The Blind Watchmaker

Truisms like ‘the world is full of things that have what it takes to be in the world’ are trivial, almost silly, until we come to apply them to a special kind of durability, durability in the form of lineages of multiple copies. DNA messages have a different kind of durability from that of rocks, and a different kind of generatability from that of dewdrops. For DNA molecules, ‘what it takes to be in the world’ comes to have a meaning that is anything but obvious and tautological. ‘What it takes to be in the world’ turns out to include the ability to build machines like you and me, the most complicated things in the known universe. Let us see how this can be so.

  Fundamentally, the reason is that the properties of DNA that we have identified turn out to be the basic ingredients necessary for any process of cumulative selection. In our computer models in Chapter 3, we deliberately built into the computer the basic ingredients of cumulative selection. If cumulative selection is really to happen in the world, some entities have got to arise whose properties constitute those basic ingredients. Let us look, now, at what those ingredients are. As we do so, we shall keep in mind the fact that these very same ingredients, at least in some rudimentary form, must have arisen spontaneously on the early Earth, otherwise cumulative selection, and therefore life, would never have got started in the first place. We are talking here not specifically about DNA, but about the basic ingredients needed for life to arise anywhere in the universe.

  When the prophet Ezekiel was in the valley of bones he prophesied to the bones and made them join up together. Then he prophesied to them and made flesh and sinews come around them. But still there was no breath in them. The vital ingredient, the ingredient of life, was missing. A dead planet has atoms, molecules and larger lumps of matter, jostling and nestling against each other at random, according to the laws of physics. Sometimes the laws of physics cause the atoms and molecules to join up together like Ezekiel’s dry bones, sometimes they cause them to split apart. Quite large accretions of atoms can form, and they can crumble and break apart again. But still there is no breath in them.

  Ezekiel called upon the four winds to put living breath into the dry bones. What is the vital ingredient that a dead planet like the early Earth must have, if it is to have a chance of eventually coming alive, as our planet did? It is not breath, not wind, not any kind of elixir or potion. It is not a substance at all, it is a property, the property of self-replication. This is the basic ingredient of cumulative selection. There must somehow, as a consequence of the ordinary laws of physics, come into being self-copying entities or, as I shall call them, replicators. In modern life this role is filled, almost entirely, by DNA molecules, but anything of which copies are made would do. We may suspect that the first replicators on the primitive Earth were not DNA molecules. It is unlikely that a fully fledged DNA molecule would spring into existence without the aid of other molecules that normally exist only in living cells. The first replicators were probably cruder and simpler than DNA.

  There are two other necessary ingredients, which will normally arise automatically from the first ingredient, self-replication itself. There must be occasional errors in the self-copying; even the DNA system very occasionally makes mistakes, and it seems likely that the first replicators on Earth were much more erratic. And at least some of the replicators should exert power over their own future. This last ingredient sounds more sinister than it actually is. All it means is that some properties of the replicators should have an influence over their probability of being replicated. At least in a rudimentary form, this is likely to be an inevitable consequence of the basic facts of selfreplication itself.

  Each replicator, then, has copies of itself made. Each copy is the same as the original, and has the same properties as the original. Among these properties, of course, is the property of making (sometimes with errors) more copies of itself. So each replicator is potentially the ‘ancestor’ of an indefinitely long line of descendant replicators, stretching into the distant future, and branching to produce, potentially, an exceedingly large number of descendant replicators. Each new copy must be made from raw materials, smaller building blocks knocking around. Presumably the replicators act as some kind of mould or template. Smaller components fall together into the mould in such a way that a duplicate of the mould is made. Then the duplicate breaks free and is able to act as a mould in its own right. Hence we have a potentially growing population of replicators. The population will not grow indefinitely, because eventually the supply of raw materials, the smaller elements that fall into the moulds, will become limiting.

  Now we introduce our second ingredient into the argument. Sometimes the copying will not be perfect. Mistakes will happen. The possibility of errors can never be totally eliminated from any copying process, although their probability can be reduced to low levels. This is what the manufacturers of hi-fi equipment are striving towards all the time, and the DNA-replication process, as we have seen, is spectacularly good at reducing errors. But modern DNA replication is a high-technology affair, with elaborate proofreading techniques that have been perfected over many generations of cumulative selection. As we have seen, the first replicators probably were relatively crude, low-fidelity contraptions in comparison.

  Now go back to our population of replicators, and see what the effect of erratic copying will be. Obviously, instead of there being a uniform population of identical replicators, we shall have a mixed population. Probably many of the products of erratic copying will be found to have lost the property of self-replication that their ‘parent’ had. But a few will retain the property of self-replication, while being different from the parent in some other respect. So we shall have copies of errors being duplicated in the population.

  When you read the word ‘error’, banish from your mind all pejorative associations. It simply means an error from the point of view of high-fidelity copying. It is possible for an error to result in an improvement. I dare say many an exquisite new dish has been created because a cook made a mistake while trying to follow a recipe. Insofar as I can claim to have had any original scientific ideas, these have sometimes been misunderstandings, or misreadings, of other people’s ideas. To return to our primeval replicators, while most miscopyings probably resulted in diminished copying effectiveness, or total loss of the self-copying property, a few might actually have turned out to be better at self-replication than the parent replicator that gave rise to them.

