Creation (9 page)

What Schrödinger argued was that living systems are the continual maintenance of energy imbalance. In essence, life is the maintenance of disequilibrium, and energy as life uses it is derived from this inequity. It is sometimes described as a far-from-equilibrium process. The entropy of the universe is bound only to increase, thereby ultimately creating a more balanced but less ordered existence. The temperature throughout the universe will eventually be the same, following the even distribution of its total energy as the second law of thermodynamics commands.
⁷
Schrödinger recognized that all living organisms evade the decay to energy equilibrium during their life spans, and continue to do so in their descendants. This has occurred continuously on Earth for almost four billion years. We consume food, and energy is extracted from it inside cells. In doing so, we construct an order within our bodies, without which decay would transpire.

This order maintained in living cells appears at first glance to be in direct contravention with the second law of thermodynamics, which dictates that entropy will always increase, and therefore organization will decrease. Chaos is the ultimate direction of all things, and living things are not chaotic (at least on the terms laid out by physics). But this apparent paradox is not a problem. The law states that the incontrovertible increase in entropy occurs within a closed system. The universe in total is a closed system, as there is, by definition, nothing but the universe. On a more local scale, living things are not a closed system. We produce waste as a result of our life-sustaining metabolism, and expel it into the rest of the universe. While order is increased and maintained during any life span within the living thing itself, this seeming contradiction of the second law is more than compensated for by an overall increase in entropy beyond the confines of that organism: that is, your waste. The entropy of the amount of waste you have generated in your life is overwhelmingly more than the reduced entropy your body maintains by being ordered. And thus, the laws of the universe remain perfectly intact.

Life is a process that stops your molecules from simply decaying into more stable forms. The process of living is the chemistry that perpetually holds off decay. And this is precisely why the concept of the primordial soup is flawed. The notion that the right ingredients in the right surroundings might generate a self-sustaining life-form ignores the underlying principle that life is a far-from-equilibrium process. The chemical activity in a soup can only accede to the second law of thermodynamics: unless it has an external source to maintain an energetic imbalance, it will only decompose. In Stanley Miller's experiment, the spark of lightning may have triggered the formation of amino acids, but did not power a system of disequilibrium. Once those chemicals had reacted, they would do so no more.

Bill Martin (University of Düsseldorf) is one of the main critics of soup-based origin-of-life science, and we will come to his work shortly. He proposes an easy experiment to challenge the concept of primordial soup: mash up a life-form of your choosing to the point where any cellular resemblance has been destroyed, but all of the ingredients are still intact. This experiment effectively occurs every time a cell dies, but spontaneous resurrection from this soup, with all of the right ingredients, remains a myth. Any model of the very origin of life that does not take into account the necessity of a continuous flow and manipulation of energy is building upon something that is already dead. Stanley Miller's iconic experiment remains important, though its comment on the origin of life is limited.
⁸
It shows, elegantly and incontrovertibly, how biomolecules will arise from basic chemistry in the right conditions. However, it reinforces the view of life as merely an assembly of chemicals contrived into a thing that can reproduce. A primordial soup is not a vital and energetic mix, as it has no way of sustaining an imbalance of energy, whether it is in a warm pond, a pumice raft, a muddy volcano, or any of the other locations that have been proposed for the origin of life. A primordial soup is condemned as a midden: a decomposing dump.

In a sense, we living things are out of step with the rest of the universe. In the
Origin of Species
, Darwin described the “struggle for existence,” meaning the fight to get food or a mate or the endurance against the elements. But it applies at a more basic level. To be alive is to struggle against entropy. Life does not violate the second law of thermodynamics, not at all. We cannot beat it, as that is the invincible force of scientific laws. In death we all submit to the will of physics, and our atoms accept their universal fate: to decompose and to be recycled, ultimately into less energetic states. Entropy strives to make the universe both more chaotic and more balanced. In doing so, entropy always increases; just like in casino gambling, the house always wins.

