How we know life shares a common ancestor

danbyStructural Bioinformatics | Data Science 389 points 8 days ago*x2

At last something I did my PhD on!

Not only does all the evidence point towards there being a Last Universal Common Ancestor (LUCA) about 3.5billion years ago but all the evidence points towards all life on earth being descended from a single abiogenesis event (process?) about 4.5-5billion years ago. There might have been other abiogenesis events (prior or concurrent) but the one we're descended from clearly beat out any competitors.

At the heart of your specific question (e.g. can't we explain all the similarities as some kind of energy optimisation over natural selection?) you're asking to what extent can we explain the similarities that we see across all living things as a consequence of convergent evolution? Convergent evolution is the idea that two separate lineages of organisms can evolve the same "solution" to a problem. This is definitely a thing and there are many examples available to study but convergent evolutionary processes typically replicate function without replicating the specific form and it is this disparity that we can use to recognise convergent evolutionary processes. Take, for instance, flight. Flight is present in insects, birds and mammals. So it is reasonable to ask if this is a consequence of common descent from a common flighted ancestor or whether it is a convergent evolutionary process arising from three different evolutionary trajectories. If you look at insect, bird or mammal wings you'll discover that the anatomy is radically different, mammal and bird wings are adapted from forelimbs and insects wings are definitely not. And mammal wings are adapted digits where birdwings are composed of the entire forelimb. So you can see that function (flight) is conserved while the specific form is not. The flipside of this observation is that if you observe an evolved system that is truly "identical" in *both* form and function then the likelihood of it not sharing a common ancestor is, for practical purposes, infinitesimal.

When considering the LUCA or abiogenesis we're less concerned with large scale phenotypic traits like flight and more concerned with analysing the molecular similarities inside the cell. What molecular functions are shared, which of those are identical in form? We are also mostly only concerned with analysing the housekeeping genes, the ones that keep core living, cellular process running. Largely because the rest of the genome is available to adapt and evolve for the specific organism's specific needs. So usually you'll look at things like DNA replication, RNA translation, DNA transcription, energy metabolism and similar.

Of these, evidence suggests that RNA translation (the process of making proteins from strings of nucleic acids) matured and became fixed first. When you survey all living things they all use the same core molecular machinery to make proteins; ribosomes 'reading' mRNA supported with a tRNA amino acid delivery system which itself uses an identical codon-to-amino acid encoding. This universally shared protein translation machinery is at the heart of the observation that all life has common descent. What are the odds that Prokaryotes, Eukaryotes and Achaea all independently evolved something as complex as the ribosome? From a chemistry POV there is nothing special about the ribosome, peptide bond catalysis could be achieved with some other enzyme, catalyst or molecular structure. If peptide bonding catalysis had evolved independently 3 times through a convergent process you'd expect to see three different mechanisms which share the same function. Instead we see only one mechanistic solution inside cells and a solution that itself is exceptionally complex.

Additionally what are the odds that all three branches of life chose an identical codon encoding for the amino acids? There's nothing especially energetically favorable about the encoding all life uses. You could rearrange it to some other equally redundant encoding and it would work just as well (note I'm not saying it is randomly arranged just that there are equally performant alternative arrangements). The most parsimonious explanation is that all living things get their codon usage from a common ancestor.

If we move on and look at DNA replication. Here we do see some marked molecular differences. Prokaryotes replicate their DNA in a manner quite different to Archaea and Eukaryotes. These differences strongly suggest that DNA replication matured and became fixed only when the archaea branched from the prokaryotes (and is likely the principle evolutionary event that separates these branches of life).

With regards abiogenesis we are interested in whether there are even more fundamental features of cells that indicate common abiogenesis. These observations are less to do with molecular biology and more about the common features of cellular biochemistry. Just about everything on the planet (putting aside viruses) stores its genetic information in DNA, uses RNA as an information intermediary and uses the exact same set of 20 amino acids to make proteins. Why would these 3 molecules be conserved if all life didn't share common descent? There is essentially no limit to the number of possible amino acids there could be. If the set of amino acids arose multiple times independently why would it always replicate this specific set? There is probably a good energetic reason that glycine and alanine would always be present but the rest are surely open to changes? All living organisms are also homo-chiral, all sugars that living organisms use and produce are right-hand chiral whereas all amino acids are left-hand chiral. There is definitely no energetic reason to favour one or the other and that is strongly indicative of every organism having evolved from an ancestor with this specific small molecular biochemistry.

