engineers. The molecular precision — pervasive in nearly all 
aspects of life s chemical systems — raises questions about the capability of 
undirected evolutionary processes to achieve such carefully crafted designs 
(see chapter 14, p. 270). The molecular fine-tuning of biochemical systems 
is exactly what would be expected if life is the product of a Creator. 

The next chapter explores another feature of life's chemistry that points 
to Divine Design: the structural and functional optimality of biochemical 
systems. 




Theo van Doesburg, Contra-Composition of Dissonances, XVI (Reproduced by permission from 
Haags Gemeentemuseum, The Hague, Netherlands/The Bridgeman Art Library) 



THE PROPER ARRANGEMENT 
OF ELEMENTS 



Before picking up a brush, many painters spend a lot of time thinking 
about the best way to position lines, shapes, colors, textures, and so forth 
to accomplish their purpose. They deliberately arrange elements to create 
a certain sense of balance. 

There are at least three different ways to achieve the desired array of ele- 
ments in a painting: Symmetric balance refers to a perfectly centered com- 
position or one that employs mirror images. Asymmetric balance describes 
an off-centered arrangement, or one with an odd, mismatched number of 
elements. Radial balance is employed when the elements of a piece radiate 
or swirl around a circular or spiral path., 

Artists depend on balance for more than just aesthetic purposes. They 
use it to communicate moods, emotions, and sentiment and to generate a 
response in their audience. For example, symmetric balance conveys a sense 
of elegance or evokes contemplation or a sense of the familiar. Asymmetric 
balance expresses movement or generates tension. An asymmetric arrange- 
ment of elements can also communicate moods like anger, excitement, and 
joy. Radial balance provides a sense of equilibrium for the viewer. 

125 



2 26 Tri. Cell's Design 

One artist known for his exceptional use of balance was Piet Mondrian 
(1872-1944) } Through a precise arrangement of red, yellow, blue, or black 
rectangular forms separated by thick black rectilinear lines, his paintings 
effuse complexity amidst their simplicity. Mondrian sought to express the 
utmost awareness of beauty, harmony, and rhythm by carefully positioning 
the lines, shapes, and colors in his work. 

Artists are not alone in their attention to balance. Engineers share similar 
concerns. In their designs, engineers — like artists — strive to achieve the 
desired effects by appropriately placing the elements in their compositions. 
They make careful use of individual components to accomplish a specific 
purpose or goal. And, as a consequence, their designs are optimized. Balance 
in an artistic work and in engineered systems requires extensive planning and 
forethought and, therefore, stands as a hallmark of intelligent design. 

Life scientists have discovered that many biochemical systems, like human 
designs, are ideal for their role in the cell. As with the other characteristics 
that define life's chemistry, the magnificent array of biochemical systems far 
exceeds the accomplishments of the finest human engineers and designers in a 
way befitting a Creator. A few recently discovered examples give a sense of the 
elegance and molecular balance of life's chemical structures and processes. 



Ideal Structures 

The last half-century or so of research has yielded remarkable details 
about the structure and function of a myriad of proteins. Based on these 
insights, most biochemists would conclude that proteins are structured in 
the most advantageous way for their specific biochemical roles. So, too, 
is DNA. 

Weil-Proportioned Proteins 

Amino acids (small subunit molecules) link together in a head-to- 
tail fashion to form the polypeptide chains that constitute proteins (see 
chapter 2, p. 42). In principle, these molecules can join up in any possible 
sequence. Some sequences generate useful proteins. Many yield junk poly- 
peptides that lack function. 

The twenty different types of amino acids used to make polypeptides 
possess a variety of chemical and physical properties (see figure 6.2). Each 



The Proper Arrangement of Elements 197 

chain's sequence (primary structure) imparts a specific chemical and physical 
profile along its length. This physicochemical profile determines how the 
polypeptide chain folds (secondary and tertiary structures) and in turn the 
way it interacts (quaternary structure) with other polypeptides to form a 
functional protein. The sequence ultimately determines the polypeptide's 
function because the sequence shapes the polypeptide s structure, and struc- 
ture dictates function (see figure 2.2, p. 44). 

Energy efficient. For the protein structures they produce, amino acid 
sequences appear to be extraordinarily optimized. In a recent study, bio- 
chemists from the University of Washington modeled the three-dimensional 
structure of 108 different proteins starting with random amino acid se- 
quences. They repeatedly varied the sequences looking for protein structures 
with the least amount of energy. (Minimum-energy structures are the most 
stable.) 

Through this process, the scientists discovered that in virtually all cases, the 
amino acid sequences that folded into the lowest-energy three-dimensional 
shapes were nearly identical to the native sequence. They concluded that the 
most effective amino acid sequence for a given protein structure is closely 
restricted to sequences highly similar to those found in nature.. 

Recent studies indicate that protein structure is optimized in a more 
general sense as well. And, this overall structural optimization represents 
another example of the impeccable chemical logic that pervades biochemical 
systems. Biochemists have long known that corresponding proteins from 
diverse organisms have different amino acid sequences. When compared, 
some positions in the sequences vary extensively, some differ to a limited 
extent, and others don't vary at all. Amino acids at these invariable (con- 
served) positions are regarded as critical to the protein's structure and 
function. Those amino acids at variable positions are considered relatively 
unimportant, though they do contribute to the protein's overall three- 
dimensional shape and in some cases its folding pattern. 

New work suggests, however, that the amino acids at variable positions 
along the polypeptide chain do not differ indiscriminately but appear care- 
fully selected for a number of considerations apart from protein structure 
and function. For example, several studies show that amino acids used in 
bacterial proteins have been chosen with metabolic efficiency in mind., 

The biosynthesis of amino acids requires the use of the cell's material 
and energy reserves. Some amino acids are much more metabolically ex- 
pensive to produce than others. All things being equal, bacteria will use 



228 The Cell's Design 

the metabolically least expensive amino acids, particularly at variable posi- 
tions. Researchers have noted that this discrimination is especially true for 
proteins produced at high levels in the cell. Along these lines, a different 
study indicates that whenever possible, free-living organisms minimize the 
use of larger, more massive amino acids because of high metabolic costs.. 

Less is more. Another study reveals an additional aspect of the elegant 
chemical logic that undergirds amino acid usage. The cell relies on proteins 
to make the amino acids necessary to build proteins. Researchers have shown 
by studying several different bacteria that the proteins which manufacture 
a particular amino acid are compositionally devoid of that amino acid. 

This absence prevents a catch-22 when the cell's reserves become depleted 
of a specific amino acid. If that amino acid was a part of the proteins that 
in turn synthesize the amino acid, then there would be no way for the cell 
to replenish its supply of that amino acid. And that lack would cause the 
supply to diminish further and further. The amino acid composition of 
proteins appears just right to ensure that the cell can generate the amino 
acids it needs at all times. 

Building resistance. The variable amino acid positions also make pro- 
teins functionally able to withstand mutations to DNA that result in a 
change to the protein's amino acid sequence. A recent study on the DNA 
repair enzyme, 3-methyladenine DNA glycosylase, illustrates the capacity of 
proteins to tolerate amino acid changes. Researchers created three separate 
pools of mutated enzymes each consisting of about one hundred thousand 
molecules. On average, mutant enzymes in the three groups contained 
from two to six amino acid changes. Yet, only 35 percent of these changes 
resulted in nonfunctional enzymes. 

In other words, 65 percent of amino acid changes leave the function of 
3-methyladenine DNA glycosylase unaltered. And, manyproteins accrued 
multiple amino acid changes without any loss of structure or function. 
(These scientists noted that other proteins found in nature also tolerate 
amino acid changes to the same extent as this DNA repair enzyme.) Inter- 
estingly, conserved amino acid positions appear to be resistant to amino 
acid changes, whereas variable positions withstand the changes without 
loss offunction. 

Based on the study of 3-methyladenine DNA glycosylase (and other 
proteins), it appears that amino acid composition and sequences ofpro- 
teins have been maximized to resist the harmful effects of amino acid 
changes caused by mutations. This sequence optimization is not a universal 



The Proper Arrangement of Elements 190 

characteristic ofproteins, however. Researchers from the University of 
Michigan have determined that structurally stable proteins designed by 
human biotechnologists are almost always susceptible to even single amino 
acid changes.. There appears to be something special about the amino acid 
sequences of proteins found in nature. 

Age-resistant. Protein sequences are not only the best possible to resist the 
harmful effects of amino acid changes. Their structures also appear just right to 
withstand the damage caused by reactive oxygen species (ROS) in the cell. 

ROS such as superoxide (O; ), the hydroxy free-radical (-OH), and 
hydrogen peroxide (HO) are derivatives of molecular oxygen (O). The 
cells machinery routinely produces these compounds during the normal 
course of metabolism. ROS randomly and indiscriminately react inside 
the cell to damage important cell components. For example, ROS attack 
the molecules that make up the cell's membrane (lipids), proteins, and 
DNA. And, reactive oxygen species are believed to play a significant role 
in the aging process. 

A recent study by a team of French scientists demonstrated that proteins 
experienced a heightened level of oxidative damage under conditions that 
promote the production of defective proteins. These abnormal proteins 
misfold, rendering them susceptible to oxidation. All things being equal, 
when the conditions in the cell support the synthesis of properly produced 
proteins, the level of oxidation plummets. Based on this finding, the re- 
searchers concluded that the structures of proteins must be the best possible 
to avoid damage from oxidation. 

Just-Right DNA 

Recent studies indicate that, like proteins, the structural features of 
DNA are also exceptional. DNA consists of two chainlike molecules (poly- 
nucleotides) that twist around each other to form the DNA double helix 
(see chapter 2, p. 48). The cell's machinery forms polynucleotide chains by 
linking together four different subunit molecules called nucleotides. The 
nucleotides used to build DNA chains are adenosine (A), guanosine (G), 
cytidine (C), and thymidine (T) (see figure 2.7, p. 49). 

DNA houses the information needed to make all the polypeptides used 
by the cell. The sequence of nucleotides in DNA strands specifies the se- 
quence of amino acids in polypeptide chains. Scientists refer to this sequence 
of nucleotides as a gene. 



23Q The Cell's Design 

Deliberate sequences. On the surface, there appears to be a problem 
relating nucleotide sequences to amino acid sequences. Clearly a one-to- 
one relationship cannot exist between the four nucleotides of DNA and 
the twenty amino acids used to assemble polypeptides. To overcome this 
mismatch, the cell uses groupings of three nucleotides (codons) to specify 
twenty different amino acids. Each nucleotide triplet, or codon, specifies 
an amino acid. 

There are sixty-four possible codons that can be used to specify the 
twenty amino acids. Because of the excess number, however, more than 
one codon can correspond to the same amino acid. In fact, up to six dif- 
ferent codons specify some amino acids — others are signified by only one. 
(Chapter 9 discusses the relationship between codons and amino acids in 
greater detail.) 

Because some codons are redundant, the amino acid sequence for a given 
polypeptide chain can be specified by several different nucleotide sequences. 
Recent studies indicate that the cell does not randomly make use of re- 
dundant codons to specify a particular amino acid in a polypeptide chain. 
Instead, there appears to be a rationale behind codon usage in genes. 

Biochemists have known for some time that highly repetitive nucleotide 
sequences are unstable and readily mutate. The most common type of 
mutation to repetitive sequences is the insertion and/or deletion (indels) 
of one or more nucleotides. 

These mutations are devastating. They almost always result in the pro- 
duction of highly defective polypeptide chains. A survey of the genomes 
from several organisms by researchers at the University of California, San 
Diego, indicates that codon usage in genes is designed to avoid the type 
of repetition that leads to unstable sequences.,, Although the details are 
beyond the scope of this book, other studies similarly indicate that codon 
usage in genes is also set up to maximize the accuracy of protein synthesis 
at the ribosome , (see chapter 2, p. 50). 

Hand-picked components. The sequence of nucleotides is not the only 
feature of DNA that is optimized. The components that make up the nucle- 
otides also appear to have been carefully chosen for unsurpassed perfor- 
mance. Nucleotides that form the strands of DNA are complex molecules 
consisting of both a phosphate moiety and a nucleobase (either adenine, 
guanine, cytosine, or thymine) joined to a five-carbon sugar (deoxyribose). 
(See figure 7.1.) In RNA, deoxyribose is replaced with the five-carbon 
sugar ribose. 



The Proper Arrangement ofElements 



131 



Adenosine 5'-monophosphate 
(AMP) 



NHi 



Adenine 



Nf-^C-,\ 




Piiospiiate 



Figure 7.1. Nucleotide 
Structure 

The subunit molecules 
that make up the strands of 

DNA and RNA consist of 
both a phosphate moiety 
and a nucleobase (either 
adenine, guanine, cytosine, 
or thymine) joined 
to a five-carbon sugar 
(deoxyribose). In RNA, 
deoxyribose is replaced 
with the five-carbon sugar 
ribose. 



The backbone of the DNA strand is formed by repeatedly linking the 
phosphate group of one nucleotide to the deoxyribose unit of another 
nucleotide. The nucleobases extend as side chains from the backbone of 
the DNA molecule and serve as interaction points (like ladder rungs) 
when the two DNA strands align and twist to form the double helix (see 
figure 7.2). 

Scientists have long wondered why the nucleotide subunits of DNA and 
RNA consist of these particular molecular components (phosphates, ad- 
enine, guanine, cytosine, thymine/uracil, deoxyribose, and ribose), because 
a myriad of sugars and numerous other nucleobases could have conceiv- 
ably become part of the cell's information storage (DNA) and processing 
systems (RNA). 

For nearly twenty years, biochemists have understood why phosphates are 
critical to the structures ofDNA and RNA.,, This chemical group is per- 
fectly suited to form a stable backbone for the DNA molecule. Phosphates 
can form bonds with two sugars at the same time (phosphodiester bonds) 
to bridge two nucleotides, while retaining a negative charge (see figure 



132 



The Cell's Design 



5' end 



H,C 



7.3). Other compounds 
can form bonds between 
two sugars but won't re- 
tain a negative charge. 
The negative charge on 
the phosphate group im- 
parts the DNA backbone 
with stability protecting 
it from cleavage by reac- 
tive water molecules. 

The specific nature of 
the phosphodiester bonds 
is also optimized. For ex- 
ample, the phosphodi- 
ester linkage that bridges 
the ribose sugars of RN A 
could involve the 5' OH 
of one ribose molecule 
with either the 2' OH 
or 3' OH ofthe adjacent 
ribose moiety. In nature, 
RNA exclusively makes 
use of 5' to 3' bonding. 
A study conducted in the 
early 1990s explains why 
life employs these types of 
bonds. It turns out that 
5' to 3' linkages impart 
much greater stability to 
the RNA molecule than 
5' to 2' bonds. ,4 

Numerous recent 
studies provide insight as 
to why deoxyribose and 
ribose were selected as 
the sugar molecules that 
make up the backbones of DNA and RNA. Deoxyribose and ribose are five- 
carbon sugars that form five-membered rings. Researchers have demonstrated 




3' end 



Figure 7.2. DNA Backbone and Side Chains 

The backbone ofthe DNA strand is formed by repeatedly 
linking the phosphate group of one nucleotide to the 
deoxyribose unit ofanother nucleotide. 



The Proper Arrangement of Elements 



133 



(Base), O (Basejj 

I II I 

(Sugar) — O ^ P — O — (Sugar) + HjO 

0~ 



Figure 7.3. The Phosphodiester Bonds of 
RNA 

Phosphates form bonds with two sugars at 
the same time (phosphodiester bonds) while 
retaining a negative charge. 



that its possible to make DN A an- 
alogs using a wide range of differ- 
ent sugars that contain four-, five-, 
and six-carbons that can adopt 
five- and six-membered rings. But 
they have shown that these DNA 
variants have undesirable proper- 
ties compared to DNA and RNA 
built with deoxyribose and ribose, 
respectively (see figure 7.4). 

For example, some of these 
DNA analogs don't form double 

helices. Others do, but the nucleotide strands interact either too strongly, too 
weakly, or they display inappropriate selectivity in their associations.,. 

Additionally, other studies show that DNA analogs made from sugars 

that form 6-membered rings adopt too many structural conformations. , 
This diversity is objectionable. If DNA assumes multiple conformations, 

then it becomes extremely difficult for the cell's machinery to properly ex- 
ecute DNA replication and repair, as well as transcription. Also researchers 
have shown that deoxyribose uniquely provides the necessary space within 
the backbone region of the DNA double helix to accommodate the large 
nucleobases. No other sugar fulfills this requirement. 

For some time, biochemists have understood why deoxyribose was selected 
for use in DNA and ribose for RNA. The primary role of DNA is information 
storage. That's why DNA must be a stable molecule. Incorporation of ribose 





2-Deoxyribose 



Figure 7.4. Differences between Deoxyribose and Ribose 

Deoxyribose and ribose are five-carbon sugars that form five- 
membered rings. Deoxyribose lacks an OH group at the 2' position. 
Ribose possesses a 2' OH moiety. 



2^4 The Cell's Design 

in DNA would make this molecule inherently unstable. The 2' OH of ribose 
can catalyze the cleavage of the sugar-phosphate backbone of DNA. This is 
not a concern, however, for deoxyribose because it lacks the 2' OH group. 

However, ribose is well-suited for RNA where some measure of insta- 
bility is preferable. One of the roles of RNA is to mediate the transfer of 
information from the nucleotide sequences of DNA to the amino acid 
sequences ofproteins (see chapter 2, p. 50, and chapter 5, p. 101). The 
cell's machinery copies mRNA from DNA when the cell needs the protein 
encoded by a particular gene housed in the DNA. 

Once produced, mRNAs continue to direct the production ofpro- 
teins at the ribosome until the cell's machinery breaks down the mRNA 
molecules (see chapter 6, p. 1 19). Fortunately, mRNA molecules can exist 
intact for only a brief period of time, in part because of the breakdown of 
the sugar-phosphate backbone mediated by the 2' OH group. The short 
lifetime of mRNAs serves the cell well. IfmRNAs unduly persisted, then 
these molecules would direct the production ofproteins at the ribosome 
beyond the point needed by the cell. 

Like deoxyribose and ribose, the nucleobases (adenine, guanine, cyto- 
sine, and thymine/uracil) found in DNA and RNA appear to be the best 
possible choices. For example, recent research demonstrates that these 
particular nucleobases display ideal photophysical properties. UV radia- 
tion emitted by the sun causes damage to DNA and RNA. The destructive 
effects of these electromagnetic wavelengths stem in large measure from 
the absorption of this radiation by the nucleobases. 

Even though DNA and RNA routinely experience photophysical 
damage, it could be far worse. It turns out that the optical properties of 
the bases found in nature minimize UV-induced damage.,. These nucle- 
obases maximally absorb UV radiation at the same wavelengths that are 
most effectively shielded by ozone. Moreover, the chemical structures 
of the nucleobases ofDNA and RNA cause the UV radiation to be ef- 
ficiently radiated away after being absorbed, limiting the opportunity 
for damage. (Additional reasons why adenine, guanine, cytosine, and 
thymine/uracil were selected for use in DNA and RNA are discussed 
in chapter 8.) 

Strategic placement. Biochemists have come to recognize that even 
the antiparallel arrangement of the nucleotide strands of the DNA mol- 
ecule is optimal . (see chapter 2, p. 48 and figure 2.7). Researchers have 
demonstrated that DNA analogs with a parallel orientation ofnucleotide 



The Proper Arrangement of Elements l^S 

Strands can be prepared in the laboratory. By comparing these novel DN A 
systems with native DNA, it is clear that aligning the nucleotide strands in 
an antiparallel fashion leads to greater stability of the DNA double helix 
found in nature. 

The antiparallel arrangement imparts topological and information- 
storage advantages, as well. The reasons why it does are beyond the scope 
of this book, but a resource for them can be found in the references.!. 



Processes at Their Peak 

Optimal composition is not limited to the structure ofproteins and 
DNA. Researchers have demonstrated that biochemical processes also 
operate at their ultimate potential. Descriptions of gene regulation and 
glycolysis make particularly fitting examples of exquisite biochemical com- 
position because both processes are central activities for life. 

Gene Regulation 

Recent studies indicate that the molecular operations responsible for 
regulating gene expression are optimized to minimize error. As mentioned 
earlier, genes are regions along the DNA molecule that specify the produc- 
tion of proteins and other products (see chapter 2, p. 48). Gene structure 
is complex, broadly consisting of two regions: the protein-coding region 
and the regulatory region^ (see figure 7.5). 

The protein-coding region contains information needed by the cell's 
biochemical machinery to produce the polypeptide chain encoded by 
that gene. The regulatory region, on the other hand, consists of "on/off 

Regulatory region 



> 



Promoter Operator Protein-coding region 



Figure 7.5. Gene Structure 

Gene structure broadly consists oftwo regions: tlie protein-coding region and the regulatory 
region. Two key sites exist within the regulatory region of a gene: the promoter and operator. 



225 The Cell's Design 

switches" and "volume control knobs" that control or regulate gene expres- 
sion. Hence, the regulatory region ultimately dictates the production of 
the polypeptide chain. 

Gene expression plays a central role in coordinating life's biochemical 
processes. Some genes are "turned on" or expressed nearly all the time. 
Biochemists refer to these genes as "housekeeping genes" because they 
specify proteins that are needed virtually all the time to maintain normal 
cellular operations. Other genes are expressed intermittently, directing the 
production of proteins only when necessary, either at certain points in the 
cell cycle or in response to specific environmental effects. 

There are two key sites within the regulatory region of a gene: the pro- 
moter and the operator. The promoter serves as the binding site for a mas- 
sive protein complex called RNA polymerase. This enzyme initiates gene 
expression by producing a messenger RNA molecule that contains a copy 
of the information found in the protein-coding region of the gene (see 
chapter 2, p. 50). The messenger RNA molecule eventually makes its way 
to a subcellular particle or ribosome in the cytoplasm. Once there, mes- 
senger RNA directs protein production. 

The strength of RNA polymerase binding at the promoter controls the 
amount of messenger RNA produced and hence the amount ofprotein 
generated at the ribosome. In this sense, the promoter functions as a volume 
control knob of sorts. 

The operator also binds proteins. Two different types ofproteins — 
activators and repressors — bind to the operator. As the names imply, ac- 
tivators turn the gene on (or activate it) when they bind, and repressors 
turn the gene off (or repress it) when they bind. In this way, the operator 
functions as a type of on/off switch for gene expression. 

Debinding of activators can also turn genes on and off. When a repressor 
debinds, the gene is activated. And, when an activator debinds, the gene is 
repressed. In other words, genes can be triggered by either activator bind- 
ing or repressor debinding. And gene activity can be halted by repressor 
binding or activator debinding. 

New work demonstrates that the specific means of regulating individual 
genes adhere to a precise pattern.:! Instead of arbitrarily being turned on 
by activator binding or repressor debinding, genes in high demand are 
turned on primarily by activator binding. Likewise, instead of randomly 
being turned off by repressor binding or activator debinding, genes in low 
demand are turned off mainly by repressor binding. 



The Proper Arrangement of Elements 1 •3'7 

This pattern of gene regulation keeps errors to a minimum. When unoc- 
cupied, undesired regulatory proteins can capriciously bind to a free opera- 
tor site. Nonspecific binding of activators and repressors causes genes to be 
expressed at an inappropriate time, leading to mistakes in gene regulation. 
When occupied, however, unspecified binding cannot occur, ensuring that 
genes accurately turn on and off at the proper time. This blueprint for gene 
regulation is optimal, displaying the type of elegant chemical logic expected 
in the work of an all-wise Creator. 

Glycolysis 

One of life's most important metabolic pathways, glycolysis, plays a key 
role in harvesting energy for use in most cells. This biochemical process 
releases energy from glucose (a six-carbon sugar) by fracturing it into two 
molecules ofpyruvate (a three-carbon compound).,. The cell captures 
a portion of this liberated chemical energy and stores it in the chemical 
bonds of special molecules for later use. 

The glycolytic pathway traps energy from glucose breakdown by using 
it to form ATP (adenosine triphosphate). This molecule has two high- 
energy chemical bonds. When broken, the energy stored in the high-energy 
bonds is made available for the cell to use. The forming and breaking of 
the high energy bonds is like recharging and discharging a battery. The cell 
couples the breakdown of ATP's high-energy bonds to energy-requiring 
biochemical processes and activities. In this way, energetically unfavorable 
processes in the cell become feasible by using the energy stored in ATP 
(see figure 7.6). 

The use of ATP to power the cell's operations displays elegant chemical 
logic. Biochemists refer to ATP as the cell's energy currency. Instead of 
inefficiently coupling the breakdown of a large number of different high- 
energy compounds to a wide range of energetically unfavorable processes in 
the cell (like a barter-based economy), the cell uses only a few high-energy 
compounds (like a currency-based economy) to satisfy the multifarious 
energy demands of the cell.., 

From an energetics standpoint, the net output of glycolysis is two mol- 
ecules of ATP for each molecule of glucose broken apart. (Two molecules 
of NADH [nicotinamide adenine dinucleotide] are also generated for each 
molecule of glucose. NADH, like ATP, is also an energy-currency molecule 
that mediates the transfer of electrons between biomolecules in the cell.) 



138 



The Cell's Design 



Adenine 



High energy bonds 






Phosphate groups 



l\ H H / 

h\i i/h 



Ribose 



OH 



OH 



ADP 



ATP 



Figure 7.6. High-Energy Bonds of ATP 

ATP (adenosine triphosphate) has two high-energy chemical bonds. When broken, the 
energy stored in the high-energy bonds is made available for the cell to use. When one 
phosphate bond is broken, the resulting molecule is called ADP (adenosine diphosphate) 



Biochemists have long considered glycolytic ATP production to be op- 
timal. The prevailing view has been that the rate of ATP production is just 
right at two ATP molecules/glucose. According to this model, at faster rates 
the energy yield would fall below two ATP molecules. At slower rates, more 
ATP molecules/glucose would be generated, but ATP amounts would fall 
below the minimum feve/ needed to satisfy the cell's energy demands. 

Recent work indicates that the prevailing view of glycolytic optimiza- 
tion is not entirely correct. The production rate of ATP is not optimal in 
glycolysis, but the amount of ATP produced is. If that's the case, then why 
isn't the yield of ATP in glycolysis higher ? This research demonstrates that 
any output other than two ATP molecules/glucose negatively impacts the 
biochemical processes that use ATP.:, 

This molecule sits at the center of a complex web of activities within the 
cell. For example, in addition to providing energy for cell operations, ATP 
also regulates metabolic pathways. Production rates that exceed two ATP 
molecules/glucose would create havoc with other cell processes that use 



The Proper Arrangement of Elements 1 og 

ATP. Production rates that fall short of two ATP molecules/glucose would 
fail to yield the maximum amount of energy possible from each glucose 
molecule. The performance of the glycolytic pathways finds balance between 
the amount of ATP produced and its global use throughout the cell. 

The Just-Right Biochemical Balance 

The examples of biochemical optimization described in this chapter are 
only a small sampling of the optimized designs that make up life's chem- 
istry. Even for those discussed, much more could be written. These few 
samples were chosen to represent the most important classes of biomolecules 
(proteins and DNA) and two biochemical processes (gene regulation and 
glycolysis) central to life. 

Artists carefully array the elements in their paintings to achieve a specific 
effect. Engineers strategically place the parts necessary to optimize their 
designs. The composition of an artistic piece or ofa system operating at 
optimal capacity doesn't just happen. Piet Mondrian carefully arranged 
rectangular shapes, lines, and colors in his pieces to achieve the effect he 
desired. An automotive engineer deliberately crafts and places the parts 
necessary to make a motor run. 

The structures of biomolecules appear carefully constructed as well. 
Proteins, some of the most important biomolecules, appear to have hand- 
selected amino acid components and sequences designed to yield structures 
optimized for stability and production costs. The molecular constituents 
of DNA also appear to have the just-right chemical properties to produce 
a stable helical structure capable of storing the information needed for the 
cell's operation. Only a meticulous Artist could arrange the biochemical 
elements in such a well-balanced fashion. 

Biochemical processes also appear to be intentionally optimized. Gene 
regulation, one of the most important biochemical activities, displays an 
exquisite balance in the way that activators and repressors are used to "turn 
on" and "turn off" genes. And, the production of ATP in one of the cell's 
most important energy harvesting pathways, glycolysis, appears to be op- 
timized for maximum energy extraction from the fuel molecule glucose 
in light of the other roles ATP plays in the cell. 

The next chapter explores another feature of life's chemistry that points 
to Divine Design: the information content of biochemical systems. 






Islamic scripture in Urdu on a wall (Reproduced by permission from Pankaj & Inky 
Shah/Gulfi mages/Getty Images) 



8 



THE ARTIST'S HANDWRITING 



In the Islamic world, calligraphy is more than just writing with a flourish. 
It's a form of fine art., In fact, many Muslims hold calligraphers in the 
highest regard. 

Because of Islam's taboo on pictorial representation, calligraphy is both 
the chief vehicle of artistic expression and an important means of teach- 
ing the tenets of the faith. Calligraphy often "illustrates" the Qur'an and 
adorns the walls and ceilings of mosques. Sometimes calligraphy is purely 
art with the letters so richly stylized that they are practically illegible. On 
other occasions calligraphy conveys the Qur'an's declarations. For Mus- 
lims, the words of the Qur'an are so treasured that only the best efforts 
and highest quality are worthy of them. 

In the Western world, calligraphy has less to do with art than with elegant 
penmanship. Instead of appearing in art pieces, so-called modern calligra- 
phy finds its way onto invitations, book covers, and the like. Calligraphy is 
more than simply expressing sentiments using fancy lettering. This special 
script communicates a stylized message. 

In the West, as in the East, calligraphy associates value with the message 
being conveyed. The elegant writing that appears on a wedding invitation 
speaks volumes about the importance of the event. Whether transmit- 
ting details for a wedding, or religious ideas, all forms of calligraphy are 

141 



242 The Cell's Design 

motivated by a desire to relay highly prized information. Whether an in- 
dividual reads the Qur'an or receives an invitation, he or she immediately 
recognizes that someone, somewhere, is responsible for the communication. 
No matter what form the message takes, the information being conveyed 
always originates in a mind. 

Information can't be separated from the activity of an intelligent agent. = 
And this connection makes this property a potent marker for intelligent 

design. 



Molecular Messages 

Over the last forty years, biochemists have learned that the cell's sys- 
tems are, at their essence, information-based. Proteins and DNA are 
information-rich molecules. And, like the outpouring from a calligra- 
pher's pen, the structural and functional expressions of molecular-level 
messages are draped with an artistic elegance and clever logic worthy of 
an esteemed Writer. 

The Protein Pipeline 

The description of cellular information begins best with proteins. These 
molecules form from polypeptides that are made when the cellular ma- 
chinery links amino acids together in ahead-to-tail fashion (see chapter 2, 
p. 42). 

Information theorists maintain that the amino acid sequence of a poly- 
peptide constitutes information. Just as letters form words, amino acids 
strung together form the "words" of the cell, polypeptides.: In language, 
some letter combinations produce meaningful communication. Others 
produce gibberish — "words" with no meaning. Amino acid sequences do 
the same. Some produce functional polypeptides, whereas others produce 
"junk" — polypeptides that serve no role.. 

Treating amino acid sequences as information has been a fruitful ap- 
proach for researchers attempting to characterize the functional utility 

of different amino acid sequences and understand the origin of proteins., 
According to information theorist Bernd-Olaf Kiippers, the structure of 

the information found in proteins is identical to the architecture of human 
language (see table 8.1). 



The Artist's Handwriting 14'^ 







Table 8.1 








Cellular Sentences 




Language 


Analog 


Proteins 


DNA 


Chanacter* 






Nucleotide 


Letter 




Amino Adds 


Codon 


Word 




Polypeptides 


Gene 


Sentence 




Protein Complexes 


Operon 


Paragraph 




Bioctiemical Pathways 


Regubn 



*Note: Letters are made from characters. 

DNA Dishes the Data 

Information theorists assert that DNA, like polypeptides, contains in- 
structions. In fact, DNA's chief function is information storage. It houses 
the directions necessary to make all the polypeptides used by the cell. The 
polynucleotide chains of DNA form when the cell's machinery links together 
four different nucleotides: A, G, C, and T (described in chapter 2, p. 48). 

The sequence of nucleotides in the DNA strands specifies the sequence 
of amino acids in polypeptide chains. These coded instructions are called 
genes. Through the use ofgenes, DNA stores the messages functionally 
expressed in the amino acid sequences of polypeptide chains. 

According to Kiippers, the structure ofhuman language also yields 
insight into the informative content of DNA. Nucleotides function as 
characters that build letters and the genes function like words. 

On the Information Highway 

The "central dogma of molecular biology" describes the "flow" of infor- 
mation inside the cell (see chapter 2, p. 50). This concept describes how 
information stored in DNA becomes functionally expressed through the 
amino acid sequences and activity of polypeptide chains as DNA is tran- 
scribed to form RNA, and RNA is translated to produce proteins. 

Found inside the nucleus of complex cells, DNA compares to the refer- 
ence section of a library. The books there can be read but cannot be re- 
moved. The material stored in these tomes must be copied, or transcribed, 
before it can be taken from the library. This process is exactly what the 
cell does. 



244 The Cell's Design 

DN A does not leave the nucleus to direct the synthesis of polypeptide 
chains. Rather, the cellular machinery copies the gene's contents by as- 
sembling another polynucleotide, messenger RN A (mRNA, see chapter 2, 
p. 50). Transcription occurs as the details in DN A are copied or transcribed 
into mRNA. 

Once assembled, mRNA migrates from the nucleus of the cell into 
the cytoplasm. At the ribosome, mRNA directs the synthesis of polypep- 
tide chains. The information content of the polynucleotide sequence is 
translated into the polypeptide amino acid sequence. It's like translating 
English into Spanish. In other words, the nucleotide language of DNA 
and RNA is translated at the ribosome into the amino acid language of 
proteins. 

The analogical language used by molecular biologists to describe the 
flow of information in biochemical systems is no accident. According to 
Kiippers, "The analogy between human language and the molecular-genetic 
language is quite strict.... Thus, central problems of the origin of biological 
information can adequately be illustrated by examples from human lan- 
guage without the sacrifice of exactitude.". Biochemical systems are, in fact, 
information systems. And everyday experience teaches that information 
only comes from a mind. 

Syntax, Semantics, and Pragmatics 

The relationship between human and biochemical languages extends 
beyond the comparisons found in table 8.1. Information theorists recognize 
multiple dimensions to human information: syntactics, semantics, and prag- 
matics. And, these properties also apply to biochemical information. 

The syntactic component of information refers merely to the ordering of 
symbols or letters in human language — or for biochemical information, the 
sequence of nucleotides and amino acids. It has nothing to do with whether 
the arrangement has meaning. In terms of human language, the letter com- 
binations "cat" and "tea" are equivalent in the syntactic dimension. 

The semantic level of information ascribes meaning to the order of sym- 
bols, letters, and so forth. This dimension arises because some sequences have 
meaning (cat) and others don't (tea). The pragmatic level of information 
recognizes that the meaning of the arrangement depends upon agreement 
between two parties: the sender and the recipient. Their agreement ascribes 
meaning to some sequences and not to others. It provides the basis for the 



The Artist's Handwriting 14S 

recipient of information to respond or take action based on the sender's 
direction. According to Kiippers, 

The identification of a character as a "symbol" presupposes certain prior 
knowledge ... in the form of an agreement between sender and recipient. 
Moreover, semantic information is unthinkable without pragmatic informa- 
tion, because the recognition of semantics as semantics must cause some 
kind ofreaction from the recipient. lo 

Biochemical information displays all three dimensions of human com- 
munication. The nucleotide sequences ofDNA and RNA and the amino 
acid order ofproteins can be described syntactically. But these sequences 
also have semantic and pragmatic dimensions. 

The nucleotide sequences ofDNA ultimately specify the amino 
acid sequences of polypeptides. Amino acid order dictates the three- 
Biochemical Linguistics 

Recent work by a team of chemical engineers and biochemists powerfully highlights 
the language content and structure of biochemical information.!. These researchers 
sought an approach to rationally design novel nonnatural peptide antibiotics. 

In the last decade or so, microbiologists and biochemists have discovered that a 
number of organisms possess relatively small peptides in their skin, saliva, sweat, and 
so forth. These peptides display antimicrobial activity and appear to be an important part 
of the immune system. The new antibiotics attract interest because they appear to be 
active against bacteria that are resistant to the most potent medicines available. 

Researchers noticed that these antimicrobial peptides are made from sequence 
combinations similar to phrases used in language. Based on this insight, the team 
treated the amino acid sequences of the antimicrobial peptides from a wide range of 
organisms as a formal language and developed a set of grammatical rules that describe 
possible arrangements of amino acids in the peptides — just like human grammar 
permits certain sequences of words and disallows others. 

This biochemical grammar consisted of 684 rules. Using these guidelines, the 
scientists came up with forty-two novel antimicrobial peptides. They displayed anti- 
microbial activity comparable to the peptides found in nature. Interestingly, the scien- 
tists compared their nonnatural peptides with peptides that had the same amino acid 
compositions but had random sequences. These random peptides lacked activity, just 
as random use of words in a sentence lacks meaning. Biochemical information ap- 
pears to be organized in the form of a molecular grammar that bears strong similarity 
to human languages. 



246 The Cell's Design 

dimensional structure of the polypeptide chain that in turn determines 
the polypeptide function. Some potential amino acid sequences yield 
nonfunctional polypeptides, whereas others specify peptides with bio- 
logically relevant function. In other words, some amino acid sequences 
(and hence nucleotide sequences) have meaning to the cell and others 
do not. And, those meaningful sequences carry out specific activities 
within the cell. 

The semantic content of nucleotide sequences finds pragmatic expres- 
sion in the activity of polypeptides. In this way, the semantic and pragmatic 
aspects of biochemical information are inextricably intertwined. 

A Sweet Message 

While DNA and proteins are typically considered the only information- 
containing molecules of biochemical systems, recent studies indicate that 
oligosaccharides house information as well. Oligosaccharides are carbohy- 
drates — a class of biomolecules that consists of compounds composed of 
carbon, hydrogen, and oxygen in the specific ratio of 1:2:1, respectively. t3 

Carbohydrates typically play important roles in the cell — a few of which 
are energy storage, the formation of cell structures, mediation of cell-to-cell 
contact, and regulation of development. They are built from small molecules 
called sugars. Monosaccharides (mono = one) are carbohydrates composed 
of a single sugar residue. Glucose and fructose are two monosaccharides 
familiar to diet-conscious people. 

Disaccharides (di = two) consist of two sugars linked together. A fa- 
miliar example is sucrose, table sugar. It consists of the sugars glucose and 
fructose combined. 

Polysaccharides (poly = many) form when numerous sugars connect. 
Starch and cellulose are common examples. Both consist of glucose linked 
into long chains. The difference between starch and cellulose stems from 
the nature of the linkage between the individual glucose molecules. (For 
examples of monosaccharides and disaccharides, see figure 8.1.) 

Oligosaccharides (oligo = few) form when a handful of sugar mol- 
ecules are linked together. Frequently, oligosaccharides are attached 
to proteins associated with the exterior surface of cell membranes and 
proteins secreted by the cell (see chapter 2, pp. 40 and 45). i- These oli- 
gosaccharides play a structural role, for example, mediating cell-to-cell 
contact. 



The Artist's Handwriting 



147 



CH7OH 




OH H 

Fructose 



\ 



H>0 



CH.OH 



CH2OH 



f 


\ 


H 








* \ 




H 




\ 




-I 


^ 


OH ^ 




/ 


r\ 




\ H 






— 




\ 



H HO, 

CH2OH 



H OH OH H 

Sucrose 

Figure 8.1. Carbohydrate Structures 

Glucose and fructose are examples of monosaccharides. Disaccharides consist of two sugars 
linked together. In this example, sucrose (table sugar) consists ofthe sugars glucose and 
fructose linked together. 



The structural complexity of oligosaccharides gives them the capacity 
to house much more information per unit length than DNA, RNA, and 
proteins. The only basis of information for DNA, RNA, and proteins is the 
sequence of nucleotides and amino acids. For oligosaccharides, information 
is not limited just to the sugar sequences. It can also be contained in the 
variety of chemical substituents that bind to the sugars, the multiple types 
of bonds that form between sugar subunits, and the branching that occurs 
along the oligosaccharide chain.,., For example, the two amino acids glycine 
and alanine can be linked in two ways: alanine-glycine or glycine-alanine. 



248 The Cell's Design 

Galactose and glucose can be joined together in thirty-six different ways. 
Each variation represents a unique piece of information. 

Oligosaccharides harbor two modes of information: stable and tran- 
sient.,. The oligosaccharides carrying stable information remain unaltered 
after being assembled by the cell's chemical systems. Typically associated 
with the cell surface, these oligosaccharides are used as a recognition system 
when the cell interacts with materials in the environment or with other 
cells. 

Those oligosaccharides with transient information are modified by the 
cell's chemical machinery during the course of biological activity. The cell 
uses the alterations to report on the status of the protein that binds the 
oligosaccharide moiety. For example, transient information plays a central 
role in quality control operations in the endoplasmic reticulum during the 
process of protein secretion. In this instance, the structure of the oligosac- 
charides lets the cell's machinery know if the protein chain has been properly 
folded. (Chapter 10, p. 198 details this process.) 

Information-rich biomolecules (proteins, DNA, RNA, and oligosac- 
charides) and the information-based biochemical systems — central to life's 
most fundamental activities — strongly indicate that a Divine hand penned 
life at its most basic level. 



Structural Calligraphy 

The case for biochemical intelligent design doesn't rest on the mere 
presence of information in biochemical systems. An incredible chemical 
"wisdom" displayed in the way the cell's information is crafted shows that 
it must have been deliberately written. 

Gene Organization 

The architectural and functional arrangement of genes illustrates 
the elegant structural properties of biochemical information. A dis- 
cussion of three textbook examples — operons, alternate splicing, and 
overlapping genes — highlight this exceptional quality of the cell's genetic 
information. 

Operons. Bacteria's genes are not randomly distributed throughout their 
genomes. Instead, they are often organized into structural units called 



The Artist's Handwriting 



149 



operons. Here, the genes are arranged in a contiguous sequence with the 
end of the first gene juxtaposed to the beginning of the second gene, and so 
on. These genes code for proteins that work together to achieve a specific 
metabolic goal. 

A classic example of an operon is the lac operon found in the bacte- 
rium Eschericia coli (E. coli). This operon was one of the first discovered 
and characterized (see figure 8.2). Other examples are discussed in most 
molecular biology textbooks.;. 

No lactose 



Promoter / Operator 




ZZh 



Repressor 



Lactose present 




^;i;C>' 



-AAAAAAAAAAAAAAA/^^t2^ 



Abundant /oc mRNA 



Lactose 



Figure 8.2. TheLae Operon 

The lac operon codes for proteins that help the bacterium £. coli metabolize lactose. When 
lactose is not present, the lac repressor protein binds to the operator and the lac operon genes 
are not expressed. When lactose is present, the lac operon proteins are produced after the 
repressor disassociates from the operator. 



250 The Cell's Design 

The lac operon codes for proteins that help the cell metabolize lactose. 
This disaccharide (see p. 146) consists of two sugars — galactose and glucose. 
Three structural genes and one regulatory gene make up the lac operon. 
One of the structural genes contains the instructions to make the protein 
(5-galactosidase. This protein cleaves lactose into its two constitutive sugars. 
Another structural gene specifies lactose permease. It helps usher lactose 
into the cell from the exterior environment. A third structural gene encodes 
a protein of unknown function, galactoside transacetylase. 

Individual gene structure is complex, broadly consisting of two regions: 
protein coding and regulatory (see figure 7.5, p. 135). The protein-coding 
region contains information that the cell s biochemical machinery needs to 
produce the polypeptide chain. The regulatory region controls the expres- 
sion of the gene and, hence, the polypeptide chains production. 

Within the regulatory region of a gene are two key sites: the promoter 
and operator. The promoter functions as the binding site for RNA poly- 
merase. This protein complex produces a messenger RNA molecule by 
reading the information found in the gene. The operator also binds pro- 
teins. Two different types of proteins, activators and repressors, bind to the 
operator. As the names imply, activatots turn the gene on when they bind, 
and repressors turn the gene off 

An operon's regulatory region precedes the structural genes. The operator 
and promoter of the lac operon control the expression of all three structural 
genes (p-galactosidase, lactose permease, galactoside transacetylase). This 
operon also contains a regulatory gene (as opposed to the regulatory region). 
It codes for a protein that binds to the lac operon operator. The protein is 
a repressor, and when it binds to the operator it prevents the expression of 
the lac operon structural genes. 

This arrangement displays appealing and powerful biochemical logic. 
Normally, the lac repressor protein is bound to the operator and the lac 
operon genes are not expressed. The cell usually doesn't need the lac operon 
proteins, because lactose is not a common nutrient fori?. coU. 

Repression of the lac operon benefits the cell because it prevents the 
wasteful production of unnecessary proteins. Grouping the lac operon 
genes together in a contiguous sequence allows the cell to regulate gene 
expression with a single repressor. 

But, when lactose is present, lac operon proteins are produced. The 
expression of these genes is initiated when this sugar binds to the lac re- 
pressor causing this protein to dissociate from the operator. Debinding of 



The Artist's Handwriting lcl 

the lac repressor allows RNA polymerase access to the promoter, which 
consequently leads to the production of the proteins needed to metabolize 
lactose through the activity of a single repressor. 

When RNA polymerase copies operon genes, including those of the 
lac operon, it produces what biochemists call a polycistronic mRNA. 
(The term cistron refers to a region of the DNA that encodes a single 
polypeptide chain.) Monocistronic (mono = one) mRNA only contains 
enough information to direct the production of a single polypeptide at 
the ribosome. Polycistronic (poly = many) mRNA, on the other hand, 
contains information the ribosome needs to simultaneously produce sev- 
eral polypeptides. 

The polycistronic mRNA copied from the lac operon simultaneously 
directs the manufacture of the three proteins needed to metabolize lactose, 
when lactose is present. This system ensures that all the, proteins necessary to 
handle this sugar are produced at appropriate levels and in a timely fashion. 
Organizing and expressing biochemical information using operons and 
polycistronic mRNA manifest an impeccable biochemical rationale. 

Bumping heads. Until recently, biochemists didn't think that genes 
found in eukaryotic genomes displayed any type of large-scale structural 
organization. According to this traditional view, eukaryotic genes are scat- 
tered throughout the genome, including those genes that specify the pro- 
teins that work together to accomplish a specific biochemical task. Recent 
work, however, suggests that such random positioning is not the case. Many 
genes in mammalian genomes are arranged in a head-to-head fashion with 
the starting points of the genes juxtaposed.,. 

For example, 1,262 pairs of head-to-head genes have been detected in 
the human genome. Approximately 63 percent of the gene pairs code for 
proteins that perform related functions and are expressed together. Like 
the operons in prokaryotes, the head-to-head pairing of genes represents 
an ordering of the biochemical information in eukaryotic genomes that ap- 
pears to be undergirded by an elegant molecular logic. According to the re- 
searchers who made this discovery, this arrangement "provides an exquisite 
mechanism of transcriptional regulation based on gene organization.",* 

Alternate splicing. The DNA sequences that make up genes in eukaryotes 
consist of stretches of nucleotides that specify the amino acid sequence 
of polypeptide chains (exons), interrupted by nucleotide sequences that 
don't code for anything (introns). After the gene is copied into an mRNA 
molecule, the intron sequences are excised and the exons spliced together 



252 The Cell's Design 

by aprotein-RNA complex known as a spliceosome2o (see figure 5.2, p. 103, 
for the splicing process, though spliceosome is not shown). 

Splicing is an extremely precise process. Mistakes in splicing are responsible 
for some human diseases. Medical disorders result because splicing errors fatally 
distort or destroy information — temporarily stored in mRNA — necessary to 
assemble polypeptide chains at ribosomes. Andimproperlyproducedpolypep- 
tides cannot carry out their functional role in the cell. In his taabookEssentials 
of Molecular Biology , George Malacinski points out why proper polypeptide 
production is critical: "A cell cannot, of course, afford to miss any of the splice 
junctions by even a single nucleotide, because this could result in an interrup- 
tion of the correct reading frame, leading to a truncated protein. "21 

Remarkably, in light of this restriction, the spliceosome joins together 
the same mRNA in different ways to produce a range of functional proteins. 
This alternate splicing occurs because not all splice sites are necessarily 
used by the spliceosome. 22 Alternate splicing allows the cell to produce 
several different proteins from the same mRNA and ultimately from the 
same gene. 

Proteins involved in the splicingprocess help determine the splicingpat- 
tern of mRNA. For example, some proteins bind to splice sites preventing 
access by the spliceosome. By varying the binding pattern of these proteins, a 
variety of mRNAs can be produced. The cell also achieves alternate splicing 
through the use of different promoters associated with the same gene (see 
chapter 7, p. 135). Each promoter produces an mRNA spliced differently 
by the spliceosome complex. 

Alternate splicing can also be mediated by varying the length of the 
mRNAs poly(A) tail. Apparently the poly(A) tail helps direct the splice- 
osome to specific splice junctions along the mRNA strand. 

Structuring genes to have noncoding regions (introns) interspersed be- 
tween coding regions (exons) is an elegant strategy that allows a single gene 
to simultaneously house the information to produce a range ofproteins. 
Still, given how exacting the splicing process must be and how sensitive 
it is to errors, that alternate splicing occurs at all is astounding. For the 
cell to successfully carry out alternate splicing, the nucleotide sequences 
and the placement of exons have to be carefully orchestrated. And to do 
that seemingly requires a Divine hand to guide the process. (See Alternate 
Splicing, p. 153.) 

Overlapping genes. In the late 1970s, biochemists studying the bacte- 
riophage (^Xl 74 (a virus that infects the bacterium ii. coli) made a startling 



The Artist's Handwriting 1 S "^ 

discovery: the genome ofthis bacteriophage directs the production of 
more proteins than it should based on the size ofits DNA. Researchers 
resolved this paradox when they demonstrated that some of the ^>X174 
genes overlap. 23 

Alternate Splicing: Tlie Word Game 

Let's play a game to illustrate how much of a mental challenge it is to proper^ place 
splice sites within a gene so genetic information can simultaneously speciiy several 
different proteins. 

TAe^/rs'/sfep. -Identify a word that contains other words, for example, splendid. The 
words spends lend, end, lid, and did can be extracted by excising letters and splicing 
the remaining ones together. The only restriction is that the sequencing of letters can't 
be altered to extract words from the root word. F<m- example, the words den and slip 
cannot be derived from splendid hecause the order of the letters has to be changed 
to come up with them. 

The next stepCome up with arbitrary letter combinations that can be added to 
the base word so it and other derived words can be uniquely extracted by excising 
strings of letters and splicing the remaining ones together. For example, x's can be 
strategically placed to make it possible to yield splendid and set the stage to extract 
spend, lend, end, lid, and did by alternate splicing: 

xsp?0£CHXcB£/cfe (x 5p X / x en X dx idx) 

Splendid can be extracted by excising all the x's and splicing together the remaining 
letters. The x's could have been placed anywhere and the word splendid extracted. 
The placement of x's used above required some planning and forethought, to make it 
possible to extract the derived words spend, lend, end, lid, and did. 

Now for the part of the game that requires some mental effort. Additional letters 
need to be inserted into xspx/xenxox/dx to make it possible to uniquely extract the 
derived words. To illustrate, start with did. 
Then z's could be added as follows: 

zxspx/xenxzdzxz/dzxz (zxspx/xenxz cfzxz /dzxz) 

By removing any letters bracketed by z's, did can be extracted. Yet, a problem arises. 
This configiu^tion no longer makes it possible to extract splendid'using the original rule 
of extracting x's and splicing together the remaining letters. Usii^ that rule leads to: 

zxspxixenxzdix zidz xz 

zsplenzdzzidzz 



]^54 T'he Cell's Design 

This problem can be rectified by replacing the ordinal rule so that instead of an x 
being excised an xz is removed: 

xzxzspxz/xzeflxzdxzxz/cfxzxz 
xz xz spxz /xz enxz dxz xz idxz xz 

splendid 

This creates a new problem, however. Removii^ letters bracketed by z no loiter 
yields did. Instead it generates: 

xzxzs pxz/xzenxzdxzxz/dxzxz 



These problems could be avoided, and the game greatly simplified, by adjustii^ the 
rules of the game to allow the participants to specify as many excision and splicing steps 
as they want in order to extract the desired word. Retumii^ to zxspx/xenxzdzxz/dzxz — if 
the splicii^ instructions are to remove both x's and z's, then splendid can be generated 
w^hile retaining the rule that ^WowdidXo be recovered: 

z X spx I iL eniL 1. d 1. n. 1. idz x z 

splendid 
zxspx/x en xz dzxz idzxz 



Now you can determine what instructions allow^ other words to be extracted through 
the excision and spUcing process. 

This conclusion was quite unsettling. Biochemists considered the re- 
lationship "one gene, one protein" to be absolute and a cornerstone of 
molecular biology. (One reason is discussed below. )24 Since the work 
on the bacteriophage cpX/ 74 genome, biochemists have identified over- 
lapping genes in other viruses as well as in bacteria, insects, fish, and 
mammals. 25 

It's possible for genes to overlap within the same D N A sequence because 
the cells biochemical machinery makes use of reading frames to access the 



The Artist's Handwriting 1 SS 

information in DNA. And, each overlapping gene is read using a different 
reading frame. =. 

The cell's machinery depends upon these reading frames to access in- 
formation because of the mismatch in the number of nucleotides (four) 
used by DNA to specify the number of amino acids (twenty) needed to 
construct proteins. Clearly, there cannot be a 1:1 correspondence between 
nucleotides in DNA and amino acids in proteins. The cell's biochemical 
information system overcomes this problem by using short sequence com- 
binations of three nucleotides (called coding triplets or codons) to signify 
each amino acid. 

There are sixty-four possible nucleotide triplets. The cell employs sixty- 
one codons to specify the twenty amino acids used by the cell to synthesize 
proteins. Some amino acids are signified by a single codon. Others are 
connoted by several different codons. The relationship between codons 
and amino acids is called the genetic code. (Chapter 9 discusses the genetic 
code and its use in the biochemical intelligent design analogy.) 

For the cell's machinery to produce proteins, the information stored in 
DNA must be copied. The transcribed information resides in molecules of 
messenger RNA (mRNA). Once assembled in RNA, the information makes 
its way to the ribosome where it directs the construction of polypeptides (see 
chapter 2, p. 50). The short model mRNA nucleotide sequence illustrates 
how the cell uses codons to specify amino acids in polypeptides. 