But by being alive, we have the opportunity to take something back from the house, or at least slow down its inevitable victory for a while. Life has evolved to extract energy from our surroundings and use it to maintain our vital information against the universal slide toward equilibrium by swapping and pumping protons from one side of a membrane to another inside a cell. Our lives, all lives, conspire to manipulate the fundamental forces of nature, and strive to do so continuously and forever. Jack Szostak is probably right, and tearing our hair out trying to encapsulate the essence of a life is merely a distraction from trying to trace back the path we know it took. But this indulgence into physics is crucial for understanding the origin of life. We know we can't go back in time and observe it. How it once happened is lost to science and history, so we do what we can to emulate it in conditions that gave rise to life's enduring imbalance. At some point, that imbalance acquired or created a system that allowed energy capture to be sustained independently. In that hatchery, the beginnings of encoded Darwinian descent could begin. But life-forms are first and foremost a sophisticated collection of chemical behaviors underwritten by the need for energy, and that informs how we go about experimentally quizzing the origin of life. In other words, we need to hunt for the signatures of metabolism.

It is clear that Luca was a living thing from which all subsequent life arose, but already carried with it many features that are essential components of the life that followed, including metabolism and genetics. In our cells there are two parts to metabolism: the first is the digestion of molecules to release energy, and the second is using that fuel to make life-sustaining molecules, including DNA and proteins. That poses something of a conundrum. From Luca onward, cells do the things on MRS. GREN's list, and we will come to the assembly of such a sophisticated system in this book's final chapter. Yet each item on the list is dependent on a chicken-and-egg problem. DNA encodes the proteins that enact cellular functions including metabolism, and these functions enact the decryption of the code itself. We've seen how the code works and how it was discovered. We've seen how it is the backbone of evolution and the template for the richness of all life. So how did DNA come to be?

The Origin of the Code

“For all inferences from experience suppose, as their foundation, that the future will resemble the past.”

David Hume,
An Inquiry Concerning Human Understanding
(1748)

H
ebrew has twenty-two letters. English has twenty-six, and Sanskrit fifty-six. Chinese languages use pictograms, which number in the thousands, depending on how you count them.

Life only has four letters in its alphabet:
A, T, C,
and
G
. Throw in a few extra glyphs and the flexibility of this alphabet goes up a touch. Linguists refer to these tweaks as diacritics: examples include the circumflex in French (
Â
) or the German umlaut (
Ö
). DNA's diacritics come in the shape of a small molecular appendage, methyl, which is simply three hydrogen atoms bound to a carbon atom, and gets tagged onto
A
or
C
. Just as in languages, these annotations are an essential feature of genetics, modifying the meaning by labeling sections of genome for particular characteristics. Most significant, this earmarking of the code marks out areas of DNA to be silenced, as if leaving the text where it lies, but scoring through entire blocks to say: “
Do not read this sentence
.”

Even with this type of flagging, the most generous number of letters in living code is much lower even than the Hebrew alphabet. Evolution has given us a comprehensive description of how the wild spectrum of species has arisen from this simple code, but very little about how it came to be. When pondering the origin of life, however one tries to define it, at some early point the origin of our alphabet is a key question.

It's not just the alphabet that is bafflingly conservative. It combines into a similarly limited vocabulary. As explained in chapter 2, in genes those four bases are arranged into triplets, each one spelling out an amino acid. When strung together, these form proteins. But there are only twenty amino acids encoded in the genes of all life-forms. Furthermore, the way amino acids are encrypted in DNA is studded with redundancy. There are sixty-four ways of arranging four letters into groups of three. Sixty-one combinations are used in genetics to spell out just the twenty amino acids (and three indicating a “period” signal to mark the end of a protein). This means that many triplets encode the same amino acid. For example,
TTA
spells out an amino acid called leucine; but so also does
TTG, CTC,
and three other variations.

This redundancy allows changes to be acquired in our genes that don't make potentially harmful changes in the proteins they encode. If, during the process of a cell splitting in two, a random DNA error switched
TTA
to
TTG,
it would still spell out leucine, and the protein containing that amino acid would be unchanged by this unforced error. If it changed the final
A
to a
T
, then leucine would be replaced with phenylalanine, an amino acid with similar properties. Such an error would therefore potentially change the nature of the protein, but perhaps not too dramatically.

We see some similar redundancy in language. In England your
favourite
colour
might be blue. But six thousand miles west, blue might alternatively be your
favorite color
. Through random mutation, almost certainly a copying error at some forgotten point in history, American English has excised a letter that Brits believe is essential. It is patently not, as the pronunciation is the same, and it's not difficult to imagine a world where my British extra
u
slowly degrades out of use altogether.