Obviously there is much more evidence and observations about common descent but these I think are among the most important molecular features without getting caught up in the finer or more complex details. I think it is also worth reading Carl Woese's letter 'The Universal Ancestor' which I really think is one of the best papers about the nature of the LUCA. http://www.pnas.org/content/95/12/6854

Dawkin's speculation

The account of the origin of life that I shall give is necessarily speculative; by definition, nobody was around to see what happened. There are a number of rival theories, but they all have certain features in common. The simplified account I shall give is probably not too far from the truth.
We do not know what chemical raw materials were abundant on earth before the coming of life, but among the plausible possibilities are water, carbon dioxide, methane, and ammonia: all simple compounds known to be present on at least some of the other planets in our solar system. Chemists have tried to imitate the chemical conditions of the young earth. They have put these simple substances in a flask and supplied a source of energy such as ultraviolet light or electric sparks-artificial simulation of primordial lightning. After a few weeks of this, something interesting is usually found inside the flask: a weak brown soup containing a large number of molecules more complex than the ones originally put in. In particular, amino acids have been found-the building blocks of proteins, one of the two great classes of biological molecules. Before these experiments were done, naturally-occurring amino acids would have been thought of as diagnostic of the presence of life. If they had been detected on, say Mars, life on that planet would have seemed a near certainty. Now, however, their existence need imply only the presence of a few simple gases in the atmosphere and some volcanoes, sunlight, or thundery weather. More recently, laboratory simulations of the chemical conditions of earth before the coming of life have yielded organic substances called purines and pyrimidines. These are building blocks of the genetic molecule, DNA itself
Processes analogous to these must have given rise to the 'primeval soup' which biologists and chemists believe constituted the seas some three to four thousand million years ago. The organic substances became locally concentrated, perhaps in drying scum round the shores, or in tiny suspended droplets. Under the further influence of energy such as ultraviolet light from the sun, they combined into larger molecules. Nowadays large organic molecules would not last long enough to be noticed: they would be quickly absorbed and broken down by bacteria or other living creatures. But bacteria and the rest of us are late-comers, and in those days large organic molecules could drift unmolested through the thickening broth.
At some point a particularly remarkable molecule was formed by accident. We will call it the Replicator. It may not necessarily have been the biggest or the most complex molecule around, but it had the extraordinary property of being able to create copies of itself This may seem a very unlikely sort of accident to happen. So it was. It was exceedingly improbable. In the lifetime of a man, things that are that improbable can be treated for practical purposes as impossible. That is why you will never win a big prize on the football pools. But in our human estimates of what is probable and what is not, we are not used to dealing in hundreds of millions of years. If you filled in pools coupons every week for a hundred million years you would very likely win several jackpots.
Actually a molecule that makes copies of itself is not as difficult to imagine as it seems at first, and it only had to arise once. Think of the replicator as a mould or template. Imagine it as a large molecule consisting of a complex chain of various sorts of building block molecules. The small building blocks were abundantly available in the soup surrounding the replicator. Now suppose that each building block has an affinity for its own kind. Then whenever a building block from out in the soup lands up next to a part of the replicator for which it has an affinity, it will tend to stick there. The building blocks that attach themselves in this way will automatically be arranged in a sequence that mimics that of the replicator itself. It is easy then to think of them joining up to form a stable chain just as in the formation of the original replicator. This process could continue as a progressive stacking up, layer upon layer. This is how crystals are formed. On the other hand, the two chains might split apart, in which case we have two replicators, each of which can go on to make further copies.
A more complex possibility is that each building block has affinity not for its own kind, but reciprocally for one particular other kind.
Then the replicator would act as a template not for an identical copy, but for a kind of 'negative', which would in its turn re-make an exact copy of the original positive. For our purposes it does not matter whether the original replication process was positive-negative or positive-positive, though it is worth remarking that the modem equivalents of the first replicator, the DNA molecules, use positive-negative replication. What does matter is that suddenly a new kind of 'stability' came into the world. Previously it is probable that no particular kind of complex molecule was very abundant in the soup, because each was dependent on building blocks happening to fall by luck into a particular stable configuration. As soon as the replicator was born it must have spread its copies rapidly throughout the seas, until the smaller building block molecules became a scarce resource, and other larger molecules were formed more and more rarely.
So we seem to arrive at a large population of identical replicas. But now we must mention an important property of any copying process: it is not perfect. Mistakes will happen. I hope there are no misprints in this book, but if you look carefully you may find one or two. They will probably not seriously distort the meaning of the sentences, because they will be 'first generation' errors. But imagine the days before printing, when books such as the Gospels were copied by hand. All scribes, however careful, are bound to make a few errors, and some are not above a little wilful 'improvement'. If they all copied from a single master original, meaning would not be greatly perverted. But let copies be made from other copies, which in their turn were made from other copies, and errors will start to become cumulative and serious. We tend to regard erratic copying as a bad thing, and in the case of human documents it is hard to think of examples where errors can be described as improvements. I suppose the scholars of the Septuagint could at least be said to have started something big when they mistranslated the Hebrew word for 'young woman' into the Greek word for 'virgin', coming up with the prophecy: 'Behold a virgin shall conceive and bear a son .. .' Anyway, as we shall see, erratic copying in biological replicators can in a real sense give rise to improvement, and it was essential for the progressive evolution of life that some errors were made. We do not know how accurately the original replicator molecules made their copies. Their modem descendants, the DNA molecules, are astonishingly faithful compared with the most high-fidelity human copying process, but even they occasionally make mistakes, and it is ultimately these mistakes that make evolution possible. Probably the original replicators were far more erratic, but in any case we may be sure that mistakes were made, and these mistakes were cumulative.
As mis-copyings were made and propagated, the primeval soup became filled by a population not of identical replicas, but of several varieties of replicating molecules, all 'descended' from the same ancestor. Would some varieties have been more numerous than others? Almost certainly yes. Some varieties would have been inherently more stable than others. Certain molecules, once formed, would be less likely than others to break up again. These types would become relatively numerous in the soup, not only as a direct logical consequence of their 'longevity', but also because they would have a long time available for making copies of themselves. Replicators of high longevity would therefore tend to become more numerous and, other things being equal, there would have been an 'evolutionary trend' towards greater longevity in the population of molecules.
But other things were probably not equal, and another property of a replicator variety that must have had even more importance in spreading it through the population was speed of replication or 'fecundity'. If replicator molecules of type A make copies of themselves on average once a week while those of type B make copies of themselves once an hour, it is not difficult to see that pretty soon type A molecules are going to be far outnumbered, even if they 'live' much longer than B molecules. There would therefore probably have been an 'evolutionary trend' towards higher 'fecundity' of molecules in the soup. A third characteristic of replicator molecules which would have been positively selected is accuracy of replication. If molecules of type X and type Y last the same length of time and replicate at the same rate, but A makes a mistake on average every tenth replication while Y makes a mistake only every hundredth replication, Y will obviously become more numerous. The A contingent in the population loses not only the errant 'children' themselves, but also all their descendants, actual or potential.
If you already know something about evolution, you may find something slightly paradoxical about the last point. Can we reconcile the idea that copying errors are an essential prerequisite for evolution to occur, with the statement that natural selection favours high copying-fidelity? The answer is that although evolution may seem, in some vague sense, a 'good thing', especially since we are the product of it, nothing actually 'wants' to evolve. Evolution is something that happens, willy-nilly, in spite of all the efforts of the replicators (and nowadays of the genes) to prevent it happening. Jacques Monod made this point very well in his Herbert Spencer lecture, after wryly remarking: 'Another curious aspect of the theory of evolution is that everybody thinks he understands it!'
To return to the primeval soup, it must have become populated by stable varieties of molecule; stable in that either the individual molecules lasted a long time, or they replicated rapidly, or they replicated accurately. Evolutionary trends toward these three kinds of stability took place in the following sense: if you had sampled the soup at two different times, the later sample would have contained a higher proportion of varieties with high longevity/fecundity/copying-fidelity. This is essentially what a biologist means by evolution when he is speaking of living creatures, and the mechanism is the same-natural selection.
Should we then call the original replicator molecules 'living'? Who cares? I might say to you 'Darwin was the greatest man who has ever lived', and you might say 'No, Newton was', but I hope we would not prolong the argument. The point is that no conclusion of substance would be affected whichever way our argument was resolved. The facts of the lives and achievements of Newton and Darwin remain totally unchanged whether we label them 'great' or not. Similarly, the story of the replicator molecules probably happened something like the way I am telling it, regardless of whether we choose to call them 'Iiving'. Human suffering has been caused because too many of us cannot grasp that words are only tools for our use, and that the mere presence in the dictionary of a word like 'living' does not mean it necessarily has to refer to something definite in the real world. Whether we call the early replicators living or not, they were the ancestors of life; they were our founding fathers.