  What does ‘better’ mean? Ultimately it means more efficient at self-replication, but what might this mean in practice? This brings us to our third ‘ingredient’. I referred to this as ‘power’, and you’ll see why in a moment. When we discussed replication as a moulding process, we saw that the last step in the process must be the new copy’s breaking free of the old mould. The time that this occupies may be influenced by a property which I shall call the ‘stickiness’ of the old mould. Suppose that in our population of replicators, which vary because of old copying errors back in their ‘ancestry’, some varieties happen to be more sticky than others. A very sticky variety clings to each new copy for an average time of more than an hour before it finally breaks free and the process can begin again. A less-sticky variety lets go of each new copy within a split second of its formation. Which of these two varieties will come to predominate in the population of replicators? There is no doubt about the answer. If this is the only property by which the two varieties differ, the sticky one is bound to become far less numerous in the population. The non-sticky one is churning out copies of non-sticky ones at thousands of times the rate that the sticky one is making copies of sticky ones. Varieties of intermediate stickiness will have intermediate rates of self-propagation. There will be an ‘evolutionary trend’ towards reduced stickiness.

  Something like this kind of elementary natural selection has been duplicated in the test-tube. There is a virus called Q-beta which lives as a parasite of the gut bacterium Escherichia coli. Q-beta has no DNA but it does contain, indeed it largely consists of, a single strand of the r
elated molecule RNA. RNA is capable of being replicated in a similar way to DNA.

  In the normal cell, protein molecules are assembled to the specification of RNA plans. These are working copies of plans, run off from the DNA masters held in the cell’s precious archives. But it is theoretically possible to build a special machine — a protein molecule like the rest of the cellular machines — that runs off RNA copies from other RNA copies. Such a machine is called an RNA-replicase molecule. The bacterial cell itself normally has no use for these machines, and doesn’t build any. But since the replicase is just a protein molecule like any other, the versatile protein-building machines of the bacterial cell can easily turn to building them, just as the machine tools in a car factory can quickly be turned over in time of war to making munitions: all they need is to be fed the right blueprints. This is where the virus comes in.

  The business part of the virus is an RNA plan. Superficially it is indistinguishable from any of the other RNA working blueprints that are floating around, after being run off the bacterium’s DNA master. But if you read the small print of the viral RNA you will find something devilish written there. The letters spell out a plan for making RNA-replicase: for making machines that make more copies of the very same RNA plans, that make more machines that make more copies of the plans, that make more …

  So the factory is hijacked by these self-interested blueprints. In a sense it was crying out to be hijacked. If you fill your factory with machines so sophisticated that they can make anything that any blueprint tells them to make, it is hardly surprising if sooner or later a blueprint arises that tells these machines to make copies of itself. The factory fills up with more and more of these rogue machines, each churning out rogue blueprints for making more machines that will make more of themselves. Finally, the unfortunate bacterium bursts and releases millions of viruses that infect new bacteria. So much for the normal life cycle of the virus in nature.

  I have called RNA-replicase and RNA respectively a machine and a blueprint. So they are, in a sense (to be disputed on other grounds in a later chapter), but they are also molecules, and it is possible for human chemists to purify them, bottle them and store them on a shelf. This is what Sol Spiegelman and his colleagues did in America in the 1960s. Then they put the two molecules together in solution, and a fascinating thing happened. In the test-tube, the RNA molecules acted as templates for the synthesis of copies of themselves, aided by the presence of the RNA-replicase. The machine tools and the blueprints had been extracted and put into cold storage, separately from one another. Then, as soon as they were given access to each other, and also to the small molecules needed as raw materials, in water, both got back to their old tricks even though they were no longer in a living cell but in a test tube.

  It is but a short step from this to natural selection and evolution in the laboratory. It is just a chemical version of the computer biomorphs. The experimental method is basically to lay out a long row of test-tubes each containing a solution of RNA-replicase, and also of raw materials, small molecules that can be used for RNA synthesis. Each test-tube contains the machine tools and the raw material, but so far it is sitting idle, doing nothing because it lacks a blueprint to work from. Now a tiny amount of RNA itself is dropped into the first test-tube. The replicase apparatus immediately gets to work and manufactures lots of copies of the newly introduced RNA molecules, which spread through the test-tube. Now a drop of the solution in the first test-tube is removed and put into the second test-tube. The process repeats itself in the second test-tube and then a drop is removed and used to seed the third test-tube, and so on.