PosHion: 1 2 3 

UCU ecu GCA AUU CGU AU 

If the cell's biochemical apparatus uses a reading frame that starts at the 
first position (U), the resulting peptide will have the sequence: serine- 
proline-alanine-isoleucine-arginine because UCU specifies serine, and so 
on (see table 9.1, p. 172). When the reading frame begins at the second 
position (C) in the nucleotide sequence, an entirely different peptide is 
generated with the sequence: leucine-leucine-glutamine-phenylalanine- 
valine. Shifting the reading frame to the third nucleotide position (U) 
yields a peptide with the sequence: serine-cysteine-asparagine-serine- 
tyrosine. (As illustrated in this example, there are only three possible 
reading frames for a nucleotide sequence.) Simply by shifting the reading 
frame by one or two nucleotides, a single sequence can encode three very 
different peptides. 



255 The Cell's Design 

This example makes it possible to see how a single nucleotide sequence 
could harbor overlapping genes. By using alternate reading frames shifted 
by one or two nucleotides, the cell's machinery can produce polypeptide 
chains with radically different amino acid sequences. 

In principle, each DNA sequence possesses three reading frames. In 
most cases only one is used and the nonoverlapping "one gene, one protein" 
relationship holds. But in some cases two reading frames are used, and two 
genes overlap onto the same nucleotide sequence. 

Because of the genetic code s redundancy, some of the information con- 
tent of DNA is not used when genes don't overlap. Overlapping genes 
represent the full use of the information content ofDNA.s, Its no acci- 
dent, then, that overlapping genes are found in some of the smallest, most 
compact genomes in nature (viruses and parasitic hactsria like Mycoplasma 
genitalium). Recently researchers discovered evidence that overlapping 
genes are also abundant in more complex eukaryotic organisms. 

The existence of any overlapping genes in nature is remarkable. Typically, 
when a gene's reading frame shifts as a result of a mutation, it almost always 
leads to catastrophic results. These so-called frameshift mutations result 
when nucleotides are accidentally inserted or deleted from a gene. And, 
as evident in the previous example with the model nucleotide sequence, 
a frame shift produces a protein with a radically different amino acid se- 
quence as the reading frame moves from the first position to the second 
or third position. 

The mutant protein is almost always nonfunctional junk. Frameshift 
mutations stand in contrast with substitution mutations, which involve 
the replacement of one nucleotide for another. 

Substitution mutations merely replace one amino acid in the polypeptide 
chain for another. All other amino acids remain unchanged. Substitution 
mutations can be catastrophic, but more often than not these types of 
errors have limited, if any, effect on protein function because the gene's 
reading frame hasn't changed. (Substitution mutations are discussed in 
greater detail in chapter 9.) 

The existence of overlapping genes points to the intentional activity 
of a Creator. Another word game helps illustrate why (see "Overlapping 
Sentence Game," p. 157).:. 

Biochemists have also identified another type of overlapping gene. In- 
stead of the overlap taking place on the same DNA strand, it occurs on 
opposite strands. To appreciate how remarkable this discovery is, it's 



The Artist's Handwriting 1 S7 

Overlapping Sentence Game 

Tiy coming up witli a sentence (or even a word for ttiat matter) that produces anotlier 
meaningful sentence if the sentence's reading frame shifts by one or two letters. 
Consider the sentence: 

The boy went to the store. 

Shift the reading frame one letter: 

T heb oyw entt ot hes tore. 

A solution to this puzzle is only possible if a judicious, if not ingenious, choice of 
words is used to construct the sentence. Even so, coming up with an example that 
works seems almost impossible. Likewise, for genes to overlap on the same nucleotide 
sequence, particularly in light of the damaging effects of frameshift mutations, a Divine 
Genius appears necessary. 

necessary to understand how genes are typically distributed between the 
polynucleotide chains of the DNA double helix. 

Usually, only one DNA strand harbors a gene. Biochemists caD this strand 
the sense strand. The other strand, aligned opposite the gene, simply serves 
as a template for DNA replication (see chapter 1 1, p. 217). This strand is 
referred to as the nonsense or antisense strand. 

A special relationship exists between the nucleotide sequences of the two 
DNA strands and consequently between the sense and antisense sequences 
associated with genes. When the DNA strands align, the adenine (A) side 
chains of one strand always pair with thymine (T) side chains from the other 
strand. Likewise, guanine (G) always pairs with cytosine (C). Biochemists 
refer to these relationships as base-pairing rules (see figure 2.7, p. 49). 

As a consequence, if biochemists know the sequence of one DNA strand, 
they can readily determine the sequence of the other strand. The DNA 
sequences ofthe two strands are complementary. 

Base-pairing rules restrict the nucleotide sequence of the antisense strand. 
The nucleotide sequence of the sense strand dictates the nucleotide sequence 
of the antisense strand. Though the sense strand codes for a functional poly- 
peptide, its highly unlikely that the nucleotide sequence ofthe antisense 
strand does. This nucleotide sequence, in principle, specifies an amino acid 
sequence. However, its doubtful that the resulting polypeptide could ever 



25§ The Cell's Design 

adopt a useful configuration because of the strict relationship between a 
proteins amino acid sequence and its function. 

While the purpose of the sense strand's nucleotide sequence is to house 
the information necessary to produce a functional protein (with full atten- 
tion given to the relationship between amino acid sequence and function), 
the purpose of the antisense strand is to serve merely as a placeholder and 
a template for the sense strand. 

In light of this constraint, it's amazing to think that both sense and anti- 
sense sequences could simultaneously specify functional proteins under any 
circumstance. The sequence of the sense strand would have to be carefully 
written so the complementary sequence of the antisense strand could si- 
multaneously serve as a template for the sense strand and encode an amino 
acid sequence that could adopt a three-dimensional configuration useful 
for some cell function. The care, thought, and preplanning required for 
genes to overlap on opposite DNA strands point to the work of an awe- 
inspiring biochemical Calligrapher. 

DNA Is a Parity Code 

Biochemists have long wondered why the nucleobases adenine (A), gua- 
nine (G), thymine/uracil (T/U), and cytosine (C) were chosen to be part 
of DNAs and RNA's structural makeup. At least sixteen other nucleobases 
could have been selected. For example, experiments designed to simulate 
the conditions of prebiotic Earth have produced diaminopurine, xanthine, 

hypoxanthine, and diaminopyrimidine in addition to A, G, T/U, and C.,i 
From an evolutionary perspective, any of them could have found their way 

into DNAs structure. 

Recent work by a chemist from Trinity University (Dublin, Ireland) 
shines new light on this question. ; When adenine, guanine, thymine, 
and cytosine are incorporated into DNA, they impart the double helix 
with a unique structural property that causes the information to behave 
like a parity code. Computer scientists and engineers use parity codes to 
minimize errors in the transfer of information (see "Parity Codes," p. 159). 
None of the other nucleobases give DNA this special quality — only the 
specific combination of A, G, T, and C. 

Every time the cell's machinery transcribes a gene or replicates the DNA 
molecule (see chapter 11, p. 217), information is transmitted. Because 
transmission errors have disastrous consequences, error minimization (and 



The Artist's Handwriting i cq 



Parity Codes 

What is a parity code and liow does it detect errors tliat arise during information 
transfer? To answer tliese questions, some appreciation for tlie way scientists and 
engineers encode information is essential. 

Data commonly consists of numbers, alphabet letters, and special symbols. For 
computers and digital-data communication hardware to store, read, process, and 
transmit data, the characters must be represented as binary numbers. Onfy two digits 
exist in binary number systems, "1" and "0". (The decimal system uses ten digits — "0 
through 9" — to represent quantities.) Binary number systems ideally fit computers and 
digital-data communication hardware because an electrical pulse or signal corresponds 
to a 1, and the absence of any signal equates to 0. 

Combinations of on-off pulses can be used to represent decimals, letters, and 
special characters. Information technologists refer to a single on-off pulse as a binary 
digit or bit. Eight bits are a byte. 

Computers usually use either a 7-bit or 8-bit code to represent characters.,, These 
7- or 8-bit sequences are called data units. To detect errors that arise during transmis- 
sion an additional bit, called a parity bit, is added to the data units. 

The value of the parity bit is assigned either a 1 or a depending on if the error- 
detection scheme is an even or odd parity code. If even, then the value of the parity 
bit is chosen so the sum of the "mi" (1) bits equals an even number. If an odd parity 
code is employed then the value of the parity bit is selected so that the sum of the 
"on" bits equals an odd number (see table 8.2). 

Errors can occur during data transmission if a 1 is received as a 0, or vice versa. 
Mistakes can also occur if a bit is lost or dropped. When either problem happens, the 
sum of "on" bits yields an odd number for an even parity code, and an even number for 
an odd parity code. When an unexpected sum of "on" bits is tabulated, the transmis- 
sion's recipient immediately knows an error has occurred. 



Table 8.2 
Parity Bit Assignment 

8 Bit Data Unit Parity Bit 

Even OcJd 

OOOOOOOQ 000000000 100000000 

1 01 00001 11 01 00001 0-^ 01 00001 

1 101 0001 01 1 01 0001 11 1 01 0001 

11111111 011111111 111111111 



250 The Cell's Design 

consequently DNAs parity code) is a critical structure in the cell's infor- 
mation systems. 

When the two DNA strands align, the adenine side chains of one strand 
always pair with thymine side chains from the other strand. Likewise, gua- 
nine always pairs with cytosine. When these side chains pair, they form 
crossbridges between the two DNA strands (see figure 2.7, p. 49). The 
lengths ofthe A-to-T and G-to-C crossbridges are nearly identical. 

Adenine and guanine are both composed of two rings and thymine and 
cytosine are composed of one. Each crossbridge consists of three rings. 

When A pairs with T, two hydrogen bonds mediate their interaction. 
Three hydrogen bonds accommodate the interaction between G and C. 
The specificity ofthe hydrogen-bonding interactions accounts for the A- 
to-T and G-to-C base-pairing rules (see figure 8.3). 

As noted previously, these base-pairing rules establish the complementary 
relationship between the nucleotide sequences ofthe two DNA strands. 
These complementary sequences play an important role in the transmission 
of information during DNA replication (see chapter 1 1, p. 217). Likewise, 
the base-pairing rules play a critical role when the cell's machinery copies a 
gene. The nucleotide sequence ofthe resulting mRNA is complementary 
to the DNA sequence that harbors the gene. 

From time to time base-pairing mistakes can happen. When A-to-T and 
G-to-C don't properly pair, the wrong information is transmitted. Quality 
control systems in the cell check for errors that might occur during DNA 
replication and transcription (see chapter 10). 

In addition to these quality control systems, another error-detection 
system resides within the informational structure of DNA in the form of 
a parity code. 

Each hydrogen bond that links together A-to-T and G-to-C consists of 
donor chemical groups and acceptor groups. In the DNA informational 
system, if hydrogen bonds are considered analogous to an electrical pulse 
in binary number systems, then donor chemical groups can be assigned a 1 
and acceptor groups a 0. For example, G would be assigned the bits Oil and 
C, 100. The parity bits correspond to the ring structure of the nucleobase. 

If the nucleobase consists of a single ring, the parity bit is assigned a 1. 
When the nucleobase possesses two rings, the parity bit assumes a value 
of 0. The binary representation for G becomes 011,0 and for C it's 100,1. 
Note that the binary depiction for these nucleobases is an even parity code. 
This arrangement makes it easy to detect transmission errors. Relating the 



The Artist's Handwriting 



161 




Guanine 



Cytosine 




Adenine 



Figure 8.3. Base-Pairing Rules and the Even Parity Code of DNA 

When the two DNA strands align, the Guanine (G) side chains ofone strand always pair with 
Cytosine (C) side chains from the other strand. Likewise, the Adenine (A) side chains from 
one DNA strand always pair with Thymine (T) side chains from the other strand. When G 
pairs with C, three hydrogen bonds (shown as dashed lines) mediate the interaction between 
these two nucleobases. Two hydrogen bonds accommodate the interaction between A and T. 



ring structure to the hydrogen bonding patterns between the nucleobases 
results in an optimal genetic alphabet. 

This extraordinary structural property ofDNA suggests that a Mind 
carefully developed the cell's information systems. The even parity code 



252 The Cell's Design 

found in DN A is identical to those used in computer hardware and software 
systems to check for errors when data is transmitted. It's as if an Intelli- 
gent Agent hand-selected the nucleobases A, G, T/U, and C to optimize 
DNAs structure so errors can be readily detected and minimized when 
any information is transmitted. 

Biochemical information also displays other astounding structural char- 
acteristics that point to the calligraphy of a Divine Writer. For example, a 
cell's information systems are organized around a code. In fact, the so-called 
genetic code defines the cell's information at its most fundamental level. 
Recently, biochemists have discovered another code — the histone code — at 
work within the genomes ofeukaryotic organisms. 

The genetic and histone codes are the focus of the next chapter. But 
before they are discussed, some provocative advances in nanotechnology — 
advances inspired by biochemical information systems — deserve some 
attention. 



On the Technology Frontier 

Some scholars maintain that biochemical information is not, strictly 
speaking, information. Instead, they insist that treating the nucleotide se- 
quence of DN A and the amino acid sequence of proteins as information is 
simply a useful analogy. Rhetorician David Depew questions if evolutionary 
biologists Richard Dawkins and Daniel Dennet 

would be happy with [the] assumption that genes "contain" information in the 
same sense that modern computers do, or with the implication that organisms 
are merely their readouts? This analogy guided the formation of molecular biol- 
ogy. Like many analogies, it generated some good science, and more recently, a 
biotechnological revolution. But in singling out genes for causal efficacy at the 
expense of other epigenetic processes it created a scientific myth..,. 

According to these skeptics, application of information theory to prob- 
lems in molecular biology is predicated on an analogy (albeit a useful one) 
between biochemical systems, human language, and information schemes. 
If taken too far, however, this analogy breaks down to the detriment of 
science and, in this case, the biochemical intelligent design analogy. 

But exciting new nano- and biotechnologies — such as DNA comput- 
ing, DNA encryption, and DNA bar coding — provide justification for the 



The Artist's Handwriting 1 f^'l 

biochemical intelligence argument. These emerging technologies reinforce 
the notion that biochemical information is indeed information. Their ap- 
plications make use of data housed in DNA in much the same way that 
humans would handle information. 

DNA Computing 

At a fundamental level, all computer operations are based on so-called 
Turing machines, named for British mathematician Alan Turing. These 
machines are not real but conceptual in nature. They consist of three com- 
ponents: input, output, and finite control. The input is a stream of data read 
and transformed by the finite control according to a specific set of rules. A 
new stream of data results from this transformation, the output. 

Input and output data streams consist ofsequences of characters called 
strings. The finite control operates one by one on each character of the input 
string to generate the output string. These transformations are relatively 
simple in nature. Complex computations and operations can be affected 
by linking together several Turing machines, so the output string of one 
Turing machine becomes the input string of another. 

DNA computing had its birth when computer scientist Leonard Adle- 
man recognized that the proteins responsible for DNA replication, repair, 
and transcription operated as Turing machines.,. This process treats the 
nucleotide sequences of DNA as input and output strings. The different 
chemical, biochemical, and physical processes used to manipulate DNA in 
the laboratory correspond to the finite control and are used to transform 
the input DNA sequences into output sequences. Complex operations 
can be accomplished by linking together simple laboratory operations 
performed on DNA with the output ofone laboratory operation serving 
as input for the next. 

Some operations that can be performed on DNA "strings" include: 
separating and fusing strands of the DNA double helix; lengthening and 
shortening individual DNA strands; cutting and linking together DNA 
molecules; and modifying, multiplying, and reading the DNA nucleotide 
sequence. 

Researchers recognize several advantages to DNA computers. > One 
is the ability to perform a massive number of operations at the same time 
(in parallel) as opposed to one at a time (serially) which is typically much 
slower. Second, DNA has the capacity to store an enormous quantity of 



1 ^4 The Cell's Design 

information. Theoretically one gram of DNA can house as much informa- 
tion as nearly one trillion CDs. And DNA computers operate, in principle, 
near theoretical capacities with regard to energy efficiency. 

The current limitations of DNA computers stem from the chemical 
nature of the process, namely the inherent incompleteness of chemical 
reactions and the error prone nature of the biomolecules that operate on 
DNA.,, (As discussed in chapter 10, biochemical processes inside test tubes 
are error prone. Inside the cell, however, "quality control" pathways correct 
most of these errors when they occur.) Much of the current research effort 
in DNA computing focuses on overcoming its limitations., 

In spite of these difficulties, researchers have already successfully dem- 
onstrated a number of applications for DNA computing. This list includes 
solving directed Hamiltonian-path problems and the knight problem (for 
a 3 X 3 chessboard)., DNA computing has also been used to perform ad- 
dition (see "Turing Machines and the Watchmaker Analogy" below).,. 

These efforts drive home the point that biochemical systems contain 
information. It's mind-boggling to think that the information-based ac- 
tivities of biochemical systems, which routinely take place in the cell, can 
be used to construct computers in a laboratory setting. The direct corre- 
spondence between input and output strings with DNA sequences makes 

Turing Machines and the Watchmaker Analogy 

Li 1994 Leonard Adleman launched UNA computing when he recognized that the cel- 
lular processes operating on ENA functioned as l\irlng machines.,. These machines 
exist only as conceptual entities. 

In the mld-1930s, Alan Turing, one of the founders of modem computer science, 
recognized that the key to solving complex problems computationally was to treat them 
as a series of simple operations.,, Each operation has an Input, a string of numbers or 
characters, operated on by a finite control that alters the Input to produce an output 
string. The ensemble Is referred to as a Turing machine. The output of the first opera- 
tion becomes the Input of the second operation and so on. 

The key point is that Turing machines exist only In human minds, yet Inside the 
cell several actual Turing machines operate on UVA This reality provides a double 
analogy for intelligent design. Not only do biochemical Turing machines highlight the 
informational aspects of OVA, but they also serve as a remarkably profound type of 
Watchmaker analogy (see chapter 4, p. 85) — except, the analogy is between the 
conceptual Turing machines In the human mind and the concrete biochemical Turing 
machines Inside the cell. 



The Artist's Handwriting 165 

it clear that DNA is at its essence information, contrary to what skeptics 
say. Molecular-level computers have long been the dream of scientists and 
engineers because this technology promises large storage capacity, small 
size, and high speed. By making use of the cell's information systems to 
build DNA computers, this dream is becoming a reality. 

DNA Encryption 

During World War II, German spies hid messages as shrunken micro- 
dots in what appeared to be harmless letters. They used a technique called 
steganography — the practice of hiding a message within a message. 

Taking their cue, researchers recently invented DNA steganography, in 
which encrypted messages are embedded within DNA sequences. 4s The 
genetic letters (nucleotides) of DNA formulate a message in much the same 
way the letters of the German alphabet did on a shrunken microdot. 

The complex nature of DNA sequences prevents anyone who intercepts 
the DNA encryption from recognizing that a message is present, let alone 
being able to decode it. To make it possible for the recipient to identify and 
extract the message, the sender bookends it with specific DNA markers. 
These marker sequences allow the recipient to "fish out" the encryption 
and read the message using laboratory techniques. As with DNA comput- 
ing, DNA steganography highlights the notion that DNA is indeed an 
information-rich molecule. 

DNA Bar Codes 

Supermarkets and department stores often use bar codes to facilitate 
the checkout process. Bar codes present information a computer can scan 
to rapidly determine the price of items while simultaneously monitoring 
the store's inventory. 

Scientists are currently exploring the bar code concept as a way to identify 
and track species. DNA bar codes consist of relatively short standardized 
segments of DNA within the genome unique to a particular species or 
subspecies in some cases. Biologists have successfully demonstrated that 
DNA bar codes can be used to identify butterfly, fly, bird, plant, and fungus 

46 

species. 

Other applications have been suggested. One proposal suggests using 
short synthetic pieces ofDNA incorporated into genes as a bar code that 



2gg The Cell's Design 

allows them to be quickly identified in laboratory experiments.,. This ap- 
plication differs from species identification. While DNA bar codes used 
to identify species are naturally part of an organism's genome, scientists 
use other types of bar codes to track genes. These man-made bar codes are 
intentionally incorporated into genes by researchers. These synthetic bar 
codes are much more like the ones used to price items at a supermarket 
checkout. 

The use of DNA as bar codes, again, underscores the informational con- 
tent of these molecules. DNA computing, steganography, and bar coding 
all make it clear that treating biochemical information as information goes 
well beyond a helpful analogy. It is indeed information. 

The Writing on the Wall 

Human experience consistently teaches that information emanates from 
intelligence. Whether written in plain or elegant scripts, messages initiate 
in a mind. In whatever form information takes, it's not limited to commu- 
nicating ideas, needs, and desires between human minds. Information has 
become an integral part of modern technology. Designers and engineers 
routinely develop and refine information systems. Computer technologies, 
among many other developing innovations, fundamentally depend upon 
such constructs. 

Over the last forty years, biochemists have come to recognize that the 
cell's biochemical systems are also, at their essence, information-based. 
Proteins, DNA, and even oligosaccharides are information-rich molecules. 
By analogy, these discoveries reinforce the biochemical design argument. 

It's not the mere presence of information that motivates the case; it's 
the structure of the information housed in proteins and DNA. The direct 
analogy between the architecture of human language and the makeup 
of biochemical systems is startling. Equally provocative is the syntactic, 
semantic, and pragmatic dimensions of biochemical information that, 
likewise, correspond to information generated and used by humans in their 
day-to-day communications and technologies. 

The structural elegance of biochemical information also points to the 
molecular calligraphy penned by a Creator's hand. An awe-inspiring orga- 
nization of genes in prokaryotes (operons) and eukaryotes (head-to-head 
orientation of genes, alternate splicing of genes, and overlapping genes) 



The Artist's Handwriting 167 

supplies powerful evidence of a deliberate purpose. This structural arrange- 
ment contains remarkably sophisticated embellishments and in many cases 
displays a brilliant logic that relates to functional expression. And, in the 
case of alternately spliced and overlapping genes, it's difficult to envision 
how these systems could have originated apart from the meticulous effort 
of a superior Intelligence. 

Random Letters 

The evolutionary paradigm currently struggles to account for the vast 
amount and complexity of biochemical information. Based on current 
understanding, information-rich molecules can't be assembled by chance 
processes. And, chemical selection doesn't seem potent enough (as pres- 
ently conceived) to bridge the gap between a random mixture of free amino 
acids and even a single functioning polypeptide, let alone the ensemble of 
proteins needed for life to exist in its most minimal form. 

Astronomer Hugh Ross and I describe the difficulties evolutionary 
models face in trying to explain the origin of biochemical information in 
our book Origins of Life. t. Although evolutionary biologists hope that a 
better understanding of the relationship between amino acid sequence and 
protein structure and function will rescue them from this plight, there is 
no real reason to think that will happen. 

In the face of these concerns, some skeptics assert that application of 
information theory to problems in molecular biology is merely a helpful 
analogy between biochemical systems and human language. If taken too 
far, however, they claim this analogy breaks down. 

Complete Sentences 

Yet, the assertion that biochemical information is not really information 
loses potency when new information-based nano- and biotechnologies — 
like DN A computing, encryption, and bar coding — are considered. These 
astounding advances profoundly justify the analogy between human lan- 
guage (and information) and biochemical information. 

It's no less provocative to think that the cell's systems actually inspired 
DNA computing. Leonard Adleman, the father of DN A computing, rec- 
ognized that biochemical information is processed using biomolecular 
Turing machines. For computer applications, Turing machines exist only 



25§ The Cell's Design 

in human minds. In the cell, Turing machines are a reality and the means 
to carry out operations in DNA-based computers. 

Perhaps the most remarkable aspect of the cell's information systems is 
the presence of an even parity code within the structural makeup of DNA. 
The parity code found in DNA directly corresponds to the parity codes 
used by computer scientists to minimize error during the transmission 
of information. DNA's parity code functions in the same way, making it 
possible for the cell's machinery to recognize when an error has occurred 
as biochemical information is being replicated or transcribed. 

This parity code is only possible if the nucleobases adenine, guanine, 
thymine (uracil), and cytosine are part of its structure. They seem to have 
been hand-selected, and DNA's structure appears to have been deliberately 
optimized to minimize transmission errors (see chapter 7, p. 134). If DNA 
was assembled with any other nucleobases, its parity code would be lost. 

The presence and structural arrangement of information add to the 
intelligent design analogy. Biochemical systems are irreducibly complex, 
finely tuned, optimized, and information-based in ways that far surpass the 
capabilities of the best human designers. Chemically based information 
systems in the cell make the elegant and stylized flourishes of the divine 
Calligrapher's pen unmistakable. 

The next chapter continues to probe the structural makeup of biochemi- 
cal information by focusing on the genetic and histone codes. These two 
aspects of the cell's information systems add even more to the weight of 
evidence for biochemical design. 



CELLULAR SYMBOLISM 



Artists routinely use symbols to represent emotions, ideas, events, and 
people. This practice appears to have reached its pinnacle with the Sym- 
bolism of the nineteenth century., As much a philosophy and ideology 
as a school of art. Symbolism was a reaction to naturalism and realism. 
The movement emerged in France and spread throughout Europe and 
beyond. 

Symbolist painters used spiritual themes, the imagination, and dreams to 
communicate what they considered truth. Scenes from nature and human 
experience depicted in esoteric and suggestive ways contained allegorical 
meaning. However, the more familiar emblems of mainstream iconography 
were avoided. Instead, Symbolists used obscure and ambiguous images that 
frequently held personal meaning. 

Whether in an art movement or in common everyday experience, the use 
of symbols involves a type of pictorial code — one that harbors significance 
and provides a vehicle to communicate ideas. Art uses symbols that may 
indicate different things to different people. But reliable communication 
requires the sender and recipient to agree upon a predetermined under- 
standing. This agreement constitutes a code, a set of rules that converts 
information from one form to another.. 



169 



270 The Cell's Design 

Codes can be used when the normal means of communication using or- 
dinary language becomes difficult or impossible. They can also be employed 
for the sake of brevity. Cable codes (like the Morse code), for instance, 
convert words into shorter "dashes and dots" that allow information to 
be sent more quickly and less expensively. 

Sometimes the converted information takes on a different form. For 
example, semaphore flags transmit instructions as a signaler uses a set of 
rules to transform letters and numbers into flag-waving patterns. 

Codes are not limited to art symbols or the various conventions used by 
humans to communicate under difficult circumstances. Biochemists have 
discovered a type of symbolism inside the cell in the form of biochemical 
codes. The genetic code — a set of rules that relays the information stored in 
the nucleotide sequences of DNA to the amino acid sequences of proteins — 
is the heart of the cell's information system (see chapter 8, p. 142). 

In one of the most significant scientific landmarks in human history, 
three biochemists — Har Gobind Khorana, Robert W. Holley, and Mar- 
shall Warren Nirenberg — deciphered this code. They won the 1968 Nobel 
Prize in Physiology or Medicine for their tremendous accomplishment. 
The discovery of the genetic code represents far more than an important 
scientific milestone. It is one of the most potent evidences for biochemical 
intelligent design. The following parable shows why. 

A Rational Response 

A pilot/lying his plane over the South Pacific sees an uncharted island in 
the distance. Deciding to explore, the pilot spirals the plane downward to take 
a closer look. As the plane descends, he spots large rocks on the island's shore 
arranged to spell SOS. The pilot then sees a grass hut locatedfarther down the 
beach. Even before he sees the footprints in the sand, the pilot reaches for the 
transmitter and radios for help. 

Though SOS is not a word, most would agree that the pilot's plea was 
rational. He easily recognized the universal distress message. The pilot knew 
the improbability of wind and waves acting on the rocks along the shore 
to form the right letters., More importantly, based on experience, the pilot 
understood that the carefully arranged stones communicated meaningful 
information — they were a code that required an intelligent agent s design 
and implementation. The island s inhabitant spelled out SOS on the shore 



Cellular Svmbolism 



171 



with the hope that whoever saw the intentionally placed rocks would know 
what he meant. 

That same type of evidence has been discovered inside the cell (see chap- 
ter 8). Biochemical machinery is, at essence, information-based. And, the 
chemical information in the cell is encoded using symbols. 

By itself, this information offers powerful evidence for an Intelligent 
Designer. But, recent discoveries go one step further. Molecular biologists 
studying the genetic code's origin have unwittingly stumbled across a "grass 
hut" in what may be the most profound evidence for intelligent activity — a 
type of fine-tuning in the code's rules. Just as the hut on the beach helped 
convince the pilot that someone was using carefully placed rocks to signal 
for help, the precision of the code adds confirmatory evidence that a mind 
programmed life's genetic code. 

The genetic code's carefully crafted rules supply it with a surprising ca- 
pacity to minimize errors. These error-minimization properties allow the 
cell's biochemical information systems to make mistakes and 5ft7/ commu- 
nicate critical information with high fidelity. It's as if the stranded island 
inhabitant could arrange the rocks in any three letter combination and still 
communicate his desperate plight. 



A Genetic SOS 

At first glance, there appears to be a mismatch between the storage 
and functional expression of information in the cell. Clearly a one-to- 
one relationship cannot exist between the four different nucleotides 
of DNA and the twenty different amino acids used to assemble poly- 
peptides. The cell's machinery compensates for this mismatch by using 
groupings comprised of three nucleotides (codons) to specify the twenty 
amino acids.' 

The cell uses a set of rules — the genetic code — to relate these nucleotide 
triplet sequences to the twenty amino acids used to make polypeptides. 
Codons represent the fundamental coding units. In the same way the 
stranded islander used three letters (SOS) to communicate, the genetic 
code uses three nucleotide "characters" to signify an amino acid. 

For all intents and purposes, the genetic code is universal among all living 
organisms. It consists of sixty-four codons. Because the genetic code only 
needs to encode twenty amino acids, some of the codons are redundant. 



272 The Cell's Design 

Different codons can code for the same amino acid. In fact, up to six dif- 
ferent codons specify some amino acids. A single codon specifies others. 
Table 9.1 describes the universal genetic code. It is presented in the 
conventional way, according to how the information apoears in mRNA 
molecules after the information stored in DNA is transcribed. (In RNA 
uracil [U] is used instead of thymine [T].) 

Table 9.1 
The Genetic Code 



5' End 


U 




C 




A 




G 




U 


uuu 


Phe 


ucu 


Ser 


UAU 


Tyr 


UGU 


Cys 




UU£ 


Phe 


ucc 


Ser 


UAC 


Tyr 


UGC 


Cys 




UUA 


Leu 


UCA 


Ser 


UAA 


End 


UGA 


End 




UUG 


Leu 


UCG 


Ser 


UAG 


End 


U6G 


Trp 


C 


CUU 


Leu 


ecu 


Pro 


CAU 


His 


C6U 


Arg 




cue 


Leu 


CCC 


Pro 


CAC 


His 


CGC 


Arg 




CUA 


Leu 


CCA 


Pro 


CAA 


Gin 


CGA 


Arg 




CUG 


Leu 


CCG 


Pro 


CA6 


Gin 


CGe 


Arg 


A 


AUU 


lie 


ACU 


Thf 


AAU 


Asn 


AGU 


Ser 




AUG 


He 


ACC 


Thr 


AAC 


Asn 


AGC 


Ser 




AUA 


lie 


ACA 


Thr 


AAA 


Ly$ 


AGA 


Arg 




AUG 


Met(Start) 


ACG 


Thr 


AAG 


Lys 


AGG 


Arg 


G 


6UU 


Val 


GCU 


Ala 


GAU 


Asp 


GGU 


Gly 




GUC 


Val 


GCC 


Ala 


GAC 


Asp 


GGC 


Gly 




GUA 


Val 


GCA 


Ala 


GAA 


Glu 


GGA 


Gly 




GUG 


Val(Start) 


GOG 


Ala 


GAG 


Glu 


GGG 


Gly 



The first nucleotide of the coding triplet begins at what biochemists call 
the 5' end ofthe sequence (see chapter 2, p. 48). Each nucleotide in the 
codons first position (5' end) can be read from the left-most column, and 
the nucleotide in the second position can be read from the row across the 
top of the table. The nucleotide in each codon's third position (the 3' end) 
can be read within each box. For example, the two codons, 5' UUU and 5' 
UUC, that specify phenylalanine (abbreviated Phe) are listed in the box 
located at the top left corner ofthe table. 

Interestingly, some codons (stop or nonsense codons) don't specify any 
amino acids. They always occur at the end of the gene informing the protein 
manufacturing machinery where the polypeptide chain ends. Stop codons 



Cellular Symbolism 



173 



serve as a form of "punctuation" for the cell's information system. (For 
example, UGA is a stop codon.) 

Some coding triplets (start codons) play a dual role in the genetic code. 
These codons not only encode amino acids but also "tell" the cell where a 
polypeptide begins. For example, the codon GUG not only encodes the 
amino acid valine, it also specifies the beginning of a polypeptide chain. 
Start codons function as a sort of "capitalization" for the information sys- 
tem ofthe cell. 

The information content of DNA and proteins — the molecules that 
ultimately define life's most fundamental structures and processes — leads 
to the conclusion that an Intelligent Designer must have been responsible 
for biochemical systems (see chapter 8). The existence of the genetic code 
makes this conclusion as rational as the pilot's actions when he radioed for 
a rescue team after spotting the message on the beach. 

A Biochemical Grass Hut 

The structure of rules for the genetic code reveals even further evidence 
that it stems from a Creator. A capacity to resist the errors that naturally 
occur as a cell uses or transmits information from one generation to the 
next is built into the code. Recent studies employing methods to quantify 
the genetic code's error-minimization properties indicate that the genetic 
code's rules have been carefully chosen and finely tuned. 

The Potential to Be Washed Away 

Why does the genetic code's error-minimization capacity provide such 
a powerful indicator for intelligent design? Translating the stored infor- 
mation ofDNA into the functional information ofproteins is the code's 
chief function. Error minimization, therefore, measures the capability of 
the genetic code to execute its function. 

The failure ofthe genetic code to transmit and translate information 
with high fidelity can be devastating to the cell. A brief explanation ofthe 
effect mutations have on the cell shows the problem. A mutation refers to 
any change that takes place in the DNA nucleotide sequence. s 

Several different types of changes to DNA sequences can occur with sub- 
stitution mutations being the most frequent. As a result of these mutations. 



274 The Cell's Design 

a nucleotide(s) in the DNA strand is replaced by another nucleotide(s). 
For example, an A may be replaced by a G or a C with a T. When substitu- 
tions occur, they alter the codon that houses the substituted nucleotide. 
And if the codon changes, then the amino acid specified by that codon 
also changes, altering the amino acid sequence of the polypeptide chain 
specified by the mutated gene. 

This mutation can then lead to a distorted chemical and physical profile 
along the polypeptide chain. If the substituted amino acid has dramatically 
different physicochemical properties from the native amino acid, then the 
polypeptide folds improperly. An improperly folded protein has reduced or 
even lost function. Mutations can be deleterious because they hold the poten- 
tial to significantly and negatively impact protein structure and function. 

Taking a Closer Look 

Simple inspection shows that the genetic code's redundancy is not haphaz- 
ard but carefully thought out — even more so than a grass hut built beyond 
the reach of the waves. Deliberate rules were set up to protect the cell from 
the harmful effects of substitution mutations. For example, six codons en- 
code the amino acid leucine (Leu). If at a particular amino acid position in 
a polypeptide. Leu is encoded by 5'CUU, substitution mutations in the 3' 
position from U to C, A, or G produce three new codons — 5'CUC, 5'CUA, 
and 5'CUG, respectively — all of which code for Leu (see table 9.1). 

The net effect leaves the amino acid sequence of the polypeptide un- 
changed. And, the cell successfully avoids the negative effects of a substi- 
tution mutation. 

Likewise, a change of C in the 5' position to a U generates a new codon, 
5'UUU, which specifies phenylalanine, an amino acid with physical and 
chemical properties similar to Leu. Changing C to an A or a G produces 
codons that code for isoleucine and valine, respectively. These two amino 
acids possess chemical and physical properties similar to leucine. Qualita- 
tively, it appears as if the genetic code has been constructed to minimize 
the errors that could result from substitution mutations. 

Calling in the Coordinates 

Recently, scientists have worked to quantitatively evaluate the error- 
minimization capacity of the genetic code. One of the first studies to 



Cellular Symbolism 



175 



perform this analysis indicated that the universal genetic code found in 
nature could withstand the potentially harmful effects of substitution 
mutations better than all but 0.02 percent (1 out of 5,000) of randomly 
generated genetic codes with different codon assignments than the one 
found throughout nature.. 

This initial work, however, did not take into account the fact that some 
types of substitution mutations occur more frequently in nature than oth- 
ers. For example, an A-to-G substitution occurs more often than either an 
A-to-C or an A-to-T mutation. When researchers incorporated this correc- 
tion into their analysis, they discovered that the naturally occurring genetic 
code performed better than one million randomly generated genetic codes 
and that the genetic code in nature resides near the global optimum for 

all possible genetic codes with respect to its error-minimization capacity. 
Nature's universal genetic code is truly one in a million! 

The genetic code's error-minimization properties are far more dramatic 
than these results indicate. When the researchers calculated the error- 
minimization capacity of the one million randomly generated genetic codes, 
they discovered that the error-minimization values formed a distribution 
with the naturally occurring genetic code lying outside the distribution 
(see figure 9.1). Researchers estimate the existence of 10 possible genetic 
codes possessing the same type and degree of redundancy as the universal 
genetic code. All of these codes fall within the error-minimization dis- 
tribution. This means of 10 possible genetic codes few, if any, have an 
error-minimization capacity that approaches the code found universally 
throughout nature. 

Out of Harm 's Way 

Some researchers have challenged the optimality of the genetic code. But, 
the scientists who discovered the remarkable error-minimization capacity of 
the genetic code have concluded that the rules of the genetic code cannot 
be accidental. A genetic code assembled through random biochemical 
events could not possess near ideal error-minimization properties. 
* Researchers argue that a force shaped the genetic code. Instead of looking 
to an intentional Programmer, these scientists appeal to natural selection. 
That is, they believe random events operated on by the forces of natural se- 
lection over and over again produced the genetic code's error-minimization 
capacity., 



176 



The Cell's Design 



25,000 H 




OvOrMCOTjo'^rNcq ■CTofloVCPi-Af'^ co'^-qvOfNco'^ 



Figure 9.1. Error Minimization Capacity of tlie Genetic Code 

This plot compares the error minimization capacity ofthe universal genetic code found 
in nature with one million random genetic codes. The horizontal axis describes the error- 
minimization capacity ofthe code with lower values corresponding to greater capacity to 
withstand error. The vertical axis describes the number of codes. The bell curve represents the 
distribution of error-minimization values for the randomly generated genetic codes. 



Natural Forces at Work 



Even though some researchers think natural selection shaped the genetic 
code, other scientific work questions the likelihood that the genetic code 
could evolve. In 1968, Nobel laureate Francis Crick argued that the genetic 
code could not undergo significant evolution. i= His rationale is easy to 
understand. Any change in codon assignments would lead to changes in 
amino acids in every polypeptide made by the cell. 

This wholesale change in polypeptide sequences would result in a large 
number of defective proteins. Nearly any conceivable change to the genetic 
code would be lethal to the cell. 

The scientists who suggest that natural selection shaped the genetic code are 
fully aware of Crick's work. Still they rely on evolution to explain the code's 



Cellular Svmbolism 



177 



optimal design because of the existence of nonuniversal genetic codes. While 
the genetic code in nature is generally regarded as universal, some nonuniversal 
genetic codes exist — codes that employ slightly different co don assignments. 
Presumably, these nonuniversal codes evolved from the universal genetic code. 
Therefore, researchers argue that such evolution is possible. 

But, the codon assignments of the nonuniversal genetic codes are nearly 
identical to those of the universal genetic code with only one or two ex- 
ceptions. Nonuniversal genetic codes can be thought of as deviants ofthe 
universal genetic code. 

Does the existence of nonuniversal codes imply that wholesale genetic 
code evolution is possible? Careful study reveals that codon changes in the 
nonuniversal genetic codes always occur in relatively small genomes, such 
as those in mitochondria. These changes involve (1) codons that occur at 
low frequencies in that particular genome or (2) stop codons. 

Changes in assignment for these codons could occur without producing 

a lethal scenario because only a small number of polypeptides in the cell or 

organelle would experience an altered amino acid sequence. So it seems limited 

evolution of the genetic code can take place, but only in special circumstances.,, 
The existence of nonuniversal genetic codes does not necessarily justify an 

evolutionary origin of the amazingly optimal genetic code found in nature. 

Is a Timely Rescue Possible? 

Even if the genetic code could change over time to yield a set of rules that 
allowed for the best possible error-minimization capacity, is there enough 
time for this process to occur? 

Biophysicist Hubert Yockey addressed this question. He determined 
that natural selection would have to explore 1.40 x 10 different genetic 
codes to discover the universal genetic code found in nature. The maximum 
time available for it to originate was estimated at 6.3 x 10, seconds. Natural 
selection would have to evaluate roughly 10 codes per second lo find the 
one that's universal. Put simply, natural selection lacks the time necessary 
to find the universal genetic code. 

Other work places the genetic code's origin coincidental with life's start. 
Operating within the evolutionary paradigm, a team headed by renowned 
origin-of-life researcher Manfred Eigen estimated the age ofthe genetic 
code at 3.8 + 0.6 billion years. ■ Current geochemical evidence places life's 
first appearance on Earth at 3.86 billion years ago. This timing means that 



278 The Cell's Design 

the genetic code's origin coincides with life's start on Earth. It appears as 
if the genetic code came out of nowhere, without any time to search out 
the best option. 

In thefaceof these types of problems, some scientists suggest that the genetic 
code found in nature emerged from a simpler code that employed codons 
consisting of one or two nucleotides.,, Over time, these simpler genetic codes 
expanded to eventually yield the universal genetic code based on coding triplets. 
The number of possible genetic codes based on one or two nucleotide codons 
is far fewer than for codes based on coding triplets. This scenario makes code 
evolution much more likely from a naturalistic standpoint. 

One complicating factor for these proposals arises, however, from the 
fact that simpler genetic codes cannot specify twenty different amino acids. 
Rather, they are limited to sixteen at most. Such a scenario would mean that 
the first life-forms had to make use of proteins that consisted of no more 
than sixteen different amino acids. Interestingly, some proteins found in 
nature, such as ferredoxins, are produced with only thirteen amino acids. 
On the surface, this observation seems to square with the idea that the 
genetic code found in nature arose from a simpler code. 

Yet, proteins like the ferredoxins are atypical. Most proteins require all 
twenty amino acids. This requirement, coupled with recent recognition 
that life in its most minimal form needs several hundred proteins (see 
chapter 3), makes these types of models for code evolution speculative at 
best. The optimal nature of the genetic code and the difficulty account- 
ing for the code's origin from an evolutionary perspective work together 
to support the conclusion that an Intelligent Designer programmed the 
genetic code, and hence, life. 



Histone's Footprints 

Biochemists have recently discovered another code associated with DN A 
that overlaps the genetic code and plays a key role in gene expression. The 
rules that define this overlying code are manifested through interactions 
between DNA and the DNA-binding proteins known as histones. 

These globular-shaped proteins organize DNA into chromosomes (see 
chapter 2, p. 51). In eukaryotes, the DNA molecules found inside the cell's 
nucleus exist in the form of chromosomes. Each of these highly condensed 
structures consists of one molecule of DNA associated with a larger number 



Cellular Svmbolisni 



179 



ofhistone proteins. Histones bind to the DNA at regular intervals along 
the length of the double helix. 

Biochemists have identified five different histone proteins — referred to 
as HI, H2A, H2B, H3, and H4. ,. Two copies each of the histones H2A, 
H2B, H3, and H4 interact to form a disk-shaped complex composed of 
eight protein subunits (an octamer; see figure 9.2). This octamer complex 
is also known as the histone core. 



.^m Histone proteins 




Nucleosome 



Figure 9.2. The Histone Octamer 

Histones bind to the DNA at regular intervals 
along the length ofthe double helix. Biochemists 
have identified five different histone proteins, 
referred to as HI, H2A, H2B, H3, and H4. Two 
copies each ofthe histones H2A, H2B, H3, 
and H4 interact to form a disk-shaped complex 
composed of eight protein subunits called the 
histone core. Histone HI binds in the linker 
region between the histone octamers. 



2gQ The Cell's Design 

At each histone-binding site, the DN A double helix winds around the 
histone core, sort of like a thread around a spool. Unlike that thread, how- 
ever, that seems to wind around the spool an endless number of times, the 
DN A strand wraps around the core only about two-and-one-half full turns. 
These turns consist of a sequence of about 150 nucleotides. 

The complex between the DNA double helix and the histone octamer 
is a nucleosome (see chapter 2, p. 51). Nucleosomes form the fundamental 
organizing structure of chromosomes. For each chromosome, nucleosomes 
occur repeatedly along the length ofthe DNA molecule to form a supra- 
molecular structure that resembles a string of beads when viewed with an 
electron microscope. A piece of linker DNA, which varies between about 
fifteen and fifty-five nucleotides in length, connects the nucleosomes to 
each other. 

In turn, the nucleosomes interact with one another by coiling the "beaded 
necklace" to form a solenoid. Histone HI mediates the interactions between 
the nucleosomes to assemble the solenoid, which further condenses to form 
higher order structures that comprise the chromosome proper. 

The association of DNA with histones plays an important role in regu- 
lating gene activity and other important processes like DNA repair. When 
the DNA double helix wraps around the histone core, the cells biochemi- 
cal machinery can't physically get to the genes, blocking transcription, for 
example. 2,1 

It's critical that the initiation sites for transcription (promoter sites) reside 
in the linker regions away from the nucleosomes, so that proteins like RNA 
polymerase can bind to these DNA regions (see chapters 7, p. 135, and 8, 
p. 148). Recent studies on the yeast genome indicate that this organization 
is often the case with nucleosomes positioned to render promoter DNA 
sequences readily accessible in linker DNA regions. The careful position- 
ing of nucleosomes along the DNA molecule typifies the elegant structural 
and functional logic that pervades many ofthe cell's biochemical systems. 
And this elegance points to the intentional handiwork of a Creator. 

So, too, does another study. Researchers from The Weizmann Institute 
of Science (Israel) demonstrated that histones prefer to bind to specific 
nucleotide sequences.;. These sequences impart the DNA double helix with 
the propensity to bend. This useful property allows the DNA molecule to 
wrap around the histone core. 

Most importantly, the research team demonstrated that the sequence 
specificity of histone binding to DNA constitutes a code within the genome 



Cellular Symbolism 



181 



that dictates the precise positioning of nucleosomes along the DNA mol- 
ecule. The nucleosome-positioning codes repeat every ten nucleotides along 
the DNA double helix at the binding site for the histone core. Using this 
newly discovered code, the scientists from The Weizmann Institute could 
successfully predict the location of nucleosomes along the length of a DNA 
molecule. 

As with the genetic code, the histone-positioning code suggests the 
work of an Intelligent Programmer. A code must be deliberately designed. 
Even more remarkable is the requirement for the genetic and the histone- 
positioning codes to work in concert with one another. The histone- 
positioning code overlays the genetic code. These two codes must establish 
the relationship between the nucleotide sequences of DNA and the amino 
acid sequences of proteins. At the same time they must precisely position 
nucleosomes to ensure the proper expression of the information defined 
by the genetic code. 

Foresight and careful planning (the work of an Intelligent Agent) are 
necessary to get these two codes to work together. If haphazardly con- 
structed, they could easily conflict, disrupting key processes within the 
cell. Remarkably, the universal genetic code is constructed to harbor over- 
lapping or parallel codes better than the vast majority of other possible 
genetic codes. =, 

Grasping tlie Meaning 

Great artists often use symbolism to communicate with efficiency and 
effectiveness. When scrutinized their works often contain messages beyond 
the obvious that give their works added significance and make them a source 
of genuine and personal satisfaction. 

Sometimes human beings take symbolism a step further and design codes 
to convey their messages. Such codes require a programmer to establish 
rules that relate one form of information to another. Life carries that type 
of code — the genetic code. Its set of rules relate the information stored in 
the nucleotide sequences of DNA to the amino acid sequences of proteins, 
and thus, it forms the heart of the cell's information system. 

The recent recognition that the genetic code possesses a unique capac- 
ity to resist errors caused by mutation imparts the biochemical intelligent 
design argument with an entirely new level of credibility. Like a giant SOS 



2§2 The Cell's Design 

shaped with letters ablaze, the optimal nature of the genetic code signals 
that an Intelligent Agent used those rules to start and sustain life. 

The fine-tuning that minimizes the likelihood of error indicates that 
the genetic code cannot be just an accident — happened upon by random 
biochemical events — nor is it likely the product of undirected evolutionary* 
processes. Genetic code evolution would be catastrophic for the cell. 

Remarkably, the genetic code originated at the time when life first ap- 
peared on Earth. And, it must have been deliberately programmed. No 
matter how much time there might have been, the code's complexity makes 
it virtually impossible that natural selection could have stumbled upon it by 
accident. Such elaborate rules require forethought and painstaking effort. 
The message they carry adds an important piece to the analogy that logically 
compels a Creator's existence and role in life's origin and history. 

Chapter 10 reveals even more of the quality control efforts that went 
into life's design. 



10 



TOTAL QUALITY 



Many art aficionados would love to own a masterpiece, but only a select 
few have the means to privately enjoy such treasures. Cost simply prohibits 
most people from being able to afford them. 

And yet, reproductions make these paintings widely accessible to millions 
of people. Through facsimiles — schools, libraries, museums, and individual 
collectors can procure images of the world's best artwork at a reasonable 
cost. Everyone benefits. 

Fine art reproductions are manufactured in different ways. Expert artists 
trained in specific art movements, genres, and styles re-create desired mas- 
terpieces by hand. But, this technique is time consuming and expensive. And 
the reproductions are never an exact match. Still, many prefer these copies 
over other types, such as prints that have a more artificial appearance. 

Recent innovations in camera, scanner, software, and ink technologies 
have overcome most of the problems, however. Giclee (a French term pro- 
nounced zhee-CLAY) reproductions have made fine art far more available. 
In this process, a high-resolution printer transfers a digital image onto a 

canvas or fine art paper. Many connoisseurs are attracted to these prints 
because the digital image captures every nuance of the original including 
the most subtle details oflighting, shadowing, and texture. 

183 



2 §4 The Cell's Design 

The resolution exceeds that of traditional lithographs. And, giclee re- 
creations are relatively inexpensive even in small quantities. Such advan- 
tages have helped make these prints well-established fixtures in the fine 
art community. 

A reproduction is only valuable, however, when it's virtually indistin- 
guishable from the original. This requirement makes quality control steps 
an instrumental part of the manufacturing process — whether a piece is 
reproduced by an expert artist or sophisticated technology. Before a mu- 
seum accepts a giclee re-creation, it must go through a rigorous quality 
assurance process. 

After a digital image captures the masterpiece, the reproduction under- 
goes a proofing procedure to ensure that all aspects of the image (color, 
detail, brightness, contrast, brush strokes, texture, etc.) correspond exactly 
to the original. Then, a museum curator further evaluates the giclee. If un- 
acceptable, it is sent back for additional changes until he is satisfied with 
the reproductions quality. 

This painstaking attention to every imaginable detail mirrors the strict 
biochemical requirements faced by the cell's machinery that manufactures 
proteins. For these biomolecules to be usable, they must be exact replicas — 
high-fidelity copies — of the information housed in the gene sequences of 
DNA (see chapter 2, p. 48). The cell's protein-manufacturing processes are 
well-designed to accomplish this task. 

Still, from time to time, mistakes happen. And, as is the case for any good 
manufacturing process, biochemical quality control systems are in place to 
identify and rectify production errors. Quality assurance checks are also 
part of other key processes in the cell, like DNA replication, for example. 

Avoiding Costly Mistakes 

Manufacturing processes often rely on assembly lines to move production 
units from station to station. Workers, robots, and machinery carefully per- 
form high-precision tasks transforming unrecognizable starting materials 
and components, one step at a time, into a finished product. Each stage is 
an engineering marvel that likely took years of research, careful planning, 
design, and construction to effectively implement. 

Some of the most critical and sophisticated steps are not those that di- 
rectly result in the final product but those that check the quality. These tasks 



Total Quality i oc 

deliberately remove defective products from the production sequence and 
ensure that no substandard finished product reaches the consumer's hands. 

Quality assurance procedures that simply evaluate and reject inferior 
products at the end of the production line may keep defective items from 
reaching consumers, but they are costly, inefficient, and of limited value. 
The best quality control measures intervene throughout the manufactur- 
ing process, particularly when mistakes are most likely to occur or are the 
most costly. 

Defective products can then be removed near the point in the manufac- 
turing sequence where the problem occurs and that saves time and resources. 
Without such intervention, defective units would be carried through to 
the assembly line's end only to be discarded. 

Effective and efficient quality control procedures don't just happen. 
Rather, they require careful planning and a detailed understanding of the 
manufacturing process, the product, and the way the consumer will use it. 
In other words, quality control procedures reflect intelligence and ingenu- 
ity and indicate a deliberate, well-designed process. 

Scientists compare many of the cell's activities to manufacturing pro- 
cesses. These comparisons provide an important conceptual handle that 
helps researchers understand the cell's operating systems. 

An astounding chemical logic undergirds these complex, well-orchestrated 
processes. Biochemists have discovered that, just like manufacturing op- 
erations designed by human engineers, key cellular processes incorporate a 
number of quality control checks. Many of them play a central role in cell 

survival and the cell's ability to propagate from generation to generation.. 
These quality assurance procedures occur at critical junctures in the cell's sys- 
tems and display remarkable chemical elegance and exquisite fine-tuning. 

Describing all the cell's quality control operations is beyond the scope 
of this book. Therefore, this discussion is limited to some of the quality 
control procedures associated with the production of one of the cell's most 
important biochemical products, proteins. 



Only the Best 

The capacity of the cell's biochemical machinery to make proteins with 
a high degree of fidelity is critical. Protein ensembles play a role in every 
cell function and take part in every cell structure (see chapter 2, p. 42). 



1 O^ The Cell's Design 

Wide-scale production of defective proteins would disrupt essential cell 
activities and result in a distorted cellular architecture. 