Richard Dawkins, The Selfish Gene

Osmotic pressure

monzzter221 991 points 1 day ago*

Actually, there is a theory, and it has been replicated in a lab.

Essentially all of our nature and functions are overcomplicated results of competition between chemical processes.

It has to do with fatty acids and amino acids in water. Do some googling and Wikipedia. It's called "abiogenesis" and it's still being heavily studied but it is very convincing.

Basically, fatty acids will bind together in a porous film, and if the ends get close enough to attract, will form a sort of bubble. When some nucleotide come close, they may traverse the barrier. However, when more than one is inside the bubble, they bond and can no longer escape.

Different random strings of nucleotides affect the osmotic pressure inside the bubble, and when two bubbles come in contact, the one with higher osmotic pressure will shrink the other one, and the bubble that shrinks will get absorbed, it's fatty acids will become a part of a larger bubble, and it's nucleotide chain will enter and bond with the other one.

This is all random, but you can see how some patterns of strings have advantages over others and are therefore selected for. The bubble with the string that has the highest osmotic pressure can "eat" all the other ones it comes into contact with.

Eventually, randomly, you get a string called RNA that can replicate itself (and other strings).

When a bubble becomes too big, it becomes unstable and will "split". In this scenario, the contents of nucleotide strings will be randomly distributed. If the contents are a replicating string, and are selected for due to a stronger osmotic pressure than all other bubbles it has encountered, you have a higher chance of the same string being in two bubbles, and thus you have the beginnings of real, reproducing proto cells. Very simple, just a fatty acid membrane and a self replicating nucleotide chain.

Of course, as time goes on, random differences in proto cells will either make them more complex but weaker (and thus "food") or stronger and more complex, and give that a few billion years and some pretty strange things have compounded into insanity. But at the core of it is chemistry.

Monomers come together like lego blocks to form a polymer

The pieces bounce around until they find their place.

Like this 'self-assembling chair' from MIT.