That's not to say that all mutations are equally benign. Drop the
r
from
friend
and you have a companion with an opposite character. Given the amount of DNA replication that goes on, harmful mutations are relatively rare, though it may not feel like it if one is unfortunate to suffer from a genetic disease, a category that includes all forms of cancer. When these types of mutations do happen, a single letter change can have catastrophic consequences. A single base change in DNA that results in a switch from one amino acid to a very different one may well cause problems. Switch the
A
to a
T
in the β–globin gene and the amino acids switch from glutamic acid to valine, which has quite different chemical properties. The result is a misshapen globin protein, which in turn deforms the shape of red blood cells into bent and elongated curves instead of the uniform round lozenges that they are meant to be. The host of this single letter copying error will have the disease sickle cell anemia, a blood disease that frequently causes premature death. Such is the harsh but mercifully unlikely nature of genetic disease.

For the most part, though, these errors are of little consequence. They are normal and happen every time a cell divides. In the copying of the whole genome during replication, proofreading does occur. The copying proteins, called DNA polymerases, check that the new strand they are making matches up with the template, ensuring that wherever there is an
A,
a
T
is set down, and not anything else. But they're not perfect, and sometimes during cell division new changes make it through the proofreading. If that occurs in a sperm or an egg, it can be the first step in the genetic game of telephone that drives evolutionary change. You are different from your parents not just because whole genes get shuffled around during sperm and egg production, but because those cells bear new single changes in their DNA, which will be random, and therefore unique to you alone. Sometimes the pairing of the
A
s and the
T
s, the
C
s and the
G
s goes awry, and one of the two strands of DNA bulges out like a mismatched zipper. If uncorrected by the proofreading proteins, this single change can be passed on, and may slightly alter the behavior of the protein it codes.
¹

How is it that we have settled on four letters, arranged into triplets? With such a neat, self-contained system, unpicking it is tricky, and knowing where to break into the circle is perplexing. One approach, though, is to work out the minimum amount of DNA required to encode the twenty amino acids that life uses to make all its proteins. If there were only three letters of genetic code, then there would be twenty-seven possible combinations of triplets, still more than enough to encode the twenty amino acids we need. But in reducing the redundancy by more than half, the buffer against potentially harmful diseases is also reduced. The three letters in the triplets are not all equal. We see patterns in the ordering of the bases in triplets and the amino acids they encode. The first base relates to the process of the source of the amino acid. Amino acids float freely in the cell, waiting to be assembled into their codified proteins.
²
Some are the products of the cell's metabolic cycles, but we cannot make nine of them, and so we have to eat them. By comparing triplets with the same first letters, we can deduce their origin as being either self-made or eaten. The second letter corresponds to a type, options including water loving (they dissolve easily) and water hating (they don't). The first two letters have a clear purpose in determining the product. The third, with all its wild-card flexibility, secures the deal, locking it into just one of the twenty. We can therefore speculate that the first form of DNA code might have been not a triplet but a twin, fixing the deciphering to essential sets of manufacture processes. The addition of a third allows both more combinations and more variation in the sequence, creating a conservative code that not only protects against the impact of catastrophic change, but gently encourages subtle modification. In short, our DNA encourages evolution.

But the underlying code is frozen, without change for probably four billion years. Alphabets are ice-cold but not frozen. They do change, although the change is imperceptibly slow. DNA, though, is indeed locked, at least in nature—though that is changing in the new world of invented biology, as you will see in part II. Francis Crick once thought that the alphabet of DNA came to be fixed as a result of a “frozen accident”: a system that worked well enough and either outcompeted other versions or was the only one. Yet it is now clear that the inequity of the letters in each triplet is no accident, and became frozen with a delicate balance between fidelity and mutation, like a loving parent encouraging children to explore but at the same time protecting them from harm.

Ghost World

We can begin to see how DNA might have originated in a simplified form and settled into its current stable existence. But the paradox here is much more complicated than the old problem of the chicken and the egg.
³
Copying DNA is dependent on proteins, and proteins are encoded in DNA. DNA is the code and protein is the active product. But there are very solid reasons to think that at the beginning of life, the origin of genetics began not with DNA, but with its simpler cousin RNA.