The problems related to defective protein production extend beyond 
global disruption of cellular activities. Molecular biologist and physician 
Michael Denton points out that frequent mistakes in protein production 
will cause the cell to self-destruct., 

The threat of autodestruction stems from the circular nature of protein 
synthesis. Proteins constitute many components of the cell's protein manufac- 
turing machinery. In other words, the cell uses proteins to make proteins (see 
chapter 5, p. 101). So, if the protein manufacturing machinery were assembled 
with defective parts, the cell would fail to accurately manufacture proteins. 
Such a manufacturing failure would cause protein production systems to be- 
come increasingly error-prone with each successive round of protein synthesis. 
Protein manufacturing systems made up of defective components would be 
more likely to produce defective proteins. This chain reaction would cascade 
out of control and quite quickly lead to the cell's self-destruction. 

Effective quality assurance procedures must be in place for protein pro- 
duction or life would not be possible. 

Manufacturing Instructions 

At most production facilities, official documents that contain the manu- 
facturing instructions are housed in a central office where they're formally 
maintained. The cell does the same. It stores DNA — the master directions 
for protein production — inside its nucleus. The nucleotide sequence of 
genes found along the DNA strands specifies the amino acid sequence of 
proteins, just like manufacturing plans describe the order of production 
steps for any manufacturing process (see chapter 2, p. 50). 

When the time comes to produce a particular protein, the cell's ma- 
chinery copies these instructions and takes them to the production floor. 
This reproduction operation results in the assembly of another type of 
polynucleotide, messenger RNA (mRNA)., 



A Biochemical Assembly Line 

The cell's protein-manufacturing machinery consists of three main com 
ponents: messenger RNA (mRNA), transfer RNA (tRNA), and ribosomes. 



Total Quality IQT 

All interact to form an assembly line that generates the polypeptides that 
constitute proteins. 

Messenger RNA 

After the manufacturing instructions for protein synthesis have been 
copied from the DN A (transcription), reviewed, and processed, the newly 
produced mRNA carries them from the cell's nucleus to the cytoplasm. 
Once there, the mRNA issues instructions to subcellular particles, the 
ribosomes, to produce the polypeptides that fold and interact to form 
proteins, (see chapter 2, p. 50). Ribosomes bind and manage the interac- 
tions between mRNA and tRNA.. 

Transfer RNA 

Like mRNA, transfer RNA (tRNA) consists of a single RNA strand. 
Unlike mRNA, tRNA adopts a precise three-dimensional structure critical 
for its role in protein synthesis. As the single tRNA strand folds to form 
its three-dimensional shape, four segments of the tRNA strand pair. This 
union gives tRNA a cloverleaf shape in two dimensions. Bending the clover 
leaf and twisting the paired regions produces an overall L-shaped archi- 
tecture. (See figure 10.1.) 

Transfer RNAs bind amino acids and carry them to the ribosome. This 
delivery makes amino acids — the starting materials for protein produc- 
tion — available to the protein synthetic machinery. Each of the twenty 
amino acids used by the cell to form proteins has at least one corresponding 
tRNA molecule. An activating enzyme (aminoacyl-tRNA synthetase) links 
each amino acid to its specific tRNA carrier. 

Each tRNA and amino acid partnership has a corresponding activating 
enzyme specific to that pair. The amino acid binds to one end of the tRNA 
"L". The other end of the tRNA, the anticodon, "reads" the manufacturing 
instructions found in mRNA. This anticodon consists of a three-nucleotide 
sequence that pairs with a codon, a complementary three-nucleotide se- 
quence in mRNA. 

The four nucleotides of mRNA, and ultimately DN A, specify the twenty 
amino acids found in proteins by using groupings of three nucleotides to 
code for each amino acid. There are sixty-four different codons that cor- 
respond to the twenty amino acids involved in protein synthesis. Some of 



(A) 



DIoop 



mG 





(Ah 


1. ' ::' ■ 1 

3' Amino acid 


5' 
(G> 


© (alanine) 
_J^ . Acceptor stem 


(G> 


-^ 




r(G>- 


-<u) 




Cc> 


-(G) 




(u) 


(u) 


"Pi-CG loop 



m,G 



Anticodon loop SH^ 

(ul 



tG) Variable loop 

ml 
iy ^ Anticodon 

Codon 



3' 3 2 1 5' 

mRNA J 



T^CG loop 



Acceptor stem 




Anticodon loop 



Total Quality 1 on 

the sixty-four codons are redundant. That is, they code for the same amino 
acid. The genetic code (see chapter 9, p. 171) is the set of rules the cell uses 
to relate nucleotide triplets in mRNA to amino acids in proteins. 

Each tRNA's anticodon matches acodon in mRNA. Because each tRNA 
binds a single and specific amino acid, the codon-anticodon pairs serve 
as the cellular hardware that implements the manufacturing instructions 
for protein production. 

Ribosomes 

These subcellular entities play a central role in protein production by 
binding and managing interactions between mRNA and tRNA. The chemi- 
cal reactions that form the bonds thatjoin amino acids together in poly- 
peptide chains are catalyzed or assisted by ribosomes. 

Proteins and RNA molecules, called ribosomal RNA (rRNA, see chap- 
ter 5, p. 102), form a functional ribosome when two subunits of different 
sizes combine. In prokaryotes, the large subunit contains two rRNA mol- 
ecules and about thirty different protein molecules. The small subunit con- 
sists of a single rRNA molecule and about twenty proteins. In eukaryotes, 
the large subunit is formed by three rRNA molecules that combine with 
around fifty distinct proteins. The small subunit consists of a single rRNA 
molecule and over thirty different proteins. The rRNAs act as scaffolding 
that organizes a myriad of ribosomal proteins. 

Ribosomes are abundant inside the cell. (A typical bacterium possesses 
about twenty thousand. They generally comprise one-fourth the total bacte- 
rial mass.) These dynamic structures readily self-assemble when mRNA and 
all of its components are present and disassemble once protein production 
is complete. 



The Manufacturing Process 

The ribosome, mRNA, and tRNA molecules work cooperatively to 
produce proteins. Using an assembly-line process, protein manufacturing 
machinery forms the polypeptide chains (that constitute proteins) one 

Figure 10.1. tRNA Structure 

The single tRNA strand folds to form its three-dimensional shape when four segments oftRNA 
pair. This pairing produces a cloverleaf shape in two dimensions. Bending the clover leaf and 
twisting the paired regions yields an upside-down L-shaped architecture. 



190 



The Cell's Design 



amino acid at a time. This protein synthetic apparatus joins together three 
to five amino acids per second. Ribosomes, in conjunction with mRNA 
and tRNAs, assemble the cell's smallest proteins, about one hundred to 
two hundred amino acids in length, in less than one minute. 

When protein synthesis begins, the ribosome complex assembles around 
mRNA. The rRNAs bind to mRNA and properly position it in the ribo- 
some. This process establishes the proper reading frame (see chapter 8, 
p. 155). The tRNA-amino acid complex that corresponds to the firstamino 
acid position in the polypeptide chain binds to a site in the ribosome called 
the P (product) site. The tRNA-amino acid complex corresponding to the 
second amino acid in the polypeptide chain binds to an adjacent site, the 
A (accepter) site. The protein synthetic machinery uses the mRNA codon- 
tRNA anticodon pairing interactions to properly position the tRNA-amino 
acid adducts. (See figure 10.2.) 



Growing 

polypeptide 

chain 




Movement 
of ribosome 



V^ V^ V" V^ V^ V^ V^ 

Codon Codon Codon Codon Codon Codon Codon 



aa 



aa:, 



aa. 



aaj 



aa. 



aa. 



aa. 



Figure 10.2. Protein Syntliesis at the Ribosome 

The mechanism ofprotein synthesis involves the binding oftRNA-amino acid adducts to 
the A site and the subsequent transfer of the amino acid to the growing polypeptide chain in 
the P site. 



Total Quality 1 ni 

Once positioned in the P and A sites, a region of rRNA in the large 
subunit (referred to as peptidyl transferase) forms a chemical bond be- 
tween the first and second amino acids in the polypeptide chain. When 
this occurs, the amino acid in the P site dissociates from its tRNA. The 
tRNA in the P site leaves the ribosomes and becomes available to bind 
another amino acid. 

The tRNA in the A site, which has the growing polypeptide chain 
attached to it, translocates to the P site. And, the tRNA-amino acid com- 
plex for the third position in the polypeptide chain enters the A site. Then 
bond formation, tRNA dissociation, and transfer from A to P site repeats. 
This entire process occurs over and over again until all the information in 
the mRNA is read and the entire polypeptide is synthesized. For each step 
in this assembly-line process, the ribosome complex advances along the 
mRNA length — one codon at a time. 



Quality Control Procedures 

As with any well-designed production process, the cell's protein synthetic 
machinery employs quality assurance protocols. Checkpoints occur at sev- 
eral critical junctures during protein manufacture, including (1) tRNA and 
rRNA production, (2) mRNA production, (3) amino acid attachment to 
tRNA, (4) the movement of tRNA to the ribosome, and (5) the position- 
ing of tRNA at the ribosome s A site. 

Maintaining the Protein Production Machinery 

Biochemists refer to tRNA and rRNA as stable RNAs because these 
molecules, once produced by the cell's machinery, persist for a long period 
of time under normal growth conditions. In contrast, mRNA has a high 
turnover rate (see chapter 6, p. 1 19). 

The biosynthesis of tRNAs and rRNAs is highly accurate. Still, from time 
to time errors creep into the production process. If left unchecked, defective 
tRNAs and rRNAs will create havoc for the cell because these molecules are 
key cogs in the biochemical machinery that manufactures proteins. In any 
production process, if the machinery that makes the product doesn't work 
properly, the product either can't be produced or won't be assembled cor- 
rectly. The stability of these biomolecules further exacerbates the potential 



292 The Cell's Design 

damage effected by defective tRNAs and rRNAs because, even if they're 
flawed, these molecules will persist in the cell. (In contrast, when flawed 
proteins are accidentally made, the cell's machinery eliminates them.) 

In recent years biochemists have discovered the strict quality control 
governing the production of tRNAs and rRNAs in all cell types.,,. When 
improperly made, the protein poly(A) polymerase adds several adenine 
nucleotides to the defective RNAs to form what biochemists call a poly (A-) 
tail (see chapter 5, p. 102). The addition of this poly (A) tail (polyadenyl- 
ation) flags the faulty RNAs for destruction. Studies on the bacterium 
E. coli show that when mistakes occur in the biosynthesis of tRNA and 
rRNA, cooperative activity between the proteins RNAase R and PNPase 
destroys the defective molecules. , 

If these three enzymes — poly(A) polymerase, RNAase R, PNPase — are 
inoperable, cell death inevitably occurs. In the process, defective tRNA 
molecules and rRNA fragments accumulate in the cell and the number of 
functional ribosomes decreases. Presumably, the defective rRNA molecules 
disrupt the assembly ofworking ribosomes. 

Placing a quality assurance check at the point of rRNA and tRNA pro- 
duction makes perfect sense. This foresight ensures that the cell's manu- 
facturing machinery is in proper working order before protein production 
even begins. If this quality control is not in place, the cell's manufacturing 
floor becomes cluttered with inoperable manufacturing equipment to its 
detriment. 

Recent work indicates that rRNA and tRNA quality control procedures 
are operable in eukaryotic organisms as well. Just like in the bacterium 
E. coli, flawed tRNA and rRNA molecules are targeted for breakdown by 
polyadenylation. (In contrast, in eukaryotes the poly (A) tail stabilizes mRNA 
and directs the splicing operations.) These latest studies suggest that this 
quality control operation may be a universal feature in the living realm. 

Operating at Peak Efficiency 

Quality control checkpoints have been discovered at criticaljunctures in 

mRNA production, export from the nucleus, and translation at ribosomes. , 
An elegant rationale places quality assurance procedures at these points in 

protein biosynthesis as well. Before the assembly process even begins, these 
safeguards generate manufacturing efficiency by ensuring that the protein 
production machinery will use the correct instructions. 



Total Quality i go 

Biochemists recently discovered that RNA polymerases (chapter 5, 
p. 101) — the protein complexes that synthesize mRNA by copying the 
information stored in the gene sequences ofDNA — use a proofreading 
mechanism to ensure that mRNA has been accurately transcribed. ,s Mes- 
senger RNA, like DNA, is a polynucleotide (see chapter 2, p. 50). Unlike 
DNA, which consists of two paired polynucleotide strands, mRNA is a 
single strand. Its nucleobase composition is similar but not identical to 
DNA. One ofthe most important differences between DNA and RNA is 
the use of uridine (U) in place of thymidine (T) in the RNA chains. 

RNA polymerases produce mRNA by using a gene s nucleotide sequence, 
located along the sense strand ofthe DNA double helix, as a template (see 
chapter 8, p. 157). RNA polymerases step along the DNA strand and add 
nucleotides to the mRNA strand one at a time. The nucleotide sequence of 
the gene dictates each of the nucleotides added to the growing mRNA chain. 
RNA polymerases rely on the same pairing rules that align the two DNA 
strands to specify the nucleotide sequence of mRNA. 

When the side chain ofthe DNA template is a C, RNA polymerase 
adds a G to the growing mRNA strand. If the DNA side chain is a G, RNA 
polymerase uses a C (because G and C always pair with each other). When 
the DNA side chain is a T, RNA polymerase incorporates an A into the 
mRNA chain, and if the RNA polymerase encounters an A, it slots in a U 
(instead of a T; see figure 10.3). 

As mRNA moves along the DNA sense strand adding nucleotides to the 
mRNA molecule, it constantly checks its work to make sure the correct 
nucleotide has been added. If an error occurs and the wrong nucleotide 
becomes incorporated into the mRNA strand, the RNA polymerase re- 
moves the incorrect nucleotide, backs up, and repeats the combination 
step. Biochemists refer to this activity as proofreading. This quality control 
operation ensures that mRNAs are accurately produced. 

In eukaryotes, newly formed mRNA undergoes several processing steps 
before it leaves the nucleus and makes its way to a ribosome (see chapter 5, 
p. 102). This processing includes adding a 7-methylguanine "cap" to one 
end ofthe mRNA and a poly A "tail" to the other end. Introns (noncod- 
ing intervening sequences within a gene) are removed and the remaining 
exons (the regions of a gene that contain information to make proteins) are 
spliced together. Biochemists have discovered that if the cell's machinery 
makes errors in processing mRNA, so-called discard pathways remove 
flawed mRNA molecules. . 



RNA polymerase 




'V?^' 



v?^ 



v?^ 



*^^<:7^i^^^^^ 



CpApTpApG^^ 




Pyrophosphatase 



Total Quality i gs 

Once processed, mRNA migrates from the cell's nucleus through nuclear 
pores to the cytoplasm where translation occurs. Another quality assur- 
ance checkpoint prevents improperly spliced mRNA from exiting the cell 
nucleus.,, This quality control step is accomplished through binding and 
debinding of proteins to mRNA. When properly spliced, certain proteins 
that are part of the splicing procedure dissociate from mRNA. If errors 
occur in splicing, however, these proteins remain attached. 

After splicing is completed, other proteins bind to the fully processed 
mRNA. If not properly spliced, these proteins can't bind to the defective 
mRNA. When it is associated with the wrong proteins, mRNA isn't granted 
passage through the nuclear pore, which is how imperfectly processed 
mRNA is prevented from reaching the ribosome. 

Certain types of errors in mRNA production escape detection by the 
quality control operations in the nucleus. Messenger RNA molecules pro- 
duced without a stop codon or with a premature stop codon occasionally 
make their way to the ribosome (see chapter 9, p. 173). Once there, these 
defective mRNA molecules stall protein production, jamming the ribo- 
some machinery. Several distinct biochemical safeguards are in place to 
destroy faulty mRNA molecules that clog the ribosomes.^ 

Exact Amino Acid Attachments 

A quality control checkpoint also occurs at the step that attaches amino 
acids to their corresponding tRNA molecules. ; This energy intensive at- 
tachment process, called charging, is highly selective. The error rate for the 
enzymes that carry out this reaction, aminoacyl-tRNA synthetase (activat- 
ing enzymes) is about 1 in 3,000. 

Activating enzymes achieve this low error rate by correctly binding the 
appropriate tRNA molecules and amino acids before catalyzing the reac- 
tion that joins these two biomolecules together. Proper tRNA binding 
is readily accomplished because of the chemical differences among the 
individual tRNAs. The binding of the correct amino acid by activating 
enzymes, however, is quite remarkable and involves careful biochemical 
fine-tuning. 

The activating enzyme isoleucyl-tRNA synthetase best illustrates the 
mechanism for selecting the correct amino acid and the fine-tuning 

Figure 10.3. RNA Polymerase Production of mRNA 

RNA polymerases produce mRNA by using a gene s nucleotide sequence as a template. RNA 
polymerases step along the DNA strand and add nucleotides to the mRNA strand one at a time. 



296 The Cell's Design 

associated with this quality control step. The enzyme is able to effectively 
discriminate between the amino acids isoleucine and valine. Both have 
nearly identical chemical and physical properties. Based on the thermo- 
dynamics consideration alone, the binding differences between these two 
amino acids should allow only a 1 in 40 error rate, not a 1 in 3,000. This 
difference in expected error rate means another mechanism must be at 
work. 

All activating enzymes perform proofreading and editing steps that 
recognize and delete mischarged amino acids from tRNAs. Activating 
enzymes proofread and edit through chemical fine-tuning that involves the 
"just-right" binding to the enzymes active site (chapter 2, p. 45). Amino 
acids that are too large can't be accommodated. Those too small become 
translocated to the enzyme's editing site once the bond between the amino 
acid and tRNA forms. In the editing site, the enzyme removes the mis- 
charged amino acid from the tRNA and starts all over again. 

New work indicates that translocation from the catalytic site to the 
editing site heavily depends on structural fine-tuning of the activating 
enzyme.!, Changing a single amino acid in isoleucyl-tRNA synthetase 
compromises the enzyme's capacity to edit mischarged tRNAs by disrupt- 
ing the translocation step. 

The proofreading and editing steps are critical. If not executed properly 
in bacteria, cell growth is inhibited.:, Faulty proofreading and editing of 
aminoacyl-tRNA synthetases have been implicated in neurodegenerative 
diseases.; 

Separating the Goodfrom the Bad 

Recent studies have identified a quality control checkpoint associated 

with the transport of tRNA-amino acid complexes to the ribosomes.:. 
Once charged with an amino acid, tRNAs require a protein, elongation 

factor Tu (EF-Tu), to escort and position them in the ribosome A site., 
For some time, biochemists regarded EF-Tu as a passive carrier that in- 
discriminately bound tRNA-amino acids adducts. These scientists now 
understand that EF-Tu actively distinguishes properly charged tRNAs from 
mischarged and uncharged tRNAs. 

Biochemists from the University of Colorado at Boulder identified the 
mechanism EF-Tu employs to discriminate the 20 correctly charged tRNA- 
amino acid adducts from 380 incorrectly charged ones.; The interaction 



Total Quality 1 nn 

between EF-Tu and properly charged tRNAs is "just right" with binding 
affinities occurring over a narrow range. Mischarged tRNAs bind to EF-Tu 
either too weakly or too strongly. 

When bound too tight, the mischarged tRNA cannot be released at the 
ribosome, and if too loose, EF-Tu cannot transport the mischarged tRNA 
to the ribosome. This finely tuned quality-control system prevents incorrect 
amino acids from incorporating into polypeptide chains by catching any errors 
that escape detection by the activating enzyme's editing mechanism. 

Less Accuracy Results in Lethal Errors 

Collectively, the quality assurance procedures associated with activating 
enzymes and EF-Tu yield an error rate for protein synthesis on the order of 
1 in 10,000 or 100 ppm (parts per million). If the protein manufacturing 
machinery did not operate with this accuracy, life would not be possible. 

The accuracy of protein synthesis can be calculated. The equation 
P = ( 1 -E). expresses the probability for producing a polypeptide chain 
without error. In this equation P represents the probability for produc- 
ing an error-free polypeptide, E the error frequency, and n the number of 
amino acids in the polypeptide chain. An error rate of 1 in 100 is intoler- 
able for the cell. At this frequency, the protein machinery has essentially 
no chance of producing an error-free polypeptide chain 1,000 amino acids 
in length and only a 36 percent probability ofproducing one 300 amino 
acids long. 

An error rate of 1 in 1,000 permits 300-amino-acid-long polypep- 
tide chains to form with an 85 percent error-free probability, but still 
1,000-amino-acid-long polypeptide chains would experience only a 37 per- 
cent chance of being assembled correctly. At a 1 in 10,000 error rate, poly- 
peptide chains of 1,000 amino acids have a greater than 90 percent chance of 
correct assembly. Given all this, an error rate of 1 in 10,000 is the minimum 
protein production efficiency for life to be possible. 

An error rate of 1 in 100,000 yields a 99 percent probability of error- 
free polypeptide assembly for chain lengths 1,000 amino acids long. If this 
is the case, then why doesn't the protein production machinery include 
additional quality control steps to push the process accuracy closer to 
1 in 100,000? 

An error rate of this magnitude would slow down the protein production 
rate to the point that it becomes harmful to the cell. The error rate of 1 in 10,000 



198 



The Cell's Design 



is "just right" to allow for high-fidelity protein synthesis at a rate fast enough to 
allow cellular chemistry to operate. The design of the protein manufacturing 
machinery recognizes the trade-offs between accuracy and production time, 
as does any well-designed production process (see chapter 13, p. 248). 

Quality Control in the Endoplasmic Reticulum 

A complex system of membrane channels and sacs (see chapter 2, p. 40), 
the endoplasmic reticulum (ER) is made up of two regions. In the rough 
endoplasmic reticulum ribosomes are associated with the outer surface of 
the ER membrane. The proteins made by these ribosomes are deposited 
into the lumen (central cavity) of the ER for further biochemical process- 
ing. The proteins transported into the lumen will eventually make their 
way into lysosomes andperoxisomes, become incorporated into the plasma 
membrane, or be secreted out of the cell. 

The processing of proteins in the lumen (posttranslational modification) 
is quite extensive..,., Posttranslational modifications include (1) formation 
and reshuffling of disulfide bonds (these bonds form between the side chains 
of cysteine amino acid residues within a protein, stabilizing its three dimen- 
sional structure), (2) folding proteins into three-dimensional structures, 
(3) addition and processing of carbohydrate units to form oligosaccharide 
attachments (see chapter 8, p. 146), (4) cleavage of the protein chains, and 
(5) assembly of protein complexes. A number of enzymes associated with 
the ER lumen mediate these posttranslational operations. 

Once posttranslation modifications are successfully executed, the fully 
mature proteins make their way to their final destination. 

Error Prone 

The complexity and intricacy of the posttranslational modifications that 
take place within the ER make these processes susceptible to errors. It's not 
uncommon for proteins in the ER lumen to wind up misfolded or to be 
improperly assembled because of unbalanced subunit production. 

Quality control activities ensure that proteins are properly produced and 
processed by the rough ER. In fact, many scientists consider the quality 
assurance procedures of the ER to be the quintessential biochemical quality 
control systems. , 



Total Quality i gq 

Biochemists have discovered that proteins in the ER lumen experience 
primary and secondary quality control checks. Primary quality control 
operations monitor general aspects of protein folding. Secondary quality 
control activities oversee posttranslational processing unique to specific 
proteins. 

One of the most remarkable features of the ER quality assurance systems 
is the ability to discriminate between misfolded proteins and partially 
folded proteins that appear misfolded but are well on their way to adopt- 
ing their intended three-dimensional architectures. If the quality control 
operations cannot efficiently make this distinction, it is devastating to 
the cell. In fact, some diseases have been linked to faulty quality control 
activities in the ER.,, 

When misfolded proteins escape detection, defective proteins accumu- 
late in the cell. On the other hand, to mistakenly discard proteins in the 
process of being properly folded would be wasteful. 

Inspected By 

Biochemists recently discovered that the ER quality control systems use 
information contained within oligosaccharides (see chapter 8, p. 146) as sen- 
sors to monitor the folding status of proteins. This process begins when the 
ER's machinery attaches an oligosaccharide (abbreviated GlcManGlcNAc) 
to newly made proteins after they've been manufactured by ribosomes and 
translocated into the lumen of the ER. Once inside the ER, two G/c units 
are then trimmed from the oligosaccharide to form Glc Man GlcNAc . 
This modified attachment signifies to the ER's machinery that it's time for 
chaperones to assist the protein with folding (see chapter 5, p. 105). 

Once completed, the remaining Glc residue is cleaved to generate the 
oligosaccharide ManGlcNAc . This attachment tells the ER's quality control 
system to scrutinize the newly folded protein for any defects. If improperly 
folded, the ER's machinery reattaches Glc to the oligosaccharide and sends 
the protein back to the chaperones for another round of folding. 

Moving On Down the Line 

Once the protein passes this stage of processing, the ER machinery 
removes a Maw group to generate ManGlcNAc. This marker triggers the 
ER machinery to send the protein to the Golgi apparatus (see chapter 2, 



2QQ The Cell's Design 



Know When to Fold 'Em 

Occasionally, the endoplasmic reticulum's (ER's) machinery becomes overwhelmed 
with unfolded proteins. This glut can stem from the overproduction of proteins or from 
errors in the oligosaccharide processing steps that guide the ER's quality control opera- 
tions... If the cell does not effectively deal with the stress on the machinery, the result 
is catastrophic. Biochemists think the inordinate accumulation of unfolded proteins in 
the ER contributes to diseases like cancer and neurodegenerative disorders.. 

When strained this way, the cell responds with something known as the unfolded 
protein response (UPR). The UFR represents a form of feedback regulation. When too 
many unfolded proteins are present in the ER, protein synthesis at the rough ER slows 
down and niRNA molecules that specify the production of proteins processed through 
the ER are degraded. The UPR can be compared to a waitress who pours soda pop 
more slowly as the foam rises to the top of the glass. 

The UHt represents one more example of the elegant molecular logic that per- 
meates life's chemistry. It also bespeaks foresight and preplanning, indicators of 
intelligent design. 



p. 40). If, however, the quality control system detects any evidence that 
proteins with the Man^GlcNAc attachment are misfolded, it targets them 
for destruction. In other words, the quality control systems of the ER con- 
tinually monitor the folding status of proteins as they're processed. If the 
structure of the bound oligosaccharide does not match the expected state of 
the protein, it triggers either a recycling step or a destruction sequence. 

If the ER's machinery deems it necessary to destroy a defective protein, 
the machinery shuttles the protein from the ER lumen to the cells cy- 
toplasm. This process is referred to as retro-translocation..,! Once in the 
cytoplasm, the defective protein becomes coated with the protein ubiquitin 
and destroyed by the proteasome (see chapter 6, p. 121). 

High-Fidelity Copies 

To reproduce a masterpiece requires exacting attention to every imaginable 
detail. Each nuance of the image must exactly correspond to the original. 

The strict biochemical requirements faced by the cell's machinery that 
manufactures proteins reflect the same impeccable quality control. To be 
usable, each protein must be an exact replica of the information housed in 
the gene that specifies the protein's amino acid sequence. 



Total Quality 90 1 

Even though the biomolecular pathways responsible for protein produc- 
tion display remarkable complexity and chemical elegance, the inherent 
nature of these chemical and physical processes inevitably causes mistakes 
to creep into the operation. The need to detect these problems as soon as 
possible necessitates quality control procedures as stringent as those in any 
manufacturing plant. 

This biochemical quality assurance further highlights the exceptional 
ingenuity that defines the cell's chemistry and reinforces the conclusion 
that life has a supernatural basis. Effective and efficient quality control 
procedures don'tjust happen. Rather, they are characterized by intentional 
foresight. Sound quality control systems require careful planning, a detailed 
understanding of the manufacturing process, the product, and the way 
that product will be used. All of these features are evident in the qual- 
ity control activities in the cell. In protein biosynthesis, the placement of 
quality assurance checkpoints occurs at strategic stages in the production 
process in away that ensures reliable protein production while generating 
manufacturing efficiency. 

This chapter focused on some of the purposeful quality assurance pro- 
cedures associated with protein biosynthesis. Other biochemical systems 
rely on quality control activities as well. References for a few examples are 
noted.,. 

Only a designer who exercises thought and care could be so deliberate as 
to orchestrate effective quality control procedures — whether for a painting s 
reproduction or for the operations found within the cell. In this context, 
the cell's quality assurance systems logically compel the conclusion that 
life's chemistry emanates from the work of a Grand Engineer — One skilled 
in making exact reproductions. The biochemical fine-tuning displayed by 
many of the quality control steps associated with protein production and 
other operations in the cell adds to this analogy. Such precise attention to 
detail clearly indicates a supreme intelligence at work (see chapter 6). 

As biochemists unveil more and more of the cell's elegant artistry, the 
evidence for a Creator mounts. The next chapter continues to build the case 
for biochemical intelligent design by considering repeated use of the same 
patterns in biochemical systems. 




Pablo Picasso, PorfnwV ofDom Mtar (Reproduced by permission from © 2008 Estate of Pablo Picasso 
Artists Rights Society [ARS], New York; Tlie Bridgeman Art Library) 



11 



A STYLE ALL HIS OWN 



Even the uninitiated can often recognize art by Pablo Picasso, partly be- 
cause of his worldwide fame. But also because distinct styles and recurring 
themes characterize his work. 

The most easily identifiable paintings come from his Cubist period. 
Picasso and his friend George Braque invented this school of art around 
1910.1 Cubists fragmented three-dimensional objects and redefined them 
as a series of interlocking planes.. 

More sophisticated patrons of the arts may recognize paintings from 
other stages of Picasso's career. Before inventing Cubism, he went through 
two periods. During his Blue Period, Picasso produced blue-tinted paintings 
that depict acrobats, harlequins, prostitutes, beggars, and artists. Orange 
and pink colors defined Picasso's Rose Period. These paintings generally 
communicate cheery themes. 

Even Picasso's Cubism went through distinct phases. While in his analyti- 
cal Cubist stage, he analyzed objects by taking them apart. During a stage 
of synthetic Cubism, he incorporated collages into his paintings. 

Picasso is not unique. Every artist identifies with particular schools of 
art and media of expression. They use colors in characteristic ways and 
typically portray the same objects and gravitate toward certain themes. 

203 



204 The Cell's Design 

And that makes it possible to associate a piece of art with a particular artist. 
Each artist has his own style. 

Recurring Designs 

Artists are not the only ones who create in characteristic ways. Other 
human designers do as well. Engineers, inventors, and architects typically 
produce works that reflect their own signature styles. This distinction was 
certainly the case for Frank Lloyd Wright (1 867-1 959). Trained as a civil 
engineer, Wright is considered among Americas greatest architects., Known 
for radical innovations, Wrights houses are characterized by open plans 
that eliminate walls between rooms. 

Like artists who generally gravitate toward the same themes — architects, 
inventors, and engineers also reuse the same techniques and technologies. 
Wright did. It was much more prudent and efficient for him to reapply a 
successful strategy (even one that was unconventional) than to invent a 
new approach, particularly when confronted with complicated problems 
that already have solutions. 

The tendency of artists and other human designers to revisit the same 
themes and reuse the same designs provides insight into the way a Creator 
might work. If human craftsmen made in God's image reuse the same tech- 
niques and technologies, it's reasonable to infer that their Creator would do 
the same. So, if life stems from his hand, then it's reasonable to expect the 
same designs to repeatedly appear throughout nature. And, those recurring 
themes will reflect the Divine Artist's signature style. 

Identical Accidents ? 

While repeated occurrences of biochemical designs logically point to 
a Creator, that's not the case for evolutionary processes. If biochemical 
systems are the product of evolution, then the same biochemical designs 
should not recur throughout nature. 

Chance, "the assumed impersonal purposeless determiner of unaccount- 
able happenings," governs biological and biochemical evolution at its most 
fundamental level. Evolutionary pathways consist of a historical sequence of 
chance genetic changes operated on by natural selection, which also consists 
of chance components. The consequences are profound. If evolutionary 



A Style All His Own ')0S 

events could be repeated, the outcome would be dramatically different 
every time. The inability of evolutionary processes to retrace the same path 
makes it highly unlikely that the same biological and biochemical designs 
should be repeated throughout nature. 

This concept ofhistorical contingency is the theme of evolutionary 
biologist Stephen!. Goulds book Wonderful Life. According to Gould: 

No finale can be specified at the start, none would ever occur a second time in 
the same way, because any pathway proceeds through thousands of improbable 
stages. Alter any early event, ever so slightly, and without apparent importance 
at the time, and evolution cascades into a radically different channels 

To help clarify the idea of historical contingency, Gould used the meta- 
phor of "replaying life's tape." If one could push the rewind button and erase 
life's history, then let the tape run again, the results would be completely 
different each time., The very essence of the evolutionary process renders 
its outcomes nonrepeatable. 



Putting the Facts to the Test 

Most scientists argue that the design so prevalent in biochemical systems 
is not true design. It only appears that way, an artifact of evolutionary pro- 
cesses. Accordingly, this apparent biochemical design stems from natural 
selection operating repeatedly on random genetic changes over vast periods 
of time to fine-tune biochemical systems. 

The idea ofhistorical contingency suggests a way to discriminate between 
the "appearance of design" and intelligent design. Does contingency account 
for the patterns observed in the biological realm? If life results exclusively 
from evolutionary processes, then shouldn't scientists expect to see few, if 
any, cases in which evolution has repeated itself? However, if life is the 
product of a Creator, then the same designs should repeatedly appear in 
biochemical systems. 



Molecular Convergence 

Over the last decade or so, scientists exploring the origin of biochemical 
systems have made a series of remarkable discoveries. When viewed from 



2Q5 The Cell's Design 

an evolutionary perspective, a number of life's molecules and processes, 
though virtually identical, appear to have originated independently, multiple 
times.. Evolutionary biologists refer to this independent origin of identical 
biomolecules and biochemical systems as molecular convergence. According 
to this concept, these molecules and processes arose separately when different 
evolutionary pathways converged on the same structure or system. 

When molecular biologists first began studying biochemical origins, they 
expected to find few, if any, instances of molecular convergence. One of 
the first examples was recognized in 1943 when two distinct forms of the 
enzyme fructose 1,6-bisphosphate aldolase were discovered in yeast and 
also in rabbit muscles. From an evolutionary perspective, it appears as if 
these two enzymes had separate evolutionary histories., 

At the time, this result was viewed as an evolutionary oddity. In the past 
decade, however, the advent of genomics — which now makes it possible to 
sequence, analyze, and compare the genomes of organisms — has made it 
evident that molecular convergence is a recurring pattern in nature rather 
than an exception to the rule. Contrary to expectations, biochemists are 
uncovering a mounting number of repeated independent biochemical 
origin events. 

Evolutionary biologists recognize five different types of molecular 
convergence:, 

1. Functional convergence describes the independent origin of bio- 
chemical functionality on more than one occasion. 

2. Mechanistic convergence refers to the multiple independent 
emergences of biochemical processes that use the same chemical 
mechanisms. 

3. Structural convergence results when two or more biomolecules 
independently adopt the same three-dimensional structure. 

4. Sequence convergence occurs when either proteins or regions of 
DNA arise separately but have identical amino acid or nucleotide 
sequences, respectively. 

5. Systemic convergence is the most remarkable of all. This type of mo- 
lecular convergence describes the independent emergence of identical 
biochemical systems. 

Table 11.1 lists one hundred recently discovered examples of molecular 
convergence. This table is neither comprehensive nor exhaustive. It simply calls 



A Style All His Own 



207 



attention to the pervasiveness of molecular convergence. (Remember, as is true 
when looking at a particular group of paintings in any gallery, it is fine to skim 
through them or move on to the next section whenever you're ready.) 



Example 



Table 11.1 
Examples of Molecular Convergence 

Reference 



RNA 



Small nucleolar RNAs in eukary- 
otes and archaea 

Hammerhead Riboi^Tne 



DNA and Genes 

Gene structure of lamprin, 
elastins, and insect structural 
proteins 

Majw histocompatibility com- 
plex DRB gene sequences in 
humans and CM and New Wwld 
monkeys 

Structure and expression of the 
Q-crystaUin gene in vertebrates 
and invertebrates 

Group I introns in mitochondria 
and chloroplasts, and hyperther- 
mophilic bacteria 



Rankir^ sequences to microsat- 
ellite nM\ in the human genome 



Proteins and Enzymes 

hnmunc^obulin G-bindir^ pro- 
teins in bacteria 



The oc/(5 hydrolase fold of hydro- 
lytic enzymes 

Peptidases 



Chner, Arina D., et al. ' 'Homolt^ of Small Nuclear RNAs in Ar- 
chaea." Science 288 (i^ril 21^000): 517-22. 

Salehi-Ashtiani, Kourosh, and Jack W. Szostak. "In Vitro E^olutim 
Suggests Multiple Origins for the Hammerhead Ribosome." Na- 
ture 414 (November 1^001): 82-84. 



Robson, Paul, et al. "The Structure and Organization of Lamprin 
Genes: Multiple-Copy Genes vdth Alternative Splicing and Conver- 
gent E^'olution with Insect Structural Proteins.' ' Molecular Biology 
andEvolution 17 (November 2000): 1739-52. 

Kiaier, K., et al. "Convei^ent Evolution of Major Histocompatibility 
Complex Molecules in Humans and New Wold Monkeys." Initnu- 
nogeneticsW (March 2000): 169-78. 

Carosa, Eleonora, et al. "Structure and Egression of the Scallop 
Q-Crystallin Gene: Evidence for Convergent E^'tJution of Promoter 
Sequences." Journal of Biological Chemistry 211 (January 4, 
2002): 656-64. 

Nesbo, Camillia L, and W. Fa^ Doolittie. ' 'Active Self-Splicing 
Group I Introns in 23S iRNA Genes of Hyperthermophilic Bacteria, 
Derived fi^m hitrons in Eukaryotic Organelles." Proceedings of the 
National Academy of Sciences, USA 100 (September 16,2003): 
10806-11. 

Vowles, Edward J. , and AMDiani Amos. "Evidence for Widespread 
Convergent Evolution around Human Microsatellites." PLoS Biol- 
ogy! (August 17,2004): el99. 



Frick, Inga-Maria, et al. "Convei^ent Ev(duti(xi among Immuno- 
globulin G-Bindir^ Bacterial Proteins." Proceedings of the National 
Academy of Sciences, USAS9 (September 15,1992): 8532-36. 

Ollis, David L, et al. ' 'The oc/(3 Hydrolase Fold.' ' Protein Engineer- 
ing 5 (AprA 1992): 197-211. 

Rawlings, Ndl D., and Alan J. Barrett. "EvtJutionary Families 

of Peptidases." Biochemical Journal 290 (February 15,1993): 
205-18. 



208 



The Cell's Design 



Myoglobins in humans and 
gastropods 



Hibulin in eultaryotes and FtsZ 
in bacteria 

D-alanine:D-alanine ligase and 
cAMP-dependent protein Idnase 

Cytoldnes in vertebrates and 

invertebrates 



Zinc peptidases 



Redox r^^ulation of glucose 
6-phospliate dehydrogenase in 
plants and cyanobacteria 

MEK ethanol dehydrogenase/ 
acetaldehyde reductase in ver- 
tebrates and Escherichia coli 



Suzuki, Tomoliiko, H. Yuasa, and Ktyoliiro Iniai. "Convergent Evolu- 
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BiophysicaActa 1308 (July 31,1996): 41-48. 

Desai, Arshad, and Timothy J. Mitchison. ' 'Hibulin and FfcsZ Struc- 
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(July 1998): 523-27. 

Denessiouk, K. A., et al. "Tvro 'Unrelated' Families of ATP-Depen- 
dent Einzymes Share Extensive Structural Similarities about Their 
Cofactor Binding Sites." Protein Science! (May 1998): 1136-46. 

Beschin, Alain, et al. "Convei^ent EvtJution of Cytoldnes." Na- 
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Makarova, Kra S., and Nidi V. Grishin. "The Zn-Peptidase Super- 
famify: Functional Convergence after Evolutionary Divergence." 

Journal of Molecular Biology 292 (September 10,1999): 11-17. 

Wendt, Urte K., et al. "Evidence for Functional Convergence of 
Redox R^ulation in GfiPDH Isoforms of Cyanobacteria and Higher 
Plants." Plant Molecular Biology 4() (June 1999): 487-94. 

Shafqat, Jawed , et al. ' 'An Ethanol-lnducible MCR Ethanol Dehy- 
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Journal of Biochemistry '263 (July 1999): 305-11. 



Carbonic anhydrase in bacteria 
and archaea 

Myo-inositol-1-phosphate syn- 
thase in eukaryotes, bacteria, 
and archaea 

Myoglobins in eukaryotes and 
myoglobin-like, heme- contain- 
ing protein in archaea 

Calmodulins in vertebrates and 
cephalochord ates 



Hieromone bindir^ proteins in 
moths 

DNA Holliday junction resolvases 
in bacteria and eukaryotic 

viruses 

The E8NA replication protein, 
RepA, in Gram-negative bac- 
teria plasmids, archaea, and 
eukaryotes 



Smith, Kory S., et al. "Carbonic Anhydrase Is an Ancient Eiizyme 
Widespread in Prokaryotes." Proceedings of the National Academy 
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Bachhawat, N. N., and S. C. Mande. "Conplex EvtJution of the 
Inositol- 1-Phosphate Synthase Gene among Archaea and Eubac- 
teria." Trends in Genetics'^ (March 2000): 111-13. 

Hou, Shaobin, Randy W. Larsen, Dmitai Boudko, Charles W. Riley, 
et al. ' 'Myoglobin-Like Aerotaxis Transducers in Archaea and Bac- 
teria." Nature 403 (February 3,2000): 540-44. 

Karabinos, Anton, and Debashish Bhattacharya. "Molecular 
Evtrfution of Calmodulin and Calmodulin-Like Genes in the Ce- 
phalochordate Branchiostoma." Journal of Molecular Evolution 51 
(August 2000): 141-48. 

Willett, Christopher S. ' "Do Pheromone Bindir^ Proteins Converge 
in Amino Add Sequence WiMn Pheromones Converge?" Journal of 
Molecular Evolution 50 (February 2000): 175-83. 

Garcia, Alonzo D., et al. ' 'Bacterial-Type HNA Holliday Junction 

Resolvases in Eukaryotic Viruses." Proceedings of the National 
Academy of Sciences, USA 91 (August 1,2000): 8926-31. 

Giraldo, Rafael, and Ram6n Diaz-Orejas. ' 'Similarities between the 
IKNA Replication Initiators of Gram-N^ative Bacteria Plasmids 
(RcpA) and Eukaryotes (0rc4p)/Archaea (Cdc6p).' ' Proceedings 
of the National Academy of Sciences, &8A(Aj^ 24,2001): 
4938-43. 



A Style All His Own 



209 



Spider silk fibrran sequences 



Alcoliol deliydrogenase in 
Drosophila and medfty, olive %, 
and flesh Qy 

Type n restriction enzymes 



Heavy metal binding domains of 
copper chaperones and copper- 
transporting ATPases 

Opsin in vertebrates and 

invertebrates 

lonotropic and nietabotropic 
neurotransmitter receptors 

G^ junction proteins in Inverte- 
brates and vertebrates 

Neurotoxins in invertebrates and 
vertebrates 

Antl-Fj-ellmlnation mechanism 
in 1 and 10 polysaccharide 
lyases 

al,4-fucosyltransferase activity 
in primates 



Aldehyde oxidase into xanthine 
dehydrogenase two separate 
times 



RuBisCo-like protein of Bacillus 
in nonphotosynthetlc bacteria 
and archaea and photosynthetic 
RuBisCo In photosynthetic 
bacteria 

Active site of creatinine aml- 
dohydrolase of Pseudomonas 
putida and hydantolnase-llke 
cyclic anildohydrolases 



Gatesy, John, et al. "Extreme Diversity, Conservation, and Conver- 
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Brogna, Saverio, et al. "The Drosophila Alcohol Dehydrogenase 
Gene May Have Evolved Independently of the Functionally Homol- 
ogous Medffy, OHve F^, and Flesh F^ Genes." Molecular Biology 
and Evolution 18 (March 2001): 322-29. 

Bujnicki, Janusz, Monika Radlinska, and Leszek Rychlewski. 
"Potyphyletlc Evolution trf" Type n Restriction Enzymes Revisited: 
Two Independent Sources of Second-Hand Folds Revealed." 
Trends in Biochemical Sciences 26 (January 2001): 9-11. 

Jordan, I. Kir^, et al. "Independent Evolution of Heavy Metal-As- 
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622-33. 

Zakon, Hardd H. "Convca^ent Evolution on the Molecular Level." 

Brain, Behavior and Evolution 59, nos. 5-6 (2002): 250-61. 

Ibid. 



Ibid. 



Ibid. 



Chamock, Simon J . , et al. ' 'Convergent Evolution Sheds Light on 
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Lyases." Proceedings of the National Academy of Sciences, 
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Dupuy, Fabrice, et al. "cxl,4-Fucosyltransferase Activity: A Sig- . 
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Rodrlguez-Trelles, Francisco, RosaTarrlo, and Francisco J. Ayala. 
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Ashida, Hlroki, et al. "A Functional Link between RuBisCO-Like 
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(October 10,2003): 286-90. 



Beuth, B., K. Nlefind, and D. Schomburg. "Crystal Structure of 
Creatinlnase from Pseudomonas putida: A Novd Fdd and a Case 
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tember 5, 2003): 287-301. 



210 



The Cell's Design 



The insect flight muscle protein 
arUirin in Diptera and Hemiptera 

The enzyme, tRNA(mlG37) 
inethyltransferase, in bacteria 
and arctiaea 

P-lactam-liydroIyzing function 
of tlie B1+B2 and B3 subclasses 
of metallo-p-Iactamases 

Catabolic enzymes for galac- 
titol, and D-tagatose in enteric 
bacteria 



Lipases and GDSL esterases/ 

lipases 

Chitosanases 



Plant and c^anobacterial 
phytochromes 

The outer membrane protein, 
OiipA, in Enterobacteriaceae 

Cardiovascular risk factor, LPA in 
hedgehogs and primates 

Lectin-like activity of cytokines 
in vertebrates and invertebrates 



Temperature adaptation of 
Aj-lactate dehydrogenases of 
Pacific damselfishes 

Scorpion and sea anemone 
toxins that bind to voltage-gated 
potassium \fx\ channels 

FeruloyI esterase A in 
microorganisms 



Schmitz, Stephan, et al. "Molecular Evolutionary Convergence of 
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Christian, Thomas, et al. "Distinct Origins of tRNA(ml G37) Methyl- 
transferase." Journal of Molecular Biology 339 (June 11,2004): 
707-19. 

Hall, Barry, Stephen Salipante, and Miriam Barlow. ' 'Indqjen- 
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Lactamases." Journal of Molecular Evolution 59 (July 2004): 
133-41. 

Shakeri-Garakani, et al. "The Genes and Enzymes for the Ca- 
tabolism of Galactitol, D-Tagatose, and Related Carbohydrates in 
Klebsiella oxytoca M5al and Other Eiiteric Bacteria Display Con- 
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2004): 717-28. 

Akoh, C. C, et al. "GDS3^ Family of Serine Esterases/Lipases." 
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Adadii, Wataru, et al. "Crystal Structure of Famify GH-8 Chitosan- 
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Lamparter, T. 'T^vdutitHi of Cyanobacterial Plant Phytochromes." 
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Gophna, U., et al. "OnpA rf a Septicemic Escherichia coli 078 — 
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Bofielli, D., J. F. Cheng, and E. M. Rubin. "Convei^ent Evolutitm 
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Beschin, A., et al. "Functional Convergence of Invertebrate and 
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Johns, Gleam C, and George N. Somero. "Evolutitmary Conver- 
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Gasparini, S., B. Gilquin, and A. Menez. ' 'CtMnparison of Sea Anem- 
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Hermoso, J. A., et al. ' 'The Crystal Structure of Faiiloyl Esterase A 
h-om Aspergillus niger Suggests Evolutive Functional Convergence 
in FeruloyI Esterase Famify." Journal of Molecular Biology 338 
(April 30,2004): 495-506. 



A Style All His Own 



211 



The proofreadii^ domain of 
the enzyme tfireon^i-tRNA syn- 
thetase ui archaea and bacteria 

Protein inhfcitors of proteases 

A^inate fyases 



Defensinsfrom Insects and 
moDusks and ABF proteins in 
nematodes 

Blue and red l^ht photorecep- 
tors in diatoms 



Korencic, Dragana, et al. "A Freestanding Proofreading Domain 
Is Required for Protein Synthesis Qualify Control Archaea." Pro- 
ceeding of the National Academy of Sciences, fS/1101 (Jufy 13, 
2004): 10260-65. 

Ottewsld, Jacek, et al. 'The Mai^ Faces of Protease- Protein In- 
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Osawa, Takuo, et al. "Ciystal Structure of the A^inate (Po^ oc-L^ 
Guluroimte) Lyase from Corynebacteriutn sp. At 1.2 A Resolution." 
Journal of Molecular Biology ?AS (Fd»ruaiy 4,2005): 1111-18. 

Froy, Oren. "Convei^ent Evolution of Invertebrate Defensins and 
Nematode Antibacterial Factors." Trends in Microbiology 13 (July 

2005): 314-19. 

Falciatore, Ai^ela, and Chris Bowler. 'The Evohition and Function 
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mental Biology 6S (2005): 317-50. 



Red l^ht photoreceptors in ferns 
and green algae 



Xanthine oxidation in liii^us 



The muscle protein troponin C in 
various insect orders 

Structure of immunt^lobulin 
and C fype lectin receptors 

The placental development 
syncytin &mi^ of proteins in 
primates and Muridae from 
separate endogenous retrovirus 
infections 

Structure and fiinction of S- 
adenosyhnethionine-binding 
proteins 

2-methyl>ufyiyi-CoA dehy- 
drogenase In potato and short/ 
branched-chain acyl-CoA dehy- 
drogenase in humans 

Dynamin-mediated endoc^osis 
in multicellu^r animals and 
ciliates 



Suetsugu, Nor^idd, et al. "A Chimeric Photoreceptor Grcne, NEO- 
CHROME, Has Arisen Twice during I%nt Evolution." Proceedings 

of the National Academy of Sciences, USA 102 (September 20, 
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Cuhrone, Antonietta, et al. "Convei^ent Evolution of Hydrox^^tion 
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276-90. 

Herranz, Raul, Jesus Mateos, and Roberto Marco. "Diversification 
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Fei^, Jianwen, et al. "Convei^ence on a Distinctive Assembfy 
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Dupressoir, Anne, et al. "Syncytin-A and Syncytin-B, Two Fuso- 
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Ko^ial, Piotr Z., and Arcad^ R. Mushegian. "Natural Histoiy of 5"- 
Adenosybnethionine-Bindii^ Proteins." BMC Structural Biology 5 
(October 14,2005): art. 19. 

Goetzman, Eric S., et al. "Convei^ent Evolution of a 2-Methylbu- 
fyiyl-CoA Dehydrogenase fiiom Isovalerj^-CoA Dehydrogenase in 

Solanum tuberosum. " Journal of Biological Chemistry 280 (Fdbru- 
aiy 11,2005): 4873-79. 

Elde, Neb C, et al. "Elucidation of Clathrin-Mediated Endocytosis 
in Tetrahymena Reveals an Evohitionari^ Convei^ent Recruitment 
of Dyimmin." PLoS Genetics 1 (November 4,2005): e:52. 



212 



The Cell's Design 



The animal glycan- recognizing 
proteins — lectins and sulfated 
g^cosaniinoglycan bindii^ 
proteins — in animals 

Sodium channel in the electric 
oi^an of the momiyriK>mi and 
gymnotiform electric fishes 

Clathrin heavy and l^ht chain 
isoforms in chordates 



Varid, i^H, and Takashi Angata. "S^lecs The Major Subfami^ of 

l-Type Lectins." GlycobiologyW (Jstnusiry 2006): 1R-27R. 



Zakon, Harold H„ et al. "Sodium Channel Genes and the Evolution 
of Diversi^ in Communication Signals of Electric Fishes: Conver- 
gent Molecular Evolution." Proceedings of the National Academy 
of Sciences, USA 103 (March 7,2006): 3675-80. 

Wakeham, Diane E., et al. "Ckthrin Heavy and L%ht Chain Iso- 
forms Originated by Independent Mechanisms of Gene Duplication 
durii^ Chordate Evolution." i*/*oc^e(//«gs of the National Academy 
of Sciences, USA 102 (May 17,2005): 7209-14. 

Peny, Andrew J . , et al. "Convei^ent Evolution of Receptors for 
Protein Import into Mitochondria." Current Biology 16 (FeJbruaiy 7, 
2006): 221-29. 

Smith, Brian 0., et al. 'The Structure of Leisltmania mexicana ICP 
Provides Evidence for Convei^ent Evolution of Cysteine Peptidase 
Inhibitors." Journal of Biological Chemistry 281 (Mardi 3,2006): 
5821-28. 

Si, Zhihai, et al. "Evolution of a Cytoplasmic Tr^artite Motif (TRIM) 
Protein in Cows that Restricts Retroviral Infection." Proceedings 

of the National Academy of Sciences, USA 103 (May 9,2006): 
7454-59. 

Woodii^, Stephen, et al. "Independent Evolution of Bitter-Taste 
Sensitivity in Humans and Chimpanzees." Nature MO (Api^ 13, 
2006): 930-34. 

Shepherd, Mark, Tamara A. Dailey, and Hany A Dailey. "A New 
Class of [2Fe-2S]-Cluster-Containii^ Protoporphyrin (DQ Ferroche- 
latases." Biochemical Journal 397 (Jufy 1,2006): 47-52. 

Rivera-Milki, E., C. A. Stuermer, and E. Malaga-TriDo. "Ancient Ori- 
gin of Reggie (FlotiDin), Reggie- Like, and Other Lqiid-Raft Proteins: 
Convei^ent Evolution of the SPFH Domain." Cellular and Molecular 
Life Sciences 63, no. 3 (Februaiy 2006): 343-57. 

Cheek, S., S. S. Krishna, and N. V. Grishin. "Structural Classilica- 
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Maier, Timm, Simon Jenni, and Nenad Ban. "Architecture of Mam- 
maUan Fatty Acid Synthase at 4.5 A Resolution." Science 311 
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NAD(P)H:quinone oxidoreductase Vasifiou, VasiUs, David Ross, and Daniel W. Nd»ert. "Update of the 
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Genomics 2 (March 2006): 329-35. 