A simpler origin

This is an interesting article

A Simpler Origin for Life By Robert Shapiro on February 12, 2007

The sudden appearance of a large self-copying molecule such as RNA was exceedingly improbable. Energy-driven networks of small molecules afford better odds as the initiators of life.

Extraordinary discoveries inspire extraordinary claims. Thus James Watson reported that, immediately after they had uncovered the structure of DNA, Francis Crick "winged into the Eagle (pub) to tell everyone within hearing that we had discovered the secret of life." Their structure--an elegant double helix--almost merited such enthusiasm. Its proportions permitted information storage in a language in which four chemicals, called bases, played the same role as twenty six letters do in the English language.

Further, the information was stored in two long chains, each of which specified the contents of its partner. This arrangement suggested a mechanism for reproduction, that was subsequently illustrated in many biochemistry texts, as well as on a tie that my wife bought for me at a crafts fair: The two strands of the DNA double helix parted company. As they did so, new DNA building blocks, called nucleotides, lined up along the separated strands and linked up. Two double helices now existed in place of one, each a replica of the original.

The Watson-Crick structure triggered an avalanche of discoveries about the way in which living cells function today. These insights also stimulated speculations about life's origins. Nobel Laureate H. J. Muller wrote that the gene material was "living material, the present-day representative of the first life," which Carl Sagan visualized as "a primitive free-living naked gene situated in a dilute solution of organic matter." In this context, "organic" specifies material containing bound carbon atoms. Organic chemistry, a subject sometimes feared by pre-medical students, is the chemistry of carbon compounds, both those present in life and those playing no part in life. Many different definitions of life have been proposed. Muller's remark would be in accord with what has been called the NASA definition of life: Life is a self-sustained chemical system capable of undergoing Darwinian evolution.

Richard Dawkins elaborated on this image of the earliest living entity in his book *The Selfish Gene*: "At some point a particularly remarkable molecule was formed by accident. We will call it the *Replicator*. It may not have been the biggest or the most complex molecule around, but it had the extraordinary property of being able to create copies of itself." When Dawkins wrote these words 30 years ago, DNA was the most likely candidate for this role. As we shall see, several other replicators have now been suggested.

When RNA Ruled the World**

Unfortunately, complications soon set in. DNA replication cannot proceed without the assistance of a number of proteins--members of a family of large molecules that are chemically very different from DNA. Proteins, like DNA, are constructed by linking subunits, amino acids in this case, together to form a long chain. Cells employ twenty of these building blocks in the proteins that they make, affording a variety of products capable of performing many different tasks--proteins are the handymen of the living cell. Their most famous subclass, the enzymes, act as expeditors, speeding up chemical processes that would otherwise take place too slowly to be of use to life.

The above account brings to mind the old riddle: Which came first, the chicken or the egg? DNA holds the recipe for protein construction. Yet that information cannot be retrieved or copied without the assistance of proteins. Which large molecule, then, appeared first in getting life started--proteins (the chicken) or DNA (the egg)?

A possible solution appeared when attention shifted to a new champion--RNA. This versatile class of molecule is, like DNA, assembled of nucleotide building blocks, but plays many roles in our cells. Certain RNAs ferry information from DNA to structures (which themselves are largely built of other kinds of RNA) that construct proteins. In carrying out its various duties, RNA can take on the form of a double helix that resembles DNA, or of a folded single strand, much like a protein. In 2006 the Nobel prizes in both chemistry and medicine were awarded for discoveries concerning the role of RNA in editing and censoring DNA instructions. Warren E. Leary could write in the *New York Times* that RNA "is swiftly emerging from the shadows of its better-known cousin DNA."

For many scientists in the origin-of-life field, those shadows had lifted two decades earlier with the discovery of ribozymes, enzyme-like substances made of RNA. A simple solution to the chicken-and-egg riddle now appeared to fall into place: Life began with the appearance of the first RNA molecule. In a germinal 1986 article, Nobel Laureate Walter Gilbert of Harvard University wrote in the journal *Nature*: "One can contemplate an RNA world, containing only RNA molecules that serve to catalyze the synthesis of themselves. & The first step of evolution proceeds then by RNA molecules performing the catalytic activities necessary to assemble themselves from a nucleotide soup." In this vision, the first self-replicating RNA that emerged from non-living matter carried out the functions now executed by RNA, DNA and proteins.

A number of additional clues seemed to support the idea that RNA appeared before proteins and DNA in the evolution of life. Many small molecules, called cofactors, play a necessary role in enzyme-catalyzed reactions. These cofactors often carry an attached RNA nucleotide with no obvious function. These structures have been considered "molecular fossils," relics descended from the time when RNA alone, without DNA or proteins, ruled the biochemical world. In addition, chemists have been able to synthesize new ribozymes that display a variety of enzyme-like activities. Many scientists found the idea of an organism that relied on ribozymes, rather than protein enzymes, very attractive.