  Occasionally, because of random copying errors, a slightly different, mutant RNA molecule spontaneously arises. If, for any reason, the new variety is competitively superior to the old one, superior in the sense that, perhaps because of its low ‘stickiness’, it gets itself replicated faster or otherwise more effectively, the new variety will obviously spread through the test-tube in which it arose, outnumbering the parental type that gave rise to it. Then, when a drop of solution is removed from that test-tube to seed the next test-tube, it will be the new mutant variety that does the seeding. If we examine the RNAs in a long succession of test-tubes, we see what can only be called evolutionary change. Competitively superior varieties of RNA produced at the end of several test-tube ‘generations’ can be bottled and named for future use. One variety for example, called V2, replicates much more rapidly than normal Q-beta RNA, probably because it is smaller. Unlike Q-beta RNA, it doesn’t have to ‘bother’ to contain the plans for making replicase. Replicase is provided free by the experimenters. V2 RNA was used as the starting point for an interesting experiment by Leslie Orgel and his colleagues in California, in which they imposed a ‘difficult’ environment.

  They added to their test-tubes a poison called ethidium bromide which inhibits the synthesis of RNA: it gums up the works of the machine tools. Orgel and colleagues began with a weak solution of the poison. At first, the rate of synthesis was slowed down by the poison, but after evolving through about nine test-tube transfer ‘generations’, a new strain of RNA that was resistant to the poison had been selected. Rate of RNA synthesis was now comparable to that of normal V2 RNA in the absence of poison. Now Orgel and his colleagues doubled the concentration of poison. Again the rate of RNA replication dropped, but after another 10 or so test-tube transfers a strain of RNA had evolved that was immune even to the higher concentration of poison. Then the concentration of the poison was doubled again. In this way, by successive doublings, they managed to evolve a strain of RNA that could self-replicate in very high concentrations of ethidium bromide, 10 times as concentrated as the poison that had inhibited the original ancestral V2 RNA. They called the new, resistant RNA V40. The evolution of V40 from V2 took about 100 test-tube transfer ‘generations’ (of course, many actual RNA-replication generations go on between each test-tube transfer).

  Orgel has also done experiments in which no enzyme was provided. He found that RNA molecules can replicate themselves spontaneously under these conditions, albeit very slowly. They seem to need some other catalyzing substance, such as zinc. This is important because, in the early days of life when replicators first arose, we cannot suppose that there were enzymes around to help them to replicate. There probably was zinc, though.

  The complementary experiment was carried out a decade ago in the laboratory of the influential German school working on the origin of life under Manfred Eigen. These workers provided replicase and RNA building blocks in the test-tube, but they did not seed the solution with RNA. Nevertheless, a particular large RNA molecule evolved spontaneously in the test-tube, and the same molecule reevolved itself again and again in subsequent independent experiments! Careful checking showed that there was no possibility of chance infection by RNA molecules. This is a remarkable result when you consider the statistical improbability of the same large molecule spontaneously arising twice. It is very much more improbable than the spontaneous typing of METHINKS IT IS LIKE A WEASEL. Like that phrase in our computer model, the particular favoured RNA molecule was built up by gradual, cumulative evolution.

  The variety of RNA produced, repeatedly, in these experiments was of the same size and structure as the molecules that Spiegelman had produced. But whereas Spiegelman’s had evolved by ‘degeneration’ from naturally occurring, larger, Q-beta viral RNA, those of the Eigen group had built themselves up from almost nothing. This particular formula is well adapted to an environment consisting of test-tubes provided with ready-made replicase. It therefore is converged upon by cumulative selection from two very different starting points. The larger, Q-beta RNA molecules are less well adapted to a test-tube environment but better adapted to the environment provided by E. coli cells.

  Experiments such as these help us to appreciate the entirely automatic and non-deliberate nature of natural selection. The replicase ‘machines’ don’t ‘know’ why they make RNA molecules: it is just a byproduct of their shape that
they do. And the RNA molecules themselves don’t work out a strategy for getting themselves duplicated. Even if they could think, there is no obvious reason why any thinking entity should be motivated to make copies of itself. If I knew how to make copies of myself, I’m not sure that I would give the project high priority in competition with all the other things I want to do: why should I? But motivation is irrelevant for molecules. It is just that the structure of the viral RNA happens to be such that it makes cellular machinery churn out copies of itself. And if any entity, anywhere in the universe, happens to have the property of being good at making more copies of itself, then automatically more and more copies of that entity will obviously come into existence. Not only that but, since they automatically form lineages and are occasionally miscopied, later versions tend to be ‘better’ at making copies of themselves than earlier versions, because of the powerful processes of cumulative selection. It is all utterly simple and automatic. It is so predictable as to be almost inevitable.

  A ‘successful’ RNA molecule in a test-tube is successful because of some direct, intrinsic property of itself, something analogous to the ‘stickiness’ of my hypothetical example. But properties like ‘stickiness’ are rather boring. They are elementary properties of the replicator itself, properties that have a direct effect on its probability of being replicated. What if the replicator has some effect upon something else, which affects something else, which affects something else, which … eventually, indirectly affects the replicator’s chance of being replicated? You can see that, if long chains of causes like this existed, the fundamental truism would still hold. Replicators that happen to have what it takes to get replicated would come to predominate in the world, no matter how long and indirect the chain of causal links by which they influence their probability of being replicated. And, by the same token, the world will come to be filled with the links in this causal chain. We shall see those links, and marvel at them.