Protein-bindii^ receptor that 
readies proteins for import into 
the mitochondria of animals; and 
plants 

ICP CI cysteine peptidase 
inhibitors 



TRIM5 anti-retroviral resistance 
factor in primates and bovines 



Protein receptors that bind bit- 
ter compounds in humans and 
chimpanzees 

Protoporphyrin (DQ ferroche- 
latase in prokaryotes and 
eukaryotes 

SPFH (stomatin-prohibitin- 
flotiDin-HflC/KHike proteins 



Dtsulfide-rich protein domains 



Fatty acid synthases in liu^i 
and animals 



A Style All His Own 



213 



Adcaiylation activity in BirA, 
lipoate protein ligase and class I 
tRNA syntlietases 

D7 and lipocalin salivary pro- 
teins in insects 

Oid shock domain of cold 
shock proteins in bacteria and 
higher plants 



Wood, Zachaiy A., et al. "Co-Repressor hiduced Orda- and Biotin 
Repressor Dimerization: A Case for Divergent Followed by Con- 
vergent Evolution." Journal of Molecular Biology 357 {March 24, 
2006): 509-23. 

Calvo, Eric, et al. "RinctiMi and EvtJution of a Mosquito Salivary 
Proton Family." Journal of Biological Chemistry 281 (January 27, 
2006): 1935-42. 

Nakaminami, Kentaro, Dale T. Karlson, and Ryozo Imai. "Func- 
tional Conservation of Cdd Shock Domains in Bacteria and 
Higher Plants." Proceedings of the National Academy of Sciences, 
USA 103 (June 27,2006): 10122-27. 



Biochemical Systems 
Bioluminescent systems 



Chlorocatediol catabolic path- 
way ill Rhodococcus opacus and 
proteobacteria 



Nucleotide excision DMA repair 
in humans and Escherichia coli 

nSA replication in bacteria and 
archaea 



ONA repair proteins 



Toxin resistance 

Biosurfactants in archaea and 
bacteria 

Glya)fytic pathways in archaea 
and bacteria 

Type m and Type IV secretion 
systems of gram-negative and 
gram-positive bacteria 

Rioi^hopantothenate biosyn- 
thesis in archaea and bacteria 



Hastings, J. W. "Biolt^cal Diversity, Chemical Mechanisms, and 
the Evolutionary Origins of Bioluminescent Systems." Journal of 
Molecular Evolution 19 (September 1983): 309-21. 

Eulberg, Dirk, et al. "EvtJutitmary Relationship between Chlo- 
rocatechol Catabolic Einzymes from Rhodococcus opacus 1 CP 
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Petit, C, and A. Sancar. "Nucleotide Evasion Repair: Rxmi E. coli 
to man:'Biochimie SV (January 2,1999): 15-25. 

Leipe, Detlef D., L. Aravind, and Eugene V. Kocmin. 'Did DNA Rep- 
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Aravind, L, D. R(dand Walk^-, and Eugene V. Koonin. "Conserved 
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Zakon, Hardd H. ' 'Convergent EvolutitHi on the Molecular Level.' ' 
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Maier, Raina M. "Biosurfactants: Evolutitm and Diveraty in Bacte- 
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Verhees, Come H., et al. "The Unique Features of Glycotytic Path- 
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Blocker, Ariel, Kaoru Komoriya, and Shin-lchi Aizawa. "Type ID Se- 
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Genschel, Ulrich. "Coenzyme A Biosynthesis: Reconstruction of 
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214 



The Cell's Design 



Crassulacean add metabolism, 
a specialized fomi of photosyn- 
thesis in the Bromeliaceae fain- 
ify (rf" plants 

Alternate splicing of tandem 
exons in ion-channel genes 
in humans and Drosophila 
melanogaster 

Viral capsid structure of viruses 
that infect archaea, bacteria, 
and eukarya 

Hub-based design of gene regu- 
latory networks 

The two Mg/i metal kx\ 
mechanism in protein phos- 
phoryltransferases and RNA 
phosphoryltransferases 

Halophilic biochemical adapta- 
tions in bacteria and archaea 



Regulatory network linking HSA 
synthesis to cell cycle in yeast 
and bacteria 

Biochemical mechanisms for ioa 
r^;ulation in invertebrates 

Apoptosis and immune response 
defenses in large nuclear and 
cytoplasmic E8NA viruses of 
eukaryotes 

Endocannabinoid system 

Nonuniversal codon usage in the 
genetic code of arthropod mito- 
chondrial genomes 

Xist RNA gene-mediated X chro- 
mosome inactivation in euthe- 
rian and marsupial mammals 



Crayn, Darrai M., Klaus Wlntea-, and J.Andrew C. Smith. "Mult^le 
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A Style All His Own 91 S 

Currently recognized examples of molecular convergence are likely just 
the tip of the iceberg. For instance, researchers from Cambridge Univer- 
sity (United Kingdom) examined the amino acid sequences of over six 
hundred peptidase enzymes. (Peptidases are proteins that break down 
other proteins by cleaving bonds between amino acids.) When viewed 
from an evolutionary standpoint, these workers discovered that there 
appear to have been over sixty separate origin events for peptidases. This 
result stands in sharp contrast to what the researchers expected to find: 
a handful ofpeptidase families with separate origins. In many cases, the 
peptidases appeared to converge on the same enzyme mechanisms and 
reaction specificities.,: 

Researchers from the National Institutes of Health recently made a simi- 
lar discovery. These scientists systematically examined protein sequences 
from 1,709 EC (enzyme commission) classes and discovered that 105 of 
them consisted of proteins that catalyzed the same reaction, but must have 
had separate evolutionary origins. 

In a separate study, this same team discovered that in at least twelve 
clear-cut cases the same essential cellular functions were carried out 
by unrelated enzymes (from an evolutionary vantage point) when the 
genomes of the bacteria Mycoplasma genitalium and Hemophilus in- 
fluenzae were compared. , The researchers noted that the genomes of 
these two microbes are small, close to the size of the minimal gene set 
(see chapter 3, p. 54). It's quite likely a greater number of convergent 
systems would be identified if the genomes ofmore complex organisms 
were compared. 

The explosion in the number of examples of molecular convergence is 
unexpected if life results from historical sequences of chance evolution- 
ary events. Yet, if life emanates from a Creator, it's reasonable to expect 
he would use the same designs repeatedly. These creations would give the 
appearance of multiple independent origin events when viewed from an 
evolutionary vantage point. 

It is beyond the scope of this book to detail each example of molecular 
convergence. Rather, a discussion of one of the most amazing examples 
of molecular convergence, the independent origins of DNA replication 
in bacteria and archaea/eukaryotes, illustrates how remarkable molecular 
convergence is from an evolutionary standpoint and why it's preferable to 
view the repeated independent origins of biochemical systems as the work 
of a Divine Artist who creates with a style all his own. 



225 The Cell's Design 

The Origin of DNA Replication 

The process of generating two "daughter" molecules identical to the 
"parent" DNA molecule — DNA replication — is essential for life. This 
duplication plays a central role in reproduction, inaugurating the cell- 
division process. Once replicated, a complex ensemble of enzymes dis- 
tributes the two newly made DNA molecules between the emerging 
daughter cells. 

Because of its extremely complex nature (described below), most bio- 
chemists previously thought DNA replication arose once, prior to the 
origin of LUC A, the last universal common ancestor. Figure 11.1 shows 
the relationship between this supposed "organism" and the evolutionary 
tree of life. 

Many biochemists have long regarded the close functional similarity of 
DNA replication, observed in all life, as evidence for the single origin of 
DNA replication prior to the emergence ofLUCA. 

The common features of DNA replication include 

1. semiconservative replication, 

2. initiation at a defined origin by an origin-replication complex, 

3. bidirectional movement of the replication fork, 

4. continuous (leading strand) replication for one DNA strand and 
discontinuous (lagging strand) replication for the other DNA 
strand, 

5. use of RNA primers, and 

6. the use of nucleases, polymerases, and ligases to replace RNA primer 
with DNA (see DNA replication discussion below). 

Surprisingly, in 1999 researchers from the National Institutes of Health 
demonstrated that the core enzymes in the DNA replication machin- 
ery of bacteria and archaea/eukaryotes (the two major trunks of the 
evolutionary tree of life) did not share a common evolutionary origin. 
From an evolutionary perspective, it appears as if two identical DNA 
replication systems emerged independently in bacteria and archaea — 
after these two evolutionary lineages supposedly diverged from the last 
universal common ancestor.,, (If evolutionary processes explain the origin 
of DNA replication, then two different systems should exist in archaea 
and bacteria.) 



A Style All His Own 



217 



Animals 



Plants 



Microsporidia 



£ coli 




Flavobacteria 



Green sulfur bacteria /. 



Borrelia burgdorferi 



Thermococcus 

Methanobacteritim 

Halococcus 

Halobacterium 
Methanococcus jannaschii 



Presumed common 
progenitor of archaebacteria 
and eukaryotes 

Presumed common 

progenitor of all 
extant organisms 
(LUCA) 



Figure 11.1. LUCA and the Tree of Life 

The proposed evolutionary relationship of life's major groups has the domains Archaea and 
Bacteria diverging separately from the Last Universal Common Ancestor (LUCA). 



DNA Replication — A Signature Style 



DN A consists of two polynucleotide chains aligned in antiparallel fash- 
ion. (The two strands are arranged parallel to one another with the starting 
point of one strand in the polynucleotide duplex located next to the ending 



21g The Cell's Design 

point of the other strand and vice versa. See chapter 2, p. 48.) The paired 
polynucleotide chains twist around each other forming the well-known 
DNA double helix. The polynucleotide chains are generated using four 
different nucleotides: adenosine (A), guanosine (G), cytidine (C), and 
thymidine (T) . (See figure 2.7, p. 49.) 

A special relationship exists between the nucleotide sequences of the two 
DNA strands.,. These sequences are considered complementary. When the 
DNA strands align, the A side chains of one strand always pair with T side 
chains from the other strand. Likewise, the G side chains from one DNA 
strand always pair with C side chains from the other strand. Biochemists 
refer to these relationships as base-pairing rules. 

As a result of this base pairing, if biochemists know the sequence of one 
DNA strand, they can readily determine the sequence of the other strand. 
Base pairing plays a critical role in DNA replication. 

Following a Pattern 

The nucleotide sequences of the parent DNA molecule function as a 
template directing the assembly ofthe DNA strands of the two daughter 
molecules. It is a semiconservative process because after replication, each 
daughter DNA molecule contains one newly formed DNA strand and one 
strand from the parent molecule (see figure 11.2). 

Conceptually, template-directed, semiconservative DNA replication 
entails the separation ofthe parent DNA double helix into two single 
strands. According to the base-pairing rules, each strand serves as a tem- 
plate for the cell's machinery to follow as it forms a new DNA strand with 
a nucleotide sequence complementary to the parent strand. Because each 
strand of the parent DNA molecule directs the production of a new DNA 
strand, two daughter molecules result. Each possesses an original strand 
from the parent molecule and a newly formed DNA strand produced by 
a template-directed synthetic process. 

The Start of It All 

DNA replication begins at specific sites along the DNA double helix. 

Figure 11.2. Semiconservative DNA Replication 

For template-directed, semiconservative D N A replication each strand serves as a template for the 
cell's machinery to assemble a new DNA strand. Each ofthe two "daughter" molecules possesses 
an original strand from the "parent" molecule and a newly formed DNA strand. 



Parental DNA 



Replicated DNA 
after one generation 



Replicated DNA 
after two generations 



220 



The Cell's Design 



Direction of replication 



Direction of replication 




Discontinuous synthesis 
of lagging strand 



Okazaki fragments 



Figure 11.3. DNA Replication Bubble 

The replication bubble forms where the DNA double helix unwinds. Because DNA 
replication proceeds in both directions away from the origin, there are two replication forks 
within each bubble. 



Typically, prokaryotic cells have only a single origin of replication. More 
complex eukaryotic cells have multiple origins. 

The DNA double helix unwinds locally at the origin of replication to 
produce a replication bubble (see figure 11.3). The bubble expands in both 
directions from the origin during the course of replication. Once the indi- 
vidual strands of the DNA double helix unwind and are exposed within 
the replication bubble, they are available to direct the production of the 
daughter strand. The site where the double helix continuously unwinds is 
the replication fork. Because DNA replication proceeds in both directions 
away from the origin, each bubble contains two replication forks. 



Moving On 

DNA replication can proceed only in a single direction, from the top of 
the DNA strand to the bottom. Because the strands that form the DNA 



A Style All His Own 221 

double helix align in an antiparallel fashion with the top of one strand jux- 
taposed to the bottom of the other strand, only one strand at each replica- 
tion fork has the proper orientation (bottom-to-top) to direct the assembly 
of a new strand in the top-to-bottom direction. For this leading strand, 
DNA replication proceeds rapidly and continuously in the direction of 
the advancing replication fork (see figure 11.3). 

DNA replication can't proceed along the strand with the top-to-bottom 
orientation until the replication bubble expands enough to expose a sizeable 
stretch ofDNA. When this happens, DNA replication moves away from 
the advancing replication fork. It can proceed only a short distance along 
the top-to-bottom oriented strand before the replication process has to 
stop and wait for more of the parent DNA strand to be unwound. After a 
sufficient length of the parent DNA template is exposed the second time, 
DNA replication can proceed again, but only briefly before it has to stop 
and wait for more DNA to become available. 

The process of discontinuous DNA replication takes place repeatedly 
until the entire strand is replicated. Each time DNA replication starts and 
stops, a small fragment of DNA is produced. These pieces ofDNA (that 
eventually comprise the daughter strand) are called Okazaki fragments 
after the biochemist who discovered them. The discontinuously produced 
strand is the lagging strand, because DNA replication for this strand lags 
behind the more rapidly, continuously produced leading strand (see figure 
11.3). 

One additional point: the leading strand at one replication fork is the 
lagging strand at the other replication fork because the replication forks at 
the two ends ofthe replication bubble advance in opposite directions. 

Considering the complexity ofDNA replication described up to this 
point, it's hard to imagine this process evolving once, let alone indepen- 
dently on two separate occasions. But there is even more that makes it dif- 
ficult to fathom how DNA replication could have occurred by naturalistic 
processes. 

The Protein Palette 

An ensemble of proteins is needed to carry out DNA replication (see 
figure 11.4). Once the origin recognition complex (which consists of sev- 
eral different proteins) identifies the replication origin, a protein called 
helicase unwinds the DNA double helix to form the replication fork. The 



222 



The Cell's Design 



DNA polymerase III 
{dimer) holoenzyme 



Single-stranded 
binding (SSB) proteins 




Direction of synthesis 



Figure 11.4. The Proteins of DNA Replication 

The ensemble ofproteins needed to carry out DNA replication include helicase, single-strand 
binding proteins, the primosome, DNA polymerases, 3'-5' exonuclease, and ligase. 



process of helix unwinding introduces torsional stress in the DNA helix 
downstream from the replication fork. Another protein, gyrase, relieves 
the stress preventing the DNA molecule from supercoiling, like the cord 
attached to the telephone receiver after the phone is hung up. 

Single-strand binding proteins bind to the DNA strands exposed by 
the unwinding process. This association keeps the fragile DNA strands 
from breaking apart. 

Once the replication fork is established and stabilized, DNA replication 
can begin. Before the newly formed daughter strands can be produced, a 
small RNA primer must be made. The protein that synthesizes new DNA 
by reading the parent DNA template strand — DNA polymerase — can't 
start from scratch. It must be primed. A massive protein complex, the 
primosome, which consists of over fifteen different proteins, produces the 
RNA primer needed by DNA polymerase. 



Primed and Ready to Go 

Once primed, DNA polymerase will continuously produce DNA along 
the leading strand. However, for the lagging strand, DNA polymerase can 
only generate DNA in spurts to produce Okazaki fragments. Each time 



A Style All His Own 



223 



DN A polymerase generates an Okazaki fragment, theprimosome complex 
must produce a new RNA primer. 

After DN A replication is completed, the RNA primers are removed from 
the continuous DN A of the leading strand and the Okazaki fragments that 
make up the lagging strand. A protein called a 3'-5' exonuclease removes 
the RNA primers. A different DNA polymerase fills in the gaps created 
by the removal of the RNA primers. Finally, a ligase protein connects all 
the Okazaki fragments together to form a continuous piece ofDNA out 
of the lagging strand. 

This cursory description ofDNA replication clearly illustrates its com- 
plexity and intricacies. (Many details were left out.) It's phenomenal to think 
this biochemical system evolved a single time, let alone twice. There is no 
obvious reason for DNA replication to take place by a semiconservative, 
RNA primer-dependent, bidirectional process that depends on leading 
and lagging strands to produce DNA daughter molecules. Even if DNA 
replication could have evolved independently on two separate occasions, 
it's reasonable to expect that functionally distinct processes would emerge 
for bacteria and archaea/eukaryotes given their idiosyncrasies. But, they 
did not. 



No Other Style Like the Creator's 

Considering the complexity oflife's chemical systems, pervasive mo- 
lecular convergence fits uncomfortably within an evolutionary framework. 
Paleontologist J. William Schopf, one of the world's leading authorities on 
Earth's early life says. 

Because biochemical systems comprise many intricately interlinked pieces, 

any particular full-blown system can only arise once Since any complete 

biochemical system is far too elaborate to have evolved more than once 
in the history of life, it is safe to assume that microbes of the primal LCA 
[last common ancestor] cell line had the same traits that characterize all its 
present-day descendents.,. 

The pattern expected by Schopf and other evolutionary biologists is 
simply not observed at the biochemical level. An inordinate number of 
examples of molecular convergence have already been discovered. In all 
likelihood, many more will be identified in the future. Each new instance 



224 '^'^^ Cell's Design 

of molecular convergence makes an evolutionary explanation for life less 
likely. 

Throughout this book, the case for biochemical design has been made 
by comparing the most salient features of life's chemistry with the hall- 
mark characteristics ofhuman designs. The close analogy between bio- 
chemical systems and human designs logically compels one conclusion: 
life's most fundamental processes and structures reflect the artistry of a 
Creator. The pervasiveness of molecular convergence — the recurrence of 
designs — throughout the biological realm adds many more works of art to 
his portfolio. The Divine Artist creates with a style all his own. 

The next chapter shows how he used the biochemistry in the cell to 
construct a mosaic beyond what humans could begin to imagine. 



12 



AN ELABORATE MOSAIC 



Mosaics made with small pieces of colored glass, stone, or other materials 
were quite the rage in the ancient world. Homes and buildings throughout 
Greece, Rome, and North Africa used this decorative art to adorn their 
interiors. In Rome, elegant floor mosaics distinguished luxurious villas. 
The walls and ceilings of the Domus Aurea, built for Nero in AD 64, were 
covered with these intricate designs., 

Early Christians adapted the use ofmosaics to decorate basilicas with 
depictions of Christ and biblical scenes. This fourth-century practice 
inaugurated a long tradition of mosaic art in churches that extended well 
into the Middle Ages. 

In the early 1970s, scientists realized that biochemical mosaics also adorn 
the surfaces and interior of cells. A montage of hundreds of different phos- 
pholipid species and proteins constitute the cell's membranes. Organized 
into two molecular layers, these membranes form a bilayer (see figures 2.4 
and 2.5, p. 47). 

At that time, biochemists S. J. Singer and Garth L. Nicolson proposed 
the fluid mosaic model to describe the structure of cell membranes (see 
chapter 2, p. 48).; This model depicts the bilayer as a two-dimensional fluid 
composed of a complex mixture of phospholipids. The bilayer acts as both 
a cellular barrier and a solvent for a variety of different types of integral 

225 



226 The Cell's Design 

andperipheral membrane proteins (see figure 2.6, p. 48). According to the 
fluid mosaic model, membranes are little more than haphazard systems with 
proteins and lipids freely diffusing laterally throughout the bilayer — at first 
glance, hardly evidence for the work of a Creator. 

Recent advances, however, indicate that the fluid mosaic model is an 
incomplete depiction. Rather than resembling a chaotic pile of stone or 
broken glass, the mosaic features of cell membranes much more closely 
resemble the skillful art form found in Byzantine and Roman churches. 
Biochemists now acknowledge that cell membranes consist of a careful 
arrangement of molecular pieces. 

This exquisite organization at the molecular level is integral to many 
functions performed by cell membranes. These supramolecular assemblies 
also require fine-tuning of their composition to exist as stable structures 
and carry out key operations. In addition, some biochemists think cell 
membranes harbor information. These three characteristics (organization, 
fine-tuning, and information) are part of the intelligent design analogy 
discussed throughout this book and reveal the meticulous work of a Di- 
vine Artist. 

A few key advances in membrane biochemistry have transformed the 
way scientists view cell membranes. These new insights represent a case 
study of sorts and show how pattern recognition — using the intelligent 
design template — can be applied to specific features of the cell in order to 
reveal the work of the Creator. 



An Intricate Design 

Cell membranes are comprised ofphospholipids that possess a wide 
range of chemical variability. Phospholipid head groups typically consist 
of a phosphate group bound to a glycerol (glycerin) backbone. That group 
binds one of several possible compounds that vary in their chemical and 
physical properties. Frequently, phospholipids are identified by their head 
group structure. Figure 2.3 (p. 46) shows, as an example, a choline molecule 
bound to the phosphate head group. Alternatively, phospholipid head 
groups bind ethanolamine, serine, glycerol, and inositol molecules. 

Phospholipids vary in tail length and structure. Their tails are typically 
long linear hydrocarbon chains linked to the glycerol backbone. The phos- 
pholipid hydrocarbon chains are commonly fourteen, sixteen, or eighteen 



An Elaborate Mosaic 



227 



carbon atoms long, but can be as short as twelve and as long as twenty-four. 
Sometimes one or both of the hydrocarbon chains possesses a permanent 
kink. 

These kinks can occur at different locations along the chain length. 
(Carbon-carbon double bonds inserted into the hydrocarbon chain cause 
the kinks.) In addition to phospholipids, the cell membranes of bacteria 
contain another type oflipid (lipopolysaccharides). The cell boundaries 
ofeukaryotic organisms also consist of several different classes of lipids 
(such as cholesterol, plasmalogens, sphingolipids, andglycolipids) beyond 
phospholipids. 

Superficially, the complex chaotic lipid compositions of cell membranes 
appear to reflect a long history of undirected evolutionary events. Ac- 
cording to this view, over vast periods of time, a variety of molecules were 
incorporated into membranes as metabolic pathways that produced the 
various phospholipids randomly emerged and diversified under the auspices 
of natural selection. 

Recent advances, however, suggest that the seemingly chaotic mix of 
phospholipids in cell membranes was deliberately planned. This molecular 
mix is necessary and points to a deep rationale that underlies the mem- 
brane's composition. 3 

Using Just tlie Riglit Pieces 

The variable length and geometry of phospholipids' hydrocarbon chains 
affect the physical properties of cell membranes. Bilayers composed of phos- 
pholipids with short hydrocarbon chains or hydrocarbon chains with kinks 
possess a fluid, liquidlike interior. On the other hand, cell membranes have 
solidlike interiors if formed from phospholipids with longer hydrocarbon 
chains and chains that are straight., 

The fluidity of the cell membrane's interior has important biological 
consequences. The bilayers physical state regulates the function of inte- 
gral proteins. Local variations in phospholipid composition also create 
regions of variable fluidity within the bilayer with some areas more solid 
and others more liquid. These differences in fluidity help segregate the cell 
membrane's components into functionally distinct domains within the 
bilayer. Without a large ensemble of phospholipids, precise regulation of 
membrane protein activity and creation of functionally distinct domains 



228 The Cell's Design 

would be impossible. Phospholipids with a wide-range of hydrocarbon 
chain lengths and shapes (straight or kinked) make it possible for the cell 
to precisely adjust bilayer fluidity. 



A Living Kaleidoscope 

Phospholipids play a critical role in controlling the activity of proteins 
associated with the cell membranes and, in some instances, those proteins 
located in the cytoplasm.. This control extends beyond simply dictating 
bilayer fluidity. Phospholipids regulate protein function through direct 
and highly specific interactions. 

Through interactions mediated by the head group, phospholipids with 
glycerol (PGs) and serine (PSs) attachments bind to target proteins. PGs 
and PSs are both negatively charged. They also have distinct chemical struc- 
tures. Both features factor into their association with proteins. PSs play a 
central role in activating proteins in the cytoplasm that are part of the cell 
signalingpathways. These pathways alter the cell's metabolism in response 
to changes taking place outside the cell. 

In bacteria, PGs activate some of the proteins involved in (1) replicat- 
ing DNA, (2) assembling the outer membrane, and (3) moving proteins 
across cell membranes. 

Phospholipids with choline (PCs) and ethanolamine (PEs) as part of 
their head groups are neutral in charge. Interestingly, these two types of 
phospholipids have regions both negatively and positively charged. (The 
charges cancel each other to yield overall electrical neutrality.) PCs and 
PEs are the major phospholipid components of cell membranes. 

Even though PCs and PEs are neutrally charged, their chemical struc- 
tures differ sufficiently so these two phospholipids play distinct roles in cell 
membranes. The primary role of PCs is bilayer formation. PEs also function 
in this capacity. Additionally, PE-rich regions in cell membranes can adopt 
nonbilayer structures. These nonbilayer phases regulate the activities of some 
proteins and play a central role in cell division and membrane fusion events. 
PEs also trigger the activity ofmembrane proteins that shuttle materials 
across cell membranes. 

Phospholipids are highly involved in a litany of biochemical processes. As 
biochemist William Dohan notes, "The wide range of processes in which 
specific involvement of phospholipids have been documented explains the 



An Elaborate Mosaic 



229 



need for diversity in phospholipid structure and why there are so many 
membrane lipids.". Far from reflecting the aimlessness of evolutionary 
processes, the complexity of cell membranes appears intentional. Each 
phospholipid is an essential part of the biochemical mosaic that adorns 
the cell's surfaces. 



Baked in tlie Creator's Kiln 

Other evidence substantiates the belief that the compositional makeup 
of cell membranes is no accident. One of the universal features that de- 
fines all cell membranes is their unilamellar structure. In other words, cell 
membranes are made up of a single bilayer. 

The structure of cell membranes stands in sharp contrast to the behavior 
of bilayers made from pure phospholipids. Purified phospholipids spontane- 
ously form bilayers in water environments. Instead of forming unilamellar 
bilayers, however, phospholipids assemble into stacks of bilayers (multila- 
mellar bilayers), or alternatively, they form spherical structures that consist 
of multiple bilayer sheets.. (These structures resemble an onion, with each 
layer corresponding to one of the bilayers in the stack.) These aggregates 
only superficially resemble the cell membrane's structure that consists of a 
single bilayer, not bilayer stacks (see figure 12.1). 

Phospholipids can be manipulated by researchers to form structures 

composed of only a single bilayer. These particular aggregates arrange into a 

hollow spherical structure called liposomes or unilamellar vesicles. However, 

they are considered physically unstable and last only for a limited lifetime. 
Liposomes readily fuse with one another and revert to multilamellar sheets 

or vesicles. I 

In other words, apart from cell membranes, phospholipids spontaneously 
assemble into multibilayer sheets. So how can cell membranes consist of 
a single bilayer phase? National Institutes of Health researcher Norman 
Gershfeld explained that single bilayer phases, similar to those that con- 
stitute cell membranes, can be permanently stable but only under unique 
conditions. : (Chemists refer to phenomena that occur under a unique set 
of conditions as critical phenomena.) 

Formation of single bilayer vesicles occurs only at a specific critical tem- 
perature. At this temperature, pure phospholipids spontaneously transform 
from either multiple bilayer sheets or unstable liposomes into stable single 



Multibi layer Sheet 




Mu Itibilayer Vesicle 




Liposome 



ggir«fc*«-**<»»w«-**i.ii 



:!^^^i^wf^- 



*,',\t t'MAfk;'*: 



An Elaborate Mosaic 



231 



bilayers.,., Above or below this temperature, the unilamellar phase collapses 
into multilamellar structures. The critical temperature varies depending on 
the specific chemical makeup of the phospholipids. In the case ofbilayers 
formed from a mixture of phospholipids, the critical temperatures depend 
on the bilayers' specific phospholipid composition. , 

Gershfeld and his team made some interesting observations along these 
lines. They noted thatphospholipids extracted from rat and squid nervous sys- 
tem tissue assemble into single bilayer structures at critical temperatures that 
correspond to the physiological temperatures of these two organisms. . 

The team also observed that for the cold-blooded sea urchin L.pictus, the 
membrane composition of the earliest cells in the embryo varies in response 
to the environment's temperature. In these cases, changes in phospholipid 
composition allowed the bilayers to adopt a unilamellar phase at a critical 
temperature that corresponded to the environmental conditions. In addi- 
tion, Gershfeld's group noted that the bacterium £". coli also adjusts its cell 
membrane phospholipid composition to maintain a single bilayer phase 
as growth temperature varies. 

These studies highlight the biological importance of the critical bilayer 
phenomena. So does other research that indicates how devastating it is for 
life when cell membranes deviate from critical conditions. Gershfeld identi- 
fied a correlation between the rupture of human red blood cells (hemolysis) 
and incubation at temperatures exceeding 37°C (the normal human body 
temperature). Transformation of the cell membrane from a single bilayer 
to multiple bilayer stacks accompanies the red blood cells' hemolysis — a 
loss of the cell membrane's critical state.,, 

Gershfeld and his collaborators even provided some evidence that cell 
membrane defects at the sites of neurodegeneration may play a role in 
Alzheimer's disease. . Presumably, collapse of the cell membranes single 
bilayer state into a multiple bilayer condition stems from altered membrane 
phospholipid composition. 

The work of Gershfeld's team provides further evidence that cell mem- 
branes are carefully crafted structures that appear to be the product of a 
Creator's painstaking handiwork. It indicates that cell membranes are highly 

Figure 12.1. Bilayer Assemblies 

A segment ofa multilamellar bilayer sheet and a cutaway of a multilamellar vesicle are depicted. 
These structures spontaneously form when phospholipids are added to water. Researchers can 
induce phospholipids to form structures composed of only a single bilayer in the laboratory. A 
cutaway ofa unilamellar vesicle or liposome is shown. 



232 The Cell's Design 

fine-tuned molecular structures dependent on an exacting set of physical 
and chemical conditions. 



Each Piece Placed by Hand 

The fine-tuning of cell membrane lipid compositions does more than 
stabilize the single bilayer phase. One recent study demonstrates that it 
also appears to critically influence the interactions between cell membranes 
and proteins. 

A team of Russian scientists, exploring the role that phospholipids play 
when the cell's machinery inserts proteins into membranes, discovered that 
successful insertion of the protein colicin E (abacterial toxin) requires a 
fairly exacting phospholipid composition. =„ Introduction of colicin E into 
bilayers requires PG levels between 25 and 30 percent. 

PGs bear a negative charge that sets up an electrical potential at the mem- 
brane's surface. This potential plays a key role in the insertion process. If the 
surface potential varies outside a narrow range of values, protein insertion 
doesn't properly take place. This restrictive range of values occurs only for 
specific concentrations ofPGs. 

Surface potential depends on the salt concentration in the environment. 
The researchers noted that as they changed the salinity, the PG concentra- 
tions in the membranes had to vary accordingly to maintain the just-right 
surface potential for protein insertion to take place. 

Interestingly, the content of negatively charged phospholipids (PGs 
and PSs) in most membranes is between 25 and 30 percent.; In fact, most 
bacteria adjust the level of PGs in their membranes in response to changes 
in the salinity of the growth medium. These observations suggest that 
the compositional fine-tuning of phospholipids needed for the import of 
colicin E into bilayers may be a general requirement for the insertion of 
most membrane proteins. 



An Astonishing Arrangement 

For nearly a quarter of a century, the fluid mosaic model provided the 
guiding framework for scientists to interpret biochemical phenomena 
associated with cell membranes. But over time discoveries continue to 
mount that suggest this model is incomplete, perhaps even in some ways 



An Elaborate Mosaic 



233 



inaccurate. In recentyears, biochemists have revised the fluid mosaic model, 
recognizing that cell membranes display far more organization than origi- 
nally conceived by Singer and Nicolson.22 



Meaningful Biochemical Messages 

Biochemists and information tlieorists typically think of DNA, RNA, proteins, and more 
recently, oligosaccharides as harboring information (see chapter 8, p. 142). These 
biomolecules are made of subunit molecules linked together to form chains. Four 
different subunits (nucleotides) make DNA and RNA, and twenty different subunits 
(amino acids) compose proteins. Oligosaccharides consist of linear and branched 
monosaccharide chains. 

Just as specific sequences of letters form words, certain sequences of nucleotides, 
amino acids, and monosaccharides strung together form the biochemical "words" of 
the cell. In language, some letter combinations produce meaningful words and others 
produce gibberish. The same is true for the subunit sequences of DNA, RNA, proteins, 
and oligosaccharides. Some produce functional biomolecules, whereas others produce 
"junk" that serves no role inside the cell. 

Recently, a team of computational biologists from Israel demonstrated that informa- 
tion can also be housed and transferred in the form of complex chemical mixtures with 
highly specific molecular compositions.^ The researchers explicitly applied this idea to 
lipid aggregates and even argued from an evolutionary standpoint that the first protocells 
consisted of micelles comprised exclusively of a diverse ensemble of lipids.:. 

According to their hypothesis, in much the same way as the basilica mosaics con- 
tained meaning in their biblical scenes, these first protocells harbored information within 
the aggregate's lipid composition. These lipid aggregates replicated and transferred 
information to the next generation whenever they split in two. It's believed this process 
occurred by the addition of compounds to the lipid aggregates. These ensembles eventu- 
ally grew so large that the conglomerate became unstable and divided. According to this 
model, over time the information housed in the specific lipid compositions gave way to 
information-rich biomolecules like RNA and eventually DNA and proteins. 

This imaginative explanation for Ufe's start has received limited acceptance among 
origin- of-life researchers. Still, the idea that lipid mixtures can harbor information raises 
an important question: Do cell membranes house information in their phospholipid 
compositions? 

The functional necessity of extensive phospholipid diversity and the high-precision 
compositions of phospholipids needed to stabilize and assemble cell membranes sug- 
gest that these structures do indeed contain information. As computational biologists 
Daniel Segre and his colleagues point out, "Whai present day cells divide, they too 
transmit considerable elements of compositional information (including specific gamuts 
of lipids, proteins and RNA) which are 'inherited' from the mother cell." 



234 



The Cell's Design 



Biochemists still consider cell membranes to be a molecular mosaic. But, 
instead of viewing them as a chaotic mixture of freely diffusing components, 
scientists regard the cell's boundaries as dynamically structured, displaying 
a hierarchy of order. This newly found order bespeaks of a Creator. 

Using Different Shapes and Sizes 

Recent studies provide strong support for the idea that there are localized 
regions of order and organization within bilayers in the immediate vicin- 
ity ofmembrane proteins. For nearly thirty years, biochemists suspected 
that integral proteins had close association with some phospholipids in 
cell membranes. For example, when membrane proteins are isolated from 
cell membranes, they are often co-purified with specific phospholipid 
species. 

Biochemists speculated that these co-purified compounds were an- 
nular or boundary lipids that formed a ring about one molecular-layer 
thick around the integral proteins. 2. Traditionally these scientists viewed 
this lipid ring as dynamic. They thought that individual phospholipids 
"hop" on and off the protein, exchanging with phospholipids in the "bulk" 
bilayer. 

But now, biochemists can directly visualize annular phospholipids in 
association with membrane proteins. One of the few studies along these 
lines examined the structure of aquaporin isolated from the lenses of 
sheep eyes (see chapter 6, p. 111). Researchers noted that this protein had 
a tightly bound layer of phospholipids surrounding it. The tight association 
between the protein and the head groups of the phospholipids appears to 
be mediated by specific interactions. 

Scientists also noticed that the hydrocarbon chains of the lipids — aligned 
along the proteins axis — followed the contour of the protein s surface. In 
some cases, the hydrocarbon chains were straight, other times they were 
kinked or bent. The net effect was to produce a uniform lipid casing around 
the protein. 

This study suggests that the annular lipids are much more intimately 
associated with integral proteins than originally thought. This close, nearly 
permanent association is critical for membrane stability. It allows the inte- 
gral protein to "fit" into the bilayer without creating defects from imperfect 
packing between it and the lipid components. These defects would make 
the membrane "leaky," a detrimental condition for the cell. 



An Elaborate Mosaic 



235 



Artistic Asymmetry 



Even before Singer and Nicolson proposed the fluid mosaic model, life 
scientists recognized that the inner and outer surfaces of cell membranes 
performed different functions. Biochemists quickly determined that these 
functional differences stem from distinct protein and phospholipid com- 
positions in the inner and outer leaflets of membrane bilayers. Because the 
inner and outer monolayers differ in composition, structure, and function, 
biochemists refer to cell membranes as asymmetric. i^ 

The asymmetry of cell membranes reflects long-range order. Ironically, 
membrane asymmetry has always been part of the fluid mosaic model, even 
though this paradigm primarily views cell membranes as chaotic rather than 
organized. The asymmetry of proteins and phospholipids is established 
by complex biochemical processes when cell membranes are assembled. 
This asymmetry is actively maintained by the cell's machinery during the 
membrane's lifetime.: (Discussion ofthese processes is beyond the scope 
ofthis book.) 

Protein asymmetry consists ofthe specific orientation of integral pro- 
teins that span the bilayer and differences in the composition of peripheral 
proteins in the inner and outer monolayers. This asymmetry allows cell 
membranes to 

1. transport materials in a single direction, 

2. detect changes in the environment outside the cell, 

3. perform specific chemical operations inside the cell, and 

4. stabilize the cell membranes through interactions between the 
cytoskeletal proteins and the interior surface ofthe bilayer. 

The asymmetric distribution of phospholipids in the inner and outer 
leaflets ofthe cell membrane is highly variable, differing from membrane 
to membrane. But, it is not random. For example, the plasma membrane 
that surrounds the cell typically has markedly higher levels of PSs, PEs, 
and Pis in the inner leaflet and higher levels of PCs and sphingomyelins 
in the outer monolayer. The inner membranes of mitochondria usually 
have greater amounts of PCs and PEs in the outer monolayer and higher 
levels of Pis and cardiolipin in the inner leaflet. The membranes ofthe 
Golgi apparatus (see chapter 2, p. 40) have higher concentrations of PEs, 
PCs, and PSs in the membrane surface in contact with the cytoplasm and 



235 The Cell's Design 

greater amounts of Pis and sphingomyelins on the membrane surface in 
contact with the Golgi's interior.,., 

Phospholipid asymmetry, like protein asymmetry, has important bio- 
logical consequences. Differences in phospholipid composition lead to 
variations in the charge, permeability, and fluidity of inner and outer leaflets 
of the membranes. These compositional differences also play an important 
role in the ability of each monolayer to support and regulate the activity 
of proteins associated with the membrane. 

Super Organized 

The discovery of annular lipids and compositional asymmetry by bio- 
chemists in the early days of the fluid mosaic model represented a small 
foreshadowing of what was to come. Over the last decade or so, life scien- 
tists have come to recognize that ordering and organization are hallmark 
features of cell membranes. These membranes are highly organized, con- 
sisting of numerous structurally and functionally discrete domains. The 
domains, in turn, appear to be arranged into supradomains, reflecting a 
hierarchy of order and organization. The membrane domains are made of 
distinct lipid and protein compositions that dictate each domain's unique 
functional role. 

Biochemists have discovered a special type of domain in cell membranes, 
called lipid rafts. : These domains are solidlike regions of the membrane 
that "float" in more fluid regions, like a raft on the sea. Typically, lipid rafts 
are enriched in cholesterol and another class of lipids called sphingomy- 
elins. Presumably, interactions between the lipid head groups maintain the 
structural integrity of the lipid raft. 

Specific types of proteins are associated with lipid rafts, typically those 
involved in signal transduction. High levels ofprotein receptors are em- 
bedded in lipid rafts. These receptors bind molecules in the environment 
and, in turn, initiate biochemical pathways that elicit a response by the 
cell to changes in its surroundings. Lipid rafts also appear to play a role in 
secretion of vesicles by the Golgi apparatus. 

The ordering and organization of the cell membranes — carefully ar- 
ranged for the myriad functions they perform — appears intentionally 
thought out. But is it? 



An Elaborate Mosaic 9^7 

Where Did This Wondrous Masterpiece Come From? 

Finely-tuned phospholipid compositions, an extensive molecular-level 
organization, and the likelihood that cell membranes harbor information 
beg the question. Can the biochemical marvel of cell membranes be ac- 
counted for apart from a Creator? 

For most biochemical systems and characteristics, a fundamental lack 
of knowledge and insight prevent a rigorous assessment of proposed evo- 
lutionary explanations. In other words, it's not possible to say whether 
evolutionary processes can generate specific aspects of life's chemistry. 

But, this limitation is not a consideration for assessing the origin of 
cell membranes. Origin-of-life researchers have focused enough attention 
on the problem of membrane origins to permit vigorous evaluation of 
the likelihood that unguided evolutionary pathways produced them. The 
origin of cell membranes has to be one of the first steps in life's emergence. 
Researchers assume, for the most part, that once membrane components 
form or appear on early Earth, they readily self-assembled to form the first 
cell membranes.,., To explain this origin, and along with it the emergence of 
the first cell, most investigators simply attempt to identify compounds — 
likely present on early Earth — with the potential to spontaneously assemble 
into bilayer structures. 

These scientists also look to define mechanisms in which bilayer struc- 
tures can encapsulate more complex self-replicating molecules and acquire 
properties that resemble those of contemporary cell membranes such as 
transport and energy transduction. 

Art Supplies 

In the quest to identify bilayer-forming molecules, origin-of-life inves- 
tigators have discovered several chemical routes that produce both simple 
amphiphilic compounds consisting of a single long hydrocarbon chain 
and more complex phospholipids. In spite of this, the origin-of-life com- 
munity hotly debates the likelihood of these chemical pathways occurring 
on the early Earth. 

In the face of the questions that surround the prebiotic synthesis of 
amphiphilic compounds, some researchers appeal to extraterrestrial ma- 
terials falling onto the early Earth to explain the source of bilayer-forming 
compounds. Analysis of carbon-containing meteorites (carbonaceous 



238 The Cell's Design 

chondrites), like the Murchison, initially indicated the presence of com- 
pounds consisting of long hydrocarbon chains. However, subsequent analy- 
sis demonstrated that these compounds more than likely resulted from 
terrestrial contamination.,, 

Recent laboratory experiments rejuvenate support for an extraterrestrial 
source of amphiphilic materials on early Earth. Scientists from NASA 
Ames Research Center, the SETI Institute, and the University of Califor- 
nia, Santa Cruz, demonstrated that irradiating simulated cometary and 
interstellar ice with UV light produces a complex mixture of compounds 
that includes bilayer-forming materials. Presumably, delivery of these ma- 
terials to early Earth provided the compounds needed to form the first 
cell membranes. 

One Piece at a Time 

Even though phospholipids are the dominant lipid species of contem- 
porary cell membranes, origin-of-life researchers think that simpler lipids 
assembled to form the first bilayers. 

Amphiphilic compounds with "water-loving" and "water-hating" regions 
all form aggregates when added to water (see chapter 2, p. 46). These ag- 
gregates take on a variety of forms depending on the amphiphile s molecular 
structure. Phospholipids with two long hydrocarbon chains can form 
bilayers. Amphiphilic compounds with a single long hydrocarbon chain 
generally form spherical structures referred to as micelles (see figure 12.2). 
Origin-of-life researchers don't regard micelles as having importance in 
forming the first protocells. 

In spite of their tendency to form micelles, some single-chain amphiphilic 
compounds form bilayers under highly specific solution (pH, for exam- 
ple) conditions and temperatures when mixed with the right materials., 
Origin-of-life researchers regard these results as key to explaining the first 

appearance of cell membranes. 

The results increase in significance in light of the observation that lipid- 
like materials extracted from the Murchison meteorite form bilayer struc- 
tures under specific solution conditions.,; Similar bilayer structures also 
form from extracts of simulated cometary and interstellar ice irradiated 
with UV light. : Researchers point to these compounds as possibly the first 
cell membrane components and as evidence that the materials necessary to 
form the first protocells' boundary structures were present on early Earth. 



An Elaborate Mosaic 



239 




OH 



IP— - 



Fatty Acid Micelle 



V 



M 



CH! 

i/ 



Octanoic Acid 



Nonanoic Acid 

Figure 12.2. Fatty Acids and Micelles 

A cutaway of a micelle is shown. Amphiphilic compounds with a single long hydrocarbon 
chain, like octanoic and nonanoic acids, usually will form these spherical structures when 
added to water. 



They also argue that these results indicate the ease with which bilayers can 
spontaneously form once the right components appear. 



A Work of Nature 's Art? 

Origin-of-life investigators speculate that when bilayer-forming com- 
pounds appeared on early Earth, cycles of dehydration and rehydration at 
the intertidal zones of islands might have encapsulated large self-replicating 
molecules (proteins, DNA, and RNA) and smaller subunit molecules 
within the bilayer s confines. Support for this idea comes, scientists claim. 



240 The Cells Design 

from experiments showing that bilayer vesicles formed from structurally 
specific phospholipids encapsulated DNA during drying and subsequent 
water addition.*, 

Researchers presume that once bilayer vesicles containing encapsulated 
self-replicating molecules formed, they could carry out the necessary chemi- 
cal processes to sustain self-replicating activity, grow, self-reproduce, and 
acquire transport and energy transduction capabilities. : 

Lipid bilayers are generally impermeable to the types of molecules needed 
to maintain the activity of encapsulated self-replicators. In spite of this, a 
few origin-of-life researchers have shown that if the chain length of the 
lipids that form the bilayers is carefully adjusted, enough of the compounds 
needed to sustain the self-replicator can pass through the bilayer... 

The studies that pertain to cell membrane origins seem to reinforce 
the view that cell membranes readily self-assembled on the early Earth. 
Once formed, these primitive bilayers also seemingly could acquire the 
functional attributes of contemporary biological membrane systems. Yet, 
this conclusion is a bit premature. 

An Unskilled Composition? 

While the work on the origin of cell membranes has been taking place, 
other research designed to characterize the structure of lipid aggregates 
and determine the principles governing cell membrane biophysics suggests 
that evolutionary models for the origin of biological membranes are over- 
simplified. The emerging tenets of membrane biophysics demand a more 
convoluted and intricate pathway than that conceived by the evolutionary 
origin-of-life community. It's an incredibly arduous process to go from 
simple lipid molecules to the bilayers found in contemporary cell mem- 
brane systems. The next section illustrates some of the problems for what 
researchers think was the first step in the evolution of cell membranes. 

Origin-of-life researchers think that the primitive membranes of the first 
cells were composed of aromatic hydrocarbons mixed with octanoic and 
nonanoic acid. (Octanoic acid consists of a linear carbon chain of eight 
carbon atoms in length and nonanoic acid involves a linear carbon chain 
nine carbon atoms long. See figure 12.2.) Bilayer-forming extracts from 
the Murchison meteorite include these compounds. 

Neither octanoic nor nonanoic acid would likely have occurred at levels 
significant enough, however, for origin-of-life scenarios. Researchers have 



An Elaborate Mosaic 



241 



recovered only extremely low levels of these compounds from the Murchi- 
son meteorite. 4. Additionally, the level of individual amphiphilic species 
decreases exponentially with increasing chain length.: While extraterres- 
trial infall could potentially deliver octanoic and nonanoic acid to early 
Earth, the levels would be far too low to participate in primitive membrane 
structures. Octanoic and nonanoic acids can form bilayer structures only 
at relatively high concentrations. 

In addition to the concentration requirements, octanoic and nonanoic 
acids also require exacting environmental conditions. These compounds 
can only form bilayers at highly specific pHs. Octanoic and nonanoic 
bilayers become unstable if the solution pH deviates from near neutral 
values. The solution temperature is also critical for bilayer stability. An- 
other complication is the solution salt level. Research shows that model 
primitive membranes fall apart in the presence of salt. These structures 
only display stability in pure water. 

Octanoic and nonanoic bilayer stability also requires the "just-right" 
molecular companions, inclusion of nonanol (a nine-carbon alcohol) ex- 
tends the pH range for nonanoic bilayers. ; Bilayer stability results from 
specific interactions between the nonanoic acid head group and nonanol. 
Such stability only occurs when nonanol is present at specific levels within 
the nonanoic bilayers. 

To date, no studies have been conducted on the long-term stability of 
octanoic and nonanoic bilayers. Quite possibly octanoic and nonanoic 
acid bilayers lack long-term stability under conditions that allow these 
compounds to form bilayers. Regardless, the strict requirements necessary 
for bilayer formation make it unlikely that these compounds could have 
ever contributed to the formation of the first cell's membranes. 

Formation of nonanoic acid bilayers (or bilayers comprised of any am- 
phiphile with a single hydrocarbon chain) is improbable because several 
"just-right" conditions must be simultaneously met. Should a bilayer struc- 
ture form, any environmental fluctuations or compositional deviations 
would cause it to destabilize and revert to micelle structures. 

The instability of primitive bilayers in salt is perhaps most problematic. 
It is difficult to imagine any aqueous location on early Earth free of salt. In 
fact, primitive bilayer stability would have been compromised at salt levels 
far less than those found in Earth's oceans today. And, early Earth's oceans 
were one and a half to two times more salty. That condition makes the 
emergence of primitive membranes even less likely. 



242 The Cell's Design 

The exacting requirements for primitive bilayer assembly also make it 
unlikely these structures could encapsulate a self-replicator via dehydration- 
hydration cycles. Once dehydrated, unless the "just-right" conditions existed 
upon rehydration, the bilayers could not reform. 

In fact, a recent survey of the scientific literature shows that every step 
in the proposed pathway from prebiotic amphiphilic compounds to con- 
temporary cell membranes strictly depends on exacting compositional and 
environmental factors. .4 These stringent requirements make it unlikely that 
cell membranes could have emerged under the conditions of early Earth. 

Acknowledging the Creator 

The zenith of Byzantine art occurred between the ninth and eleventh 
centuries. Some of the world's most beautiful mosaics were produced during 
that time. The mosaics of the Hagia Sophia in Constantinople include a 
wall covered with one of the most famous. Emperor Kneeling before Christ 
depicts an emperor acknowledging Jesus Christ as Lord and Savior. . 

Unlike this highly valued mosaic, however, the first depictions of cell 
membranes portrayed them as little more than haphazard disorganized 
systems with proteins and lipids freely diffusing laterally throughout the 
bilayer formed by phospholipids. In the early 1970s, cell membranes were 
described as a fluid mosaic. 

Advances over the last thirty-five years, however, dramatically changed 
how scientists think about cell membranes. Biochemists now understand 
the cell's boundaries as highly structured, highly organized systems that 
display local ordering in the vicinity of membrane proteins (annular lipids) 
and long-range ordering (membrane asymmetry, membrane domains, and 
lipid rafts). In the 1980s and early 1990s, Norman Gershfeld's team dem- 
onstrated that cell membranes require extraordinary fine-tuning of their 
phospholipid composition to exist as stable unilamellar structures. More 
recent work indicates that a high-precision phospholipid composition ap- 
pears necessary for membrane proteins to be inserted into bilayers during 
cell membrane assembly. 

Only in recent years have biochemists come to appreciate why such a 
complex ensemble of phospholipids make up cell membranes. Instead of 
reflecting the outworking of a history of undirected evolutionary processes, 
the seemingly chaotic mix of phospholipids in cell membranes is quite 



An Elaborate Mosaic 



243 



necessary and points to a rationale that undergirds the membrane's compo- 
sition. Phospholipids do more than form the cell membrane's bilayer. They 
control the bilayer s physical properties and play a key role in regulating 
the activity of proteins associated with the membrane. Some biochemists 
have even suggested that cell membranes harbor information. 

The hallmark features of cell membranes are the same features found 
on the wall of the churches in Constantinople. This artwork consists of 
the careful, well-thought-out choice of stone and glass pieces deliberately 
organized and arranged in a precise way to yield a specific depiction of 
Christ. In this sense, that mosaic conveys the information the artist wanted 
to communicate to its viewers. 

When the features of cell membranes are viewed through the grid of the 
intelligent design template, they continue to build a powerful weight-of- 
evidence case for biochemical intelligent design. Cell membranes supply 
an excellent case study of how pattern recognition can be used to interpret 
new biochemical insights as additional support for the Creator's handiwork. 
It takes a brilliant mind to produce the complex pieces that communicate 
apowerful message. Only a Divine Mind could put them together in such 
a way that they came to life. 



13 



COLORING OUTSIDE 
THE LINES 



Not all the world s art treasures hang on museum walls. Some are affixed to 
refrigerator doors. Drawings and paintings produced by small hands won't 
usually command much of a price at an auction, but for proud parents the 
artistic renderings of their children are priceless. 

Works of art reflect the ability and sophistication of the artists that 
produce them. Art created by little ones doesn't compare with the work 
of the worlds masters. Though adorable, the musings of children reflect 
their lack of experience, skill, and perhaps even talent. On the other hand, 
masterpieces are widely appreciated because they express the artist's im- 
mense insight, originality, and depth of emotion. 

Like art, the characteristics of life's chemical systems reflect the iden- 
tity and capability of their maker. As demonstrated through analogical 
comparisons in previous chapters, many biochemical systems display an 
elegance that points to a Creator. 

Still, most evolutionary biologists reject the notion of intelligent design, 
partly because of the apparent defects and faulty designs of some biochemi- 
cal systems., These imperfections represent potentially powerful disanalo- 
gies (see chapter 1, p. 31) weakening the conclusion that life's chemistry is 
the work of a Creator. Sometimes, for skeptics, life's chemistry more closely 
resembles a child's drawing than a magnificent masterpiece. 

245 



246 The Cell's Design 

The Problem of Imperfections 

Most scientists acknowledge the appearance of design in biochemical 
systems but argue that it's not true design. Rather, they claim this char- 
acteristic is an artifact of evolutionary processes that stems from natural 
selection operating repeatedly on random inheritable variations over vast 
periods of time to produce and fine-tune biochemical systems. 

Like a small child coloring outside the lines of a picture — blind, undi- 
rected, chance processes of evolution are just as likely to produce "jury- 
rigged" structures as they are to produce fine-tuned structures. The like- 
lihood of these makeshift outcomes led the late evolutionary biologist 
Stephen Jay Gould to argue in his classic essay The Panda's Thumb that 

biological imperfections would "win no prize in an engineering derby.". 
Instead, they make a compelling case for evolution. From an evolutionary 

standpoint, if a "design" somehow works — even imperfectly — there is no 
impetus for it to further evolve. 

For Gould, "odd arrangements and funny solutions are the proof of 
evolution — paths that a sensible God would never tread but that a natural 
process, constrained by history, follows perforce." In other words, even 
though biochemical systems are replete with elegant design features, the 
assortment of imperfections in life's chemistry undermines the case for 
biochemical intelligent design. From an evolutionist viewpoint, an all- 
powerful, all-knowing Designer would never scribble so haphazardly. 