The hypothesis that life began with RNA was presented as a likely reality, rather than a speculation, in journals, textbooks and the media. Yet the clues I have cited only support the weaker conclusion that RNA preceded DNA and proteins; they provide no information about the origin of life, which may have involved stages prior to the RNA world in which other living entities ruled supreme. Just the same, and despite the difficulties that I will discuss in the next section, perhaps two-thirds of scientists publishing in the origin-of life field (as judged by a count of papers published in 2006 in the journal *Origins of Life and Evolution of the Biosphere*) still support the idea that life began with the spontaneous formation of RNA or a related self-copying molecule. Confusingly, researchers use the term "RNA World" to refer to both the strong and the weak claims about RNA's role prior to DNA and proteins. Here, I will use the term "RNA first" for the strong claim that RNA was involved in the origin of life.

The Soup Kettle is Empty**

The attractive features of RNA World prompted Gerald Joyce of the Scripps Research Institute and Leslie Orgel of the Salk Institute to picture it as "the molecular biologist's dream" within a volume devoted to that topic. They also used the term "the prebiotic chemist's nightmare" to describe another part of the picture: How did that first self-replicating RNA arise? Enormous obstacles block Gilbert's picture of the origin of life, sufficient to provoke another Nobelist, Christian De Duve of Rockefeller University, to ask rhetorically, "Did God make RNA?"

RNA's building blocks, nucleotides, are complex substances as organic molecules go. They each contain a sugar, a phosphate and one of four nitrogen-containing bases as sub-subunits. Thus, each RNA nucleotide contains 9 or 10 carbon atoms, numerous nitrogen and oxygen atoms and the phosphate group, all connected in a precise three-dimensional pattern. Many alternative ways exist for making those connections, yielding thousands of plausible nucleotides that could readily join in place of the standard ones but that are not represented in RNA. That number is itself dwarfed by the hundreds of thousands to millions of stable organic molecules of similar size that are not nucleotides.

The RNA nucleotides are familiar to chemists because of their abundance in life and their resulting commercial availability. In a form of molecular vitalism, some scientists have presumed that nature has an innate tendency to produce life's building blocks preferentially, rather than the hordes of other molecules that can also be derived from the rules of organic chemistry. This idea drew inspiration from a well known experiment published in 1953 by Stanley Miller. He applied a spark discharge to a mixture of simple gases that were then thought to represent the atmosphere of the early Earth. Two amino acids of the set of 20 used to construct proteins were formed in significant quantities, with others from that set present in small amounts. (A description of the Miller experiment and the chemical structures of an amino acid and a nucleotide can be found in "The Origin of Life on the Earth," by L. E. Orgel; Scientific American, October 1994.) In addition, more than 80 different amino acids, some present and others absent from living systems, have been identified as components of the Murchison meteorite, which fell in Australia in 1969. Nature has apparently been generous in providing a supply of these particular building blocks. By extrapolation of these results, some writers have presumed that *all* of life's building could be formed with ease in Miller-type experiments and were present in meteorites and other extraterrestrial bodies. This is not the case.

A careful examination of the results of the analysis of several meteorites led the scientists who conducted the work to a different conclusion: inanimate nature has a bias toward the formation of molecules made of fewer rather than greater numbers of carbon atoms, and thus shows no partiality in favor of creating the building blocks of our kind of life. (When larger carbon-containing molecules are produced, they tend to be insoluble, hydrogen-poor substances that organic chemists call tars.) I have observed a similar pattern in the results of many spark discharge experiments.

Amino acids, such as those produced or found in these experiments, are far less complex than nucleotides. Their defining features are an amino group (a nitrogen and two hydrogens) and a carboxylic acid group (a carbon, two oxygens and a hydrogen) both attached to the same carbon. The simplest of the 20 used to build natural proteins contains only two carbon atoms. Seventeen of the set contain six or fewer carbons. The amino acids and other substances that were prominent in the Miller experiment contained two and three carbon atoms. By contrast, no nucleotides of any kind have been reported as products of spark discharge experiments or in studies of meteorites, nor have the smaller units (nucleosides) that contain a sugar and base but lack the phosphate.

To rescue the RNA-first concept from this otherwise lethal defect, its advocates have created a discipline called prebiotic synthesis. They have attempted to show that RNA and its components can be prepared in their laboratories in a sequence of carefully controlled reactions, normally carried out in water at temperatures observed on Earth. Such a sequence would start usually with compounds of carbon that had been produced in spark discharge experiments or found in meteorites. The observation of a specific organic chemical in any quantity (even as part of a complex mixture) in one of the above sources would justify its classification as "prebiotic," a substance that supposedly had been proved to be present on the early Earth. Once awarded this distinction, the chemical could then be used in pure form, in any quantity, in another prebiotic reaction. The products of such a reaction would also be considered "prebiotic" and employed in the next step in the sequence.

The use of reaction sequences of this type (without any reference to the origin of life) has long been an honored practice in the traditional field of synthetic organic chemistry. My own PhD thesis advisor, Robert B. Woodward, was awarded the Nobel Prize for his brilliant syntheses of quinine, cholesterol, chlorophyll and many other substances. It mattered little if kilograms of starting material were required to produce milligrams of product. The point was the demonstration that humans could produce, however inefficiently, substances found in nature. Unfortunately, neither chemists nor laboratories were present on the early Earth to produce RNA.