Again, by looking at how modern life-forms work, we can infer earlier, cryptic roles for the mechanics in cells. RNA is the middle part of Francis Crick's misnamed central dogma: DNA makes RNA makes proteins. In order to understand how this sequence might have come about, it's useful to think of it in steps. We know of no way to directly make protein from DNA without the go-between RNA, so we could suppose that the first part, “DNA makes . . . ,” might have been added after the concluding step “RNA makes protein”—RNA being the coded transcript from which the proteins are made. RNA, a single strand, is less chemically stable than DNA with its paired helices; it is more prone to falling apart. DNA retains the code for proteins with one strand reflecting the other, providing a mirrored backup service: where there is an
A
the other strand holds a
T,
and where one holds a
G
the other bears a
C
. Therefore, it's not unreasonable to imagine that DNA emerged later as a more secure form of data storage.

More recently, a pathway for that transition has even been suggested by looking at how error prone DNA and RNA are when copying one to another and back again. A Harvard team lead by Irene Chen compared how faithful the copying is when making RNA from RNA, RNA from DNA, and DNA from RNA. This is akin to testing the prowess of an Internet translation engine by inputting a sentence, translating it, and then back again to see how mangled it gets. Unequivocally, using DNA as a template came out on top. When copying RNA from a DNA template, the transcript was most faithful. This suggests that a move from an RNA world to the one we have today could have occurred without static—the message would be preserved. But DNA copied from RNA was riddled with errors.
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With this concept in mind, it seems reasonable that as an information-storage device DNA is more robust, more secure, and more faithful than RNA. The transition from a world where RNA was the information bearer into the biological era that we know is referred to as genetic takeover; once that annexing had occurred, it seemed we could never go back.

That chicken-and-egg conundrum—DNA codes, protein acts—is at least partially solved with RNA as well, as on occasion RNA can do both. A second clue for thinking there was a world sporting the signs of life that was populated by RNA, not DNA, comes from the cell's protein factory, the ribosome. When it is time for a gene to make a protein, the process goes like this: the gene, set in DNA in the host's genome, receives an instruction to be turned on. A protein unscrews the double helix, like unwinding a wire cable tie, and separates the two strands. Another protein clamps onto the coding strand (the other is a mirror, and performs minimal function) at the three letters
ATG
. This codon is for the amino acid methionine, but also marks the beginning of a gene—the start codon. From there it walks mechanically forward, copying the DNA into a mirrored RNA molecule: where it sees
ATG,
the RNA will read
UAC
.
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When the transcription of the DNA is complete, the wispy RNA molecule floats off, bearing the message of the gene, and is helpfully called messenger RNA. The ribosome then picks up this transcript and ingests it, one letter at a time. It reads the code three letters at a time, each codon specifying an amino acid, which is delivered to the ribosome from the cell's milieu. As each codon is read in turn, the ribosome picks up the amino acids and strings them together to make a protein, which is expelled into the cell, dispatched to serve its purpose.

The ribosome itself is made of several parts, just as many of the active parts of life-forms are.
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These smaller parts, by jiggling themselves into position, self-assemble far more easily than flat-pack furniture. But what is interesting for our purposes is that more than half of those parts are made not of protein, but of RNA. These long, heavily folded slivers of RNA link together with proteins to make the working ribosomes, and function just like proteins in that they enact a process. With these types of RNA molecules, therefore, we have both information and function. With RNA as the forefather of DNA on the early earth, the paradox of DNA and protein—the former encoding the latter and the latter making the former—vanishes. This idea is referred to as the RNA world hypothesis. We can get around the chicken-and-egg problem by not needing either. At some ancient juncture from mere chemistry to biology, the central dogma of “DNA makes RNA makes proteins” was simply “RNA makes.”

The First Photocopiers

NNNNNN
UGCUCGAUUGGUAACAGUUUGAAU GGGUUGAAGUAU–GAGACCG
NNNNNN

Can you see the family resemblance? This is R3C, the child of Gerald Joyce and Tracey Lincoln from the Scripps Research Institute in California. If evolutionary genetics is the process of tracking the slight changes in our genes back through time to reconstruct the Darwinian replicators of the past, R3C might be the end of the line.