But, Bad Designs Can Be Good 

Careful consideration suggests that imperfections may not be as big a 
problem for the biochemical intelligent design analogy as they appear at 
first glance. Perhaps a Creator's intentional activity can explain suboptimal 
biochemical systems. 

From Better to Worse 

Some bad designs are truly less-than-perfect. From an intelligent design 
perspective, they merely reflect the unavoidable consequences of the laws 
of nature instituted by the Creator. For instance, this universe and all it 
contains, including life, is subject to the second law of thermodynam- 
ics (entropy). When optimal biochemical systems experience this law's 



Coloring Outside tlie Lines 9 4.7 

unrelenting effects, they tend toward disorder. Over time, flaws creep in, 
and the decay becomes permanent when it leads to changes in the nucle- 
otide sequences ofDNA. 

Mutations. Chemical and physical insults to DNA inevitably cause 
abnormalities. So do errors made by the cell's machinery during DNA 
replication. The cell possesses machinery that can repair this damage, but 
sometimes errors occur and the repair is not completely effective. Then the 
nucleotide sequence of DNA becomes permanently altered.. 

Biochemists have identified numerous types of mutations. For example, 
substitutions replace one nucleotide in the DNA sequence with another. 
Insertions add nucleotides to the DNA sequence and deletions remove 
them. 

Gene mutations are seldom beneficial because they alter the informa- 
tion contained in the gene and cause the structure of the protein specified 
by that gene to become distorted (see chapter 9, p. 173). This structure- 
altering effect makes most mutations harmful, although sometimes their 
effect can be neutral. 

When deleterious mutations occur, natural selection often prevents their 
propagation to the next generation because they often compromise the 
fitness and reproductive success of the organism experiencing the altered 
DNA sequence. Still, natural selection is not always diligent. Sometimes 
mildly harmful mutations escape notice. Over time, the accumulation of 
these damaging mutations can transform an optimally designed biochemi- 
cal system into one with substandard performance. 

Less than peak performance. Nonuniversal genetic codes (discussed 
in chapter 9, p. 177) supply an excellent example of how mutations and 
other natural processes degrade optimal systems — in this case, the universal 
genetic code that is optimized to withstand errors caused by substitution 
mutations. Deviants of the universal genetic code, nonuniversal genetic 
codes arise when changes occur in tRNA molecules in such a way that 
the assignments of stop codons or low frequency codons are altered (see 
chapter 10, p. 187). 

Compared to the universal code, these nonuniversal codes do not 
possess the same capacity to withstand mutational error. The processes 
that generate nonuniversal codes transform a highly optimized master- 
piece into a system that appears far less deliberate. The "new" codon 
assignments may not be design defects but ultimately the consequence 
of the second law of thermodynamics. The appearance of a faulty design 



248 The Cell's Design 



The Second Law of Thermodynamics 

Even though the second law of thermodynamics causes systems to tend toward disor- 
der, its operation is absolutely necessary for life to be possible. The effects of entropy 
leads to the "downhill" flow of energy that makes it possible for cells to carry out 
all of their metabolic abilities. Entropy also drives the formation of cell membranes, 
the precise folding of proteins, and the assembly of the UNA double helix. From an 
intelligent design perspective, the second law of thermodynamics reflects the provi- 
dential care of the Creator. The decay associated with the second law appears to be 
an unavoidable trade-off. 



doesn't necessarily indicate an evolutionary origin but may instead re- 
flect the effects of entropy superimposed on once optimal biochemical 
systems. 

Planned That Way 

Engineers who invent complex systems often face trade-offs and must 
purposely design some components to be suboptimal in order to achieve 
the maximum overall performance. In fact, if a system consists of finite 
resources and must accomplish numerous objectives, then the system must 
represent a compromise. Inevitably its objectives will compete with one 
another. Any attempt to maximize performance in one area will degrade 
performance in others. 

When confronted with trade-offs, the engineer carefully manages them 
in such a way as to achieve optimal performance for the system as a whole. 
And this overall efficiency can be accomplished only by intentionally sub- 
optimizing individual aspects of the system's design. = 

The conflict between performance and robustness is a specific trade-off 
often encountered. Usually high performance systems do not do well under a 
wide range of conditions. To address this compromise, engineers frequently 
design systems to underperform, enabling those systems to operate under 
a variety of conditions. 

Given the trade-offs, this idea makes sense within the context of the 
biochemical intelligent design argument — in some instances, suboptimal 
designs result from the Creator's intent. They may not be disanalogies that 
militate against intelligent design at all. Instead suboptimal designs round 
out the comparison between man and his Maker. 



Coloring Outside tlie Lines 94.Q 

Lack of Understanding 

Life's chemistry is complex. Biochemists lack detailed understanding 
of the structure and functional behavior of most biochemical systems, 
even those that have been the subject of focused investigation. Rarely do 
biochemists understand how a specific process interacts with others inside 
the cell, let alone globally throughout the organism. 

"When evolutionary biologists label a biochemical system "imperfect," they 
do so largely from ignorance. Any claim that a certain aspect of life's chem- 
istry exemplifies poor design is largely based on a scientist's authority, not a 
comprehensive understanding of that system and its interrelationship to other 
biomolecular processes. All too often biochemists gain new insight into the 
operation of a so-called imperfect biochemical system only to discover another 
marvelous illustration of the elegant designs that define life's chemistry. 

Based on current knowledge, however, some systems truly appear to be 
poorly designed. Limited knowledge about these systems doesn't permit 
the case for biochemical intelligent design to be made. These seemingly 
faulty designs, however, provide an opportunity to scientifically test the 
biochemical intelligent design hypothesis. If life is indeed the product of 
a Creator, then new discoveries should yield insights that transform these 
biochemical aberrations into remarkable works of art. 



From Funny to Fantastic 

A few representative examples such as glycolysis, bilirubin production, 
uric acid metabolism, junk DN A, and genetic redundancy show how time 
can produce the kind of scientific advance that rehabilitates the image of 
biochemical systems that at one time or other acquired the reputation as 
bad designs. 

Glycolysis 

One of life's most important metabolic pathways, glycolysis plays a key 
role in harvesting energy for use by most cells. This biochemical process 
fractures six-carbon sugar glucose into two molecules of pyruvate, a three- 
carbon compound. The cell captures a portion of the chemical energy 
released by glucose breakdown for later use. Some organisms further break 
down pyruvate to yield even more energy.. 



2^r) The Cell's Design 

Early on in the glycolytic pathway, glucose is transformed into another 
six-carbon sugar, fructose 6-phosphate, through a sequence of chemical 
reactions that involve the addition of a phosphate group and a rearrange- 
ment of the glucose molecule. Fructose 6-phosphate is then converted into 
fructose 1,6-bisphosphate by adding a phosphate group. 

The process uses some of the cell's energy reserves. Because it takes energy 
to generate energy from glucose breakdown, biochemists refer to the gen- 
eration offructose 1,6-bisphosphate from glucose as the "pump-priming" 
reaction. 

Phosphofructokinase is the protein that converts fructose 6-phosphate 
into fructose 1,6-bisphosphate. The cell controls glycolysis by regulating 
phosphofructokinase activity. In other words, the cell can turn glycolysis 
on and off by activating or inhibiting phosphofructokinase. The cell can 
also change the gylcolytic rate by increasing or decreasing the activity of 
this protein. 7 Phosphofructokinase is somewhat analogous to an on-off 
light switch with a dimmer knob. 

Regulating glycolysis via phosphofructokinase represents elegant bio- 
chemical logic because this protein catalyzes an energy-consuming step. By 
shutting down glycolysis before the cell uses energy to prime the glycolytic 
pathway, the cell avoids wasting energy. 

Once the reaction catalyzed by phosphofructokinase takes place, there is 
no turning back. The cell has committed valuable energy stores to glycolysis. 
Stopping glycolysis before the cell makes this commitment conserves the 
cell's energy resources and makes them available for other processes. 

A futile cycle. In sharp contrast to the elegant phosphofructokinase 
regulation of glycolysis is the back conversion offructose 1,6-bisphos- 
phate to fructose 6-phosphate. This reaction is catalyzed by the protein 
fructose 1,6-bisphosphatase. This chemical conversion undoes the work 
of phosphofructokinase, throwing away the energy that the cell used 
to convert fructose 6-phosphate to fructose 1,6-bisphosphate. Just like 
a toddler quickly undoes a mother's hard work shortly after she cleans 
the house. 

The paired reactions catalyzed by phosphofructokinase and fructose 
1,6-bisphosphatase are known as a futile cycle. These two proteins cause 
fructose 6-phosphate and fructose 1,6-bisphosphate to endlessly cycle back 
and forth wasting the cell's energy resources. Historically, biochemists have 
regarded this futile cycle as an imperfection produced by evolutionary 
processes.! 



Coloring Outside tlie Lines 9S1 

Greater understanding. Discovering the way these two reactions relate 
to each other, however, has changed the mind of most biochemists. The 
futile cycle associated with glycolysis actually plays a critical role in regulat- 
ing this key pathway by amplifying the biochemical signals that activate 
and inhibit the breakdown of glucose. A hypothetical futile cycle in which 
compound A gets converted to compound B and compound B converts 
back to A shows how this works. 

Suppose the conversion of A to B occurs at a rate of 100 molecules per 
second and B to A occurs at 90 molecules per second. The overall conver- 
sion rate of A to B is 10 molecules per second. Increasing the rate of the 
forward reaction by 10 percent and decreasing the reverse reaction rate by 
10 percent results in an overall increase in the production of A from 10 
molecules per second to 29 molecules per second. If the futile cycle didn't 
exist, however, and there was no reverse reaction, an increase in the produc- 
tion of A by 10 percent merely increases the flux from 10 to 11 molecules 
per second (see figure 13.1). Without the futile cycle, the cell lacks a quick 
and sensitive response to changes in its energy requirements. 

Another function for futile cycles is heat production. By cycling back 
and forth between fructose-6-phosphate and fructose-l,6-bisphosphate, 
the cell's chemical energy is converted into heat, which helps provide or- 
ganisms with necessary warmth. 

Even though the futile cycle of glycolysis appears to be a metabolic im- 
perfection, more comprehensive understanding of this operation within 
the context of the cell's chemistry reveals this process to be an elegant 
design feature. 

Bilirubin 

Biochemists would never enter the metabolic pathways that break down 
hemoglobin's components in any show featuring masterpieces. (Hemoglo- 
bin is the oxygen-transporting protein found in red blood cells.) This critical 
degradation process employs seemingly unnecessary steps, consumes exten- 
sive amounts of energy, and generates atoxic end product (bilirubin). 

Hemoglobin consists of four protein chains that interact to form a tetra- 
meric (tetra = four, mer = unit) conglomerate. A complex ring system (the 
heme group) that includes an iron atom associates with the hemoglobin 
tetramer. The heme group binds oxygen serving as the "business" part of 
hemoglobin.. 



(A) 



Fructose-6-ph osphate 



Phosphofructokinase 



Fructose-1, 6-bisphosphatase 



Fructose-1,6-bisphosphate 



® 



Fru ctose-6-phos p hate 



Phosphofructoki nase 



10 Molecules/Sec 

I 10% 

11 Molecules/Sec 



Fructose-1 , 6-bisphosphate 



® 



Fructose-6-phosphate 



100 Molecules/Sec 



10% 



Phosphofructokinase 



110 Molecules/Sec 



Fructose-1, 6- 

bisphosphatase 



81 Molecules/Sec 

T 10% 

90 Molecules/Sec 



Fructose-1, 6-bisphosphate 



Figure 13.1. The Futile Cycle of Glycolysis 

This futile cycle actually plays a critical role in regulating glycolysis by amplifying the 
biochemical signals that activate and inhibit glycolysis. 



Coloring Outside tlie Lines 9S^ 

When red blood cells die, the spleen's biochemical pathways degrade the 
red blood cell's contents (including hemoglobin). Parts of the hemoglobin 
are recycled and parts are eliminated from the body. The protein chains are 
broken down into their constitutive amino acids, which find new use. So 
does the iron atom. The heme ring, on the other hand, is eliminated. 

Prior to elimination, an enzyme (heme oxygenase) converts the heme 
ring into a linear molecule, biliverdin, in an energy-intensive process. For 
birds and reptiles, the process stops here. Biliverdin is water-soluble and 
readily excreted from the body of these animals. 

In mammals, however, another enzyme (biliverdin reductase) converts 
biliverdin to bilirubin in a process that also uses energy. That's where the 
problems begin. 

A futile cycle. Because bilirubin lacks appreciable water solubility, it 
cannot be readily eliminated until blood serum albumin carries it to the 
liver. Once there, an enzyme adds two sugar groups to the bilirubin (a 
process that also requires substantial energy) making it water-soluble and 
suitable for elimination.,., 

In other words, mammals employ several seemingly unnecessary energy- 
intensive steps to convert biliverdin (a compound easily eliminated) into 
bilirubin (a molecule that can't be secreted). Further compounding the 
inefficiency is the back conversion of bilirubin into biliverdin. This rever- 
sion readily occurs in the presence of oxygen and reactive oxygen species 
(ROS), ever-present in the cell. The energy used to convert biliverdin to 
bilirubin is wasted and the process has to be repeated — sometimes again 
and again. 

Lastly, bilirubin is toxic. This compound causes jaundice, brain dam- 
age, and other disorders. On the surface, heme degradation appears ill- 
conceived — something expected for a product of evolution, not for a God 
whose creation would stay within the well-defined lines of perfection. 

Greater understanding. Researchers from Johns Hopkins University, 
however, recently made a series of discoveries that demonstrate elegant 
artistry in all aspects of bilirubin metabolism... It turns out bilirubin is 
an effective antioxidant that reacts with oxygen and ROS. This property 
protects the cell from oxidative damage, the destruction caused by ROS 
when these compounds indiscriminately react with biomolecules. 

That explains bilirubins formation. Its water insolubility, a detriment 
for elimination, causes bilirubin to partition into the cell membrane. In 
this location bilirubin guards the membrane components from harmful 



254 The Cell's Design 

reactions with oxygen. As for the futile cycle, the reversion of bilirubin 
back to biliverdin allows the cell to regenerate bilirubin each time after it 
detoxifies oxygen and ROS — again and again. This cycle amplifies biliru- 
bin's antioxidative potential. Bilirubin eliminates ten thousand times its 
level of oxygen and ROS. These compounds are highly destructive ifleft 
unchecked in the cell. 

This new discovery makes it untenable to view bilirubin metabolism as 
a senseless process, an imperfection produced by evolution. Rather, these 
pathways make sense. Bilirubin metabolism stands as impressive "bio- 
technology" that buffers the cell's structures against the harmful effects of 
oxidative compounds. 

Uric Acid Metabolism 

Kidney stones develop in one out of ten people during their lifetime and 
account for nearly ten out of one thousand hospital admissions.,, These 
mineral deposits can result whenever a chemical imbalance occurs in the 
kidney. The type of stone that forms depends upon the exact nature of that 
imbalance and reflects different etiologies. Calcium oxalate stones result 
from dehydration or excess levels of oxalate (found in certain vegetables, 
nuts, berries, chocolate, and tea ,) in the diet. On the other hand, sodium 
urate stones stem from an inborn error in metabolism that leads to exces- 
sive production of uric acid. 

As a normal metabolic activity, the cell turns over biomolecules, continu- 
ally replacing "older" molecules with newly synthesized ones. This turnover 
allows cells to maintain their structural and functional integrity. The cell 
recycles most of the adenine and guanine generated from the breakdown 
of nucleotides (the building blocks of DNA and RNA) through salvage 
pathways, but it targets a significant portion of adenine and guanine for 
breakdown and secretion in the form ofuric acid.: 

In blood serum, uric acid possesses low solubility. This condition causes 
it to readily precipitate out in the kidney and urinary tract when dehydra- 
tion occurs or when the body generates an excessive amount (which can 
occur if the enzymes of the salvage pathway are defective). 

Aflawed process. Except for primates, all mammals further metabolize 
uric acid to a more soluble derivative. Evolutionary biologists think the 
enzymes responsible for this transformation were lost in the evolutionary 
process that led to primates. For evolutionists, the elimination of adenine 



Coloring Outside tlie Lines 9SS 

and guanine in the form of uric acid is the type of evidence that makes a 
potent case for evolution, because it appears to be a poor design.,. 

Why would an all-powerful and all-knowing Creator put in place such an 
imperfect biochemical process — one that leaves human beings susceptible 
to kidney stones and other disorders, like gout? Evolutionists maintain that 
the adenine and guanine elimination pathways represent nothing more 
than an evolutionary "kludge" job, an imperfection that barely suffices, 
not the Creator's exacting handiwork. 

Greater understanding. Evolutionists who adopt this perspective, how- 
ever, fail to consider uric acid's full range of metabolic properties. This 
compound is a potent antioxidant that scavenges the chemically corrosive 
hydroxyl free radical, singlet oxygen, and superoxide anion, all produced 
by the metabolic pathways the cell uses to harvest chemical energy. The 
maximal levels of uric acid in the blood serum, though precariously poised 
to precipitate as stones in the urinary tract, help prevent cancer and may 
contribute to long human life spans. For other mammals, the conversion 
of uric acid to more soluble forms before elimination deprives them of a 
key antioxidant and limits the length of their lives. 

When considered more broadly, it's been discovered that the primate 
adenine and guanine elimination pathways reflect an elegant design that 
finds an important use for a waste product. There's a trade-off, however. If 
an inborn metabolic error occurs in the salvage pathway enzymes or if one 
eats an unbalanced diet, then kidney stones (and gout) can result — a small 
price to pay for cancer prevention and longer life expectancies. 

Junk DNA 

Many evolutionary biologists regard "junk" DNA as one of the most 
potent pieces of evidence for biological evolution.: According to this view, 
junk DNA results when undirected biochemical processes and random 
molecular and physical events transform a functional DNA segment into 
a useless molecular artifact. This segment remains part of an organism's 
genome solely because of its attachment to functional DNA. 

Junk DNA persists from generation to generation.:; The amount varies 
from organism to organism, ranging from 30 percent to nearly 100 percent 
of an organism's genome.:: 

Evolutionary biologists highlight the fact that in many instances identi- 
cal segments of "junk" DNA appear in a wide range of related organisms. 



256 The Cell's Design 

Frequently these segments share the same genome location. For evolu- 
tionists, this pattern clearly indicates that these organisms also shared an 
ancestor. 

Accordingly, scientists believe that the junk segment arose prior to the 
time those organisms diverged from their common predecessor. =4 Skeptical 
of other explanations, evolutionists wonder why a Creator would purposely 
introduce nonfunctional junk DNA at the exact location in the genomes 
of different, but seemingly related organisms. 

Numerous classes of junk DNA have been identified. The most widely 
recognized include pseudogenes, endogenous retroviruses, and LINE and 
SINE sequences. 

Pseudogenes. Evolutionary biologists consider pseudogenes to be the 
dead remains of once functional genes. According to this view, severe muta- 
tions destroyed the capacity of the cell's machinery to "read" and process 
the information in these genes. Still, pseudogenes possess tell-tale signa- 
tures that allow molecular biologists to recognize them as genes, albeit 
nonfunctional.: 

Several classes of pseudogenes have been identified (see figure 13.2). 
Unitary pseudogenes, a relatively rare type, occur as single copies in an organ- 
ism's genome.; These pseudogenes arise when a functional gene experiences 
such severe mutations that it's rendered nonfunctional. The loss of this 
gene presumably doesn't compromise the organism's fitness if it engages 
in a lifestyle that largely makes the gene unnecessary. 

Duplicated pseudogenes are the largest pseudogene class. Molecular bi- 
ologists suggest that these DNA segments arose when one or more genes 
underwent duplication in the genome. Afterwards, the copies experienced 
severe mutations that rendered them unrecognizable as a functional gene by 
the cell's machinery. Loss of duplicated gene function has little, if any, effect 
on an organism's fitness because an intact functional copy still exists.. 

As conceived by molecular biologists, the pathway that produces processed 
pseudogenes is quite complex. The mechanism that generates them overlaps 
with the one used by the cell's machinery to make proteins. 

Genes contain the information the cell needs for this process. As the first 
step in protein synthesis, the cell's machinery copies the gene in the form 
ofRNA, a biomolecule class that structurally resembles DNA. The RNA 
message migrates to a subcellular particle, a ribosome. Once there, the cell s 
machinery "reads" the information stored in the RNA message to form the 
protein encoded by messenger RNA... 



Functional Gene Unitary Pseudogene 

Exon Exon Exon Exon Exon Exon 

(DNA) intron I Intron \. Intron Intron 

Transcription Duplication 

1 V Duplicated Pseudogene 

Exon Exon Exon Exon Exon Exon Exon Exon Exon 

™Py Intron Intron Intron Intron Intron Intron Intron (Duplicated) 

(RNA) I I 

Processing Mutations 

I \ 

Exon Exon Exon Exon Exon Exon Exon Exon Exon 

Processed ^~ T"'":r. I- H:!!^^^ - ^^'"-^^^ 

9^"^ I \ Intron Intron Intron Intron Intron 9^"^ 

(RNA) , ' . „ T ... (Duplicated) 

Translation Reverse Transcription 

\ 

Processed Pseudogene 

Exon Exon Exon 

^ " r~"-- I --■■"■ > Processed gene 
j (RNA) 

Reverse Transcription 

\ 
Exon Exon Exon 

■ f "t I 'I - DNA 

I 
Proteins Insertion into genome 

I 

Exon Exon Exon Exon Exon Exon 
Processed pseudogene - I .'".... f [ •'••r'fJ - T'l^'T - IT''''^'^ "I - Gene 

I Intron Intron 

Mutations 

I 
Exon Exon Exon Exon Exon Exon 

Processed. mutated Hi -UK -Ijjt,' H:::Z:KZZhC~D- ^^ne 

pseudogene Intron Intron 



Figure 13.2. Pseudogenes 

Evolutionary biologists consider pseudogenes to be the dead, useless remains ofonce 
functional genes. Molecular biologists recognize three classes of pseudogenes: unitary, 
duplicated, and processed. 




OInQ The Cell's Design 

Before the RNA message migrates to the ribosome, the cell's machinery 
alters it in several ways. These changes include removing segments in the 
message that correspond to noncoding regions found in the gene (introns), 
splicing together the RNA segments that correspond to the gene-coding 
regions (exons), and modifying and making additions to the ends of the 
RNA molecule. 2, 

Processed pseudogenes are thought to arise when the reverse transcriptase 
enzyme generates DN A from the processed RNA message. Once produced 
and inserted back into the genome, processed pseudogenes resemble the 
genes from which they originate. Yet they also contain telltale signs of hav- 
ing been processed. These pseudogenes are nonfunctional because they lack 
the regions surrounding the functional genes that initiate the production 
of the RNA message. 

Endogenous retroviruses. These retroviruses are permanently incorpo- 
rated into the host organism's genome. Like all viruses, retroviruses consist 
ofprotein capsules that house genetic material (either DNA or RNA). 

Viruses infect organisms by invading specific cell types of their hosts. 
Once viruses attach to the target cell's surface, they inject their genetic 
material into the healthy cell. Then the viral genetic material exploits the 
cell's machinery to produce more viral genetic material and proteins, which 
combine forming new viral particles. When the newly formed viruses escape 
from the host cell, the infection cycle repeats. 

Instead of DNA, RNA is the genetic material used by retroviruses. After it 
is injected into the host cell, reverse transcriptase uses the retroviral RNA to 
make DNA. This newly made DNA can then direct the production of new 
retroviral particles. : (HIV, the virus responsible for AIDS, is a retrovirus.) 

The DNA copy of the retroviral genetic material can become incor- 
porated into the host cell's genome. If the retroviral DNA suffers severe 
mutations, the retrovirus becomes disabled. When this happens, the ret- 
rovirus DNA presumably remains nonfunctional in the host genome and 
is referred to as an endogenous retrovirus. 

SINEs and LINEs. These two types of noncoding DNA are known as 
transposable elements — pieces ofDNA thatjump around the genome or 
transpose. In the process of moving around, transposable elements direct 
the cell's machinery to make additional copies and consequently increase 
the number of these elements. 

SINEs (short interspersed nuclear elements) and LINEs (long inter- 
spersed nuclear elements) belong to a class of transposable elements called 



Coloring Outside tlie Lines 9SQ 

retroposons. Molecular biologists believe SINEs and LINEs duplicate and 
move around the genome through an RNA intermediate and the work of 
reverse transcriptase. 

Making a difference. Junk DNA atone time represented an insurmount- 
able challenge to the biochemical intelligent design argument and appeared 
to make an ironclad case for evolution. Now, recent advances suggest other- 
wise. Much to the surprise of scientists, junk DNA has function. 

Based on the characteristics possessed by pseudogenes, few molecular 
biologists would have ever thought junk DNA plays any role in the cells 
operation. However, several recent studies unexpectedly identified func- 
tions for both duplicated and processed pseudogenes. Some duplicated 

pseudogenes help regulate the expression of their corresponding genes. ,3 
And, many processed pseudogenes code for functional proteins. 

The scientific community is also well on its way to establishing func- 
tional roles for endogenous retroviruses and their compositional elements. 
Recent advances indicate that this class of noncoding DNA regulates gene 
expression and helps the cell ward off retroviral infections by disrupting the 
assembly of retroviruses after they take over the cell's machinery. 

As with pseudogenes and endogenous retroviruses, molecular biolo- 
gists now recognize that the SINE DNA found in the genomes of a wide 
range of organisms plays an important part in regulating gene expression 
and offers protection when the cell becomes distressed. Researchers have 
also identified another potential function for SINEs — regulation of gene 
expression during the course ofdevelopment. 

SINEs possess regions that the cells machinery methylates (attaches the 
methyl chemical functional group). This process turns genes off Depending 
on the tissue type, SINEs display varying patterns of DNA methylation. 
These diverse patterns implicate SINEs in the differential gene expression 
that occurs during development. n 

Much in the same way the scientific community acknowledges function 
for SINE DNA, molecular biologists now recognize that LINEs critically 
regulate gene expression. For example, researchers have identified a central 
role for LINE DNA in X chromosome inactivation. This inactivation 
occurs in healthy females to compensate for duplicate genes found on the 
two X chromosomes.,; (Females have two X chromosomes. Males have an 
X and a Y chromosome.) The inactivation of one set ofX chromosomal 
genes ensures proper levels of gene expression in females. If X chromosome 
inactivation doesn't occur, genetic disorders result.,, 



260 



The Cell's Desisn 



The scientific community now thinks LINE DNA controls monoallelic 
gene expression, a situation in which only one of the two genes inherited 
from both parents is used. 4, This process completely "turns off" the other 
gene. 

Many scientists now maintain that even though they can't direcdy identify 
functional roles for many classes of noncoding DNA, these DNA segments 
must be functional because so many distantly related or unrelated organ- 
isms share them.,: Scientists reason that these noncoding DNA classes must 
serve in a critical capacity. If they didn't, mutations would readily accrue in 
them. These noncoding DNA segments must have resisted change, other- 
wise mutations would have rendered them nonfunctional. And, that would 
have been harmful to the organism. 

Genetic Redundancy 

Many biochemists consider duplicate biochemical systems to be yet 
another example of a bad design. From an evolutionary standpoint, redun- 
dant systems arise as the result of random gene duplication events. This 
repetition appears senseless and unnecessary, something an all-powerful, 
all-knowing Creator would never do. 

However, sometimes engineers intentionally design systems with 
duplicate components. On this basis, it could be argued that biochemical 
redundancy is a good design feature. These systems would, in principle, 
buffer against the harmful effects of mutations. If mutations disable one 
of the system s components, then another copy of that component is avail- 
able to take its place. 

But in contrast to biochemical systems — which appear to be haphaz- 
ardly redundant — redundancy in human designs is not aimless. It is well 
thought out. Because of cost and efficiency concerns, engineers introduce 
redundant components into their designs judiciously, limiting them to 
only those parts critical for the systems operation. 

Typically only one of the redundant components operates at a time. 
It functions as the primary system while the other provides backup. The 
backup system kicks into operation only when the primary system fails. 
Engineers refer to this type of system as a responsive backup circuit. 

Redundant biochemical systems didn't appear to display the same 
exquisite operational control as human designs, at least not until a team of 
geneticists from Israel recently published their work on gene regulation., 



Coloring Outside tlie Lines 25 1 

These researchers examined the gene regulation patterns for duplicated 
genes and noted that, more often than not, they functioned as a responsive 
backup circuit, just like those found in human designs. In other words, 
these scientists discovered that only one of the duplicated genes was active. 
The other was down regulated or turned off It became active only if the 
primary gene became mutated. 

In light of this discovery, it's difficult to maintain that biochemical 
redundancy is a bad design. Rather, duplicate systems appear to have the 
same purpose and function as redundancies in human designs. 



Deliberate Scribbles 

In some instances biochemical systems appear to be purposely subopti- 
mized to balance trade-offs. A few representative examples such as protein 
synthesis, the carbon fixation reaction of photosynthesis, and the interplay 
between the motor proteins kinesin and dynein highlight how intentional 
suboptimization leads to an overall optimal performance for critical bio- 
chemical systems. 

Protein Synthesis 

The production of a myriad of proteins inside the cell occurs at struc- 
tures called ribosomes (see chapter 2, p. 39). They assemble each protein 
chain by linking together twenty different amino acid building blocks in 
a unique combination. The amino acid sequence then dictates, in part, the 
way each protein chain "folds" into the precise three-dimensional structure 
that determines its function... 

Highly inefficient. Researchers have recently come to recognize that 
cells employ a wasteful process when producing proteins. Roughly 30 per- 
cent of all proteins synthesized must be degraded by the cell because they 
are improperly made.' Anyone with experience in manufacturing would 
agree that a production process with a 30 percent defect rate needs much 
improvement. 

These problems challenge the notion that a Creator produced life's 
chemistry. However, the seemingly wasteful process of protein synthesis 
actually plays a critical role in the ability of the immune system to respond 
rapidly to viral infections. 



252 The Cell's Design 

After proteins outlive thieir usefulness to ttie cell or become damaged in 
the process of carrying out tfieir cellular function, they are degraded. Their 
breakdown occurs in a highly orchestrated fashion catalyzed by a large pro- 
tein complex called a proteasome.4, Degradation releases the proteins amino 
acids and makes them available for use in the production of new proteins. 

In addition to recycling amino acids, the cell also uses small protein 
fragments produced during the breakdown process to communicate to 
the immune system what's happening inside the cell. The cell incorporates 
these protein-degradation fragments into a complex assembly of molecules 
known as the class 1 major histocompatibility complex (MHC). The MHC 
eventually makes its way to the cell surface. Once there, the MHC presents 
the protein fragments to the immune system.-. 

These protein fragments inform the immune system when viruses infect 
cells. Upon infection, viral particles invade the cell and take over the cel- 
lular machinery. Viral DN A directs the production of viral proteins. Some 
of these proteins are eventually degraded and subsequently presented to 
the immune system via the class 1 MHC . In this way, the immune system 
"knows" when cells fall victim to a viral infection (see figure 13.3). 

A new discovery. Scientists once believed the cell used only aged viral 
proteins to produce the complexes that signal the immune system of a viral 
infection. This limitation creates a dilemma. If the cell waits until viral pro- 
teins age, the immune response can't be rapid enough to destroy the infected 
cell before the virus invasion gets too far along. 

Researchers have found, however, that defective proteins produced by 
the ribosome are degraded immediately after their production by protea- 
somes. The defective protein fragments then make their way to the cell 
surface as part of the class 1 MHC . As soon as a viral infection occurs, the 
immune system becomes aware of the presence of viral particles inside the 
cell through the production of defective viral proteins. 

This cutting-edge discovery reveals elegant design in the inefficiency 
of protein synthesis. The high level of defective proteins produced by the 
cell allows for an efficient immune response to viral infection — the perfect 
plan of a Master who colors inside the lines. 

Rubisco 

Perhaps the most important chemical reaction in nature is the addition 
of carbon dioxide to the five-carbon sugar ribulose 1,5-bisphosphate. (This 



Coloring Outside the Lines 



263 



70% of Cellular Protein 



30% of Cellular Protein 



Cellular or Viral DNA 



Cellular DNA 



Viral DNA 



Gene 



Gene 



'?-^_. mRNA 



mRNA 



RibosomG 

Properly folded 
protein chain 



/ 



\ 



i 



Protein 
chain 




/ 

Accomplishes function 
{or becomes damaged) 

^^ XZlft Protein 






~ J ^^.^ fragments 
Ammo acids 



^^r ^^^r ^^^0 ^1^^ ^'""''^A ^^a^ 




1^ 



<its- 






/ 






r^S-S^ 



(\J' 



[--i. 



-u^ 



Jhl^k |||j||||B 



Improperly made 



M. 



proteins 

^ Immediately 

\^'''-0],<j7^' degraded ' 






/ 



.^ Protein 

y\^ fragment 



Cell surface 
Immune system 




Figure 13.3. Two Metabolic Fates of Proteins 

The cell incorporates the protein-degradation fragments into a complex assembly of 
molecules called the class 1 major histocompatibility complex (MHC). At the cell stirface 
the MHC presents the protein fragments to the immtine system. The inefficiency of protein 
synthesis allows for a highly efficient immune response to viral infection. 



process is referred to as the carbon fixation reaction of photosynthesis.) 
This chemical transformation, which is the first step in the so-called dark 
reactions of photosynthesis, sustains virtually every life-form in Earths 
surface biosphere. In the dark reaction, these two compounds produce a 



254 The Cell's Design 

transiently existing six-carbon species that breaks down into two three- 
carbon compounds. Once formed, these three-carbon entities get swept 
away by a series of reactions that ultimately yield six-carbon sugars, the 
foodstuff at the base of the food chain. s, 

Highly inefficient. The protein that catalyzes the addition of carbon 
dioxide to ribulose 1,5-bisphosphate is rubisco (ribulose 1,5-bisphosphate 
carboxylase/oxygenase). Because of its central role in photosynthesis and its 
primary importance in ecosystems, rubisco is the most abundant protein 
in nature. In spite of its significance, rubisco has acquired the reputation 
among biochemists as a wasteful enzyme. 

The rubisco-catalyzed reaction of carbon dioxide and ribulose 1,5-bis- 
phosphate proceeds slowly. Prone to errors, rubisco confuses molecular 
oxygen for carbon dioxide, further compounding its inefficiency. When 
rubisco makes this mistake, oxygen combines with ribulose 1,5-bisphos- 
phate to form unwanted compounds. Photorespiration, an undesired pro- 
cess, detracts from the carbon fixation reaction that inaugurates the dark 
reactions of photosynthesis, necessitating many more copies of rubisco than 
would be required if this enzyme operated with greater efficiency. 

Such wastefulness has prompted some biochemists to focus their efforts 
on developing genetically engineered plants with novel forms of rubisco 
that would operate with greater efficacy than those found in nature. The 
hope is that these genetically modified plants would boost food produc- 
tion around the world. 

A new discovery. Recent work by scientists from Australia, however, is 
changing the way biochemists view rubisco. These researchers point out 
that rubisco s slow turnover and struggles to discriminate between molecu- 
lar oxygen and carbon dioxide stem from the small linear and symmetric 
nonpolar nature of both gases. In other words, rubisco's confusion is not 
its fault, but rather results from the inherent chemical nature of the two 
gases. To overcome this confusion, rubisco uses the chemical intermedi- 
ate that forms during the process that adds carbon dioxide to ribulose 
1,5-bisphosphate (the transition state complex) to indirectly discriminate 
between carbon dioxide and oxygen. 

This indirect discrimination has unavoidable consequences, however. 
It slows down the carbon fixation reaction. The reason for the slow down 
has to do with the similarity between the transition state complex and 
the six-carbon compound produced by the carbon fixation reaction. This 
similarity makes it more difficult for rubisco to release the product once it 



Coloring Outside tlie Lines 96S 

forms at the enzyme s catalytic site, hindering the rate of chemical conver- 
sion. The bottom line: Rubisco faces a trade-off between rate ofreaction 
and discrimination between the gases. 

A survey of rubiscos from a variety of plants reveals a pattern that stems 
from this trade-off. Rubiscos exposed to an environment with a relatively 
low carbon dioxide-to-oxygen ratio bind the transition state complex more 
tightly in order to distinguish carbon dioxide from oxygen. By contrast, 
rubiscos in an environment with higher carbon dioxide-to-oxygen ratios 
bind the transition state complex more loosely. This difference in bind- 
ing dictates reaction rate. Rubiscos in a low carbon dioxide-to-oxygen 
environment convert carbon dioxide and ribulose 1,5-bisphosphate into 
a six-carbon compound at a relatively slow rate. Rubiscos in relatively high 
carbon dioxide-to-oxygen environments complete the carbon fixation reac- 
tion more rapidly. 

Based on this pattern, the researchers from Australia concluded that 
rubiscos found throughout nature are perfectly optimized for their envi- 
ronments and the slow carbon fixation reaction is a necessary trade-off for 
this enzyme to make the difficult discrimination between carbon dioxide 
and molecular oxygen. These workers conclude that "despite appearing 
sluggish and confused, most rubiscos may be near-optimally adapted to 
their different gaseous and thermal environments. "s. 

In other words, biochemists likely can't improve upon the elegant de- 
sign of the rubiscos found in nature. This enzyme no longer deserves the 
reputation as a poorly designed product of evolutionary processes; rather, 
its deliberate design adds the necessary depth to an amazing work of art. 

Dynein andKinesin 

The molecular motors dynein and kinesin transport cellular cargo along 
microtubules (see chapter 4, pp. 81 and 93). Part of the cell's cy to skeleton, 
microtubules display polarity with "plus" and "minus" ends. Microtubules 
form an astrallike structural array within the cell. Their minus ends cluster 
near the nucleus at the center of the cell. The plus ends locate to the cell's 
peripheral regions. 

Dynein and kinesin transport cellular cargo along microtubules in single 
and opposite directions. These motor proteins recognize microtubule po- 
larity and use the directional nature of the cytoskeletal elements to move 
materials either toward or away from the cell's center. Kinesin moves cargo 



266 



The Cell's Design 



toward the plus ends of microtubules at the cell's periphery. Its structural 
simplicity makes kinesin a highly efficient and robust transporter. 

Highly inefficient. Dynein moves materials toward the minus ends lo- 
cated near the cell's nucleus. In contrast to kinesin, dynein's greater structural 
complexity makes this motor cumbersome and inefficient by comparison. 
On this basis, dynein appears to be best explained as the imperfect product 
of evolutionary process, not the work of a Creator. 

A new discovery. Recent work paints a different picture of dynein's 
operation. 56 Though kinesin is simple and efficient, its simplicity limits 
the cell's ability to regulate its activity. Kinesin can only exist in two func- 
tional states, either fully active or fully inactive. Dynein's complexity, on 
the other hand, provides the cell with several means to dynamically tune 
its activity. This motorized carrier can speed up or slow down depending 
on the cell's needs. 

From a design standpoint, a trade-off between efficiency and the cell's 
ability to regulate motor activity exists for dynein and kinesin. These mo- 
lecular motors both appear optimally designed for allowing the motors to 
function individually and cooperatively in a variety of cellular situations. 



Perfect Imperfections 

Biomolecular imperfections represent potentially devastating disan- 
alogies for the biochemical intelligent design argument. The abundant 
elegant designs that characterize life's chemical systems, which seemingly 
make such a strong case for a Creator, are often overshadowed by poorly 
performing biochemical systems. Bad biochemical designs are unworthy 
of intelligent agency. 

According to evolutionary biologists, the blind undirected processes of 
evolution can just as readily account for good designs through the repeated 
action of natural selection on random genetic variation. But evolution- 
ary processes are also just as likely to generate "jury-rigged" structures. 
Biochemical imperfections seem to indicate the amateurish scribbling of 
happenstance, not the intentional expertise of an all-powerful, all-knowing 
Designer. 

But, imperfections may not be as big a problem for the biochemical intel- 
ligent design argument as they first appear. Rather than representing disan- 
alogies that mitigate against the biochemical intelligent design argument. 



Coloring Outside tlie Lines 967 

suboptimal biochemical designs could result from the outworkings of the 
second law of thermodynamics. Entropy introduces defects into elegantly 
designed biochemical systems through genetic mutations. 

And, some poor designs are not really bad at all. Instead, these seemingly 
poor designs actually add to the list of analogical features shared by human 
designs and the Creator. Any engineer who designs a complex multiobjective 
system faces trade-offs and must carefully introduce suboptimal features 
in order to achieve overall performance. 

This important design principle, relied on by human engineers, appears in 
living color in the cell's chemistry. Recent advances have made it possible for 
biochemists to identify trade-offs in a number of biochemical systems. 

Prior to these new insights, scientists considered many of these systems to 
be cumbersome and inefficient — certainly not the work of the all-powerful, 
all-knowing Creator described in the Bible. All too often, evolutionary bi- 
ologists quickly pronounced sentence on the quality of life's biomolecular 
designs without fully understanding their structure, function, and inter- 
relationship to other biochemical processes. This misjudgment clearly has 
been the case for so-called junk DNA sequences. 

The recognition that several examples of bad biochemical design are, 
in fact, optimal neutralizes one of the most potent challenges against bio- 
chemical intelligent design. These discoveries also make it distinctly possible 
that when other biochemical imperfections are more fully understood, they 
too may reveal themselves to be perfect. 

The next chapter pulls together the components of the Creator's artistry 
in the cell to more fully reveal his masterpiece. 



14 



THE MASTERPIECE 
AUTHENTICATED 



An exhibit opened on May 3, 2004, that caused quite a stir in the art world. 
The Mitchell-Innes and Nash gallery in New York City unveiled part of a 
collection that had never before been displayed — a 1970 album of twenty- 
six drawings and watercolors created by a ninety-one-year-old Picasso., 

Throughout his life Picasso developed such sketchbooks. Now his 
family controls most of them and limits their access. The so-called Berg- 
gruen Album (named for art dealer Heinz Berggruen) provides a rare 
and intimate glimpse into the art and thoughts of Picasso. Put together 
over the span of about seven days, Picasso produced about four works 
per day and carefully dated each one. 

Nature's sketchbook compiled by the day-to-day research efforts of bio- 
chemists, biophysicists, and molecular biologists over the last half-century 
also reveals remarkable insights into the work of its Creator. This process 
marks a continuous unveiling of the biochemical masterpiece. With each 
new discovery, life's most fundamental structures and activities continue 
to generate a stir in the scientific world and beyond. 

269 



270 The Cell's Design 

Life — A Magnificent Masterpiece 

The sheer beauty and artistry of Ufe's chemical systems is undeniable. So, 
too, is the appearance of design. For those who regard this glorious treasure as 
the handiwork of a Creator, the page-by-page details supplied by researchers 
provide a rare and intimate glimpse into the art and thoughts of the Divine 
Master. 

Even scientists who maintain that undirected processes (natural selec- 
tion operating iteratively on random genetic change) produced the elegant 
chemical systems in the living realm find this appearance of biochemical 
design awe-inspiring.. 

Careful consideration of the hallmark characteristics of biochemical 
systems suggests the work of a Mastermind. The few pages from the sketch 
pad made available in this book were carefully selected and organized to 
cast the intuition of design into a formal argument. 

Rather than relying on a single biochemical feature (like irreducible com- 
plexity) to argue for a Creator's role in life's origin, the case for biochemical 
intelligent design is erected upon a weight of evidence argument. Each 
feature, in and of itself, points to the work of a Creator. And collectively, 
the individual strands of evidence intertwine and mutually support one 
another to make the case that much more compelling. 

Skeptics are within their rights to regard a single piece of evidence or 
a single line of reasoning as marginal in its support for intelligent design. 
However, if a litany of diverse evidence exists, it becomes less tenable to 
reject a supernatural basis for life as unfounded. 

Can Evolution Explain Life's Chemical Picture? 

When attempting to make any scientific case, all the evidence should be 
examined to come to the most valid conclusion. The fact that evolutionary 
explanations have been offered to account for life's elegant chemical systems 
can't be ignored. For example, some scientists claim that biochemical fine- 
tuning and optimization result when the forces of natural selection operate 
iteratively on random genetic variation over eons of time to precisely hone 
the structural and functional features of life's chemistry. 

Origin-of-life researchers maintain that information-rich biomolecules, 
like DN A and proteins, emerged under the influence of chemical selection. 
According to this idea, it's notjust random processes alone that explain the 



The Masterpiece Authenticated 971 

origin of information-harboring molecules. Rather, the intrinsic chemical 
and physical properties of subunit molecules (amino acids and nucleotides, 
for example) and the resulting physicochemical features of information- 
containing polymers (proteins, DNA, and RNA) efficiently guided random 
processes and led to the emergence of biochemical information systems 
over vast periods of time. 

Evolutionary Stepping Stones 

Evolutionary biologists also claim that irreducibly complex systems 
(and chicken-and-egg systems) did not have to arise all at once but could 
emerge in a stepwise fashion.., According to this model, the biomolecules 
of irreducibly complex biochemical systems originally played other roles 
in the cell and were later recruited or co-opted, one-by-one, to be part of 
transitional systems that eventually led to the irreducibly complex systems 
of contemporary biochemical operations. 

For instance, some evolutionary biologists claim that the bacterial flagel- 
lum (see chapter 4, p. 71) evolved from the type III secretion apparatus 
through the process of co-option. Pathogenic bacteria use the type III 
secretion system to export proteins into the cells of the host organism. The 
molecular architecture of the type III secretion system closely resembles 
the part of the flagellum embedded in the bacterial cell envelope. 

Speculation has the first flagellum arising from the merger of the type III 
secretion apparatus and a filamentous protein system. Presumably, both 
structures provided the microbe with prior services, neither of which had 
anything to do with motility. These evolutionary explanations have not 
gone unchallenged, however. 

Evolutions critics point out that these explanations seem plausible, but 
only on the surface. In essence, they are no more than evolutionary "just-so" 
stories. Invariably, the naturalistic scenarios proposed to account for the 
origin of irreducibly complex systems are highly speculative and lack any type 
of detailed mechanistic undergirding. This problem is clearly the case for all 
the evolutionary explanations offered to account for the emergence of the 
bacterial flagellum. Biologists Mark Pallen and Nicholas Matzke state that 

the flagellar research community has scarcely begun to consider how these 
systems have evolved. This neglect probably stems from a reluctance to 
engage in the "armchair speculation" inherent in building evolutionary 
models. 



272 The Cell's Design 

Compounding the speculative nature of the evolutionary explanations for 
the origin of the bacterial flagellum is the nagging problem of which came 
first: the flagellum or the type III secretion machine. According to Milton 
Saier, a biologist from the University of California, San Diego, insufficient 
information exists to determine from an evolutionary framework whether 
(1) the type III secretion apparatus came first or (2) the bacterial flagellum 
came first, or (3) both structures evolved from the same precursor system.. If 
evolutionary analyses indicate that the type III secretion machine emerged 
from the flagellum, it thoroughly undermines the co-option explanation. 

On the other hand, the type III secretion system — the proposed evolu- 
tionary stepping stone to the bacterial flagellum — is an irreducibly complex 
structure. It's an elegant machine that, like many other biomolecular ma- 
chines, bears an uncanny resemblance to humanly crafted devices. In other 
words, the type III secretion machinery, in and of its own right, evinces 
biochemical intelligent design. Further evidence for intelligent design comes 
from the recognition that highly similar flagellar systems appear to have 
emerged independently (from an evolutionary perspective) in bacteria and 
archaea.. This remarkable example of convergence fits awkwardly within 
an evolutionary context but makes perfect sense if a Creator repeatedly 
employed the same blueprint when he made flagellar systems in archaea 
and bacteria (see chapter 11). 

Evolutionary biologists own the burden of proof. If irreducibly complex 
systems do, indeed, have an evolutionary origin, the scientific commu- 
nity must provide a detailed mechanistic accounting for each step in the 
sequence of molecular events that yielded the system. Additionally, they 
must demonstrate that this sequence of steps could have happened in the 
available time and with the resources at its disposal. 

It's not enough to merely propose a chronology of events that "may have 
happened" or "most likely took place." Yet, virtually every evolutionary 
explanation for irreducibly complex biochemical systems is littered with 
these types of qualifiers. - 

Is the Probability Probable? 

As for the origin of information-rich biomolecules, evoking chemical 
selection as a mechanistic explanation for the origin of proteins and nucleic 
acids — like DNA and RNA — again, at a surface level seems plausible. But 
as astronomer Hugh Ross and I show in our book Origins of Life, chemical 



The Masterpiece Authenticated 9 7^ 

selection seems to play a minor, almost negligible, role in the formation of 
information-containing molecules. For all intents and purposes, the for- 
mation of biochemical information systems is a probability problem. And 
based on what's currently known, it appears superastronomically improbable 
for the essential gene set to emerge through natural means alone. n 

Still, this probability analysis is incomplete because the fundamental 
relationships among sequence, structure, and function for proteins and 
DN A are still notknown. When these relationships are better understood, 
it may turn out that it is much easier for mechanistic processes to generate 
information-rich molecules. But these future insights could also make the 
probabilities ofproducing functional biomolecules even more remote. 
The bottom line: Current knowledge about the capability of evolution- 
ary processes is insufficient to either establish or rule out an evolutionary 
origin of biochemical information systems. 

What Are the Odds? 

While it's impossible at this point in time to calculate the probabil- 
ity of functional biomolecules like proteins emerging through natural 
means, scientists can rigorously assess the likelihood that the genetic code 
arose through natural processes. Simply put, there does not appear to be 
enough time for evolutionary processes to stumble upon the universal 
genetic code — a code that displays exceptional levels of design in terms 
of its error-minimization capacity (see chapter 9, p. 174) and its ability to 
harbor overlapping codes. 

Biophysicist Hubert Yockey determined that natural selection would 
have to explore 1.40 x 10 different genetic codes to discover the universal 
genetic code found in nature. Yockey estimated 6.3 x 10 seconds is the 
maximum time available for the code to originate. Natural selection would 
have to evaluate roughly 10 codes per ^econc? to find the universal genetic 
code. ; The universal genetic code that defines biochemical information 
doesn't appear to have an evolutionary origin. 

The origin of cell membranes has to be one of the first steps in the origin 
of life. These structures play critical biochemical roles. 

Even though biochemists and biophysicists have identified plausible 
pathways that could produce the first components of primitive cell mem- 
branes and have uncovered physicochemical processes that could, in prin- 
ciple, have yielded the vesicles, they have ultimately failed to explain the 



274 The Cell's Design 

origin of cell membranes. Numerous experiments demonstrate that every 
step in the proposed pathway from prebiotic amphiphilic compounds to 
contemporary cell membranes strictly depends on exacting compositional 
and environmental factors.,, These stringent requirements make it unlikely 
that cell membranes could ever emerge on early Earth — unless guided by 
the hand ofan intelligent being. 

The proposed evolutionary explanations for fine-tuning and optimization 
of biochemical systems in no way invalidate the case for biochemical intel- 
ligent design. These two elegant design features of biochemical systems are 
precisely what can be expected if life is the product of a Creator. According 
to the late evolutionary biologist Stephen Jay Gould, "Textbooks like to 

illustrate evolution with examples ofoptimal design But ideal design 

is a lousy argument for evolution, for it mimics the postulated action of 
an omnipotent creator." - 

According to Gould, the optimal design of biochemical systems could 
point equally to the work of a Creator or evolutionary fine-tuning. How- 
ever, Gould as well as other evolutionary biologists think the seemingly bad 
designs in nature make an unequivocal case for an evolutionary explana- 
tion for life's origin and history. The blind undirected chance processes of 
evolution are just as likely to produce "jury-rigged" structures as they are 
to produce fine-tuned structures. Evolutionists claim that even though 
biochemical systems are replete with elegant design features, the assortment 
of imperfections in life's chemistry undermines the case for biochemical 
intelligent design. An all-powerful, all-knowing Designer would never 
produce such faulty work. 

Can Disanologies Be Explained? 

When employing analogical reasoning, the ways in which the compared 
system, events, or objects differ must be considered (see chapter 1, p. 31). 
Biochemical imperfections match the expected pattern for evolution and 
potentially represent powerful disanalogies, wreaking havoc on the conclu- 
sion that life's chemistry is the work of a Creator. 

Yet, imperfections may not be as big a problem for the biochemical 
intelligent design argument as they appear on the surface (see chapter 12). 
Faulty designs could result from the outworkings of the second law of ther- 
modynamics that introduces defects into elegantly designed biochemical 
systems through genetic mutations. 



The Masterpiece Authenticated 97S 

And, some bad designs may not be bad at all. Seemingly poor designs 
may represent the intentional actions of the Creator. When engineers 
design finite multiobjective complex systems, they face trade-offs and 
must carefully introduce suboptimal features in order to achieve overall 
optimal performance. 

This important design principle, relied on by human engineers, appears 
to be in full effect in the cell's chemistry. Recent advances have made it 
possible for biochemists to identify trade-offs in a number of biochemical 
systems. Prior to these new insights, biochemists considered many of these 
systems cumbersome and inefficient. All too often, evolutionary biologists 
are quick to pronounce sentence on the quality of life's biomolecular designs 
without fully understanding their structure, function, and interrelationship 
to other biochemical processes. 

The recognition that several examples of bad biochemical design are, 
in fact, optimal neutralizes one of the most potent challenges against bio- 
chemical intelligent design. Such discoveries make it distinctly possible that 
other biochemical imperfections may actually be perfect when more fully 
understood. Instead of representing disanalogies that mitigate against the 
biochemical intelligent design argument, suboptimal biochemical designs 
actually add to the list of analogical features shared with human designs. 
Just as human designers intentionally introduce suboptimal features in 
their designs to achieve overall optimality, so too does the Creator (see 
chapter 13, p. 248). 

Is There a Consistent Style? 

The idea of historical contingency championed by Stephen Jay Gould 
provides another way to discriminate between the "appearance of design" 
and intelligent design. Does contingency account for the patterns observed 
in the biological realm?,. 

If life results exclusively from evolutionary processes, then scientists 
should expect to see few, if any, cases in which evolution repeated itself. 
Chance governs biological and biochemical evolution at its most funda- 
mental level. Evolutionary pathways consist of a historical sequence of 
chance genetic changes operated on by natural selection, which also consists 
of chance components. The consequences are profound. If evolutionary 
events could be repeated, the outcome would be dramatically different 
every time. 



'21 f\ The Cell's Design 

If life is tlie product of a Creator, however, then the same designs should 
repeatedly appear in biochemical systems. Human engineers routinely reuse 
the same techniques and technologies. 