I will cite one example of prebiotic synthesis, published in 1995 by *Nature* and featured in the *New York Times*. The RNA base cytosine was prepared in high yield by heating two purified chemicals in a sealed glass tube at 100 degrees Celsius for about a day. One of the reagents, cyanoacetaldehyde, is a reactive substance capable of combining with a number of common chemicals that may have been present on the early Earth. These competitors were excluded. An extremely high concentration was needed to coax the other participant, urea, to react at a sufficient rate for the reaction to succeed. The product, cytosine, can self-destruct by simple reaction with water. When the urea concentration was lowered, or the reaction allowed to continue too long, any cytosine that was produced was subsequently destroyed. This destructive reaction had been discovered in my laboratory, as part of my continuing research on environmental damage to DNA. Our own cells deal with it by maintaining a suite of enzymes that specialize in DNA repair.

The exceptionally high urea concentration was rationalized in the *Nature* paper by invoking a vision of drying lagoons on the early Earth. In a published rebuttal, I calculated that a large lagoon would have to be evaporated to the size of a puddle, without loss of its contents, to achieve that concentration. No such feature exists on Earth today.

The drying lagoon claim is not unique. In a similar spirit, other prebiotic chemists have invoked freezing glacial lakes, mountainside freshwater ponds, flowing streams, beaches, dry deserts, volcanic aquifers and the entire global ocean (frozen or warm as needed) to support their requirement that the "nucleotide soup" necessary for RNA synthesis would somehow have come into existence on the early Earth.

The analogy that comes to mind is that of a golfer, who having played a golf ball through an 18-hole course, then assumed that the ball could also play itself around the course in his absence. He had demonstrated the possibility of the event; it was only necessary to presume that some combination of natural forces (earthquakes, winds, tornadoes and floods, for example) could produce the same result, given enough time. No physical law need be broken for spontaneous RNA formation to happen, but the chances against it are so immense, that the suggestion implies that the non-living world had an innate desire to generate RNA. The majority of origin-of-life scientists who still support the RNA-first theory either accept this concept (implicitly, if not explicitly) or feel that the immensely unfavorable odds were simply overcome by good luck.

A Simpler Replicator?**

Many chemists, confronted with these difficulties, have fled the RNA-first hypothesis as if it were a building on fire. One group, however, still captured by the vision of the self-copying molecule, has opted for an exit that leads to similar hazards. In these revised theories, a simpler replicator arose first and governed life in a "pre-RNA world." Variations have been proposed in which the bases, the sugar or the entire backbone of RNA have been replaced by simpler substances, more accessible to prebiotic syntheses. Presumably, this first replicator would also have the catalytic capabilities of RNA. Because no trace of this hypothetical primal replicator and catalyst has been recognized so far in modern biology, RNA must have completely taken over all of its functions at some point following its emergence.

Further, the spontaneous appearance of any such replicator without the assistance of a chemist faces implausibilities that dwarf those involved in the preparation of a mere nucleotide soup. Let us presume that a soup enriched in the building blocks of all of these proposed replicators has somehow been assembled, under conditions that favor their connection into chains. They would be accompanied by hordes of defective building blocks, the inclusion of which would ruin the ability of the chain to act as a replicator. The simplest flawed unit would be a terminator, a component that had only one "arm" available for connection, rather than the two needed to support further growth of the chain.

There is no reason to presume than an indifferent nature would not combine units at random, producing an immense variety of hybrid short, terminated chains, rather than the much longer one of uniform backbone geometry needed to support replicator and catalytic functions. Probability calculations could be made, but I prefer a variation on a much-used analogy. Picture a gorilla (very long arms are needed) at an immense keyboard connected to a word processor. The keyboard contains not only the symbols used in English and European languages but also a huge excess drawn from every other known language and all of the symbol sets stored in a typical computer. The chances for the spontaneous assembly of a replicator in the pool I described above can be compared to those of the gorilla composing, in English, a coherent recipe for the preparation of chili con carne. With similar considerations in mind Gerald F. Joyce of the Scripps Research Institute and Leslie Orgel of the Salk Institute concluded that the spontaneous appearance of RNA chains on the lifeless Earth "would have been a near miracle." I would extend this conclusion to all of the proposed RNA substitutes that I mentioned above.

Life With Small Molecules**

Nobel Laureate Christian de Duve has called for "a rejection of improbabilities so incommensurably high that they can only be called miracles, phenomena that fall outside the scope of scientific inquiry." DNA, RNA, proteins and other elaborate large molecules must then be set aside as participants in the origin of life. Inanimate nature provides us with a variety of mixtures of small molecules, whose behavior is governed by scientific laws, rather than by human intervention.

Fortunately, an alternative group of theories that can employ these materials has existed for decades. The theories employ a thermodynamic rather than a genetic definition of life, under a scheme put forth by Carl Sagan in the Encyclopedia Britannica: A localized region which increases in order (decreases in entropy) through cycles driven by an energy flow would be considered alive. This small-molecule approach is rooted in the ideas of the Soviet biologist Alexander Oparin, and current notable spokesmen include de Duve, Freeman Dyson of the Institute for Advanced Study, Stuart Kauffman of the Santa Fe Institute, Doron Lancet of the Weizmann Institute, Harold Morowitz of George Mason University and the independent researcher Gnter Wchtershuser. I estimate that about a third of the chemists involved in the study of the origin of life subscribe to theories based on this idea. Origin-of-life proposals of this type differ in specific details; here I will try to list five common requirements (and add some ideas of my own).

(1) A boundary is needed to separate life from non-life.** Life is distinguished by its great degree of organization, yet the second law of thermodynamics requires that the universe move in a direction in which disorder, or entropy, increases. A loophole, however, allows entropy to decrease in a limited area, provided that a greater increase occurs outside the area. When living cells grow and multiply, they convert chemical energy or radiation to heat at the same time. The released heat increases the entropy of the environment, compensating for the decrease in living systems. The boundary maintains this division of the world into pockets of life and the nonliving environment in which they must sustain themselves.

Today, sophisticated double-layered cell membranes, made of chemicals classified as lipids, separate living cells from their environment. When life began, some natural feature probably served the same purpose. David W. Deamer of the University of California, Santa Cruz, has observed membrane-like structures in meteorites. Other proposals have suggested natural boundaries not used by life today, such as iron sulfide membranes, mineral surfaces (in which electrostatic interactions segregate selected molecules from their environment), small ponds and aerosols.

(2) An energy source is needed to drive the organization process.** We consume carbohydrates and fats, and combine them with oxygen that we inhale, to keep ourselves alive. Microorganisms are more versatile, and can use minerals in place of the food or the oxygen. In either case, the transformations that are involved are called redox reactions. They involve the transfer of electrons from an electron rich (or reduced) substance to an electron poor (or oxidized) one. Plants can capture solar energy directly, and adapt it for the functions of life. Other forms of energy are used by cells in specialized circumstances--for example, differences in acidity on opposite sides of a membrane. Yet others, such as radioactivity and abrupt temperature differences, might be used by life elsewhere in the universe. Here I will consider redox reactions as the energy source.

(3) A coupling mechanism must link the release of energy to the organization process that produces and sustains life.** The release of energy does not necessarily produce a useful result. Chemical energy is released when gasoline is burned within the cylinders of my automobile, but the vehicle will not move unless that energy is used to turn the wheels. A mechanical connection, or coupling, is required. Each day, in our own cells, each of us degrades pounds of a nucleotide called ATP. The energy released by this favorable reaction serves to drive processes that are less favorable but necessary for our biochemistry. Linkage is achieved when the reactions share a common intermediate, and the process is speeded up by the intervention of an enzyme. One assumption of the small-molecule approach is that coupled reactions and primitive catalysts sufficient to get life started exist in nature.

(4) A chemical network must be formed, to permit adaptation and evolution.** We come now to the heart of the matter. Imagine for example that an energetically favorable redox reaction of a naturally-occurring mineral is linked to the conversion of an organic chemical A to another one B within a compartment. The favorable, energy releasing, entropy-increasing reaction of the mineral drives the A-to-B transformation. I call this key transformation a driver reaction, for it serves as the engine that mobilizes the organization process. If B simply reconverts back to A or escapes from the compartment, we would not be on a path that leads to increased organization. By contrast, if a multi-step chemical pathway--say, B to C to D to A--reconverts B to A, then the steps in that circular process (or cycle) would be favored because they replenish the supply of A, allowing the continuing discharge of energy by the mineral reaction.

If we visualize the cycle as a circular railway line, the energy source keeps the trains traveling around it one way. Each station may also be the hub for a number of branch lines, such as one connecting station D to another station, E. Trains could travel in either direction along that branch, depleting or augmenting the cycle's traffic. Thanks to the continual depletion of A, however, material is drawn from D to A. The resulting depletion of D in turn tends to draw material from E to D. In this way, material is "pulled" along the branch lines into the central cycle, maximizing the energy release that accompanies the driver reaction.

The cycle could also adapt to changing circumstances. As a child, I was fascinated by the way in which water, released from a leaky hydrant, would find a path downhill to the nearest sewer. If falling leaves or dropped refuse blocked that path, the water would back up until another route was found around the obstacle. In the same way, if a change in the acidity or in some other environmental circumstance should hinder a step in the pathway from B to A, material would back up until another route was found. Additional changes of this type would convert the original cycle into a network. This trial-and-error exploration of the chemical "landscape" might also turn up compounds that could catalyze important steps in the cycle, increasing the efficiency with which the network utilized the energy source.

(5) The network must grow and reproduce.** To survive and grow, the network must gain material at a rate that compensates for the paths that remove it. Diffusion of network materials out of the compartment into the external world is favored by entropy and will occur to some extent, especially at the start of life when the boundary is a crude one established by the environment rather than one of the highly effective cell membranes available today after billions of years of evolution. Some side reactions may produce gases, which escape, or form tars, which will drop out of solution. If these processes together should exceed the rate at which the network gains material, then it would be extinguished. Exhaustion of the external fuel would have the same effect. We can imagine, on the early Earth, a situation where many startups of this type occur, involving many alternative driver reactions and external energy sources. Finally, a particularly hardy one would take root and sustain itself.