Over the course of the last decade or so, scientists exploring the origin of 
biochemical systems have discovered that a number of life's molecules and 
processes, though virtually identical, appear to have originated indepen- 
dently, multiple times (see chapter 11). 

Evolutionary biologists refer to the independent origin of identical 
biomolecules and biochemical systems as molecular convergence. Repeated 
creations would give the appearance of multiple independent origin events 
when viewed from an evolutionary vantage point. So the explosion in 
the number of examples of molecular convergence is unexpected iflife 
resulted from historical sequences of chance evolutionary events. Yet, if 
life emanated from a Creator, it is reasonable to expect that he used the 
same designs repeatedly as he created. 



Reasoning to the Best Explanation for Life 

The highly speculative, proposed evolutionary scenarios for life's chem- 
istry don't necessarily weaken the case for biochemical intelligent design. 
Even in light of these evolutionary explanations, the defining features of 
biochemical systems are precisely what would be expected if life is the prod- 
uct of a Creator. This line of thinking is an example of what philosophers 
refer to as abductive reasoning.,. 

Commonly used by scientists to evaluate hypotheses, abductive reason- 
ing takes the following form: 

X is observed. 

If Y were true, then X would be expected. 

There is good reason to believe that Y is true. 

In the case of biochemical systems: 

Design is observed in biochemical systems. 

Iflife stemmed from the direct work of a Creator, the elegant design of 

biochemical systems would be expected. 
There is good reason to believe that life is the product of a Creator. 



The Masterpiece Authenticated 977 

In other words, the same reasoning process that scientists use, day in 
and day out, to evaluate a hypothesis rationally and logically leads to the 
expectation that life, at its most fundamental level, stemmed from a Cre- 
ator s handiwork. 



Making the Case for a Divine Artist 

Arguments for intelligent design typically fall into one of two catego- 
ries: those that rely on probabilities and those based on analogies. In the 
biochemical arena, probability arguments primarily focus on the inability 
(or at least the claimed inability) of natural mechanistic processes to gener- 
ate the information-rich biomolecules (DNA and proteins, for example) 
central to life's chemical systems. 

The Problems with Probabilities 

This book has avoided probability arguments for two reasons. Based on 
current understanding, the case for biochemical intelligent design is unat- 
tainable through the use of probabilities. Biochemists lack the necessary un- 
derstanding of the relationship between amino acid sequences and protein 
structure and function. Without this critical knowledge, it's impossible to 
determine the likelihood, one way or the other, of evolutionary processes 
spawning the information-based systems of life's systems. 

In addition, at their very essence, probability-based design arguments are 
negative in scope. Instead of making a positive case for the specific features 
found in nature, probability arguments fixate on what natural processes 
can or can't do. In the end, this approach proves nothing because a nega- 
tive can't be proven. 

Even Dembsk is explanatory filter (see chapter 1, p. 25) depends upon 
probabilities (or more appropriately, improbabilities). Though this tech- 
nique is touted as a method that positively detects the work of an intel- 
ligent agent in nature, it considers a feature in the natural realm to be the 
product of intentional design only after natural processes are demonstrated 
incapable of generating that feature. As with all probability arguments, 
the explanatory filter is ultimately a commentary on what natural mecha- 
nisms can or can't do. And this insight can never be achieved apart from 
an omniscient viewpoint. 



OTQ The Cell's Design 

An Analogical Analysis 

In the tradition of William Paley's Watchmaker analogy (see chapter 4, 
p. 85), this book makes the case for biochemical intelligent design based 
on analogical reasoning. Many have considered this approach ineffective 
based on the work of philosopher David Hume (171 1-1776) and myriad 
others who came after him. Critics of analogical reasoning rightfully reacted 
against weak or poorly constructed analogies and justifiably rejected the 
conclusions drawn from them. 

This rejection, however, doesn't mean that it is impossible to make a 
logically compelling case for intelligent design based on analogy. Rather, it 
sets up the imperative to properly and carefully employ analogical thinking 
(see chapter 1, p. 3 1). 

One effective form of analogical reasoning, particularly commonplace in 
science, is pattern recognition. For instance, analytical chemists routinely 
use pattern recognition to identify unknown chemical compounds by 
comparing the physical, chemical, and spectral properties for a series of 
known standards with those of an unknown substance. These scientists feel 
confident they can identify an unknown compound when its characteristics 
closely match those of a known chemical entity. This approach can only 
succeed, however, if the researchers have a predetermined pattern available 
to compare against the unknown material. 

Likewise, it's necessary to define ahead of time an intelligent design 
pattern that can be used as a template to compare with life's chemistry for 
successful use of this technique. If life is the product of a Creator, then 
the defining features of biochemical systems should line up with the intel- 
ligent design template. If it is not, then the defining characteristics will be 
different. 

Unfortunately, no universal pattern for intelligent design is currently 
known. The only unequivocal example available to construct the template is 
the behavior of human designers. But it may not be legitimate to generalize 
human behavior into a set of criteria that universally describes the activity 
of any intelligent designer. Human designers could very well create in an 
anomalous fashion. 

This problem was circumvented by linking the behavior of human 
designers to the activities of the Intelligent Agent responsible for creat- 
ing life. This book identifies that Creator as the God of the Old and 
New Testaments. The biblical account of humanity's origin establishes 



The Masterpiece Authenticated 97Q 

the desired connection between human designers and their Maker. The 
Genesis 1 creation account (and Genesis 5) teaches that God created 
human beings, male and female, in his image.,, This declaration implies 
that humans bear a similarity to God, at least in some ways. 

Just as God is a Creator, so too human beings (who bear his image) are 
minicreators. This resemblance implies that the hallmark characteristics of 
humanly produced systems will mirror those of divinely designed systems, 
if the Divine Artist is the God described in the Bible. The expectation, 
however, is that the hallmark characteristics ofman-made systems would, 
at best, imperfectly reflect divine design. As a corollary to this idea, the 
cell's chemical systems should be clearly superior to anything produced by 
the best human designers. 

The analogical comparison used to argue for biochemical intelligent 
design is an integral part of day-to-day decision making. Analogical reason- 
ing is not neat and tidy. Its conclusions are not certain, but instead they 
depend upon a weight of evidence. Properly employed, analogical thinking 
can produce sound conclusions. In general, the conclusions drawn from 
analogies engender increasing confidence as the number of comparisons 
and the number ofrelevant similarities for each increases. 

The Weight of Evidence 

The examples discussed throughout this book reveal some of the defin- 
ing features of life's chemical systems that correspond to the distinctive 
characteristics of systems designed by humans. A summary of the features 
from these systems tips the scales in favor of creation authenticating the 
masterpiece. 

Irreducible complexity. As highlighted in Behe's Darwin's Black Box, 
biochemical systems typically are irreducibly complex. They are composed 
of numerous components, all of which must be present for the system 
to have any function at all. Many man-made systems are also irreducibly 
complex; therefore, this feature indicates intelligent design. 

Chicken-and-eggsystems. Which came first ? Many biochemical systems 
are made up of components that mutually require each other for all the com- 
ponents to be produced. For example, ribosomes make proteins, yet, in turn, 
are formed from proteins. So proteins can't be made without ribosomes, and 
ribosomes can't be made without proteins. The mutual interdependence of 
the components of many biochemical systems signifies intelligent design. 



280 



The Cell's Design 



Fine-tuning. Many biochemical structures and activities depend on 
the precise location and orientation of atoms in three-dimensional space. 
Man-made systems often require a high-degree of precision to function. 
Fine-tuning reflects intelligent design. 

Optimization. Many biochemical structures and activities are designed 
to carry out a specific activity while operating at peak performance. Man- 
made systems often are planned in the same way. Optimization demonstrates 
the work of an Intelligent Agent. 

Biochemical information systems. Information comes from intelligence. 
At their essence, the cells biochemical systems are information-based. The 
presence of information in the cell, therefore, must emanate from an Intel- 
ligent Designer. 

Structure of biochemical information. The evidence for intelligent 
design goes beyond the mere existence of information-based biochemical 
systems. Biochemical information displays provocative structural features, 
such as language structure and the organization and regulation of genes, 
that also point to the work of a Creator. 

Biochemical codes. The information-based biochemical systems of the 
cell employ encoded information. The genetic code, the histone code, and 
even the parity code of DN A are three examples. The encoded information 
of the cell requires an Intelligent Designer to generate it. 

Genetic code fine-tuning. The rules that comprise the genetic code are 
better designed than any conceivable alternative code to resist errors that 
occur as the genetic code translates stored information into functional 
information. This fine-tuning strongly indicates that a superior Intelli- 
gence designed the genetic code. The universal genetic code also has been 
optimized to house multiple parallel codes. 

Quality control. Designed processes incorporate quality control systems 
to ensure the efficient and reproducible production of quality product. 
Many biochemical systems employ sophisticated quality control processes 
and consequently reflect the work of an Intelligent Designer. 

Molecular convergence. Several biochemical systems and/or biomol- 
ecules isolated from different organisms are structurally, functionally, and 
mechanistically identical. These biochemical systems have independent 
origins. Given these systems' complexity, it is unwarranted to conclude that 
blind random natural processes independently produced them. Rather, 
molecular convergence reflects the work of a single Creator that employs 
a common blueprint to bring these systems into existence. 



The Masterpiece Authenticated 981 

Strategic redundancy. Engineers frequently design systems with re- 
dundancy, particularly for those components that play a critical role in 
the operation of the system. When engineers incorporate duplicate parts 
into their designs, the redundant components form a responsive backup 
circuit. Many duplicated genes in genomes operate as a responsive backup 
circuit, reflecting the work of a Creator. 

Trade-offs and intentional suboptimization. When engineers design 
complex systems, they often face trade-offs and must purposely design com- 
ponents in the system to be suboptimal in order to achieve overall optimal 
performance. Many biochemical systems display evidence of intentional 
suboptimization to balance trade-offs pointing to the work of a Divine 
Engineer. 

In light of these criteria, it is significant that so many disparate character- 
istics of life's chemistry bear an uncanny resemblance to human designs. And 
for each category that is part of the biochemical intelligent design analogy, 
numerous examples abound in cells — far more than could be described in 
this work. In a sense, the information presented grossly understates the 
case for biochemical intelligent design. 

Piling On Extra Pounds 

Many additional provocative aspects of life's chemistry also signify the 
work of a Creator. These features are not necessarily a formal part of the 
biochemical intelligent design analogy yet are very much a part of the case 
for divine artistry. Some of the features specifically discussed add to the 
increasing weight of evidence for a Creator. 

Life's minimum complexity. Life in its bare minimal form is remarkably 
complex. Minimal life seems irreducibly complex. There appears to be a 
lower bound of several hundred genes, below which life cannot be pushed 
and still be recognized as "life." In Darwin's Black Box, Behe demonstrated 
that individual biochemical systems are irreducibly complex. In its totality, 
life appears that way as well. 

Molecular-level organization of simplest life. Over the last decade or so, 
microbiologists have come to recognize that prokaryotes (the simplest life- 
forms) display an exquisite spatial and temporal organization at the molecular 
level. Common experience teaches that it takes thought and intentional effort 
to carefully organize a space for functional use. By analogy, the surprising 
internal organization of prokaryotic cells bespeaks of intelligent design. 



ya-j The Cell's Design 

Exquisite molecular logic. Often, the design and operation of biochemi- 
cal systems are remarkably clever. Many aspects of life s chemistry display an 
eerie though appealing molecular logic that indicates a Creator's wisdom. 

Preplanning. Planning ahead indicates purpose and reflects design. 
Many biochemical processes, like the assembly of the bacterial flagellum, 
consist of a sequence of molecular events and chemical reactions. Often 
the initial steps or initial structures of the pathways elegantly anticipate 
the pathway's final steps. Biochemical preplanning points to divine inten- 
tionality in life's chemistry. 

Molecular motors. Individual proteins and protein complexes literally 
are direct structural and functional analogs to machines made by humans. 
These molecular motors revitalize the Watchmaker argument for a Creator s 
existence. 

Cell membranes. These structures, which establish the cell's external and 
internal boundaries, require precise chemical compositions to form stable 
structures. Cell membranes also display exquisite organization that includes 
asymmetric inner and outer surfaces, dynamic structural and functional 
domains, and many specialized embedded machines. 

The designs of biochemical systems inspire human designs. Some of 
the most important advances in nanoscience and nanotechnology come 
from insight gained from life's chemical operations. Apart from this insight, 
researchers struggle to discover, let alone implement, the principles needed 
to build molecular devices. The fact that biochemical systems can inspire 
human design indicates that life's chemistry was produced by the One who 
made humankind. 

Man cant do it better. Frequently, humans fail in their attempts to 
duplicate the cell's complex and elegant chemical processes in the labora- 
tory. When humans mimic biochemical processes, they find that their best 
efforts are cumbersome and lead to crude and inefficient systems. It doesn't 
seem reasonable to believe that blind random processes can account for the 
elegance of life's chemistry when the best researchers utilizing state-of-the- 
art technology can't produce even remotely comparable systems. 



A Profound Implication 

This book makes the case for biochemical design by comparing the most 
salient features of life's chemistry with the hallmark characteristics of human 



The Masterpiece Authenticated 9 8'^ 

designs. The close match between biochemical systems and the pattern for 
intelligent design based on the behavior of human designers logically com- 
pels the conclusion that life's most fundamental processes and structures 
stem from the work of a Divine Designer. 

The significance of the biochemical intelligent design argument extends 
beyond the conclusion that life's chemistry represents the work of a Divine 
Being. It displays the handiwork of the God described in the Old and New 
Testaments. The close analogy between the qualities of human and bio- 
chemical designs is quite provocative and points to a resonance between 
the human mind and the Divine Mind responsible for creating biochemi- 
cal systems. This connection finds explanation in the biblical text, which 
declares that humans are made in God's image. The biochemical intelligent 
design analogy viewed in the context of Scripture supports the notion that 
humans were made to be in a relationship with the Creator. 



EPILOGUE 



Though it stands on its own. The Cell's Design is a sequel to Origins of Life, 
a book I coauthored with astronomer Hugh Ross. In it, we explored how 
the first life-forms (eubacteria and archaea) on Earth came into existence 
and presented a way to test those beginnings as a creation event. We also 
made the case that life's origins are miraculous and presented the first-ever 
scientifically testable creation model for life's beginnings, part of Reasons 
To Believe s creation model research program., (Reasons To Believe [RTB] 
is a think tank devoted to exploring the connection between the frontiers 
of science and Christianity.) 

This effort represents a new approach in the creation/evolution contro- 
versy, one that directly responds to the concern raised by many scientists 
who contend that creation is not science, because it cannot be falsified. 

The RTB creation model is based on the biblical descriptions of God's 
creative work found in Scripture. The ongoing process of building the 
creation model starts by collating the biblical data from the major accounts 
and individual scriptural passages that describe God's creative actions. 
Once interpreted, the biblical data is recast in scientific terms rendering the 
biblical creation account testable. Biblical statements about God's creative 
activity are subjected to experimental validation. They also lead to predic- 
tions regarding future scientific discoveries. 

This approach makes creation a scientific endeavor. Creation becomes 
testable and falls within the domain of science. The model's predictions 

285 



286 Epilogue 

delineate the features we'd expect to see in the record of nature — God's 
fingerprints — if the creation model has validity. 

The biblical text inspires the creation model's tenets and constrains the 
overall model. However, within these constraints, the model finds consider- 
able freedom for adjustments and fine-tuning as scientists and theologians 
make new discoveries. 

The RTB creation model for the origin of life comes primarily from 
Genesis 1:2, Psalm 104:5-6, and Deuteronomy 32: 10-1 1 .iBased on these 
passages, the model predicts that (1) life appears early in Earth's history 
while our planet was still in its primordial state, (2) life originated and 
persisted through the hostile conditions of early Earth, (3) life originated 
abruptly on Earth, and (4) Earth's first life displays complexity. Remark- 
ably, the latest advances in origin-of-life research continue to substantiate 
these predictions. 

The RTB origins-of-life model makes other important predictions. One 
of the most significant is that life's chemistry displays hallmark characteris- 
tics of intelligent design. The Cell's Design demonstrates how this important 
prediction finds satisfaction in the latest advances in biochemistry. 

Within the context of the RTB origin-of-life creation model, the bio- 
chemical evidence for design goes beyond a mere inference to testable 
predictions based on intelligent causation. And in that context, RTB's 
model places creation squarely within the domain of science. 



NOTES 



Introduction A Rare Find 

I.Robert P. Wo\ff, About Philosophy, 2nd ed. (Englewood Cliffs, NJ: Prentice-Hall, 1981), 193-97. 

2. Fazale Rana and Hugh Ross, Origins of Life: Biblical and Evolutionary Models Face ('^(Colorado 
Springs: NavPress, 2004), 1 3- 1 5 ; Joe Aguirre, "Biochemistry and the Bible: Collaborators in Design," 
Facts for Faith, no. 3, third quarter 2000,34-41. 

3. Richard Dawkins, The Blind Watchmaker: Why the Evidence of Evolution Reveals a Universe without 
Design (New York: Norton, 1996), 1. 

4. See, for example, Michael J. Behe, Darwin's Black Box: The Biochemical Challenge to Evolution 
(New York: Free Press, 1996). 

5. Francis Crick, What Mad Pursuit (New York: Basic Books, 1988), 138. 

6. "A Scientific Dissent from Darwinism," Discovery Institute, February 2007, http:// www, disco very 
.org/scripts/viewDB/filesDB-download.php?command=download&id = 660. 

7. Behe, Darwin's Black Box, 39. 

8. For example, Bruce H. Weber, "Biochemical Complexity: Emergence or Design ?" Rhetoric & Public 
Affairs I (1998): 61 1-16; Philip Kitcher, "Born-Again Creationism," \n Intelligent Design Creationism and 
Us Critics: Philosophical, Theological and Scientific Perspectives, ed. Robert T. Pennock (Cambridge, MA: 
MIT Press, 2001), 257-87; Matthew J. Brauer and Daniel R. Brumbaugh, "Biology Remystified: The 
Scientific Claims of the New Creationists," in Intelligent Design Creationism and Its Critics, 289-334. 

9. Michael J. Behe, William A. Dembski, and Stephen C. Meyer, Science and Evidencefor Design in 
the Universe (San Francisco: Ignatius, 2000), 133-49. 

Chapter 1 Masterpiece or Forgery? 

l.For more details, see Mark Harris's website. The Picasso Conspiracy, http://web.org.uk/picasso/ 
Welcome.html (accessed February 6,2007). 

2. Guillermo Gonzalez and Jay W. Richards, The Privileged Planet: How Our Place in the Cosmos Is 
Designed for Discovery (Washington, DC: Regnery, 2004), 293-31 1. 

3. William A. Dembski, The Design Inference: Eliminating Chance through Small Probabilities (New 
York: Cambridge University Press, 1998). For a lay level discussion of the ideas found in The Design 

287 



288 Notes 

Inference, see William A. Demhski, Inteltigent Design: The Bridge between Science and Theology (Downers 
Grove, IL: InterVarsity, 1999). 

4. Dembski, Intelligent Design, 122-52. 

5. Ibid., 139-44. 

6. Ibid., 146-49. 

7. Michael J. Behe, Darwin's Black Box: The Biochemical Challenge to Evolution (New York: Free 
Press, 1996), 39-48. 

8. Philosophers Branden Fitelson, Christopher Stephens, and Elliott Sober have raised questions 
about the validity ofthe explanatory filter as a design detection system. Part oftheir criticism is that the 
application ofthe explanatory filter requires omniscience. See Branden Fitelson, Christopher Stephens, 
and Elliott Sober, "How Not to Detect Design — Critical Notice: William A. Dembski, The Design 
Inference" Philosophy of Science 66 (September 1999): 472-88, reprinted in Robert T. Pennock, ed.. 
Intelligent Design Creationism andlts Critics: Philosophical, Theological, and Scientific Perspectives (Cam- 
bridge, MA: MIT Press, 2001), 597-615. It should be noted that Dembski has replied to the concerns 
raised by Fitelson, Stephens, and Sober and some ofthe concerns raised by other critics. See William A. 
Dembski, No Free Lunch: Why Specified Complexity Cannot Be Purchased without Intelligence (Lanham, 
MD: Roman & Littlefield, 2002). 

9. For a popular level treatment of this idea, see Christian de Duve's Vital Dust: Life as a Cosmic 
Imperative (New York: Basic Books, 1995). 

10. For a recent critique of evolutionary explanations for life's origin, see Fazale Rana and Hugh Ross, 
Origins of Life: Biblical and Evolutionary Models Face ('^(Colorado Springs: NavPress, 2004). 

1 1 . Dembski, Intelligent Design, 121 . 

12. Genesis 1 :26-27: "Then God said, 'Let us make man in our image, in our likeness, and let them 
rule over the fish ofthe sea and the birds ofthe air, over the livestock, over all the earth, and over all the 
creatures that move along the ground.' So God created man in his own image, in the image of God he 
created him; male and female he created them." Genesis 5:1-2: "This is the written account of Adam's 
line. When God created man, he made him in the likeness of God. He created them male and female 
and blessed them. And when they were created, he called them 'man.'" 

13. C.John Collins, Science and Faith: Friends or iwyi (Wheaton: Crossway, 2003), 124-27; Ken- 
neth Richard Samples, "The Historic Christian View of Man," in A World of Difference (Grand Rapids: 
Baker, 2007), 171-88. 

14. MillardJ. Erickson, Christian Theology, 2nd ed. (Grand Rapids: Baker, 1998), 517-36; Wayne 
Grudem, Systematic Theology: An Introduction to Biblical Doctrine (Grand Rapids: Zondervan, 1994), 
442-50. 

15. Much ofthe material for this discussion comes from Patrick J. Hurley s book, A Concise Introduc- 
tion to Logic, 6th ed. (Belmont, CA: Wadsworth, 1997), 493-592. 

16. Romans 1:20: "For since the creation ofthe world God's invisible qualities — his eternal power 
and divine nature — have been clearly seen, being understood from what has been made, so that men are 
without excuse." 

Chapter 2 Mapping the Territory 

1. "Picture Gallery: Johannes Vermeer 'van Delft," Kunsthistorisches Museum Vienna, http://www 
.khm.at/system2E.html?/staticE/page242.html (accessed August 25, 2005). 

2. Anna Oliver, "The Use of Maps in Contemporary Art," (MA diss., CardifFSchool of Art, 200 I -2003), 
http://www.annao.pwp.blueyonder.co.uk/text dissert at i on. htm#art . 

3. Ibid. 

4. Details about the cell's structural and chemical makeup can be found in any introductory biology 
textbook. For this chapter, the book consulted was Karen Arms and Pamela S. Camp, Biology, 3rd ed. 
(Philadelphia: Saunders College Publishing, 1987). 

5. Denyse O'Leary, "Cool Animations: The World inside the Cell," April 17, 2007, The ID Report, 
h ttp:// www. arn.Qrg/blogs/index.php/2/2 007/04/2 1/cool animations the world inside the eel . 



Notes 



Chapter 3 The Bare Essentials 



289 



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7. Colin Patterson, ^vo/arion, 2nd ed. (Ithaca, NY: Comstock, 1999), 23. 

8. Alexis Dufresne et al., "Genome Sequence ofthe Cy dLnohacltr'xuva Prochlorococcus marinus SSI20, 
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9. Pennisi, "Microbial Genomes Come Tumbling In," 1433. 

10. GofFeau, "Life with 482 Genes," 445; Eraser et al., "Minimal Gene Complement," 397-403; 
J.Travis, "Small Wonder: Microbial Hitchhiker Has Few Genes," Science News 161 (May 4,2002): 275; 



290 Notes 

Huber et al., "New Phylum ofArchaea," 63-67; Boucher and Doolittle, "Something New Under the 
Sea," 27-28; Waters et al., "Genome of Nanoarchaeutn equitans" 12984-88. 

1 1. Craig M. Stephens and Michael T. Laub, "Microbial Genomics; All That You Can't Leave Behind," 
Current Biology 13 (July 15, 2003): R57I-R573. 

12. Arcady R. Mushegian and Eugene V. Koonin, "A Minimal Gene Set for Cellular Life Derived by 
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13. Nikos Kyrpides, Ross Overbeek, and Christos Ouzounis, "Universal Protein Families and the 
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14. J. Kirk Harris et al., "The Genetic Core ofthe Universal Ancestor," Genome Research 13 (March 
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15. Jack Maniloff, "The Minimal Cell Genome: 'On Being the Right Size,"' Proceedings ofthe National 
Academy of Sciences, USA93 (September 17,1996): 10004-6; Mitsuhiro Itaya, "An Estimation of Minimal 
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Staphylococcus aureus" Molecular Microbiology 43, no. 6 (March 2002): 1387-400; S. Y. Gerdes et al., 
"Experimental Determination and System Level Analysis of Essential Genes in Escherichia coli MG 1655," 

Journal of Bacteriology 185, no. 19 (October 2003): 5673-84; Michael A.Jacobs et al., "Comprehensive 
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16. Rosario Gil et al., "Extreme Genome Reduction in Buchnera spp.: Toward the Minimal Genome 
Needed for Symbiotic Life," Proceedings ofthe National Academy of Sciences, USA 99 (April 2, 2002): 
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Smaller," Science 314 (October 13, 2006): 259-60. 

17. Rosario Gil et al., "The Genome Sequence of Blochmannia floridanus: Comparative Analysis 
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18. Atsushi Nakabachi et al., "The 160-Kilobase Genome ofthe Bacterial Endosymbiont Carsonella" 
Science 3\4 (October 13, 2006): 267. 

19. The genome sizes of viruses are extremely small. These parasites, however, are not useful to assess 
life's minimal complexity because they are not "living" organisms. Viruses cannot reproduce on their 
own, extract energy from the environment, or engage in metabolism. 

20. Carl Zimmer, "Tinker, Tailor: Can Ventor Stitch Together a Genome from Scratch?" Science 299 
(February 14, 2003): 1006-7. 

21.Jeronimo Cello, Aniko V. Paul, and Eckard Wimmer, "Chemical Synthesis of Poliovirus cDNA 

Generation of Infectious Virus in the Absence of Natural Template," Science 297 (August 9, 2002) 

1016-18; Hamilton O. Smith et al., "Generating a Synthetic Genome by Whole Genome Assembly 

g)XI 74 Bacteriophage from Synthetic Oligonucleotides," Proceedings ofthe National Academy of Sciences, 

USA 100 (December 23,2003): 15440-45; Sarah J. Kodumal et al., "Total Synthesis ofLong DNA Se- 



Notes 9Q 1 

quences: Synthesis of a Contiguous 32-kb Polyketide Synthase Gene Cluster," Proceedings of the National 
Academy of Sciences, USA 101 (November 2, 2004): 15573-78. 

22. M. Castellanos, D. B. Wilson, and M. L. Shuler, "A Modular Minimal Cell Model: Purine and 
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23. Vincent Noireaux and Albert Libchaber, "A Vesicle Bioreactor as a Step Toward an Artificial Cell As- 
sembly," Proceedings of the National Academy of Sciences, USA 101 (December 21, 2004): 17669-74. 

24. David Deamer, "A Giant Step Towards Artificial Life?" Trends in Biotechnology 23 (July 2005): 
336-38. 

25. Ibid. 

26. Lucy Shapiro and Richard Losick, "Protein Localization and Cell Fate in Bacteria," Science 276 
(May 2,1997): 712 — 18; Richard Losick and Lucy Shapiro, "Changing Views on the Nature of the Bacterial 
Cell: From Biochemistry to Cytology," Journal of Bacteriology 181 (July 1999): 4143-45; Lucy Shapiro 
and Richard Losick, "Dynamic Spatial Regulation in the Bacterial Cell," Cell 100 (January 7, 2000): 
89-98; Lucy Shapiro, Harley H. McAdams, and Richard Losick, "Generating and Exploiting Polarity 
in Bacteria," Science 298 (December 6,2002): 1942-46; Zemer Gitai, "The New Bacterial Cell Biology: 
Moving Parts and Subcellular Architecture," Cell 120 (March 11,2005): 577-86. 

27. Shapiro and Losick, "Protein Localization," 712-18. 

28. Michaela E. Sharpe and Jeff Erring ton, "Upheaval in the Bacterial Nucleoid: An Active Chromo- 
some Segregation Mechanism," Trends in Genetics 15 (February 1,1999): 70-74; Gideon Scott Gordon 
and Andrew Wright, "DNA Segregation in Bacteria," Annual Review of Microbiology 54 (October 2000): 
681-70 8; David J. Sherratt, "Bacterial Chromosome Dynamics," Science 301 (August 8,2003): 7 80-85; 
Patrick H. Viollier et al., "Rapid and Sequential Movement oflndividual Chromosomal Loci to Specific 
Subcellular Locations during Bacterial DNA Replication," Proceedings of the National Academy of Sciences, 
USA 101 (June 22,2004): 9257-62. 

29. Joe Pogliano et al., "Multicopy Plasmids Are Clustered and Localized in Escherichia coli" Proceed- 
ings ofthe National Academy of Sciences, USA 98 (April 10,2001): 4486-91. 

30. Katherine P. Lemon and AlanD. Grossman, "Localization of Bacterial DNA Polymerase: Evidence 
for a Factory Model of Replication," Science 282 (November 20, 1998): 1516-19; Richard Losick and 
Lucy Shapiro, "Bringing the Mountain to Mohammed," Science 282 (November 20, 1998): 1430-31. 

3 1 . Sherry C. Wang and Lucy Shapiro, "The Topoisomerase IV ParC Subunit Colocalizes with the 
Caulobacter Replisome and Is Required for Polar Localization of Replication Origins," Proceedings of the 
National Academy of Sciences, USA 101 (June 22, 2004): 9251-56. 

32. Ken Begg, "Ring ofBright Metal," Nature 354 (November 14, 1991): 109-10; Erfei Bi and Joe 
Lutkenhaus, "FtsZ Ring Structure Associated with Division in Escherichia coli" Nature 354 (Novem- 
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33. Danielle N. Margalit et al., "Targeting Cell Division: Small-Molecule Inhibitors of FtsZ GTPase 
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34. Petra Anne Levin, Iren G. Kurtser, and Alan D. Grossman, "Identification and Characterization 
of a Negative Regulator of FtsZ Ring Formation in Bacillus subtilis" Proceedings of the National Academy 
of Sciences, USA 96 (August 17, 1999): 9642-47; Christine Jacobs and Lucy Shapiro, "Bacterial Cell 
Division: A Moveable Feast," Proceedings ofthe National Academy of Sciences, USA 96 (May 25, 1999): 
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292 Notes 

Ring Required for Proper Placement ofthe Division Site Is a Mobile Structure that Changes Its Cellular 
Location During the Escherichia coH Division Cycle," Proceedings of the National Academy of Sciences, 
USA 9% (January 30,2001): 980-85. 

35. Zemer Gitai and Lucy Shapiro, "Bacterial Cell Division Spirals into Control," Proceedings ofthe 
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36. Zemer Gitai, "The New Bacterial Cell Biology: Moving Parts and Subcellular Architecture," 
Ce// 120 (March I 1 , 2005) : 577-86. 

37. Yu-Ling Shih, Trung Le, and Lawrence Rothfield, "Division Site Selection in Escherichia coli 
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38. Cheryl A. Kerfeld et al., "Protein Structures Forming the Shell of Primitive Bacterial Organelles," 
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39. Michael J. Behe, Darwin's Black Box: The Biochemical Challenge to Evolution (New York: Free 
Press, 1996) 

40. Fazale Rana and Hugh Ross, Origins of Life: Biblical and Evolutionary Models Pace (_7"{Colorado 
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Chapter 4 Such a Clean Machine 

l."Ken Eberts," VisionArt, http://www.solarshadingsvstems.com/galleries/artist popup. asp ?artist_ 
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2. Michael Polanyi, "Life Transcending Physics and Chemistry," Chemical and Engineering News 45 
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3. Michael J. Behe, Darwin's Black Box: The Biochemical Challenge to Evolution (New York: Free 
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4. David F. Blair, "How Bacteria Sense and Swim," Annual Review of Microbiology 49 (October 
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USA 100 (July 22,2003): 8748-51. 

6. For example, a cursory survey ofthe prestigious journal Nature over the last several years turns up 
the following papers: Scott A. Lloyd et al., "Structure ofthe C-Terminal Domain of FliG, a Component 
ofthe Rotor in the Bacterial Flagellar Motor," Nature AOO (July 29, 1999): 472-75; William S. Ryu, 
Richard M. Berry, and Howard C. Berg, "Torque-Generating Units ofthe Flagellar Motor of Escherichia 
coli Have a High Duty Ratio," Nature A03 (January 27,2000): 444-47; Fadel A. Samateyet al., "Structure 
ofthe Bacterial Flagellar Hook and Implication for the Molecular Universal Joint Mechanism," Nature 43 1 
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Bacterial Flagellar Motor," Nature A31 (October 6,2005): 916-19. 

7. Matti Saraste, "Oxidative Phosphorylation at the Fin de Siecle" Science 283 (March 5, 1999): 
1488-93. 

8. Hiroyuki Noji, "The Rotary Enzyme ofthe Cell: The Rotation of Fl-ATPase," Science 282 (De- 
cember4, 1998): 1844-45; William S. Allison, "F,-ATPase: A Molecular Motor that Hydrolyzes ATP 
with Sequential Opening and Closing of Catalytic Sites Coupled to Rotation of Its y Subunit," Accounts of 
Chemical Research 31 (December 1998): 819-26; Hiroyuki Noji and Masasuke Yoshida, "The Rotary Ma- 
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9. Vinit K. Rastogi and Mark E. Girvin, "Structural Changes Linked to Proton Translocation by 
Subunit c ofthe ATP Synthase," Nature M)! (November 18,1999): 263-6 8 ; Joachim Weber and Alan E. 
Senior, "ATP Synthesis Driven by Proton Transport in F1-F2-ATP Synthase," FEBS Letters 545 (June 12, 
2003): 61-70; Wolfgang Junge and Nathan Nelson, "Nature's Rotary Electromotors," Science 308 (April 29, 
2005): 642-44. 



Notes 9Q^ 

10. E.J. Boekema et al., "Visualization of a Peripheral Stalk in V-Type ATPase: Evidence for the Sta- 
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(April 29, 2005): 654-59. 

ll.Shoko Kawasaki-Nishi et al., "Proton Translocation Driven by ATP Hydrolysis in V-ATPases," 
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12. F. Xavier Gomis-Ruth et al., "The Bacterial Conjugation Protein TrwB Resembles Ring Helicases 
and Fj-ATPase," iVamre409 (February 1,2001): 637-41. 

13.1. Tato et al., "TrwB, the Coupling Protein Involved in DN A Transport during Bacterial Conjuga- 
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2005): 8156-61. 

14. Shimon Schuldinet, "The Ins and Outs of Drug Transport," A'a/ure 443 (September 14,2006): 
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Mechanism," Science 313 (September 1, 2006): 1295-98; Satoshi Murakami et al., "Crystal Structures 
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2006): 173-79. 

15. For an accessible discussion of peristaltic pumps, see Wikipedia contributors, "Peristaltic Pump," 
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16. S. Kalir et al., "Ordering Genes in a Flagella Pathway by Analysis of Expression Kinetics from Liv- 
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17. Alan A. Simpson et al., "Structure of the Bacteriophage tp29 DN A Packaging Motor," Nature 408 
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18. Michael J. Pelczar Jr., E. C. S. Chan, and Merna Foss Pelczat, Elements of Microbiology (New York: 
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19.Thorsten Hugel et al., "Experimental Test of Connector Rotation during DNA Packaging into 
Bacteriophage ip29 Capsids," PLoS Biology 5 (March 2007): e59. 
20. Ibid. 
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Isomerization and Phosphate-Release Steps," Nature 396 (November 26, 1998): 3 80-83; Ian Dobbie 
et al., "Elastic Bending and Active Tilting of Myosin Heads During Muscle Contraction," Nature 396 
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294 Notes 

Lever Arm Movement during the Consecutive Steps of ATP Hydrolysis," Biochemistry 38 (May 18, 
1999): 6428-40; J. E. T. Corrie et al., "Dynamic Measurement of Myosin Light-Chain-Domain Tilt and 
Twist in Muscle Contraction," Nature 400 (July 29, 1999): 425-30; Josh E. Baker et al„ "A Large and 
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23. Stephen M. King, "The Dynein Microtubule Motor," Biochimica et Biophysica Acta (BBA) / 
Molecular Cell Research 1496 (March 17,2000): 60-75. 

24. Richard B. Vallee and Peter Hook, "A Magnificent Machine," Nature 421 (February 13, 2003): 
701-2; Stan A. Burgess et al., "Dynein Structure and Power Stroke," Nature All (February 13, 2003): 
715-18. 

25. R. A. Cross, "Molecular Motors: Dynein's Gearbox," Current Biology 14 (May4,2004): R355-56; 
Roop Mallik et al., "Cytoplasmic Dynein Functions as a Gear in Response to Load," Nature All (Febru- 
ary 12, 2004): 649-52. 

26. Patrick Cramer et al., "Architecture of RN A Polymerase II and Implications for the Transcription 
Mechanism," Science 288 (April 28, 2000): 640-49. 

27. Joan Weliky Conaway and Ronald C. Conaway, "Light at the End ofthe Channel," Science 288 
(April 28, 2000): 632-33. 

28. Katharine Sanderson, "Crystallography Grabs Chemistry Nobel: Structural Determination of RNA 
Polymerase Unlocked Secrets of Cells," news@nature.com, October 4,2006, doi: 10. 1038/news06 1002-7, 
http://www.nature.com/news/2006/Q6IQ02/full/news06IQQ2-7.html . 

29. Jonathan B. Vivona and Zvi Kelman, "The Diverse Spectrum of Sliding Clamp Interacting Pro- 
teins," FEBSLetters 546 (July 10, 2003): 167-72; Gregory D. Bowman, Mike O'Donnell, andJohn 
Kuriyan, "Structural Analysis of a Eukaryotic Sliding DN A Clamp-Clamp Loader Complex," Nature 429 
(June 17, 2004): 724-30; Spencer Campbell and Anthony Maxwell, "The ATP-Operated Clamp of 
Human DNA Topoisomerase lice: Hyperstimulation ofATPase by 'Piggy-Back' Binding? Journal of 
Molecular Biology 320 (July 5,2002): 171-88. 

30. Brett W. Lennon, Charles H. Williamsjr., and Martha L. Ludwig, "Twists in Catalysis: Alternating 
Conformations of Escherichia coli Thioredoxin Reductase," Science 289 (August 18, 2000): 1190-94. 

3 1 . William Paley, Natural Theology; or, Evidences of the Existence and Attributes of the Deity Col- 
lected from the Appearances of Nature, 12th ed. (1802; Weybridge, Surrey, UK: printed by S. Hamilton, 

1809), 1-3. 

32. David Hume, "Dialogues Concerning Natural Religion" in Classics of Western Philosophy, ed. Ste- 
ven M. Cahn, 3rd ed. (1779; repr., Indianapolis: Hackett, 1990), 880. Hume makes this point through 
a fictional character. 

33. B. C.Johnson, The Atheist Debater's Handbook (Buffalo: Prometheus Books, 1981), 45. 

34. David Depew, "Intelligent Design and Irreducible Complexity: A Rejoinder," Rhetoric and Public 
Affairs 1, no. 4 (1998): 571-78. 

35. Robert F. Service, "Borrowing from Biology to Power the Petite," Science 283 (January 1,1999): 
27-28. 

36.Jimin Wang, "Recent Cyanobacterial Kai Protein Structures Suggest a Rotary Clock," Structure 13 
(May 2005): 735-41. 
37. Ibid. 

38. Paley, Natural Theology, 3. 

39. Service, "Borrowing from Biology," 27-28. 

40. Ricky K. Soong et al., "Poweringan Inorganic Nanodevice with a Biomolecular Motor," Science 290 
(November 24, 2000): 1555-58. 

4 1 . Peixuan Guo, "Bacterial Virus cp29DNA-PackagingMotor and Irs Potential Applications in Gene 
Therapy and Nanotechnology," Methods in Molecular Biology 300 (January 2005): 285-324. 

42. Ibid. 



Notes 9QS 

43. Joe Alper, "Chemists Look to Follow Biology Lead," Science 295 {March 29, 2002): 2396-97; 
Nadrian C. Seeman and Angela M. Belcher, "Emulating Biology: Building Nanostructures from the Bot- 
tom Up," Proceedings of the National Academy of Sciences, USA 99 (April 30,2002): 645 1-55; George M. 
Whitesides, "The Once and Future Nanomachine," Scientific American, September 2001,78-83. 

44. CorinnaWu, "Molecular Motors Spin Slowly but Surely," Science News 156 (September 11, 
1999): 165. 

45. See, for example, Jovica D. Badjic et al., "A Molecular Elevator," Science 303 (March 19, 2004): 
1845-49; David I. Gittins et al., "A Nanometre-Scale Electronic Switch Consisting of a Metal Cluster 
and Redox-Addressable Groups," Nature 408 (November 2, 2000): 67-69; Thoi D. Nguyen et al., "A 
Reversible Molecular Valve," Proceedings of the National Academy of Sciences, USA 102 (July 19, 2005): 

10029-34; Thomas C. Bedard and Jeffrey S. Moore, "Design and Synthesis of Molecular Turnstiles," 
Journal of the American Chemical Society 117 (November 1, 1995): 10622-71; T. Ross Kelly, Imanol 
Tellitu, and Jose Perez Sestelo, "In Search of Molecular Ratchets," Angewandte Chemie 36 (September 17, 
1997): 1866-68; Richard A. Bissell et al., "A Chemically and Electrochemically Switchable Molecular 
Shuttle," Nature 369 (May 12,1994): 133-3 7; Peter R. Ashton et al., "Acid-Base Controllable Molecular 
Shuttles," Journal of 'the American Chemical Society 120 (November 25,1998): I 1932-42. 

46. See, for example, Jonathan Clayden and Jennifer H. Pink, "Concerted Rotation in a Tertiary 
Aromatic Amide: Towards a Simple Molecular Gear," Angewandte Chemie 37 (August 3, 1998): 1937-39; 
Anne Marie Schoevaars et al„ "Toward a Switchable Molecular Rotor: Unexpected Dynamic Behavior of 
Functionalized Overcrowded Alkenes," Journal of Organic Chemistry 62 (July 25,1997): 4943-48. 

47. T. Ross Kelly, Harshani De Silva, and Richard A. Silva, "Unidirectional Rotary Motion in a 
Molecular System," Nature 401 (September 9, 1999): 150-52; Nagatoshi Komura et al., "Light-Driven 
Monodirectional Molecular Rotor," Nature 401 (September9, 1 999): 15 2-55. 

48. Komura et al., "Molecular Rotor," 152-55. 

49. Kelly, De Silva, and Silva, "Rotary Motion," 150-52. 

50. Anthony P. Davis, "Synthetic Molecular Motors," Nature 401 (September9, 1 999): 120-21 . 

5 1 . Jose V. Hernandez, Euan R. Kay, and David A. Leigh, "A Reversible Synthetic Rotary Molecular 
Motor," Science 306 (November 26,2004): 153 2-37; Stephen P. Fletcher et al., "A Reversible, Unidirec- 
tional Molecular Rotary Motor Driven by Chemical Energy," Science 310 (October 7,2005): 80-82; Jay 
Siegel, "Inventing the Nanomolecular Wheel," Science 310 (October 7,2005): 63-64. 

52. Joel S. Bader et al., "DN A Transport by a Micro machined Brownian Ratchet Device," Proceedings 
ofthe National Academy of Sciences, USA 96 (November 9, 1999): 13165-69. 
53. Ibid. 

54. Ronald D. Vale, "The Molecular Motor Toolbox for Intracellular Transport," Cell 111 (Febru- 
ary 21,2003): 467-80. 

55. For example, Deborah B. Stone, Rex P. Hjelm, and Robert A. Mendelson, "Solution Structures 
ofDimeric Kinesin and Ned Motors," Biochemistry 38 (April 20, 1999): 4938-47. 

56. For example, Wei Hua et al., "Coupling of Kinesin Steps to ATP Hydrolysis," Nature 388 (July 24, 
1997): 390-93; Karel Svoboda et al., "Direct Observation of Kinesin Stepping by Optical Trapping 
Interferometry," Nature 365 (October 21, 1993): 721-27; Yasushi Okada and Nobutaka Hirokawa, 
"A Processive Single-Headed Motor: Kinesin Superfamily Protein KIFIA," Science 2H3 (February 19, 
1999): 1152-57. 

57. R. Dean Astumian and Imre Derenyi, "A Chemically Reversible Brownian Motor: Application 
to Kinesin and Ned," Biophysical Journal 11 (August 1999): 993-1002. 

58. Kent E. S. Matlack et al., "BiP Acts as a Molecular Ratchet during Posttranslational Transport of 
Prepro-a Factor Across the ER Membrane," Cell 91 (May 28,1999): 553-64. 

59. Saveez Saffarian et al., "Interstitial Collagenase Is a Brownian Ratchet Driven by Proteolysis of 
Collagen," Science 3Q(i (October 1, 2004): 108-11. 

60. Paley, Natural Theology, 2. 

6 1 . Kazuhiko Kinosita Jr. et al., "A Rotary Molecular Motor That Can Work at Near 100% Efficiency," 
Philosophical Transactions of the Royal Society B 355 (April 29,2000): 473-89. 



296 Notes 

Chapter 5 Which Came First? 

1. "Biography of M. C. Escher," The M. C. Escher Company B. V., http://www.mcescher.com/ (accessed 
January 11,2006); World ofEscher, http://www.worldofescher.com/ (accessed January 11, 2006). 

2. Wikipedia contributors, "Radio-Frequency Identification," Wikipedia, The Free Encyclopedia, http:// 
en.wikipedia.org/wiki/Radio frequency identification (accessedJune 24, 2006). 

3. "The Chicken or the Egg?" RFID Journal, http://www.rfidiournal.com/article/article- 
print/2261/-l/l (accessedJune 22, 2006). 

4. Iris Fry, The Emergence of Life on Earth: A Historical and Scientific Overview (New Brunswick, NJ: 
Rutgers University Press, 2000), 100-101. 

5. Fazale Rana and Hugh Ross, Origins of Life: Biblical and Evolutionary Models Face Off (Colorndo 
Springs: NavPress, 2004), 109-21. 

6. Leslie Orgel quoted in ibid., 1 15. 

7. Alan G. Atherly, Jack R. Girton, and John F. McDonald, The Science of Genetics (Fort Worth: 
Saunders College Publishing, 1999): 3 15-21. 

8. Ibid., 321-28. 

9. Harvey Lodish et A., Molecular Cell Biology, 4th ed. (New York: Freeman, 2000): 125-27. 

10. For example, see Graeme L. Conn et al., "Crystal Structure of a Conserved Ribosomal Protein-RNA 
Complex," Science 284 (May 14,1999): 1171-74; Jamie H. Cate et al., "X-Ray Crystal Structures of 705 
Ribosome Functional Complexes," Science 2S5 (September 24, 1999): 2095-2104; Gloria M. Culver et al., 
"Identification of an RNA-Protein Bridge Spanning the Ribosomal Subunit Interface," Science 285 (Septem- 
ber 24, 1999): 2133-35; William M. demons Jr. et al., "Structure ofa Bacterial 30S Ribosomal Subunit 
at 5.5 A Resolution," Nature 400 (August 26,1999): 833-40; Nenad Ban et al., "Placement ofProtein and 
RNA Structures into a 5 A-Resolution Map ofthe 50S Ribosomal Subunit," A'atore 400 (August 26,1999): 
841-47; Sultan C. Agalarov et al., "Structure ofthe S15, S6, S18-rRNA Complex: Assembly ofthe 30S 
Ribosome Central Domain," Science 288 (April 7,2000): 107-12; Nenad Ban et al., "The Complete Atomic 
Structure of the Large Ribosomal Subunit at 2.4 A Resolution," Science 289 (August 11, 2000): 905-20; 
Brian T. Wimberly et al., "Structure ofthe 30S Ribosomal Subunit," Nature 407 (September 21, 2000): 
327-39; Andrew P. Carter et al., "Functional Insights from the Structure ofthe 30S Ribosomal Subunit 
and Its Interactions with Antibiotics," Nature 401 (September 2 1 ,2000): 340-48; Marat M. Yusupov et al., 
"Crystal Structure ofthe Ribosome at 5.5 A Resolution," Science 292 (May 4,2001): 883-96. 

1 I.Thomas R. Cech, "The Ribosome Is aRibozyme," Science 289 (August 11,2000): 878-79; Poul 
Nissen et al., "The Structural Basis of Ribosome Activity in Peptide Bond Synthesis," Science 289 (Au- 
gust 11, 2000): 920-30; Gregory W. Muth, Lori Ortoleva-Donnelly, and Scott A. Strobel, "A Single 
Adenosine with aNeutrn] pK in the Ribosomal Peptidyl Transferase Center," Science 289 (August 11, 
2000): 947-50. 

12. For example, John Dresios, Panagiotis Panopoulos, and Dennis Synetos, "Eukaryotic Ribosomal 
Proteins Lacking a Eubacterial Counterpart: Important Players in Ribosomal Function," Mo/ecu/ar 
Microbiology 59 (March 2006): 165 1-63. 

13. Lodish et al.. Molecular Cell Biology, 128-37. 
14. Ibid., 120-25. 

15. Ibid., 130-32. 

16. Ibid., 62-64; EIke Deuerling and Bernd Bukau, "Chaperone- Assisted Folding of Newly Synthesized 
Proteins in the Cytosol," Critical Reviews in Biochemistry and Molecular Biology 39 (October-December 
2004): 261-77. 

17.Yun-Chi Tang et al., "Structural Features ofthe GroEL-GroES Nano-Cage Required for Rapid 
Folding ofEncapsuIated Protein," Cell 125 (June 2, 2006): 903-14. 

Chapter 6 Inordinate Attention to Detail 

1. Wikipedia contributors, "John Everett Millais," Wikipedia, The Free Encyclopedia, http :// 
en.wikipedia.org/wiki/Millais (accessedJune 21, 2006). 



Notes 



297 



2.W ikipedia contributors. "Mannerism," Wikipedia, The Free Encyclopedia, http-. //en. wikipedia.org/ 
wiki/Mannerism (accessed June 22, 2006). 

3. Wikipedia contributors, "Pre-Raphaelite Brotherhood," Wikipedia, The Free Encyclopedia, http:// 
en. wikipedia.org/wiki/Pre-Raphaelite Brotherhood (accessed June 22, 2006). 

4. Deepa Rajamani et al„ "Anchor Residues in Protein-Protein Interactions," Proceedings of the National 
Academy of Sciences, USA 101 (August 3, 2004): 11287-92. 

5. Some recently discovered examples of biochemical fine-tuning can be found at http:// www. reasons 
.org/ as part of the Todays New Reason To Believe (TNRTB) feature. Some examples that have appeared 
recently under the TNRTB banner include: Won-Ho Cho et al., "CDC7 Kinase Phosphorylates Serine 
Residues Adjacent to Acidic Amino Acids in Minichromosome Maintenance 2 Protein," Proceedings 
of the National Academy of Sciences, USA 103 (August 1, 2006): 11521-26; Daniel F. Jarosz et al., "A 
Single Amino Acid Governs Enhanced Activity of DinB DNA Polymerases on Damaged Templates," 
Science 439 (January 12, 2006): 225-28; William H. McClain, "Surprising Contribution to Amino- 
acylation and Translation of Non-Watson-Crick Pairs in tRNA," Proceedings of the National Academy 
of Sciences, USA 103 (March 21, 2006): 4570-75; Kobra Haghighi et al., "A Mutation in the Human 
Phospholamban Gene, Deleting Arginine 14, Results in Lethal, Hereditary Cardiomyopathy," Proceed- 
ings of the National Academy of Sciences, USA 103 (January 31,2006): 1388-93; Surajit Ganguly et al., 
"Melatonin Synthesis: 14-3-3-Dependent Activation and Inhibition of Arylalkylamine A'-Acetyltransferase 
Mediated by Phosphoserine-205" Proceedings of the National Academy of Sciences, USA 102 (January 25, 
2005): 1222-27; Yohei Kir i no et al., "Specific Correlation between the Wobble Modification Deficiency 
in Mutant tRNAs and the Clinical Features of a Human Mitochondrial Disease," Proceedings of the 
National Academy of Sciences, USA 102 (May 17, 2005): 7127-32; Yoshie Hanzawa, Tracy Money, and 
Desmond Bradley, "A Single Amino Acid Converts a Repressor to an Activator of Flowering," Proceed- 
ings of the National Academy of Sciences, USA 102 (May 24, 2005): 7748-53; Stefan Trobro and Johan 
Aqvist, "Mechanism of Peptide Bond Synthesis on the Ribosome," Proceedings ofthe National Academy 
of Sciences, USA 102 (August 30, 2005): 12395-400; TianbingXia et al., "RNA-Protein Recognition: 
Single-Residue Ultrafast Dynamical Control of Structural Specificity and Function," Proceedings of the 
National Academy oj"Sciences, USA 102 (September 13,2005): 13013-18; A.J. Rader et al., "Identification 
of Core Amino Acids Stabilizing Rhodopsin," Proceedings ofthe National Academy of Sciences, USA 101 
(May 11, 2004): 7246-5 1 ; Rajamani et al., "Anchor Residues," 1 1287-92; Lina Salomonsson et al„ "A 
Single-Amino Acid Lid Renders a Gas-Tight Compartment within a Membrane-Bound Transporter," 
Proceedings of the National Academy of Sciences, USA 101 (August 10,2004): 1 1 6 1 7-2 1 ; Gianguido Coffa 
and Alan R. Brash, "A Single Active Site Residue Directs Oxygenation Stereospecificity in Lipoxygenases: 
Stereocontrol Is Linked to the Position of Oxygenation," Proceedings of the National Academy of Sciences, 
USA 101 (November 2, 2004): 15579-84; Isabel Martinez-Argudo, Richard Little, and Ray Dixon, "A 
Crucial Arginine Residue Is Required for a Conformational Switch in NifL to Regulate Nitrogen Fixation 
in Azotobacter vinelandii" Proceedings of the National Academy of Sciences, USA 101 (November 16,2004): 

16316-21; Oded Danziger et al., "Conversion ofthe Allosteric Transition of GroEL from Concerted 
to Sequential by the Single Mutation Asp-155 •+ Ala," Proceedings of the National Academy of Sciences, 
USA 100 (November 25,2003): 13797-802; Hu Pan et al., "Structure of tRNA Pseudouridine Synthase 
TruB and Its RNA Complex: RNA Recognition through a Combination of Rigid Docking and Induced 
Fit," Proceedings ofthe National Academy of Sciences, USA 100 (October 28,2003): 12648-53; Yoshimitsu 
Kuwabara et al., "Unique Amino Acids Cluster for Switching from the Dehydrogenase to Oxidase Form 
of Xanthine Oxidoreductase? Proceedings of the National Academy of Sciences, USA 100 (July 8,2003): 
8170-75. This sampling represents the tip of the iceberg. Countless examples of biochemical fine-tuning 
are littered throughout the scientific literature. 