A system of reproduction must eventually develop. If our network is housed in a lipid membrane, then physical forces may split it, after it has grown enough. (Freeman Dyson has described such a system as a "garbage-bag world" in contrast to the "neat and beautiful scene" of the RNA world.) A system that functions in a compartment within a mineral may overflow into adjacent compartments. Whatever the mechanism may be, this dispersal into separated units protects the system from total extinction by a localized destructive event. Once independent units were established, they could evolve in different ways and compete with one another for raw materials; we would have made the transition from life that emerges from nonliving matter through the action of an available energy source to life that adapts to its environment by Darwinian evolution.

Changing the Paradigm**

Systems of the type I have described usually have been classified under the heading "metabolism first," which implies that they do not contain a mechanism for heredity. In other words, they contain no obvious molecule or structure that allows the information stored in them (their heredity) to be duplicated and passed on to their descendants. However a collection of small items holds the same information as a list that describes the items. For example, my wife gives me a shopping list for the supermarket; the collection of grocery items that I return with contains the same information as the list. Doron Lancet has given the name "compositional genome" to heredity stored in small molecules, rather than a list such as DNA or RNA.

The small molecule approach to the origin of life makes several demands upon nature (a compartment, an external energy supply, a driver reaction coupled to that supply, and the existence of a chemical network that contains that reaction). These requirements are general in nature, however, and are immensely more probable than the elaborate multi-step pathways needed to form a molecule that can function as a replicator.

Over the years, many theoretical papers have advanced particular metabolism first schemes, but relatively little experimental work has been presented in support of them. In those cases where experiments have been published, they have usually served to demonstrate the plausibility of individual steps in a proposed cycle. The greatest amount of new data has perhaps come from Gnter Wchtershuser and his colleagues at the Technische Universitt Mnchen. They have demonstrated portions of a cycle involving the combination and separation of amino acids, in the presence of metal sulfide catalysts. The energetic driving force for the transformations is supplied by the oxidation of carbon monoxide to carbon dioxide. They have not yet demonstrated the operation of a complete cycle or its ability to sustain itself and undergo further evolution. A "smoking gun" experiment displaying those three features is needed to establish the validity of the small molecule approach.

The principal initial task is the identification of candidate driver reactions--small molecule transformations (A to B in the example before) that are coupled to an abundant external energy source (such as the oxidation of carbon monoxide or a mineral). Once a plausible driver reaction has been identified, there should be no need to specify the rest of the system in advance. The selected components (including the energy source) plus a mixture of other small molecules normally produced by natural processes (and likely to have been abundant on the early Earth) could be combined in a suitable reaction vessel. If an evolving network were established, we would expect the concentration of the participants in the network to increase and alter with time. New catalysts that increased the rate of key reactions might appear, while irrelevant materials would decrease in quantity. The reactor would need an input device to allow replenishment of the energy supply and raw materials, and an outlet to permit the removal of waste products and chemicals that were not part of the network.

In such experiments, failures would be easily identified. The energy might be dissipated without producing any significant changes in the concentrations of the other chemicals or the chemicals might simply be converted to a tar, which would clog the apparatus. A success might demonstrate the initial steps on the road to life. These steps need not duplicate those that took place on the early Earth. It is more important that the general principle be demonstrated and made available for further investigation. Many potential paths to life may exist, with the choice dictated by the local environment.

An understanding of the initial steps leading to life would not reveal the specific events that led to the familiar DNA-RNA-protein-based organisms of today. However, because we know that evolution does not anticipate future events, we can presume that nucleotides first appeared in metabolism to serve some other purpose, perhaps as catalysts or as containers for the storage of chemical energy (the nucleotide ATP still serves this function today). Some chance event or circumstance may have led to the connection of nucleotides to form RNA. The most obvious function of RNA today is to serve as a structural element that assists in the formation of bonds between amino acids in the synthesis of proteins. The first RNAs may have served the same purpose, but without any preference for specific amino acids. Many further steps in evolution would be needed to "invent" the elaborate mechanisms for replication and specific protein synthesis that we observe in life today.

If the general small-molecule paradigm were confirmed, then our expectations of the place of life in the universe would change. A highly implausible start for life, as in the RNA-first scenario, implies a universe in which we are alone. In the words of the late Jacques Monod, "The universe was not pregnant with life nor the biosphere with man. Our number came up in the Monte Carlo game." The small-molecule alternative, however, is in harmony with the views of biologist Stuart Kauffman: "If this is all true, life is vastly more probable than we have supposed. Not only are we at home in the universe, but we are far more likely to share it with unknown companions."

The first cell

In a sense, the first cell never died. She lives within all of us, as do our ancestors. They're just... distributed among their descendants.

The first photo sensitive cells may have senses movement like seeing shadows across a light when your eyes are shut.



Say hey to Owlbert Einstein

Curator of the Big Ideas Network

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