6. Mario Borgina et al., "Cellular and Molecular Biology of the Aquaporin Water Channels," Annual 
Review of Biochemistry 68 (July 1999): 425-58. 

7. Ibid. 



298 Notes 

8. David F. Savage et al., "Architecture and Selectivity in Aquaporins: 2.5 A X-Ray Structure of 
Aquaporin Z,"PLoS Biology 1, no. 3 (December 22,2003): doi: 1 0. 137 l/journai.pbio. 0000072, littp:// 
biologv.plosiournals.org/ perlserv/ ?request=get-document&doi= 10.1371 /journal. pbio. 0000072. 

9. Ibid. 

10. See, for example, BertL.de Groot and Helmut GrubmuUer, "Water Permeation across Biological 
Membranes: Mechanism and Dynamics of Aquaporin-1 and GlpF," Science 294 (December 14, 2001): 
2353-57; William E. C. Harries et al., "The Channel Architecture of Aquaporin at a Ilk Resolution," 
Proceedings of the National Academy of Sciences, USA 101 (September 28, 2004): 14045-50. 

1 1 . Eric Beitz et al., "Molecular Dissection of Water and Glycerol Permeability of the Aquaglyceroporin 
from Plasmodium falciparum by Mutational Analysis," Proceedings of the National Academy of Sciences, 
USA 101 (February 3, 2004): 1153-58. 

12. John K. Lee et al., "Structural Basis for Conductance by the Archaeal Aquaporin AqpM at 1.68 A," 
Proceedings of the National Academy of Sciences, USA 102 (December 27, 2005): 18932-37. 

13. Ibid. 

14. Kun Liu et al., "Conversion of Aquaporin 6 from an Anion Channel to a Water-Selective Chan- 
nel by a Single Amino Acid Substitution," Proceedings of the National Academy of Sciences, USA 102 
(February 8, 2005): 2192-97. 

15. Peter R. Bergethon and Elizabeth R. Simons, Biophysical Chemistry: Molecules to Membranes 
(New York: Springer- Verlag, 1990), 253-57. 

16. Some examples include: Nicolas Reyes and David C. Gadsby, "Ion Permeation through the 
Na., K*-ATPase," Nature 443 (September 28, 2006): 470-74; Eric Gouaux and Roderick MacKin- 
non, "Principles of Selective Ion Transport in Channels and Pumps," Science 310 (December 2, 2005): 
1461-65; Francis I. Valiyaveetil et al., "Glycine as aD-AminoAcid Surrogate in the K. -Selectivity Filter," 

Proceedings of the National Academy of Sciences, USA 101 (December 7, 2004): 17045-49; Lei Zheng 
et al., "The Mechanism of Ammonia Transport Based on the Crystal Structure of AmtB of Escherichia 
coll" Proceedings ofthe National Academy of Sciences, USAWl (December 7,2004): 17090-95; Sheila E. 
Unkles et al., "Two Perfectly Conserved Arginine Residues Are Required for Substrate Binding in a High- 
Affinity Nitrate Transporter," Proceedings ofthe National Academy of Sciences, USA 101 (Decembet 14, 
2004): 17549-54; Yong Zhao, Todd Scheuer, and William A. Caterall, "Reversed Voltage-Dependent 
Gating of a Bacterial Sodium Channel with Proline Substitutions in the S6 Transmembrane Segment," 
Proceedings of the National Academy of Sciences, USA 101 (December 21, 2004): 17873-78; Tinatin I. 
Brelidze, Xiaowei Niu, and Karl L. Magleby, "A Ring of Eight Conserved Negatively Charged Amino 
Acids Doubles the Conductance of BK Channels and Prevents Inward Rectification," Proceedings ofthe 
National Academy of Sciences, USA 100 (July 22,2003): 9017-22. 

17.Lubert Stryer, Biochemistry, 3rd ed. (New York: W. H. Freeman, 1988), 261-74. 

18. E. Leikina et al., "Type I Collagen Is Thermally Unstable at Body Temperature," Proceedings of 
the National Academy of Sciences, USA 99 (February 5,2002): 1314-18; Anton V. Persikov and Barbara 
Brodsky, "Unstable Molecules Form Stable Tissues," Proceedings of the National Academy of Sciences, 
t/5A 99 (February 5, 2002): 1101-3. 

19. Yulei Wang et al., "Precision and Functional Specificity in mRNA Decay," Proceedings of the 
National Academy of Sciences, USA 99 (April 30,2002): 5860-65; Jonathan A. Bernstein et al., "Global 
Analysis of mRNA Decay and Abundance in Escherichia coli at Single-Gene Resolution Using Two- 
Color Fluorescent DNA Microarrays," Proceedings oj the National Academy of Sciences, USA 99 (July 23, 
2002): 9697-9702. 

20. Michael H. Glickman and Noam Adir, "The Proleasome and the Delicate Balance between De- 
struction and Rescue," PLoS Biology 2 (January 20,2004): doi: 10. 1371/journal. pbio. 002001 3, http:// 
biologv.plosiournals.org/ perlserv/ ?request=get-document&doi= 10.1371 %2Fjournal.pbio.00200 I 3. 

21.Stryer, Biochemistry, 794-95. 

22. Linda L. Breeden, "Periodic Transcription: A Cycle within a Cycle," Current Biology 13 (Janu- 
ary 8, 2003): R31-R38. 



Notes 9QQ 

Chapter 7 The Proper Arrangement of Elements 

l.Sheiley Esaak, "Balance," About.com, http://arthistorv.ab out. eom/cs/glossaries/g/b balance.htm 
(accessedJune 22, 2006). 

2.Wikipedia contributors, "Piet Mondrian," Wikipedia, The Free Encyclopedia, http://en.wikipedia 
.org/wiki/Piet_Mondrian (accessed July 11, 2006). 

3. Brian Kuhlman and David Baker, "Native Protein Sequences Are Close ro Optimal for Their 
S,Xr\xc\.uvQ,s," Proceedings of the National Academy of Sciences, USA97 (September 12,2000): 10383-88. 

4. Hiroshi Akashi and Takashi Gojobori, "Metabolic Efficiency and Amino Acid Composition in 
the Proteomes of Escherichia coli and Bacillus subtilis" Proceedings of the National Academy of Sciences, 
USA 99 (March 19,2002): 3695-3700; Hiroshi Akashi, "Metabolic Economics and Microbial Proteome 
Evolution," Bioinformatics 19, suppl. 2 (October 2003): iil 5; Esley M. Heizer Jr. et al., "Amino Acid Cost 
and Codon-Usage Biases in 6 Prokaryotic Genomes: A Whole-Genome Analysis," Molecular Biology 
and Evolution 23 (September 2006), doi:10.1093/molbev/msl029, http://mbe.oxfordiournals.org/ 
cgi/content/full/23/9/1670. 

5. Herve Seligmann, "Cost-Minimization of Amino Acid Usage," Journal of Molecular Evolution 56 
(February 2003): 151-61. 

6. Rui Alves and Michael A. Savageau, "Evidence of Selecrion for Low Cognate Amino Acid Bias in 
Amino Acid Biosynthetic Enzymes," Molecular Microbiology 56, no. 4 (May 2005): 1017-34. 

7. Haiwei H. Guo, Juno Choe, and Lawrence A. Loeb, "Protein Toletance to Random Amino Acid 
Change," Proceedings of the National Academy of Sciences, USA 101 (June 22, 2004): 9205-10. 

8. Darin M. Taverna and Richard A. Goldstein, "Why Are Proteins So Robust to Site Mutations?" 
Journal of Molecular Biology 315 (January 2002): 479-84. 

9. Sandeep Raha and Brian H. Robinson, "Mitochondria, Oxygen Free Radicals, Disease and Ageing," 
Trends in Biochemistry 25 (October 1,2000): 502-8. 

10. Robert Arking, The Biology of Aging: Observations and Principles, 2nd ed. (Sunderland, MA: 
Sinauer, 1998), 398-414. 

11. Martin Ackermann and Lin Chao, "DNA Sequences Shaped by Selection for Stability," PLoS 
Genetics 2 (February 2006): e22. 

12. Hiroshi Akashi, "Synonymous Codon Usage in Drosophila melanogaster: Natural Selection 
and Translational Accuracy," Genetics 136 (March 1994): 927-35; Xuhua Xia, "How Optimized Is the 
Translational Machinery m Escherichia coli. Salmonella typhimurium and Saccharomyces cerevisiae? Ge- 
netics 149 (May 1998): 37-44; Marco Archetti, "Selection on Codon Usage for Error Minimization at 
the Protein heyeX," Journal of Molecular Evolution 59 (September 2004): 400-15; Eduardo P. C. Rocha, 
"Codon Usage Bias from tRNA's Point ofView: Redundancy, Specialization, and Efficient Decoding 
for Translation Optimization," Genome Research 14 (November 2004): 2279-86. 

13. F. H. Westheimer, "Why Nature Chose Phosphates," Science 235 (March 6,1987): 1 173-78. 

14. Ryszard Kierzek, Liyan He, and Douglas H. Turner, "Association of 2'-5 ' Oligoribonucleo tides," 
Nucleic Acids Research 20 (X^n\ 11,1992): 1685-90. 

15. Albert Eschenmoser, "Chemical Etiology of Nucleic Acid Structure," Science 284 (June 25,1999): 
2118-24. 

16. Eveline Lescrinier, Matheus Froeyen, and Piet Herdewijn, "Difference in Conformational Diversity 
between Nucleic Acids with a Six-Membered 'Sugar' Unit and Natural 'Furanose' Nucleic Acids," Nucleic 
Acids Research 31 (June 15, 2003): 2975-89. 

17. Caspar Banfalvi, "Why Ribose Was Selected as the Sugar Component ofNucleic Acids," DNA 
and CellBiology 25 (March 2006): 189-96. 

18. Jean-Marc L. Pecourt, Jorge Peon, and Bern Kohler, "Ultrafast Internal Conversion ofElec- 
tronically Excited RNA and DNA Nucleotides in "Water" Journal of the American Chemical Society 122 
(September 27,2000): 9348-49. 

19. Reiner Veitia and Chris Ottolenghi, "Placing Parallel Stranded DNA in an Evolutionary Context," 
Journal of Theoretical Biology 206 (September 2000): 317-22. 

20. Ibid. 



300 Notes 

2 1 . George M. Malacinski, Essentials of Molecular Biology, 4th ed. (Boston: Jones and Bartlett, 2003), 
223-83. 

22. Guy Shinar et al., "Rules for Biological Regulation Based on Error Minimization," Proceedings of 
the National Academy of Sciences, USA 103 (March 14,2006): 3999-4004. 

23.Lubert ^iry&r. Biochemistry, 3rd ed. (New York: Freeman, 1988), 349-96. 

24. Ibid., 315-30. 

25. Alicia Esteban del Valle and J. Carlos Aledo, "What Process Is Glycolytic Stoichiometry Optimal 
Vorl" Journal of Molecular Evolution 62 (April 2006): 488-95. 

Chapter 8 The Artist's Handwriting 

1. Wikipedia contributors, "Calligraphy," Wikipedia, The Eree Encyclopedia, http://en.wikipedia.org/ 
wiki/Calligraphy (accessed July 1 3,2006); Wikipedia contriburors, "Islamic Calligraphy," Wikipedia, The 
Free Encyclopedia, http://en.wikipedia.org/wiki/Arabic calligraphy (accessed July 12,2007); Wikipedia 
contributors, "Sheikh HamduUah," Wikipedia, The Eree Encyclopedia, http://en.wikipedia.org/wiki/ 
Sheikh_Hamdullah (accessed July 12, 2006). 

2. Peter Kreeft, Fundamentals of the Eaith: Essays in Christian Apologetics (San Francisco: Ignatius, 
1988), 25-26. 

3. Bernd-Olaf Kiippers, Information and the Origin of Life (Cambridge, MA: MIT Press, 1990), 
6-27. 

4. See, for example, Michael Denton, Evolution: A Theory in Crisis (Bethesda, MD: Adler & Adler, 
1986), 308-25; Waiter L. Bradley and Charles B. Thaxton, "Information and the Origin of Life," in The 
Creation Hypothesis: Scientific Evidence for an Intelligent Designer, ed. J. P. Moreland (Downers Grove, 
IL: InterVarsity, 1994), 188-90. 

5. Harvey Lodish et al., Molecular Cell Biology, 4th ed. (New York: Freeman, 2000), 257. 

6. Hubert P. Yockey, Information Theory, Evolution, and the Origin of Life (New York: Cambridge 
University Press, 2005); Hubert P. Yockey, Information Theory and Molecular Biology (Cambridge: 
Cambridge University Press, 1992); Kiippers, Information and the Origin of Life. 

7. Kiippers, Information and the Origin of Life, 24-25. 
8. Ibid., 23. 

9. Ibid., 31-56. 
10. Ibid., 32-33. 

1 1 . Christopher Loose et al., "A Linguistic Model for the Rational Design of Antimicrobial Peptides," 
Nature 443 (October 19, 2006): 867-69. 

12. Michael ZaslofF, "Antimicrobial Peptides of Multicellular Organisms," Nature 415 (January 24, 
2002): 389-95. 

13. Biochemists use the general formula C H . O (where n can be any number) to represent 
carbohydrates. 

14. See, for example, Lubert Stryer, Biochemistry, 3rd ed. (New York: Freeman, 1988), 343-46. 

15. Mark A. Lehrman, "Oligosaccharide-Based Information in Endoplasmic Reticulum Quality Con- 
trol and Other Biological Systems," Journal of Biological Chemistry 276 (March 23,2001): 8623-26. 

16. Ibid. 

17. See, for example, George M. Malacinski, Essentials of Molecular Biology, 4th ed. (Boston: Jones 
and Bartlett, 2003), 233-47. 

18. Yuan-Yuan Li et al., "Systematic Analysis of Head-to-Head Gene Organization: Evolutionary 
Conservation and Potential Biological Relevance," PLoS Computational Biology 2 (July 2006): e74. 

19. Ibid. 

20. Alan G. Atherly, Jack R. Girton, and John F. McDonald, The Science of Genetics (Fort Worth: 
Saunders College Publishing, 1999), 321-28. 

2 1 . Malacinski, Essentials of Molecular Biology, 261-65. 

22. Ibid. 



Notes ^01 

23. B. G. Barrell, G. M. Air, and Clyde A. Hutchison III, "Overlapping Genes in Bacteriophage 
cpX174," Nature 16A (November 4, 1976): 34-4 1 ; M. Smith et al., "DNA Sequence at the C Termini 
of the Overlapping Genes A and B in Bacteriophage cpX174," A'^afwre 265 (February 24, 1977): 702-5; 
Frederick Sanger et al., "Nucleotide Sequences of Bacteriophage tpX174 DNA," Nature 265 (Febru- 
ary 24,1977): 687-89. 

24. Gina B. Kolata, "Overlapping Genes: More Than Anomalies?" Science 196 (June 10, 1977): 
1187-88. 

25. Denis C. Shaw et al., "Gene K, A New Overlapping Gene in Bacteriophage G4," Nature 272 
(April 5,1978): 5 10-15; Walter Fiers et al., "Complete Sequence ofSV40 DNA," Nature 11?> (May 11, 
1978): 113-20; Charlotte A. Spencer, R. Daniel Gietz, and Ross B. Hogdetts, "Overlapping Transcrip- 
tion Units in the DOPA Decarboxylase Region of Drosophilia" Nature 322 (July 17, 1986): 279-81; 
Jacek M.Jankowski et al., "In Vitro Expression of Two Proteins from Overlapping Reading Frames in a 
Eukaryotic DNA Sequence, "JoMrna/ of Molecular Evolution 24 (December 1986): 61 -7 1 ; Maya Shmulevitz 
et al., "Sequential Partially Overlapping Gene Arrangement in the Tricistronic S 1 Genome Segments of 
Avian Reovirus and Nelson Bay Reovirus: Implications for Translation Initiation," Journal of Virology 76 
(January 2002): 609- 1 8; Yoko Fukuda, Takanori Washio, and Masaru Tomita, "Comparative Study of 
Overlapping Genes in the Genomes of Mycoplasma genitalium and Mycoplasma pneumoniae" Nucleic Acids 
Research 21 (April 15, 1999): 1 847-53; Paul R. Cooper et al., "Divergently Transcribed Overlapping Genes 
Expressed in Liver and Kidney and Located in the llpl5.5 Imprinted Domain," Genomics 49 (April 1, 
1998): 38-5 1; Marilyn Kozak, "Extensively Overlapping Reading Frames in a Second Mammalian Gene," 

EMBO Reports 2 (September 2001): 768-69; Martin Klemke, Ralph H. Kehlenbach, and Wieland B. 
Huttner, "Two Overlapping Reading Frames in a Single Exon Encode Interacting Proteins — A Novel 
Way of Gene Usage," EMBO Journal 20 (July 16,2001): 3 849-60. 

26. Malacinski, Essentials of Molecular Biology, 111-18. 
21. Yockey, Information Theory, Evolution, 85-92. 

28. Wen-Yu Chung et al., "A First Look atARFome: Dual-Coding Genes in Mammalian Genomes," 
PLoS Computational Biology 3 (May 18, 2007): e91. 

29. The rules of the "Overlapping Sentence Game" do not correspond exactly to overlapping genes 
because of the redundancy of the genetic code in which several codons can specify the same amino acids. 
This situation would be equivalent to words in English having multiple spellings. 

30. John P. Adelman et al., "Two Mammalian Genes Transcribed from Opposite Strands of the Same 
DNA," Science 235 (1987): 1514-17; Mariano Labrador et al., "Molecular Biology: Protein Encoding 
by Both DNA Strands," Nature 4^9 (February 22,2001): 1000. 

31. Stanley L. Miller, "The Endogenous Synthesis of Organic Compounds," in The Molecular Origins 
of Life: Assembling Pieces of the Puzzle, ed. Andre Brack (New York: Cambridge University Press, 1998), 
59-85. 

32. Donall A. Mac Donaill, "A Parity Code Interpretation ofNucleotide Alphabet Composition," 
Chemical Communications, no. 18 (September 21, 2002): 2062-63; Donall A. Mac Donaill, "Why 
Nature Chose A, C, G and U/T: An Error-Coding Perspective ofNucleotide Alphabet Composition," 
Origins of Life and Evolution of the Biosphere33 (October 2003): 433-55. 

33. Robert A. Stern and Nancy Stern, An Introduction to Computers and Information Processing, 
2nd ed. (New York: Wiley & Sons, 1985), 124-36. 

34. David Depew, "Intelligent Design and Irreducible Complexity: A Rejoinder," Rhetoric & Public 
Affairs 1 (1998): 571-78. 

35. Leonard M. Adleman, "Computing with DNA," Scientific American, August 1998, 54-6 1. 

36. Ibid. 

37. Gheorghe Paun, Grzegorz Rozenberg, and Arto Salomaa, DNA Computing: New Computing 
Paradigms (Berlin: Springer-Verlag, 1998), 19-4 1. 

38. Paun, Rozenberg, and Salomaa, Z)7VA Computing, 1-6; Adleman, "Computing with DNA," 
54-61. 



302 Notes 

39.1vars Peterson, "Computing with DNA: Getting DNA-Based Computers Off the Drawing Board 
and Into the Wet Lab," Sc/enceN^H-s 150 (July 13,1996): 26-27. 

40. Charles Seife, "Molecular Computing: RNA Works Out Knight Moves," Science 287 (February 1 8, 
2000): 1 182-83; Dirk Faulhammer et al., "Molecular Computation: RNA Solutions to Chess Problems," 
Proceedings of the National Academy of Sciences, USA 97 (February 15, 2000): 1385-89; Anthony G. 
Frutos et al., "Demonstration of a Word Design Strategy for DNA Computing on Surfaces," Nucleic 
Acids Research 25 (December 1,1997): 4748-57; Anthony G. Frutos, Lloyd M. Smith, and Robert M. 
Corn, "Enzymatic Ligation Reactions of DNA 'Words' on Surfaces for DNA Computing," JowrHa/ o/ 
the American Chemical Society 120 (October 14, 1998): 10277-82; Adrian Cho, "DNA Computing: 
Hairpins Trigger an Automatic Solution," Science 288 (May 19, 2000): 1152-53; Kensaku Sakamoto 
et al., "Molecular Computation by DNA Hairpin Formation," Science 288 (May 19,2000): 1223-26. 

4 I.Leonard M. Adleman, "Molecular Computation of Solutions to Combinatorial Problems," Sci- 
ence 266 (November 1 1,1994): 1021-24; Seife, "Molecular Computing," 1 182-83; Faulhammer et al., 
"Molecular Computation," 1385-89. 

42. Frank Guarnieri, Makiko Fliss, and Carter Bancroft, "Making DNA Add," Science 273 (July 12, 
1996): 220-23. 

43. Adleman, "Computing with DNA," 54-61 . 

44. Paun, Rozenberg, and Salomaa, DA'A Computing, 65-70. 

45. Catherine Taylor Clelland, Viviana Risca, and Carter Bancroft, "Hiding Messages in DNA Mi- 
crodots," A'aftire 399 (June 10,1999): 533-34. 

46. Paul D. N. Hebert et al., "Ten Species in One: DNA Barcoding Reveals Cryptic Species in 
the Neotropical Skipper Butterfly Astraptes fulgerator" Proceedings of the National Academy of Sciences, 
USA 101 (October 12, 2004): 14812-17; Paul D. N. Herbert et al., "Identification ofBirds through 
DNA Barcodes," PLoS Biology 2 (October 2004): e312; W.John Kress et al., "Use of DNA Barcodes 
to Identify Flowering Plants," Proceedings of the National Academy of Sciences, USA 102 (June 7,2005): 
8369-74; M. Alex Smith et al., "DNA Barcodes Reveal Cryptic Host-Specificity within the Presumed 
Polyphagous Members of a Genus of Parasitoid Flies (Diptera: Tachinidae)," Proceedings of the National 
Academy of Sciences, USA 103 (March 7, 2006): 3657-62; Mehrdad Hajibabaei et al., "DNA Barcodes 
Distinguish Species of Tropical Lepidoptera," Proceedings of the National Academy of Sciences, USA 103 
(January 24, 2006): 968-71; Keith A. Seifert et al., "Prospects for Fungus Identification Using CO] 
DNA Barcodes, with Penicillium as a Test Case," Proceedings of the National Academy of Sciences, USA 104 
(March 6, 2007): 3901-6. 

47. Robert G. Eason et al., "Characterization of Synthetic DNA Bar Codes in Saccharomyces cerevi- 
siae Gene-Deletion Strains," Proceedings of the National Academy of Sciences, USA 101 (July 27, 2004): 

11046-51. 

48. Fazale Rana and Hugh Ross, Origins of Life: Biblical and Evolutionary Models Face Off (Colorado 
Springs: NavPress, 2004), 135-141. 

Chapter 9 Cellular Symbolism 

1. Wikipedia contributors, "Symbolism (Arts)," Wikipedia, The Free Encyclopedia, http://en.wikipedia 
.org/wiki/Symbolism_(arts) (accessed August 28,2006). 

2. Wikipedia contributors, "Code," Wikipedia, The Free Encyclopedia, http://en.wikipedia.org/ wiki/ 
Code (accessed September 1, 2006). 

3. Peter Kreeft, Fundamentals of the Faith: Essays in Christian Apologetics (San Francisco: Ignatius, 
1988), 25-26. 

4. Harvey Lodish et al.. Molecular Cell Biology, 4th ed. (New York: Freeman, 2000), 1 17-20. 

5. Lubert Stryer, Biochemistry, 3rd ed. (New York: Freeman, 1988), 675-76. 

6. David Haig and Laurence D. Hurst, "A Quantitative Measure of Error Minimization in the Genetic 
Code," Journal of Molecular Evolution 33 (November 1991): 412-17. 

7.Gretchen Vogel, "Tracking the History of the Genetic Code," Science 281 (July 17,1998): 329-3 1; 
Stephen J. Freeland and Laurence D. Hurst, "The Genetic Code Is One in a Million," Journal of Molecular 



Notes ^0^ 

Evolution 47 (September 1998): 238-48; Stephen J. Freeland et al., "Early Fixarion of an Optimal Genetic 
Code," Molecular Biology and Evolution 17 (April 2000): 511-18. 

8. Freeland and Hurst, "Genetic Code," 238-48. 

9. Massimo Di Giulio, "The Origin ofthe Genetic Code," Trends in Biochemical Sciences 25 (Febru- 
ary 1,2000): 44; Massimo Di Giulio and Mario Medugno, "The Level and Landscape of Optimization 
in the Origin ofthe Genetic Code," Journal of MolecularEvolution 52 (April 2001): 372-82; Massimo 
Di Giulio, "A Blind Empiricism against the Coevolution Theory ofthe Origin ofthe Genetic Code," 

Journal oj Molecular Evolution 53 (December 2001): 724-32. 

10. J. Gregory Caporaso, Michael Yarus, and Robin D. Knight, "Error Minimization and Coding 
Triplet/Binding Site Associations Are Independent Features ofthe Canonical Genetic Code" Journal 
of Molecular Evolution 61 (November 2005): 597-607; Stephen J. Freeland, Tao Wu, and Nick Keul- 
mann, "The Case for an Error Minimizing Standard Genetic Code," Origin of Life and Evolution of the 
Biosphere 33 (October 2003): 457-77; Stephen J. Freeland, Robin D. Knight, and Laura F. Landweber, 
"Measuring Adaptation within the Genetic Code," Trends in Biochemical Sciences 25 (February 1,2000): 
44-45; StephenJ. Freeland and Laurence D. Hurst, "Load Minimization ofthe Genetic Code: History 
Does Not Explain the Pattern," Proceedings of the Royal Society of London B 265 (November 7, 1998): 
2111-19; Terres A. Ronneberg, Laura F. Landweber, and StephenJ. Freeland, "Testing a Biosynthetic 
Theory of the Genetic Code: Fact or Artifact?" Proceedings of the National Academy of Sciences, USA 97 
(December 5,2000): 13690-95; RaminAmirnovin, "An Analysis of the Metabolic Theory of the Origin 
ofthe Genetic Code," Journal of Molecular Evolution 44 (May 1997): 473-76. 

1 1. Robin D. Knight, Stephen J. Freeland, and Laura F. Landweber, "Selection, History and Chemistry: 
The Three Faces ofthe Genetic Code," Trends in Biochemical Sciences 24 (June 1,1999): 241-47. 

12. F. H. C. Crick, "The Origin ofthe Genetic Code," Journal of Molecular Biology 38 (December 
1968): 367-79. 

13. Syozo Osawaet al., "Evolution ofthe Mitochondrial Genetic Code. I. Origin ofAGR Serine and 
Stop Codons in Metazoan Mitochondria, "/owrna/ of Molecular Evolution 29 (Septembet 1989): 202-~: 
Dennis W. Schultz and Michael Yarus, "On Malleability in the Genetic Code," Journal of Molecular 
Evolution 42 (May 1996): 597-601; Eors Szathmary, "Codon Swapping as a Possible Evolutionary 
Mechanism," Journal of Molecular Evolution 32 (February 1991): 178-82. 

14. Hubert P. Yockey, Information Theory and Molecular Biology (Cambridge: Cambridge Universirv 
Press, 1992), 180-83. 

15. Manfred Eigen et al„ "How Old Is the Genetic Code? Statistical Geometry oftRNA Provides 
an Answer," Science 244 (May 12,1989): 673-79. 

16. For a comprehensive list of references to the scientific literature, see Fazale Rana and Hugh Ross, 
"An Early or Late Appearance?" in Origins of Life: Biblical and Evolutionary Models Face C_T(Colorado 
Springs: NavPress, 2004), 63-79 and notes. 

17. Yockey, Information Theory, 184-96; Alfonso Jimenez-Sanchez, "On the Origin and Evolution 
of the Genetic Code," Journal of Molecular Evolution 41 (December 1995): 712-16; Huan-Lin Wu, 
Stefan Bagby, and Jean van den Elsen, "Evolution of the Genetic Triplet Code via Two Types of Doublet 
Codons," Journal of Molecular Evolution 61 (July 2005): 54-64. 

18. Yockey, Information Theory, 1 84-96. 

19. Lodish, Molecular Cell Biology, 321-27. 
20.1bid., 384-90. 

2 1 . Guo-Cheng Yuan et al., "Genome-Scale Identification of Nucleosome Positions in S. cerevisiae" 
Science309 (July 22,2005): 626-30; Edward A. Sekinger, Zarmik Moqtaderi, and Kevin Struhl, "Intrinsic 
Histone-DNA Interactions and Low Nucleosome Density Are Important for Preferential Accessibility 
of Promoter Regions in Yeast," Mo/ecw/ar CeW /S (June 1 0,2005): 735-48; Fatih Ozsolak et al., "High- 
Throughput Mapping ofthe Chromatin Structure of Human Promoters," Nature Biotechnology 25 
(February 2007): 244-48; Ben Wong et al., "Characterization ofZ-DNA as a Nucleosome-Boundary 
Element in Yeast Saccharomyces cerevisiae" Proceedings of the National Academy of Sciences, USA 104 
(February 13,2007): 2229-34. 



304 Notes 

22. Eran Segal etal., "AGenomic Code for Nucleosome Positioning," Natui'e442 (August 17,2006): 
772-78. 

23. Shalev Itzkovitz and UriAlon, "The Genetic Code Is Nearly Optimal for Allowing Additional 
Inform at ion within Protein-Coding Sequences," Genome Research I 7 (April 2007): 405-12. 

Chapter 10 Total Quality 

l.Wikipedia contributors, "Giclee," Wikipedia, The Free Encyclopedia, http://en.wikipedia.org/wiki/ 
Giclee (accessed December 14, 2006). 

2. Stella M. Hurtley, "Frontiers in Cell Biology: Quality Control," Sciencelii (December3,1999): 
188 I ; Lars Ellgaard, Mauri zio Molinari, and Ari Helenius, "Setting the Standards: Quality Control in 
the Secretory Pathway," Science 2^6 (December 3, 1999): 18 82-88; Sue Wickner, Michael R. Maurizi, 
and Susan Gottesman, "Posttranslational Quality Control: Folding, Refolding, and Degrading Proteins," 
SdcKce 2 86 (December 3, 1999): 1 888-93 ; Michaellbba and Dierer Soil, "QualityControl Mechanisms 
During Translation," Science 286(December3,1999): 1893-97; To mas Lindahl and Richard D. Wood, 
"Quality ControlbyDNA Repair," Science2i6 (December 3, 1 999) : 1897-1905. 

3. Michael Denton, Evolution: A Theory in Crisis (Bethesda, M D: Adler cS; Adler, 1986), 264-68. 

4. Harvey Lodish et d\.. Molecular Cell Biology, 4th ed. (New York: Freeman, 2000), 111-16. 

5. Ibid., 125-34. 

6. Lubert Slryer, Biochemistry, 3rded. (New York: Freeman, 1988), 746-64. 

7. Ibid., 739-42. 

8. Ibid., 733-35. 

9. Lodish et al.. Molecular Cell Biology, 1 17-20. 

10. Murray P. Deutscher, "Degradation of Stable RN A in Bacteria," Journal of Biological Chemistry 278 
(November 14,2003): 45041-44; Murray P. Deutscher, "Degradation of RNA in Bacteria: Comparison 
ofmRNA and Stable RNA," Nucleic Acids Research 34 (February 2006): 659-66. 

1 1. Deutscher, "Degradation of Stable RNA," 45041 -44; Deutscher, " Degradation of RNA in Bac- 
teria," 659-66. 

12. Zhongwei Li et al., "RNA Quality Control: Degradation of Defective Transfer RNA," EMBO 
Journal 21 (March 1,2002): 1 1 32-3 8 ; Zhuan-Fen Che ngand Murray P. Deutscher, "Quality Control of 

Ribosomal RNA Mediated by Polynucleotide Phosphorylase and RNase R," Proceedings of the National 
Academy of Sciences, USA 100 (May 27, 2003): 6388-6393. 

13. Letian Kuai et al., "Polyadenylation of rRNA in Saccharomyces cerevisiae" Proceedings of the Na- 
tional Academy of Sciences, USA 101 (June 8, 2004): 8581-86; Stepanka Vafiacova et al., "A New Yeast 
Poly(A) Polymerase Complex Involved in RNA Quality Control," PLoS Biology 3 (June 2005): el89; 
Sujatha Kadaba, Xuying Wang, and James T. Anderson, "Nuclear RNA Surveillance in Saccharomyces 
cerevisiae: Trf4p-Dependent Polyadenylation of Nascent Hypomethylated tRNA and an Aberrant Form 
of 5S rRNA," RNA 12 (March 2006): 508-2 1 ; Shimyn Slomovic et al., "Polyadenylation of Ribosomal 
RNA in Human CeMa" Nucleic Acids Research 34 (July 2006): 2966-75. 

14. Lynne E. Maquat and Gordon G. Carmichael, "Quality Control ofmRNA Function," Cell 104 
(January 26,2001): 173-76. 

15. Nikolay Zenkin, Yulia Yuzenkova, and Konstantin Severinov, "Transcript-Assisted Transcriptional 
Proofreading," Science 313 (July 28, 2006): 518-20; Patrick Cramer, "Self-Correcting Messages," Sci- 
ence 313 (July 28, 2006): 447-48. 

16. Alan G. Atherly, Jack R. Girton, and John F. McDonald, The Science of Genetics (Fort Worth: 
Saunders College Publishing, 1999), 3 15-2 1 . 

17. Ibid. 

1 8. See, for example, Cecile Bousquet-Antonelli, Carlo Presutti, and David Tollervey, "Identification 
of a Regulated Pathway for Nuclear Pre-mRNA Turnover," Cell 102 (September 15, 2000): 765-75; 
Maquat and Carmichael, "Quality Control," 173-76; Laura Milligan et al., "A Nuclear Surveillance 
Pathway for mRNAs with Defective Polyadenylation," Molecular and Cellular Biology 25 (November 
2005): 9996-10004. 



Notes 3Q5 

19. See, for example, Maquat and Carmichael, "Quality Control," 173-76; Zhaolan Zhou et al., 
"The Protein Aly Links Pre-Messenger-RNA Splicing to Nuclear Export in Metazoans," Nature 407 
(September 21,2000): 401-4. 

20. For example, Maquat and Carmichael, "Quality Control," 173-76. 

2 1 . As a case in point, see David Tollervey, "RNA Lost in Translation," Nature 440 (March 23,2006): 
425-26; Meenakshi K. Doma and Roy Parker, "Endonucleolytic Cleavage ofEukaryotic mRNAs with 
Stalls in Translation Elongation, 'Wa/Hre 440 (March 23,2006): 561-64; Audrey Stevens et al., "f-Globin 
mRNA Decay in Erythroid Cells: UG Site-Preferred Endonucleolytic Cleavage That Is Augmented by 
a Premature Termination Codon," Proceedings of the National Academy of Sciences, USA 99 (October 1, 
2002): 12741-46; Joshua T. Mendell, Colette MJ. ap Rhys, and Harry C. Dietz, "Separable Roles for 
rentl/hUpfl in Altered Splicing and Decay ofNonsense Transcripts," Science 298 (October 11,2002): 
419-22. 

22. Stryer, Biochemistry, 735-37; Ibba and Soil, "Quality Control Mechanisms," 1893-97. 

23. Anthony C. Bishop, Tyzoon K. Nomanbhoy, and Paul Schimmel, "B!ockingSite-to-Site Transloca- 
tion of Misactivated Amino Acid by Mutation of a Class 1 tRNA Synthetase," Proceedings of the National 
Academy of Sciences, USA 99 (January 22, 2002): 585-90. 

24. Jamie M. Bacher, Valerie de Crecy-Lagard, and Paul R. Schimmel, "Inhibited Cell Growth and 
Protein Functional Changes from an Editing-Defective tRNA Synthetase," Proceedings of the National 
Academy of Sciences, USA 102 (February 1, 2005): 1697-1701. 

25. Jeong Woong Lee et al„ "Editing-Defective tRNA Synthetase Causes Protein Misfolding and 
Neurodegeneration," A'aft/re 443 (September 7, 2006): 50-55. 

26. Ibba and Soil, "Quality Control Mechanisms," 1893-97. 

27. Stryer, Biochemistry, 754-55. 

28. Frederick J. LaRiviere, Alexey D. Wolf son, and Olke C. Uhlenbeck, "Uniform Binding ofAmino- 
acyl-tRNAs to Elongation Factor Tu by Thermodynamic Compensation," Science 294 (October 5,200 1): 
165-68; Michael Ibba, "Discriminating Right from Wrong," Science 294 (October 5,2001): 70-7 1 . 

29. Stryer, Biochemistry, 756. 

30. Lodish et &\., Molecular Cell Biology, 696-722. 

3 1 . Ari Helenius, "Quality Control in the Secretory Assembly Line," Philosophical Transactions of 
the Royal Society of London B 356 (February 28, 2001): 147-50; Christopher M. Cabral, Yan Liu, and 
Richard N. Sifers, "Dissecting Glycoprotein Quality Control in the Secretory Pathway," Trends in Bio- 
chemical Sciences 26 (October 2001): 619-24; Roberto Sitia and Ineke Braakman, "Quality Control in 
the Endoplasmic Reticulum Protein Factory," Nature 426 (December 18,2003): 891-94. 

32.Ellgaard, Molinari, and Helenius, "Setting the Standards," 1882-88. 

33. Helenius, "Quality Control," 147-50; Cabral, Liu, and Sifers, "Dissecting Glycoprotein Quality 
Control," 619-24; Sitia and Braakman, "Quality Control," 891-94. 

34. Cabral, Liu, and Sifers, "Dissecting Glycoprotein Quality Control," 6 1 9-24; Mark A. Lehrman, 
"Oligosaccharide-Based Information in Endoplasmic Reticulum Quality Control and Other Biological 
Systems," Journal of Biological Chemistry 276 (March 23, 2001): 8623-26. 

35. Lehrman, "Oligosaccharide-Based Information," 8623-26. 

36. Jean Marx, "A Stressful Situation," Sc/eHce 313 (September 15,2006): 1564-66. 

37. David Ron, "Stressed Cells Cope with Protein Overload," Science 313 (July 7, 2006): 52-53; 
Julie HoUien and Jonathan S. Weissman, "Decay of Endoplasmic Reticulum-Localized mRNAs during 
the Unfolded Protein Response," Science 313 (July 7,2006): 104-7. 

38. See, for example, Brendan N. Lilley and Hidde L. Ploegh, "A Membrane Protein Required for 
Dislocation of Misfolded Proteins from the ER," Nature429 (June 24,2004): 834-40; Yihong Ye et al., 
"A Membrane Protein Complex Mediates Retro-Translocation from the ER Lumen into the Cytosol," 
Nature429 (June 24,2004): 841-47; Brendan N. Lilley and Hidde L. Ploegh, "Multiprotein Complexes 
that Link Dislocation, Ubiquitination, and Extraction ofMisfolded Proteins from the Endoplasmic 
Reticulum Membrane," Proceedings of the National Academy of Sciences, USA 102 (October 24,2005): 
14296-301. 



306 Notes 

39. See, for example, Christopher M. Dobson, "Protein Folding and Misfolding," Nature 426 (De- 
cember 18,2003): 884-90; Alfred L. Goldberg, "Protein Degradation and Protection against Misfolded 
or Damaged Proteins," Nature 426 (December 18, 2003): 895-99; Dennis J. Selkoe, "Folding Proteins 
in Fatal Ways," Nature 426 (December 18, 2003): 900-904; Wickner, Maurizi, and Gottesman, "Post- 
translational Quality Control," 1888-93; Lindahl and Wood, "Quality Control," 1897-1905. 

Chapter 11 A Style All His Own 

l.Wikipedia contributors, "Pablo Picasso," Wikipedia, The Free Encyclopedia, http://en.wikipedia 
.org/wiki/Pablo_Picasso (accessed May 24,2006). 

2. "Cubism," Answers.com, http://www.answers.com/cubism (accessed September 16, 2006). 

3. "Wright, Frank Lloyd," The Columbia Encyclopedia, http://education.vahoo.com/reference/ 
encyclopedia/entry/Wright-FL (accessed June 8,2006). 

4. "Chance," Merriam-Webster's Collegiate Dictionary, 11th ed., Merriam-Webster, 2007, hup:// 
unabridged.merriam-webster.com/ (accessed November 9,2007). 

S.StephenJ. Gould, Wonderful Life: The Burgess Shale and the Nature of History (New York: Norton, 
1989), 51. 

6. Ibid., 48. 

7. John Cafferky, Evolutions Hand: Searching for the Creator in Contemporary Science (Toronto: 
eastendbooks, 1997), 66-69. 

8. See, for example, Russell F. Doolittle, "Convergent Evolution: The Need to Be Explicit," Trends in 
Biochemical Sciences 19 (January 1994): 15-18; Eugene V. Koonin, L. Aravind, and Alexy S. Kondrashov, 
"The Impact of Comparative Genomics on Our Understanding of Evolution," Cell 101 (June 9,2000): 
573-76; Harold H. Zakon, "Convergent Evolution on the Molecular Level," Brain, Behavior and Evolu- 
tion 59, nos. 5-6 (2002): 250-61. 

9. Michael Y. Galperin, D. Roland Walker, and Eugene V. Koonin, "Analogous Enzymes: Independent 
Inventions in Enzyme Evolution," Genome Research 8 (August 1998): 779-90. 

10. Ibid. 

1 1 . Doolittle, "Convergent Evolution," 15-18. 

12. Neil D. Rawlings and Alan J. Barrett, "Evolutionary Families of Peptidases," Biochemical Jour- 
W290 (February 15,1993): 205-18. 

13. Galperin, Walker, and Koonin, "Analogous Enzymes," 779-90. 

14. Eugene V. Koonin, Arcady R. Mushegian, and Peer Bork, " Non-0 rthologous Gene Displacement," 
Trends in Genetics 12 (September 1996): 334-36. 

15.Detlef D. Leipe, L. Aravind, and Eugene V. Koonin, "Did DNA Replication Evolve Twice Indepen- 
dently?" A^Mc/e/cAc/rfs ffesearc/i 27 (September 1,1999): 3389-3401. 

16. The material for this section was taken from Alan G. Atherly, Jack R. Girton, and John F. McDonald, 
The Science of Genetics (Fort Worth: Saunders College Publishing, 1999), 256-77'. 

17. J. William Schopf, "When Did Life Begin?" in Life's Origin: The Beginnings of Biological Evolution, 
ed. J. William Schopf (Berkeley: University of California Press, 2002), 163. 

Chapter 12 An Elaborate Mosaic 

l.Wikipedia contributors, "Mosaic," Wikipedia, The Free Encyclopedia, http://en.wikipedia.org/ 
wiki/Mosaic (accessed April 17, 2007). 

2. S.J. Singer and Garth L. Nicolson, "The Fluid Mosaic Model ofthe Structure of Cell Membranes," 
Science 175 (February 18, 1972): 720-3 1 . 

3.W. Dohan, "Molecular Basis for Membrane Phospholipid Diversity: Why Are There So Many 
L'lpidsl" Annual Review of Biochemistry 66 (July 1997): 199-232. 

4. Miles D. Houslay and Keith K. Stanley, Dynamics of Biological Membranes: Influence on Synthesis, 
Structure and Function (New York: John Wiley & Sons, 1982), 51-65. 

5. Ibid., 105-25. 



Notes "^07 

6. D oh an, "M olecular Basis," 199-23 2. 

7. Ibid. 

8. Ibid. 

9. Danilo D. Lasic, "The Mechanism of Vesicle Formation," Biochemical Journal 256 (November 15, 
1988): 1-11. 

10. Ibid. 

11. See, for example, Barry L. Lentz, TamraJ. Carpenter, and Dennis R. Alford, "Spontaneous Fu- 
sion of Phosphatidylcholine Small Unilamellar Vesicles in the Fluid Phase," Biochemistry 26 (August 25, 
1987): 5389-97. 

12. Norman L. Gershfeld, "The Critical Unilamellar Lipid State: A Perspective for Membrane Bilayer 
Assembly," Bioc/i/m/ca etBiosphysica Acta 988 (December 6, 1989): 335-50. 

13. See, for example, Norman L. Gershfeld et al., "Critical Temperature tor Unilamellar Vesicle For- 
mation in Dimyristoylphosphatidylcholine Dispersions from Specific Heat Measurements," Biophysical 

Journals (September 1993): 1174-79. 

14. Norman L. Gershfeld, "Spontaneous Assembly of a Phospholipid Bilayer as a Critical Phenom- 
enon: Influence of Temperature, Composition, and Physical State" Journal of Physical Chemistry 93 
(June 29,1989): 5256-61. 

15. Lionel Ginsberg, D. L. Gilbert, and Norman L. Gershfeld, "Membrane Bilayer Assembly in Neural 
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Journal of Membrane Biology 119 (January 1991): 65-73. 

16. K. E. Tremper and Norman L. Gershfeld, "Temperature Dependence of Membrane Lipid Com- 
position in Early Blastula Embryos of Lytechinus pictus: Selective Sorting of Phospholipids into Nascent 
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17. A. J. Jin et al., "A Singular State of Membrane Lipids at Cell Growth Temperatures," Biochemis- 
try 38 (October 5,1999): 13275-78. 

18. Norman L. Gershfeld and M. Murayama, "Thermal Instability of Red Blood Cell Membrane 
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67-72. 

19. Lionel Ginsberg, John H. Xuereb, and Norman L. Gershfeld, "Membrane Instability, Plasm alogen 
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20. StanJslav D. Zakharov et al., "Tuning the Membrane Surface Potential for Efficient Toxin Import," 
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2I.Dohan, "Molecular Basis," 199-232. 

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Donald M. Engelman, "Membranes Are More Mosaic than Fluid," Nature 43 8 (December I, 2005): 
578-80. 

23. Daniel Segre and Doron Lancet, " Composing Life," EMBO Reports 1 (September 2000): 217-22; 
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24. Daniel Segre et al., "The Lipid World," Origins of Life and the Evolution of the Biosphere 31 (Feb- 
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25. Ibid. 

26. Houslay and Stanley, Dynamics of Biological Membranes, 9 8-105. 

27. Tamir Gonen et al., "Lipid-Protein Interactions in Double-Layered Two-Dimensional AQPO 
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28. Houslay and Stanley, Dynamics of Biological Membranes, 152-205. 

29. Philippe F. Devaux, "Static and Dynamic Lipid Asymmetry in Cell Membranes," Biochemistry 30 
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30. Houslay and Stanley, Dynamics of Biological Membranes, 152-205. 



308 Notes 

31. G. Vereb et al., "Dynamic, Yet Structured," 8053-58; Donald M. Engelman, "Membranes," 
578-80. 

32. Kai Simons and Elina Ikonen, "Functional Rafts in Cell Membranes," Nature 387 (June 5,1997): 
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33. Geoffrey Zubay, Origins of Life on the Earth and in the Cosmos, 2nd ed. (San Diego: Academic 
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34. Ibid., 347-50; Arthur L. Weber, "Origin ofFatty Acid Synthesis: Thermodynamics and Kinetics 
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liam R. Hargreaves, S. Mulvihill, and David W. Deamer, "Synthesis ofPhospholipids and Membranes in 
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of Phosphatidylcholine under Possible Primitive Earth Conditions," Journal of Molecular Evolution 18 
(May 1982): 196-202; M. Rao, J. Eichberg, and J. Oro, "Synthesis of Phosphatidylethanolamine under 
Possible Primitive Earth Conditions," Journal of Molecular Evolution 25 (May 1987): 1-6. 

35. Stanley L. Miller and Jeffrey L. Bada, "Submarine Hot Springs and the Origin of Life," Nature 334 
(August 18, 1998): 609- 1 1 ; Nils G. Holm and Eva M. Andersson, "Hydrothermal Systems," in The 
Molecular Origins of Life: Assembling Pieces of the Puzzle, ed. Andre Brack (Cambridge: Cambridge 
University Press, 1998), 86-99; Charles B. Thaxton, Walter L. Bradley, and Roger L. Olsen, The Mystery 
of Life's Origin: Reassessing Current Theories (Dallas: Lewis and Stanley, 1984), 56,177-78. 

36. David W. Deamer, Elizabeth Harang Mahon, and Giovanni Bosco, "Self-Assembly and Function 
of Primitive Membrane Structures," in Early Life on Earth: Nobel Symposium No. 84, ed. Stefan Bengtson 
(New York: Columbia University Press, 1994), 107-123; David W. Deamer, "Membrane Compartments 
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(Cambridge: Cambridge University Press, 1998), 189-205. 

37. John R. Cronin, "Clues from the Origin of the Solar System: Meteorites," in The Molecular 
Origins of Life: Assembling Pieces of the Puzzle, ed. Andre Brack (Cambridge: Cambridge University 
Press, 1998), 119-46. 

38. Jason P. Dworkin et al., "Self-Assembling Amphiphilic Molecules: Synthesis in Simulated Inter- 
stellar/Precometary Ices," Proceedings of the National Academy of Sciences, USA 98 (January 30, 2001): 
815-19; Ron Cowen, "Life's Housing May Come from Space," Science News, February 3, 2001,68. 

39. J. N. Israelachvili, S. Marcelja, and R. G. Horn, "Physical Principles of Membrane Organization," 
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40. William R. Hargreaves and David W. Deamer, "Liposomes from Ionic, Single-Chain Amphiphiles," 
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4 1 . Deamer, Mahon, and Bosco, "Self-Assembly," 107-23; Deamer, "Membrane Compartments," 
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naceous Chondrite: Surface Properties and Membrane Formation," Origins of Life and Evolution ofthe 
Biosphere 19 (January 1989): 21-38; David W. Deamer, "Boundary Structures Are Formed by Organic 
Components ofthe Murchison Carbonaceous Chondrite," Nature 317 (October 31,1985): 792-94. 

42. Dworkin et al., "Self- Assembling Amphiphilic Molecules," 815-19. 

43. Deamer, Mahon, and Bosco, "Self-Assembly," 107-23; David W. Deamer and Gail L. Barchfeld, 
"Encapsulation of Macromolecules by Lipid Vesicles under Simulated Prebiotic Conditions," Journal of 
Molecular Evolution 18 (May 1982): 203-6; David W. Deamer, "The First Living Systems: A Bioenergetic 
Perspective," Microbiology and Molecular Biology Reviews 61 (June 1997): 239-61. 

44. Deamer, Mahon, and Bosco, "Self-Assembly," 107-23; Deamer, "Membrane Compartments," 
189-205. 

45. Deamer, "Membrane Compartments," 189-205. 

46. Deamer, Mahon, and Bosco, "Self-Assembly," 107-23; Deamer, "Membrane Compartments," 
189-205. 



Notes ^OQ 

47. James G. Lawless and George U. Yuen, "Quantification ofM oiiocarboxylic Acids in tiie M urchison 
Carbonaceous MeteorJle," Nature 282 (November 22,1979): 396-98. 

48. Deamer, Mahon, and Bosco, "Self-Assembly," 107-23; Deamer, "Membrane Compartments," 
189-205. 

49. Deamer, "Boundary Structures," 792-94. 

50. Hargreaves and Deamer, "Liposomes," 3759-68. 

5 1 . Matt Kaplan, "A Fresh Start: Life May Have Begun Not in the Sea but in Some Warm Little 
Freshwater Pond," New Scientist, May 11,2002,7. 

52. Charles L. Apel, David W. Deamer, and Michael N. Mautner, "Self-Assembled Vesicles of Mono- 
carboxylic Acids and Alcohols: Conditions for Stability and for the Encapsulation of Biopolymers," 
Biochimica et Biophysica Acta 1559 (February 10,2002): 1-9. 

53. Kaplan, "Fresh Start," 7. 

54. Jacquelyn A. Thomas and F. R. Rana, "The Influence of Environmental Conditions, Lipid Com- 
position, and Phase Behavior on the Origin of Cell Membranes," Origins of Life and Evolution of Bio- 
spheres 37 (June 2007): 267-85. 

55.Wikipedia contributors, "Mosaic," http://en.wikipedia.org/wiki/Mosaic . 

Chapter 13 Coloring Outside the Lines 

l.See, for example, Edward J. Behrman, George A. Marzluf, and Ronald Bentley, "Evidence from 
Biochemical Pathways in Favor or Unfinished Evolution Rather than Intelligent TiQs'ign" journal of 
Chemical Education ^{ (July 2004): 1051-52. 

2. Stephen Jay Gould, The Panda's Thumb: More Reflections in Natural History (New York: Morton, 
1980), 24. 

3. Ibid., 20-21. 

4. Roderic D. M. Page and Edward C. Holmes, Molecular Evolution: A Phylogenetic Approach (Maiden, 
MA: Blackwell Science, 1998), 63-65; y^Qn-Yls'wxnghi, Molecular Evolution (Sunderland, MA: Sinauer 
Associates, 1997), 23-30. 

5. Private correspondence with Dr. Mark Wharton, November 28,2005. Dr. Wharton holds aPhD in 
aerospace engineering from the Georgia Institute of Technology and has worked for the NASA Marshall 
Space Flight Center since 1990. He is an internationally recognized expert in the control of structures 
and is the principal investigator ofthe International Space Station experiment. 

6. Lubert Stryer, Biochemistry, 3rd ed. (New York: Freeman, 1988), 349-96. 

7. Ibid., 359-61. 

8. Ibid., 442-44. 
9. Ibid., 150-71. 
10. Ibid., 596-97. 

1 1 . David A. Greenberg, "The Jaundice of the Cell," Proceedings of the National Academy of Sciences, 
USA 99 (December 10,2002): 15837-39. 

12. Sylvain Dore et al., "Bilirubin, Formed by Activation of Heme Oxygenase-2, Protects Neurons 
against Oxidative Stress Injury," Proceedings ofthe National Academy of Sciences, USA 96 (March 2,1999): 
2445-50; David E. Baraiiano et al., "Biliverdin Reductase: A Major Physiologic Cytoprotectant,".Pra'm/- 
ings ofthe National Academy of Sciences, USA 99 (December 10,2002): 16093-98. 

13. "Kidney Stones," ehealthMD, http://www.ehealthmd.com/library/kidnevstones/KS what is 
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14. "Kidney Stones," Urology Channel, Healthcommunities.com . http://www.uroIogychannel.com/ 
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15. Stryer, Biochemistry, 619-22. 
16. Ibid. 

17. Urology channel, http://www.urologvchannel.com/kidnevstones/index.shtml . 

18. Stryer, Biochemistry, 619-22. 

19. Gould, The Panda's Thumb, 19-26. 



310 Notes 

20. Stryer, Biochemistry, 619-22. 

2 1 . Edward E. Max, "Plagiarized Errors and Molecular Genetics: Another Argument in the Evolution- 
Creation Controversy," TalkOrigins Archive, May 5, 2003, http://vv'ww.talkori gins.org/faqs/mol gen/ 
(accessed August 12,2003). 

22. Li, Molecular Evolution, 395-99. 
23. Ibid., 379-84. 

24. Max, "Plagiarized Errors and Molecular Genetics," http://www.talkorigins.org/faqs/molgen/ . 

25. Page and Holmes, Molecular Evolution, 56-57. 

26. Max, "Plagiarized Errors and Molecular Genetics," http://www.talkorigins.org/faqs/molgen/ . 

27. Page and Holmes, Molecular Evolution, 56-57. 

28. Harvey Lodish et al., Molecular Cell Biology, 4th ed. (New York: Freeman, 2000), 62-65. 

29. Ibid., 410-22. 

30. Page and Holmes, Molecular Evolution, 56-57. 

3 1 . Michael J. Pelczar Jr., E. C. S. Chan, andMernaFoss Pelczar, Elements of Microbiology (New York: 
McGraw-Hill, 1981), 180-212. 

32. Alan G. Atherly, Jack R. Girton, and John F. McDonald, The Science of Genetics (Fort Worth: 
Saunders College Publishing, 1999), 597-604. 

33. Page and Holmes, Molecular Evolution, 80- 85 . 

34. Ibid. 

35. See, for example, Sergei A. Korneev, Ji-Ho Park, and Michael O'Shea, "Neuronal Expression of 
Neural Nitric Oxide Synthase (nNOS) Protein Is Supressed by an Antisense RNA Transcribed from an 
NO S Pseudogene," Journal of Neuroscience 19 (September 15,1999): 7711-20; Shinji Hirotsune et al., 
"An Expressed Pseudogene Regulates the Messenger-RNA Stability of Its Homologous Coding Gene," 
Nature 423 (May 1,2003): 91-96; Evgeniy S. Balakirev and Francisco J. Ayala, "Pseudogenes: Are They 
'Junk' or Functional DN A?" Annual Review of Genetics 31 (December 2003): 123-51; Shinji Hirotsune 
et al., "Addendum: An Expressed Pseudogene Regulates the Messenger-RNA Stability of Its Homologous 
Coding Gene," Nature 426 (November 6,2003): 100. 

36. Esther Betran et al., "Evolution of the Phosphoglycerate mutase Processed Gene in Human and 
Chimpanzee Revealing the Origin of a New Primate Gene," Molecular Biology and Evolution 19 (May 
2002): 654-63; Orjan Svensson, Lars Arvestad, and Jens Lagergren, "Genome- Wide Survey for Biologi- 
cally Functional Pseudogenes," PLoS Computational Biology 2 (May 5,2006): e46; Nicolas Vinckenbosch, 
Isabelle Dupanloup, and Henrik Kaessmann, "Evolutionary Fate of Retroposed Gene Copies in the Human 
Genome," Proceedings of the National Academy of Sciences, USA 103 (February 28,2006): 3220-25. 

37. Jerzy Jurka, "Subfamily Structure and Evolution ofthe Human LI Family of Repetitive Sequences," 
Journal of Molecular Evolution 29 (December 1989): 496-503; Atherly, Girton, and McDonald, Science 

of Genetics, 597-60 8; for example, Greg Towers et al., "A Conserved Mechanism of Retrovirus Restriction 
in Mammals," Proceedings ofthe National Academy of Sciences, USA 97 (October 24, 2000): 12295-99; 
Jonathan P. Stoye, "An Intracellular Block to Primate Lentivirus Replication," Proceedings of the National 
Academy of Sciences, USA 99 (September 3, 2002): 11549-5 1; Caroline Besnier, Yasuhiro Takeuchi, 
and Greg Towers, "Restriction of Lentivirus in Monkeys," Proceedings of the National Academy of Sci- 
ences, USA 99 (September 3,2002): 11920-25; Theodora Hatziioannou et al., "Restriction of Multiple 
Divergent Retroviruses by Lvl and Refl," EMBO Journal 22 (February 3, 2003): 385-94; Clare Lynch 
and Michael Tristem, "A Co -Opted gypsy-Type LTR-Retrotransposon Is Conserved in the Genomes of 
Humans, Sheep, Mice, and Rats," Current Biology 13 (September 2,2003): 1518-23; VeraSchramke and 
Robin Allshire, "Hairpin RNAs and Retrotransposon LTRs Effect RNAi and Chromatin-Based Gene 
Silencing," Science 301 (August 22, 2003): 1069-74; Wenhu Pi et al., "The LTR Enhancer ofERV-9 
Human Endogenous Retrovirus Is Active in Oocytes and Progenitor Cells in Transgenic Zebrafish 
and Humans," Proceedings of the National Academy of Sciences, USA 101 (January 20, 2004): 805-10; 
Catherine A. Dunn, Patrik Medstrand, and Dixie L. Mager, "An Endogenous Retroviral Long Terminal 
Repeat Is the Dominant Promoter for Human Bl , 3 - Galactosyltransferase 5 in the Colon," Proceedings of 
the National Academy of Sciences, USA 100 (October 28,2003): 12841-46; Francois Mallet et al., "The 



Motes '^11 

Endogenous Retro viral Locus ERVW E 1 Is a Bona Fide Gene Involved in Hominoid Placental Physiology," 
Proceedings of the National Academy of Sciences, USA 101 (February 10,2004): 1731-36. 

38. Wen-Man Liu et ai., "Cell Stress and Translational Inhibitors Transiently Increase the Abundance 
of Mammalian SINE Transcripts," Nucleic Acids Research 23 (May 25, 1995): 1758-65; Tzu-Huey Li 
et al., "Physiological Stresses Increase Mouse Short Interspersed Element (SINE) RNA Expression In 
Vivo," Gene 239 (November 1, 1999): 367-72; Richard H. Kimura, Prabhakara V. Choudary, and 
Carl W. Schmid, "Silk Worm Bml SINE RNA Increases Following Cellular Insults," Nucleic Acids 
Research 27 (August 15, 1999): 3380-87; Wen-Ming Chu et al., "Potential Alu Function: Regulation 
of the Activity of Double-Stranded RNA-Activated Kinase PKR," Molecular and Cellular Biology 18 
(January 1998): 58-68. 

39. Wen-Man Liu et al., "Alu Transcripts: Cytoplasmic Localisation and Regulation by DNA Methyl- 
ation," Nucleic Acids Research 22 (March 25, 1994): 1087-95; Wen-Man Liu and Carl W. Schmid, 
"Proposed Roles for DNA Methylation in Alu Transcriptional Repression and Mutational Inactivation," 
Nucleic Acid Research 21 (March 25,1993): 1351-59; Carol M. Rubin et al., "Alu Repeated DNAs Are 
Differentially Methylated in Primate Germ Cells," Nucleic Acids Research 22 (November 25, 1994): 
5121-27; IgorN. Chesnokov and CarlW. Schmid, "Specific Alu Binding Protein from Human Sperm 
Chromatin Prevents DNA Methyhtion" Journal of Biological Chemistry 270 (August 4,1995): 18539-42; 
Utha Hellmann-Blumberg et al., "Developmental Differences in Methylation of Human Alu Repeats," 
Molecular and Cellular Biology 13 (August 1993): 4523-30. 

40. Jeffrey A. Bailey et al., "Molecular Evidence for a Relationship Between LINE- 1 Elements and 
X Chromosome Inactivation: The Lyon Repeat Hypothesis," Proceedings of the National Academy of 
Sciences, USA 97 (June 6,2000): 6634-39; Christine Moulton Clemson et al., "The X Chromosome Is 
Organized into a Gene-Rich Outer Rim and an Internal Core Containing Silenced Nongenic Sequences," 
Proceedings of the National Academy of Sciences, USA 103 (May 16, 2006): 7688-93. 

4 I.Edith Heard, Philippe Clerc, and Philip Avner, "X-Chromosome Inactivation in Mammals," 
Annual Review of Genetics 31 (December 1997): 571-610. 

42. Jack J. Pasternuk,An Introduction to Human Molecular Genetics: Mechanisms of Inherited Diseases 
(Bethesda, MD: Fitzgerald Science, 1999), 3 1-3 2. 

43. Elena Allen et al., "High Concentrations of Long Interspersed Nuclear Element Sequence Dis- 
tinguish Monoallelically Expressed Genes," Proceedings of the National Academy of Sciences, USA 100 
(August 23,2003): 9940-45. 

44. Lynch and Tristem, "Co-Opted gypsy-Type LTR-Retrotransposon," 15 1 8-23; Matthew P. Hare 
and Stephen R. Palumbi, "High Intron Sequence Conservation across Three Mammalian Orders Sug- 
gest Functional Constraints," Molecular Biology and Evolution 20 (June 2003): 969-78; J. W. Thomas 
et al., "Comparative Analyses of Multi-Species Sequences from Targeted Genomic Regions," Nature'424 
(August 14,2003): 788-93; Nicholas J. Kaplinsky et al., "Utility and Distribut ion of Conserved Noncod- 
ing Sequences in the Grasses," Proceedings of the National Academy of Sciences, USA 99 (April 30,2002): 
6 147-51; Emmanouil T. Dermitzakis et al., "Evolutionary Discrimination ofMammalian Conserved 
Non-Genie Sequences (CNGs)," Science 302 (November 7, 2003): 1033-35; Gill Bejerano et al., "Ul- 
traconserved Elements in the Human Genome," Science 304 (May 28,2004): 1321-25; Michael Kamal, 
Xiaohiu Xie, and Eric S. Lander, "A Large Family of Ancient Repeat Elements in the Human Genome Is 
under Strong Selection," Proceedings of the National Academy of Sciences, USA 103 (February 21,2006): 
2740-45; Eliot C. Bush and Bruce T. Lahn, "Selective Constraint on Noncoding Regions of Hominid 
Genomes," PLoS Computational Biology 1 (December 16,2005): e73. 

45. Ran Kafri, Melissa Levy, and Yitzhak Pilpel, "The Regulatory Utilization of Genetic Redun- 
dancy through Responsive Backup Circuits," Proceedings of the National Academy of Sciences, USA 103 
(August 1,2006): 11653-58. 

46. Lodish et al.. Molecular CellBiology, 62-65. 

47. Ulrich Schubert et al., "Rapid Degradation of a Large Fraction of Newly Synthesized Proteins by 
Proteasomes," A^amre 404 (April 13,2000): 770-74. 



312 Notes 

48. Michael Gross, Travels to the Nanoworld: Miniature Machinery in Nature and Technology (New 
York: Plenum Trade, 1999), 86-90. 

49. Eric Pamer and Peter Cress well, "Mechanisms ofMHC Class I-Restricted Antigen Processing," 
Annual Review of Immunology 16 (April 1998): 323-58; Kenneth L. Rock and Alfred L. Goldberg, 

"Degradation ofCell Proteins and the Generation ofMHC Class I-Presented Peptides? Annual Review 
of Immunology 17 (April 1999): 739-79. 

50. HansjorgSchild and Hans-GeorgRammensee, "Perfect Use of Imperfection," Nature 404 (2000): 
709-10; J. Travis, "Trashed Proteins May Help Immune System," Science News 157 (2000): 245; Eric A.J. 
Reits et al., "The Major Substrates for TAP in vivo Are Derived from Newly Synthesized Proteins," 
Nature AQ A (2000): 774-78. 

51. Robert C. Bohinski, Modern Concepts in Biochemistry y 4th ed. (Boston: Allyn and Bacon, 1983), 
373-80. 

52. Ibid. 

53. Guillaume G. B. Tcherkez, Graham D. Farquhar, and T. John Andrews, "Despite Slow Catalysis 
and Confused Substrate Specificity, All Ribulose Bisphosphate Carboxylases May Be Nearly Perfectly 
Optimized," Proceedings of the National Academy of Sciences, USA 103 (May 9, 2006): 7246-5 1. 

54. Ibid. 

55. Ronald D. Vale, "The Molecular Motor Toolbox for Intracellular Transport," Cell 1 12 (Febru- 
ary 1, 2003): 467-80; Stephen M. King, "The Dynein Microtubule Motor," Biochimica et Biophysica 
Acta (BBA)ZMolecular Cell Research 1496 (March 17, 2000): 60-75. 

56. Roop Mallik and Steven P. Gross, "Molecular Motors: Strategies to Get Along," Current Biol- 
ogy 14 (November 23, 2004): R971-82. 

Chapter 14 The Masterpiece Authenticated 

1. Natasha Gural, "A Revealing Look at Picasso's Last Years," Boston Globe, May 5, 2004. 

2. See, for example, Ursula Goodenough, The Sacred Depths of Nature (New York: Oxford University 
Press, 1998). 

3. See, for example, Kenneth R. Miller, Finding Darwin's God: A Scientist's Search for Common Ground 
between God and Evolution (New York: Cliff Street Books, 1999), 129-64. 

4. See, for example, Mark J. Pallen and Nicholas J. Matzke, "From The Origin of Species to the Origin 
of Bacterial Flagella," Nature Reviews Microbiology A (October 2006): 784-90; Renyi Liu and Howard 
Ochman, "Stepwise Formation of the Bacterial Flagellar System," Proceedings of the National Academy of 
Sciences, USA 104 (April 24, 2007): 7 1 I 6-2 1 . 

5- See, for example, Ariel Blocker, Kaoru Komoriya, and Shin-Ichi Aizawa, "Type III Secretion 
Systems and Bacterial Flagella: Insights into Their Function from Structural Similarities," Proceedings of 
the National Academy of Sciences, USA 100 (March 18,2003): 3027-30. 

6. The phrase "just-so" refers to Rudyard Kipling's Just-So Stories, This book, first published in 1902, 
contains mythical accounts ofhow various natural phenomena came about like "How the Whale Got 
His Throat," "How the Leopard Got His Spots," and "How the Camel Got His Hump," to name a few. 
This phrase is also an academic term used to describe ad hoc, unverifiable, unfalsifiable narrative accounts 
ofhow some organism or biological trait came into existence. 

7. Pallen and Matzke, "Origin of Species to the Origin of Bacterial Flagella," 784-90. 

8. Milton H. Saier Jr., "Evolution of Bacterial Type III Protein Secretion Systems," Trends in Micro- 
biology 12 (March 2004): 113-15. 

9. Sonia L. Bardy, Sandy Y. M. Ng, and Ken F. Jarrell, "Prokaryotic Motility Structures," Microbiol- 
ogy 149 (February 2003): 295-304. 

10. Michael J. Behe, Darwin's Black Box: The Biochemical Challenge to Evolution (New York: Free 
Press, 1996), 165-86. 

11. Fazale Rana and Hugh Ross, Origins of Life: Biblical and Evolutionary Models Face Off(Co\orado 
Springs: NavPress, 2004), 159-68. 



Notes 



313 



12. Hubert P. Yockey, Information Theory and Molecular Biology (Cambridge: Cambridge University 
Press, 1992), 180-83. 

13. Jacquelyn A. Thomas and F. R. Ran a, "The Influence of Environmental Conditions, Lipid Com- 
position, and Phase Behavior on the Origin of Cell Membranes," Origins of Life and Evolution of Bio- 
spheres 37 (June 2007): 267-85. 

14. Stephen Jay Gould, The Panda's Thumb: More Reflections in Natural History (New York: Norton, 
1980), 20. 

15. John Cafferky, Evolution's Hand: Searching for the Creator in Contemporary Science (Toronto: 
eastendbooks, 1997), 66-69. 

16. For a good discussion of abductive reasoning and its relationship to the inference of the best 
explanation, see Stephen C. Meyer, "Modern Science and the Return ofthe 'God Hypothesis,'" in Sci- 
ence and Christianity : Four Views, ed. Richard F. Carlson (Downers Grove, IL: InterVarsity Press, 2000), 

127-74. 

17. Genesis 1:26-27; 5:1-2 (see chap. 1, n. 12). 

18. Kenneth Richard Samples, "The Historic Christian View of Man," in A World of Difference (Grand 
Rapids: Baker, 2007), 171-88. 

Epilogue 

1 . For an overview, see Hugh Ross, Creation as Science: A Testable Model Approach to End the Creation/ 
Evolution Wars (Colorado Springs: NavPress, 2006). 

2. Genesis 1:2: "Now the earth was formless and empty, darkness was over the surface ofthe deep, 
and the Spirit ofGod was hovering over the waters." Psalm 104:5-6: "He set the earth on its founda- 
tions; it can never be moved. You covered it with the deep as with a garment; the waters stood above the 
mountains." Deuteronomy 32:10-11: "In a desert land he found him, in a barren and howling waste. He 
shielded him and cared for him; he guarded him as the apple of his eye, like an eagle that stirs up its nest 
and hovers over its young, that spreads its wings to catch them and carries them on its pinions." 

3.Fazale Rana and Hugh Ross, Origins of Life: Biblical and Evolutionary Models Face C_T(Colorado 
Springs: NavPress, 2004), 35-46. 



GLOSSARY 



actin. The protein that constitutes microfilaments, one of three types of 
filaments that make up the cytoskeleton. 

activators. Proteins that bind to the operator. Activators turn a gene on when 
they bind. 

adenine. One of four nucleobases found in DNA and RNA. 

adenosine (A). One of four nucleotides used to build DNA chains. The other 
three are cytidine, guanosine, and thymidine. 

amino acid. An organic compound that has both amino (NHs) and carboxyl 
(COOH) groups. Amino acidsjoin together in a chainlike fashion to 
form proteins. 

amphiphilic. A chemical compound in which part of its molecular structure 
is water-soluble and part is water-insoluble. Cell membranes consist of 
amphiphilic materials. 

anion. A negatively charged chemical specie. 

anticodon. Each tRNAs anticodon matches a codon in mRNA. The codon- 
anticodon pairs are part of the cellular hardware that implements the 
manufacturing instructions for protein production. 

antioxidant. Any compound that protects biochemical systems from the 
harmful effects of oxygen or reactive oxygen species by reacting with 
them and converting these compounds into benign materials. 

314 



Glossary 315 

antiparallel. Refers to the alignment of two polynucleotide chains. The two 
strands are arranged parallel to one another with each starting point of a 
strand in the polynucleotide duplex located next to the ending point of 
the other strand. 

antisense strand. One of two strands in a DNA double helix. It normally does 
not harbor a gene but simply serves as a template for DNA replication. 
The other strand is known as the sense strand. 

aquaglyceroporins. Proteins that form channels in cell membranes that 

provide conduits for glycerol and related materials to flow in and out of 
the cell. 

aquaporins. Proteins that form channels in cell membranes that provide 
conduits for water to flow in and out of the cell. 

archaea. One of life's three domains. Bacteria-like microorganisms comprise 
archaea. While these microbes superficially resemble bacteria, they are 
genetically and biochemically distinct. Some origin-of-life researchers 
think that archaea were the first organisms to emerge on Earth. 

ATP (adenosine triphosphate). The cell uses this compound as a source of 
chemical energy to drive the operation of cellular processes. 

ATPases. A class of proteins that break down ATP, an energy-storing molecule 
within the cell. 

autotrophs. Chemoautotrophs and photoautotrophs are the two types ot 

autotrophs. Autotrophs survive by generating the organic materials they 
need using inorganic compounds or light as energy sources. 

bacteria. One of life's major domains consisting of single-celled organisms that 
lack a nucleus and other organelles. 

base-pairing rules. Rules that establish the complementary relationship 

between the nucleotide sequences of the two DNA strands. 

bilayer. The sheet that is spontaneously formed by phospholipids when added 
to water. When organized into a bilayer, phospholipid molecules align 
into two monolayers with the phospholipid tails of one monolayer 
contacting the phospholipid tails of its companion monolayer. 

biochemistry. The study of the chemical processes and compounds that 
constitute life. 

biomolecule. A molecule that is found in living organisms or plays an 
important role in life processes. 



316 Glossary 

biosynthesis. The production of life molecules by biochemical systems. 

bottom-up approach. An approach to account for the origin of life from an 
evolutionary standpoint. The bottom-up approach starts with simple 
chemical systems and seeks to identify pathways that lead to increased 
complexity, culminating in the first life-form. 

Brownian motion. The random, zigzag movement of microscopic objects 
suspended in a liquid or gas. This motion stems from the net force 
exerted on the suspended object by the gas or liquid molecules. 

Brownian ratchet. A device that restricts Brownian motion using a barrier to 
power directional movement. Brownian ratchets require energy input 
to erect and maintain the barriers that prevent motion in unwanted 
directions. 

carbonaceous chondrites. Carbon-containing meteorites, like the Murchison 
meteorite. 

carbohydrate. A biomolecule that consists of carbon, hydrogen, and oxygen 
in the specific ratio of 1:2:1, respectively. Carbohydrates include sugars, 
starches, and celluloses. 

catalyze. To facilitate a chemical reaction. 

cell. The fundamental unit of life and the smallest entity that can be considered 
"life." All organisms consist of one or more cells. 

cell membrane. The outer layer of the cell (comprised of lipids and proteins), 
which protects the cell's inner parts from the cell's surroundings while 
allowing materials to enter and exit the cell. 

cellulose. A large sugar molecule that consists of glucose subunits. The cell wall 
in plants is composed of cellulose. 

central dogma of molecular biology. This concept describes the flow of 
information inside the cell. Information stored in DNA is copied to 
form a messenger RNA molecule (transcription). This molecule, in turn, 
directs the formation of proteins at ribosomes (translation). 

centromere. The central region of the chromosome. This region plays a role in 
separating chromosomes during cell division. 

chemoautotroph. A type of autotroph. Chemoautotrophs use chemical 

energy extracted from the environment as an energy source to produce 
organic materials. 



Glossary 317 

chromosome. Complexes formed from a single DNA molecule and histone 
proteins. Chromosomes are found in the nucleus of eukaryotic 
organisms. 

codon. The fundamental unit of the genetic code. Codons consist of groupings 
of three nucleotides. Codons are used to specify the twenty different 
amino acids used to make proteins. 

complementary. Refers to the sequences of the two polynucleotide chains 
that make up the DNA double helix. Because of the base-pairing rules 
(A pairs with T, and G pairs with C), the sequence of one polynucleotide 
chain dictates the sequence of the other chain. 

cyanobacteria. A group of bacteria with the capacity for photosynthesis. 
Cyanobacteria are also called blue-green algae. 

cytidine (C). One of four nucleotides used to build DNA chains. The other 
three are adenosine, guanosine, and thymidine. 

cytoplasm. Forms the cell's internal matrix and is made up of water, salts, and 
organic molecules. 

cytosine. One of four nucleobases found in DNA and RNA. 

cytoskeleton. A fibrous network of proteins that form the cell's internal 
structural framework. It assembles and disassembles at various locales 
with the cytoplasm as needed. The cytoskeleton is made of three 
filaments: microtubules, intermediate filaments, and microfilaments. 

daughter cells. Two cells produced during cell division, with DNA identical to 
the parent cell. 

disaccharide. A carbohydrate that consists of two sugars linked together. Table 
sugar (sucrose) is an example. 

disulfide bond. A bond formed between the side chains of cysteine amino acid 
residues within a protein, stabilizing its three-dimensional structure. 

DNA. The cell's genetic material, which consists of two polynucleotide chains 
that twist around each other to form the double helix. Polynucleotide 
chains are made by linking four subunit molecules called nucleotides. The 
four nucleotides are adenosine, cytidine, guanosine, and thymidine — 
abbreviated as A, C, G, and T, respectively. 

DNA polymerase. An enzyme that duplicates DNA molecules during cell 
replication. 



318 Glossary 

DNA replication. The biochemical process that generates two "daughter" 
molecules identical to the "parent" DNA molecule. 

domain. All of life is divided into one of three domains: Eubacteria, Archaea, 
or Eukarya. 

double helix. Describes the molecular topology of a DNA molecule. 

electron micrograph. The image produced by an electron microscope. 

endogenous retrovirus. Presumably nonfunctional retroviral DNA that has 
become permanently incorporated into the host organisms genome. 

entropy. The measure of energy quality and disorder of a system. 

enzyme. A protein that catalyzes or assists a chemical process. 

essential genome size. The number of distinct genes necessary to sustain the 
minimal metabolic and structural requirements for life. 

eubacteria. One of life's three domains. These organisms are single-celled and 
lack internal structures such as a nucleus. 

eukarya. One of life's three domains comprised of organisms that possess a 
nucleus as part of their cellular makeup. Eukarya includes one-celled 
protists and multicellular fungi, plants, and animals. 

eukaryote. One of two types of cells. It contains internal membrane systems, a 
nucleus, organelles, a cytoskeleton, and other components that organize 
the cell contents at the subcellular and even molecular level. 

evolution. Biological changes that occur in populations of organisms through 
time. 

evolutionary pathways. The proposed sequence of changes that transforms an 
ancestral population into a novel group. 

evolutionary tree of life. A treelike diagram showing proposed evolutionary 
interrelationships among various species or other biological groups 
believed to have a common ancestor. 

exon. Nucleotide sequence in a gene that codes for part of the amino acid 
sequence of polypeptide chains. 

explanatory filter. A methodology proposed by philosopher and 

mathematician William Dembski to detect the activity of an intelligent 
agent. According to the explanatory filter, if an event, system, or object 
is intentionally produced by an intelligent designer then it will (1) be 



Glossary 3 J O , 

contingent, (2) be complex, and (3) display an independently specified 
pattern. 

fluid mosaic model. A model that provides the framework for understanding 
membrane structure and function. This model views the phospholipid 
bilayer as a two-dimensional fluid that serves as both a cellular barrier 
and a solvent for integral membrane proteins. It allows the membrane 
proteins and lipids to freely diffuse laterally throughout the cell 
membrane. 

frameshift mutation. A mutation that results when nucleotides are 

accidentally inserted or deleted from a gene, leading to a shift in the 
gene s reading frame. 

futile cycle. Paired reactions that cycle back and forth within a cell. 

gene. The nucleotide sequence along the DNA strands that codes the amino 
acid sequence of a particular polypeptide. 

gene expression. Refers to the production of the protein encoded by the gene. 

gene product. Any functional molecule specified by a gene including proteins, 
tRNA, and rRNA. 

gene regulation. The control of gene expression. 

genetic code. A set of rules that relays the information stored in the nucleotide 
sequences of DNA to the amino acid sequences of proteins. 

genome. An organisms total genetic makeup. 

genomics. A new life-science discipline that focuses on sequencing and 
characterizing the structure and function of genomes. 

glucose. A six-carbon sugar that releases energy in the process of glycolysis that 
is used by the cell for energy. 

glycerol. A thtee-carbon compound that forms the backbone of 
phospholipids. 

glycolysis. This biochemical process releases energy from glucose by fracturing 
it into two molecules of pyruvate. The cell captures a portion of this 
liberated chemical energy and stores it for later use. 

glycolytic pathway. The metabolic process of glycolysis that harvests energy 
for use by the cell. 



320 Glossary 

Golgi apparatus. Stacks of membranes in eukaryotic cells that function in the 
processing and sorting of proteins and lipids destined for other parts of 
the cell and secretion. 

guanine. One of four nucleobases found in DNA. 

guanosine (G). One of four nucleotides used to build DNA chains. The other 
three are adenosine, cytidine, and thymidine. 

heterotroph. An organism that ingests the organic materials needed for its 
maintenance and growth. 

housekeeping gene. A gene that is expressed, or turned on, nearly all the time 
because it specifies a protein needed virtually all the time to maintain 
normal cellular operations. 

hydrolytic reaction. A chemical reaction that involves the cleavage of chemical 
bonds by water. 

hydrophilic. "Water-loving"; hydrophilic compounds dissolve readily in water. 

hydrophobic. "Water-hating"; hydrophobic compounds are insoluble in water. 

indel. A type of genetic mutation that involves the insertion and/or deletion of 
one or more nucleotides from a DNA sequence. 

information. Results when data is processed, manipulated, and organized in a 
way that adds to the knowledge of the receiver. 

intron. A nucleotide sequence in a gene that does not code for anything. 

invariable (conserved) position. A position in the amino acid sequence of 
a polypeptide that doesn't vary in response to mutational pressures. 
Biochemists regard conserved amino acids as critical to the protein's 
structure and function. 

junk DNA. A region of a genome that does not code for proteins or other 
functional products. Evolutionary biologists believe that junk DNA 
results when undirected biochemical processes and random molecular 
and physical events transform a functional DNA segment into a useless, 
molecular artifact. 

kinesin. A highly efficient and robust molecular motor that moves cellular 
cargo. Kinesin binds with its cargo and then "walks" in only one 
direction along mictotubules that form part of the cell's cytoskeleton. 

knock-out experiment. A protocol that involves either random or systematic 
mutation of genes to determine those that are indispensable for Ufe. 



Glossary 321 

lipid. A class of chemical compounds that shares the combined properties of 
solubility in organic solvents and insolubility in water. 

lipid bilayer. The tail-to-tail arrangement of phospholipid molecules that 
forms the matrix of cell membranes. 

LUCA (Last Universal Common Ancestor). The hypothetical organism that 
supposedly gave rise to all life on Earth. 

lumen. The single space inside organelles. 

macroevolution. Biological evolution at the genus level or higher. 

Macroevolutionary changes entail major changes in anatomy and 
physiology. 

macromolecule. Any large molecule made up of smaller molecules called 
subunits. 

membrane. A structure that separates the parts of the cell. Internal membrane 
systems separate organelles within the cell while another membrane 
forms a boundary for the cell from its exterior surroundings. 

metabolism. The sum total of chemical reactions that take place in living 
systems. 

microbe. Any single-cell organism. 

microevolution. Evolutionary changes within a species due primarily to 
altered frequencies of genes within a population. 

mitosis. The process of cell division that yields two daughter cells identical to 
the mother cell. 

model. A mathematical or descriptive depiction of a phenomenon in nature. 
This term is roughly synonymous to a theory or hypothesis. 

monolayer. An assembly of molecules that forms a single layer, one molecule 
in thickness. 

monomer. A chemical compound that can be linked with other chemical 

compounds to form a larger, more complex molecule. Monomers are also 
referred to as subunits. 

monosaccharides. Carbohydrates composed of a single-sugar residue, such as 
glucose and fructose. 

mRNA (messenger RNA). A single-stranded molecule similar in composition 
to DNA. The cell assembles mRNA using the nucleotide sequence of 



322 Glossary 

a gene as a template. At the ribosome, mRNA directs the synthesis of 
polypeptide chains. 

mutation. Any change that occurs in a DNA sequence. 

nanotechnology. The scientific discipline that seeks to develop molecular-scale 
devices and systems. 

natural selection. The differential survival of organisms within a population in 
response to environmental, competitive, and predatory challenges. 

nonsense (or stop) codon. This type of codon doesn't specify any amino 

acids and always occurs at the end of the nucleotide sequence of a gene 
informing the protein manufacturing machinery where the polypeptide 
chain ends. 

nonuniversal genetic code. A code that employs slightly different codon 

assignments compared to the universal genetic code; it can be thought of 
as a deviant of the universal genetic code. 

nucleobase. A part of RNA or DNA that extends as a side chain from the 
backbone of the DNA molecule and serves as an interaction point 
(like ladder rungs) when the two DNA strands align and twist to form 
the double helix. Nucleobases include adenine, cytosine, guanine, and 
thymine. 

nucleolus. A dense area within the nucleus of a cell where ribosomes are 
assembled. 

nucleosome. The fundamental organizing structure of chromosomes. A 
nucleosome consists of DNA wrapped around a histone core and 
occurs repeatedly along the length of the DNA molecule to form a 
supramolecular structure that resembles a string of beads. 

nucleotide sequence. A sequential string of nucleotides along a DNA strand. 

nucleotide. A molecule used by the cell to build polynucleotide chains that 
form DNA. The four nucleotides used are adenosine (A), cytidine (C), 
guanosine (G), and thymidine (T). 

oligosaccharide. A carbohydrate formed when a handful of sugar molecules 
are linked together. 

operator. One of two key sites within the regulatory region of a gene. The 
operator binds two types of proteins: the activators and the repressors. 
The operator functions as a type of on/off switch for gene expression. 



Glossary 32" 

operon. A grouping of juxtaposed genes found in bacteria that are involved in 
the same cellular processes. 

organelle. A structure found inside cells, typically surrounded by membranes, 
that carries out specialized functions. 

peptide. A polymer formed by linking together amino acids. 

phosphate group. A chemical group consisting of a central phosphorus atom 
bound to four oxygen atoms. Phosphate groups help form the backbone 
of DNA and RNA molecules and play an important role in energy usage 
by the cell. 

phosphodiester bond. A bond that forms between a phosphate group and 
two sugars at the same time to bridge two nucleotides, while retaining a 
negative charge. 

phospholipid. An amphiphilic compound formed from phosphate, glycerol, 
fatty acids, and amino alcohol. Phospholipids are one of the major 
components of cell membranes. 

photoautotroph. An organism that produces food stuff by using light energy. 

plasmid. Small piece of circular DNA found in bacteria. Plasmids exist 
independent of the bacteria's primary chromosome. 

poly (A) tail. A sequence of adenosine nucleotides added to the end of RNA 
molecules. 

polymer. A large chainlike molecule that consists of smaller subunits (called 
monomers) linked together. 

polynucleotide. Chainlike molecules of nucleotides. DNA and RNA are 
examples. 

polypeptide. A synonym for peptide. 

polysaccharide. A carbohydrate formed when numerous sugars connect. 
Starch and cellulose are common examples. 

posttranslational modification. The processing of proteins after production 
at the ribosomes. 

primordial soup. The hypothetical mixture of chemical compounds on early 
Earth that provided the raw materials chemical evolutionary processes 
supposedly used to generate the first life-forms. 

prokaryote. A single-celled organism that lacks subcellular structures, 
specifically a nucleus. Bacteria and archaea are both prokaryotes. 



324 Glossary 

promoter. One of two key sites within the regulatory region of a gene. The 

promoter serves as the binding site for RNA polymerase, an enzyme that 
initiates gene expression by producing an mRNA molecule. 

proteasome. A massive protein complex that destroys damaged proteins. 

protein coding region. One of two major regions in the gene. It contains 

information needed by the cell's biochemical machinery to produce the 
polypeptide or protein chain encoded by that gene. 

protein. A biomolecule made by linking amino acids together in a chainlike 
fashion. Proteins catalyze chemical reactions, harvest chemical energy, 
serve in the cell's defense systems, store and transport molecules, and 
more. 

pseudogene. Considered to be the dead, useless remains of a once functional 
gene. 

pyruvate. A three-carbon compound produced in the breakdown of a six- 
carbon compound (glucose) during the process of glycolysis. 

reading frame. A contiguous and nonoverlapping set of three-nucleotide 
codons in DNA. There are three possible reading frames in a single 
strand of DNA. 

regulatory region. One of two major regions in the gene. In effect, the 
regulatory region consists of "on/off switches" and "volume control 
knobs" that regulate gene expression, thereby determining the 
production of the polypeptide chain. 

repressor. A protein that binds to DNA. Repressors turn the gene off when 

they bind, halting gene expression. When a repressor debinds, the gene is 
activated. 

reverse transcription. The process in which mRNA is used as a template to 
produce the corresponding DNA molecule. This operation, catalyzed by 
the enzyme reverse transcriptase, reverses transcription. 

ribose. A five-carbon sugar that forms part of RNA's molecular structure. 

ribosome. A subcellular particle made up of proteins and RNA molecules. 
This structure plays the central role in protein synthesis. 

RNA polymerase. A complex protein that is involved in the production of 
mRNA. 



Glossary 3~'^5 

rRNA (ribosomal RNA). These RNA molecules form the scaffolding of 

ribosomes. Ribosomal RNA molecules also catalyze the formation of the 
chemical bonds between amino acids during protein synthesis. 

sense strand. The DNA strand in the double helix that harbors a gene. The 
other strand is referred to as the antisense strand. 

sequencing. The process of determining the nucleotide sequence ofDNA 
strands or the amino acid sequence of proteins. 

solenoid. A structure formed from coiled nucleosomes. It condenses to form 
higher-order structures that comprise the chromosome. 

stop codons. See nonsense codons. 

substitution mutation. Replacement of a nucleotide in a DNA sequence with 
another. This kind of mutation can be catastrophic but more often has a 
limited effect on protein function. 

sucrose. A disaccharide formed from the combination of the sugars glucose 
and fructose; commonly known as table sugar. 

thymidine (T). One of four nucleotides used to build DNA chains. The other 
three are adenosine, cytidine, and guanosine. 

thymine. One of four nucleobases found in DNA. 

top-down approach. An approach to account for the origin of life from an 
evolutionary standpoint. This approach starts with life and seeks to 
identify pathways that lead backwards to the first life-form. 

transcription. The process of copying mRNA from DNA. 

transcription factor. A protein that regulates gene expression (transcription) 
by binding to DNA. 

translation. The synthesis of polypeptide chains, directed by mRNA at the 
ribosome. 

tRNA (transfer RNA). An RNA molecule that binds an amino acid, then 
delivers it to the ribosome. Each of the twenty amino acids used by the 
cell to form proteins has at least one corresponding tRNA molecule. 

Turing machine. A conceptual machine that processes complex computations 
and operations through a relatively simple process of input, output, and 
finite control according to a specific set of rules. 



326 Glossary 

universal genetic code. The set of rules, found throughout the living realm, 

that relate the nucleotide sequences of DNA to the amino acid sequences 
of proteins. These rules are used during the process of translation. 

uracil. A single-ringed nucleobase found in RNA. 

vesicle. A small, round membrane-bound sac. 

viral capsid. A protein shell that contains the genetic material (DNA or RNA) 
of viruses. 

virus. A subcellular particle composed of a protein capsid that houses genetic 
material (either DNA or RNA). 



INDEX 



AAA ring, 81-83 

A (accepter) site, 190-91 

AcrA/AcrB/TolC complex, ll>-lAJ(i-ll 

activating enzymes, 195-97 

adenine, 158,160-61,254-55 

alpha helix, 43-44 

amino acids, 43, 1 54 

changes, 128-29 

hydrophiiic, 1 12 

hydrophobic, 112, 115 

sequences, 49-50,126-2 8,130,142-43,145-46 

side groups, 1 12-15 
amphiphilic compounds, origin of, 237-38, 242 
AQPZchannel, 112-13 
aquaglyce roporins, 111-12, 115-17 
aquaporins, 112-13, 115-17,234 
arginine-196, 115 
artists 

Millais, SirJohn Everett, 109-10 

Mondrian, Piet, 126 

Picasso, Pablo, 23-24, 203 

Russell, Charles M., 16 

Vermeer, Jan, 35 
artwork 

Artist's Studio, The, 34-35 

calligraphy, 140-42 

Contra-Composition of Dissonances, XVI, 126 

mosaic, 225 

Portrait of Dora Maar, 202 

Riders of the Open Range, 14 
Unknown Masterpiece, Vie, 22-24, 28, 31-32 



asymmetry, 235-36 

ATP (adenosine triphosphate), 1 37-39 

ATPase, 78 

F,Fo,71-73,78,89 

V-type, 73 
autotrophs, 56-57 

bacteria, 66 

bacterialflagellum, 70-71,74-75, 271-72 

bacteriophage (^X174, 152-54 

base-pairing 

mistakes, 160 

rules, 157-58, 160-61,218 
Behe, Michael, 18-20 
beta pleated sheet, A3-AA 
bilayer, 225-27 

fluidity, 227-28 

lipid, 240 

multilamellar vesicles, 229 

origins, 238-40 

primitive, 242 

sheets, 229-31 

structures, 237 

unilamellar vesicles, 229-31 
bilayer-forming molecules, 237-39 
bilirubin, 253-54 
biliverdin, 253-54 

biochemical design, 17-18, 123,201,224 
biochemical imperfections. 5eesuboptimal designs 
biochemical information, 142-68,280 
biochemical messages, 233 



327 



328 



biochemical redundancy, 260-61, 281 
biochemical systems, 20, 26-27 
biochemistry, 16-18 
biomolecular function, 110-11 
biomolecular precision, 110-11 
BiP protein, 93-95 
Brownian motion, 91-92 
Brownian ratchets, 91-95 
Buchnera, 60 

carbohydrates, 146-48 

carbonaceous chondrites. See meteorites 

carbon dioxide, 264-65 

carbon fixation reactions, 65-66, 264-65 

carboxysome, 65 

Carsonetla ruddii, 60 

cell 

artificial, 61 

chemical composition, 16 

cycle, 121-22 

quality control, 160,184-85,191-97,280 

reading frame, 154 
cell membranes, 36,38,45,242-43,282 

asymmetry, 235 

domains, 236 

evolution, 240 

fluidity, 227-28 

monolayers, 235-36 

organization, 236, 281 

origin, 237-40,273-74 

primitive, 241, 273 

stability, 234 

structure, 225-26, 229 

wall, 42 
cell theory, 36 

cell types. See eukaryotes; prokaryotes 
chaperones, 1 06-7 
chaperonins, 106-7 
charging reaction, 195-96 
chicken-and-egg systems, 97-99,107-8,271,279 

proteins and DNA, 98-99,101 
chloroplasts, 41-42 
chromosomes, 50-51 
class 1 major histocompatibility complex (MHC), 

262-63 
coding triplets. See codons 
codons, 130,154,171-74,187-89 

anticodon, 187-89 

codon changes, 177 

stop codons, 172-73 
colicin E, 232 



collagenase, 118 

collagens, 117 

collagen triple helix, 118 

cometary ice, 238 

Creator, identifying, 28-29, 278 

Creator's signature, 29,33 

Crick, Francis, 17 

cytoplasm, 36, 38 

cytosine, 158,160-61 

cytoskeleton, 39,64-65 

Darwin 's Black Box, 18-20 
dehydration-hydration cycles, 242 
Dembski, William, 25 

deoxyribose, 130-34 
Design Inference, The, 25 

design, appearance of, 205, 270 
DNA 
advancing replication fork, 220-21 
analogs, 132-33 
association with histones, 180 
bacterial, 63 
bar codes, 1 65-66 
computers, 163-65 
daughter molecule, 218 
double helix, 218-21 
encryption, 165 

information storage, 49-50, 52,143-44 
junk, 255-60 
LINE, 260 
noncoding, 255-60 
packaging motor, 89 
parent molecule, 218 
polymerase, 63-64, 222-23 
repair enzyme, 128 
replication, 84, 99-101,160,216-23 

bubble, 220-21 

evolution of, 216 

fork, 221-22 
replication, semiconservative, 218-19 
SINE, 259 
strands, 129-32,218 

antisense strand, 157-58 

sense strand, 157-58 
strings, 163-64 
structure, 48-49 
sugar-phosphate backbone, 134 
topoisomerases, 64 
transcription, 101 
translocator motor, 78 
viral, 80-81 
dynein, 81-83,265-66 



Index 



329 



EF-Tu, 196-97 

encapsulated self-replicating molecules, 240 
endogenous retroviruses, 258-59 
endoplasmic reticulum (ER), 40, 93-94, 198 

ER lumen, 198-99 

ER machinery, 199-200 
endosymbionts, 59 
entropy, 246-48 
enzyme, 43,45 

commission classes, 215 

editing site, 196 

proofreading, 196 
error minimization, 158-60 
eukaryotes, 36-38,62-65,101,151,189 
evolution, 20 

case for, 246 
evolutionary pathways, 204-5, 270-75 
evolutionary tree of life, 216-17 
exons, 102-3,152 

explanatory filter, 25-27, 277, 288n8 
extracellular matrix (ECM), 42,95 

ferredoxins, 178 

fibrils, 118 

filaments, 39. Seealso microtubules 

fluid mosaic model, 48,225-26, 232-33,235 

fructose, 250,252 

FtsZ protein, 64 

FtsZ ring, 65 

futile cycle, 250-52,254 

gene 

expression, 136, 259-60 

head-to-head pairing, 151 

organization, 148-49 

overlapping, 152-58 

regulation, 121-22,135-37,139,259 

structure, 135-36,150 
genetic code, 170-74, 176, 181-82,280 

error minimization, 171,173,174-76 

evolution, 175-78,182 

nonuni versal, 176-77,247 

origin, 177-78,182 

universal, 171-72,174-76,247,273 
genetic information, 148 
genetic letters, 165. Seealso nucleotides 
genome, 54-55 

minimum genome size, 56-60 
genomics, 55 

Gershfeld, Norman, 229-31 
giclee, 183-84 
glutamate-125, 115 



glycine, 1 15 

glycolysis, 137-39,249-52 

God as Creator, 283,285-86 

god ofthe gaps, 19,32-33 

Golgi apparatus, 40 

Gonzalez, Guillermo, 24-25 

Gould, Stephen Jay, 205, 246 

GroEL-GroES, 107 

guanine, 102,158,160-61,254-55 

heat production, 251 
helicase, 221-22 
heme degradation, 253 
hemoglobin, 251, 253 
hemolysis, 231 

Hemophilus influenzae, 55,215 
heterotrophs, 55 
high-energy bonds, 138 
histidine, 115 
histones, 50,178-79 

association with DNA, 180 

histone-positioning code, 181 

octamer, 178-80 
historical contingency, 204-5, 275-76 
humanity, 29-30 

human origin, biblical account of, 29, 278-79 
hydrocarbon chains, 226-28, 234 
hydrogen 

bonds, 160-61 

ions, 1 15-17 

image ofGod, 29-30 

immune system, 262-63 

indels, 130 

information-rich biomolecules, 272-73 

information theory, 162 

Intelligent Design, 26 

intelligent design argument, 19-20, 33,166-67, 

205,243,266,270,274,278,282-83 
introns, 102-3,152 
irreducible complexity, 18-19,26,32,66-67,96, 

108,271-72,279 

junk DNA, 255-60 

Kai proteins, 88 
Kar2p protein. See BiP protein 
kidney stones, 254-55 
kinesin, 93,265-66 

Last Universal Common Ancestor (LUCA), 58, 

216-17 
leucine (Leu), 174 



330 



Index 



life's minimal complexity, 54-62, 66, 281 
LlNEs (long interspersed nuclear elements), 

258-59 
lipids, 45,227 

aggregates, 233 

annular, 234 

composition, 232 

rafts, 236 
liposome, 229-31 
lumen, 40 
lysosomes, 41 

matrix metalloproteinases (MMP), 95 
membranes. See cell membranes 
meteorites, 237-38 

Murchison, 240-41 
micelles, 23 8-39 
microtubules, 93, 265-66 
minimalism, 53 
Min proteins, 64 
mitochondria, 41 
molecular biology, 50, 52 

molecular convergence, 205-6, 223-24, 275-76, 
280 

examples of, 206-15 
molecular grammar, 145 
molecular messages, 142,144-45 
molecular motors, 70, 87, 89-90,96,282. Seea/so 

motors 
motors 

Brownian ratchets, 91-93 

DNA packaging, 89 

DNA translocator, 78 

F,F ATPase, 71-73,88 

rotary, 71-72,77 

single-molecule rotary, 90 

synthetic molecular, 90 

viral, 77 
mRNA (messenger RNA), 50-52, 102, 1 1 9, 1 34, 
144,152,186-87 

degradation, 119-20 

monocistronic, 151 

polycistronic, 151 

production, 193-95 

transcription, 101 
multidrug transporter (MT), 77 
mutations, 173-74,247,256 

DNA, 128-30 

frameshift, 156 

substitution, 156,173-75 
Mycoplasma genitalium, 57-58, 215 
myosin, 81-82 



NADH (nicotinamide adenine dinucleotide), 137 

Nanoarchaeum equitanSy 57-5 8 

nanodevices, 87-90 

nanotechnology, 87-89 

natural selection, 175-78 

nonanoic acids, 239-41 

noncoding DNA, 255-60 

nucleobases, 130-31,134, 158,168 

nucleosomes, 50, 180 

nucleosome-positioning code, 181 
nucleotides, 49,129-31,134-35,154 

sequence, 145-46,157-58,160,180,193 

Seealso thymidine; uridine 
nucleus, 36,39 

octanoic acids, 239-41 
Okazaki fragments, 220-23 
oligosaccharides 

GlcManGlcNAc, 199-200 
operons, 74-75,148-49 

lac operon, 149-5 1 
organelles, 36 
Origins of Life, 67 
oxidation, 129 
oxygen, 264-65 

P (product) site, 190-91 
Paley, William, 85-86 
parasites/parasitic microbes, 57-58 
parity code, 158-62,168 
pattern recognition, 27-30, 278 
Pelagibacter ubique, 55 
peptidases, 215 
peptides, 154 

antibiotics, 145 

antimicrobial, 145 
peristaltic pump, 73-74, 76-77 
peroxisomes, 41 
phosphates, 130-32 
phosphodiester bonds, 131-33 
phosphofructokinase, 250, 252 
phospholipid, 45,226-29,242-43 

asymmetry, 235-36 

composition, 232 

head groups, 226 

with choline (PCs), 228 

with ethanolamine (PEs), 228 

with glycerol (PCs), 228, 232 

with serine (PSs), 228 
photorespiration, 264 
photosynthesis, 262-64 
plasmids, 63 



Index 



331 



poly (A) tail, 102, 192 
polynucleotides, 129 

chains, 48-49,143-44, 217-18 
polypeptides, 43 

chains, 49-50, 126-27, 130 

subunits, 101 
posttranslational modification, 198-99 
prebiotic Earth, 241-42 
Privileged Planet, The, 24 
probability arguments, 277 
prokaryotes, 36-38, 54,62-65,67,101,189 
proteasome, 121 
protein, 120, 126-28,142-43,42-43 

asymmetry, 235 

autodestruction, 1 86 

complexes, 84-85 

degradation, 120-21 
protein-degradation fragments, 262-63 

folding, 105-7,199-200 

function, 228 

insertion, 232 

membtane, 47-48, 234 

sequences, 129 

structure, 43-45 

synthesis, 101-2,105,119,154, 185-90, 
200-201,261-62 
error rate, 197-98 
protein-coding region, 135-36, 150 
proteins 

abnormal, 129 

activators, 136-37, 150 

FtsZ, 64 

globular, 50 

integral, 46-47, 234 

Min, 64-65 

MreB, 65 

peripheral, 46-47 

repressors, 136-37,150 

TrwB, 73 

viral, 77-78,262 
proton wire, 116 
pseudogenes, 256-59 
pump-priming reaction, 250 

quality control, 160,184-85,191-97,200-201, 
280 

radio frequency identification (RFID), 98 
reactive oxygen species (ROS), 129, 253-54 
reason 

abductive, 276-77 

analogical, 30-31, 86,278-79 

inductive, 31 



red blood cells, 253 

regulatory region, 135-36,150 

retroposons, 258-59 

retro-translocation, 200 

reverse reaction, 251 

ribose, 130-34 

ribosomes, 39-40,102,104-5,189-90 

Richards, Jay, 24-25 

RNA, 131-33 

message, 256-58 

polymerase, 84,101,136,193-94 

primer, 222-23 

RNA-world hypothesis, 99 

ttanslation, 101 
Ross, Hugh, 67 

rRNA (ribosomal RNA), 102, 189-91 
RTB creation model, 285-86 
rubisco, 262-65 

salinity, 232, 241 

second law of thermodynamics, 246-48 

SINEs (short interspersed nuclear elements), 

258-59 
solenoid, 50, 180 
spliceosome, 102-3, 151-52 
splicing, 151-54,195 

suboptimal designs, 245-49,266-67,274-75,281 
sugats, 133,146-47,130-32 

thioredoxin teductase, 84-85 

thymidine, 50,193. See also nucleotides 

thymine, 158, 160-61 

transcription, 101 

transition state complex, 264-65 

translation, 101 

transposable elements, 258 

tRNA (transfer RNA), 105,187-89,191 

binding, 195-96 

tRNA-amino acid complex, 190-91,196 
Turing machines, 163, 167-68 
type III secretion, 271-72 

ubiquitin, 120-21 

ubiquitination, 1 20-21 

unfolded protein response (UPR), 200 

uracil, 158,160 

uric acid, 254-55 

uridine, 50, 193. Seealso nucleotides 

UV radiation, 134 

viral capsid, 78 
vital DNA, 80-81 



332 Inde 

viral proteins, 71 -IH, 262 water molecules, 1 16-17 

virus structure, 79 Wright, Frank Lloyd, 204 

Watchmaker argument, 85-86,88, 91, 96, 164 X chromosome inactivation, 259 

criticism of, 86-87 



Dr. Fazale Rana is the vice president of research and apologetics at Reasons 
To Believe. Scientific research in biochemistry provided him with the ini- 
tial evidence that life must have a Creator. Acting on a personal challenge 
to read the Bible, he found scriptural evidence that convinced him of the 
Creator's identity. 

After graduating from West Virginia State College (WVSC) with a BS 
degree in chemistry. Dr. Rana earned a PhD in chemistry with an empha- 
sis in biochemistry at Ohio University (OU). A presidential scholar. Dr. 
Rana was elected into two honors societies at WVSC and won the Donald 
Clippinger Research Award two different years at OU. He conducted post- 
doctoral work at the Universities of Virginia and Georgia. Before joining 
Reasons To Believe, he worked for seven years on product development for 
Proctor & Gamble. Dr. Rana also holds an adjunct faculty position at Biola 
University, teaching in the master's in science and religion program. 

Several articles by Dr. Rana have been published in peer-reviewed sci- 
entific journals such as Biochemistry, Applied Spectroscopy, FEBS Letters, 
Journal of Microbiology Methods, and The Journal of Chemical Education. 
Recently he published an article on cell membrane origins in Origins of Life 
and Evolution of Biospheres. He has delivered numerous presentations at 
international scientific meetings. Dr. Rana also has one patent and co-wrote 
a chapter on antimicrobial peptides iox Biological and Synthetic Membranes. 
In addition, he coauthored with Hugh Ross the books Origins of Life and 
Who Was Adam? 

Dr. Rana travels around the country, speaking on science and faith issues 
at churches, business firms, and university campuses. He is also a frequent 
guest on radio and television shows. 

Dr. Rana and his wife. Amy, currently live in Southern California, where 
they homeschool their children.