The Blind Watchmaker

  Every living cell, even a single bacterial cell, can be thought of as a gigantic chemical factory. DNA patterns, or genes, exert their effects by influencing the course of events in the chemical factory, and they do this via their influence on the three-dimensional shape of protein molecules. The word gigantic may seem surprising for a cell, especially when you remember that 10 million bacterial cells could sit on the surface of a pin’s head. But you will also remember that each of these cells is capable of holding the whole text of the New Testament and, moreover, it is gigantic when measured by the number of sophisticated machines that it contains. Each machine is a large protein molecule, put together under the influence of a particular stretch of DNA. Protein molecules called enzymes are machines in the sense that each one causes a particular chemical reaction to take place. Each kind of protein machine churns out its own particular chemical product. To do this it uses raw materials that are drifting around in the cell, being, very probably, the products of other protein machines. To get an idea of the size of these protein machines, each one is made of about 6,000 atoms, which is very large by molecular standards. There are about a million of these large pieces of apparatus in a cell, and there are more than 2,000 different kinds of them, each kind specialized to do a particular operation in the chemical factory — the cell. It is the characteristic chemical products of such enzymes that give a cell its individual shape and behaviour.

  Since all body cells contain the same genes, it might seem surprising that all body cells aren’t the same as each other. The reason is that a different subset of genes is read in different kinds of cells, the others being ignored. In liver cells, those parts of the DNA ROM specifically relevant to the building of kidney cells are not read, and vice versa. The shape and behaviour of a cell depend upon which genes inside that cell are being read and translated into their protein products. This in turn depends on the chemicals already in the cell, which depends partly on which genes have previously been read in the cell, and partly on neighbouring cells. When one cell divides into two, the two daughter cells aren’t necessarily the same as each other. In the original fertilized egg, for instance, certain chemicals congregate at one end of the cell, others at the other end. When such a polarized cell divides, the two daughter cells receive different chemical allocations. This means that different genes will be read in the two daughter cells, and a kind of self-reinforcing divergence gets going. The final shape of the whole body, the size of its limbs, the wiring up of its brain, the timing of its behaviour patterns, are all the indirect consequences of interactions between different kinds of cells, whose differences in their turn arise through different genes being read. These diverging processes are best thought of as locally autonomous in the manner of the ‘recursive’ procedure of Chapter 3, rather than as coordinated in some grand central design.

  ‘Action’, in the sense used in this chapter, is what a geneticist is talking about when he mentions the ‘phenotypic effect’ of a gene. DNA has effects upon bodies, upon eye colour, hair crinkliness, strength of aggressive behaviour and thousands of other attributes, all of which are called phenotypic effects. DNA exerts these effects initially locally, after being read by RNA and translated into protein chains, which then affect cell shape and behaviour. This is one of the two ways in which the information in the pattern of DNA can be read out. The other way is that it can be duplicated into a new DNA strand. This is the copying that we discussed earlier.

  There is a fundamental distinction between these two routes of transmission of the DNA information, vertical and horizontal transmission. The information is transmitted vertically to other DNA in cells (that make other cells) that make sperms or eggs. Hence it is transmitted vertically to the next generation and then, vertically again, to an indefinite number of future generations. I shall call this ‘archival DNA’. It is potentially immortal. The succession of cells along which archival DNA travels is called the germ line. The germ line is that set of cells, within a body, which is ancestral to sperms or eggs and hence ancestral to future generations. DNA is also transmitted sideways or horizontally: to DNA in non-germ-line cells such as liver cells or skin cells; within such cells to RNA, thence to protein and various effects on embryonic development and therefore on adult form and behaviour. You can think of horizontal transmission and vertical transmission as corresponding to the two sub-programs called DEVELOPMENT and REPRODUCTION in Chapter 3.

  Natural selection is all about the differential success of rival DNA in getting itself transmitted vertically in the species archives. ‘Rival DNA’ means alternative contents of particular addresses in the chromosomes of the species. Some genes are more successful than rival genes at remaining in the archives. Although vertical transmission down the archives of the species is ultimately what ‘success’ means, the criterion for success is normally the action that the genes have on bodies, by means of their sideways transmission. This, too, is just like the biomorph computer model. For instance, suppose that in tigers there is a particular gene which, by means of its sideways influence in cells of the jaw, causes the teeth to be a little sharper than those that would be grown under the influence of a rival gene. A tiger with extra-sharp teeth can kill prey more efficiently than a normal tiger; hence it has more offspring; hence it passes on, vertically, more copies of the gene that makes sharp teeth. It passes on all its other genes at the same time, of course, but only the specific ‘sharp-teeth gene’ will find itself, on average, in the bodies of sharp-toothed tigers. The gene itself benefits, in terms of its vertical transmission, from the average effects that it has on a whole series of bodies.

  DNA’s performance as an archival medium is spectacular. In its capacity to preserve a message it far outdoes tablets of stone. Cows and pea plants (and, indeed, all the rest of us) have an almost identical gene called the histone H4 gene. The DNA text is 306 characters long. We can’t say that it occupies the same addresses in all species, because we can’t meaningfully compare address labels across species. But what we can say is that there is a length of 306 characters in cows, which is virtually identical to a length of 306 characters in peas. Cows and peas differ from each other in only two characters out of these 306. We don’t know exactly how long ago the common ancestor of cows and peas lived, but fossil evidence suggests that it was somewhere between 1,000 and 2,000 million years ago. Call it 1.5 billion years ago. Over this unimaginably (for humans) long time, each of the two lineages that branched from that remote ancestor has preserved 305 out of the 306 characters (on average: it could be that one lineage has preserved all 306 of them and the other has preserved 304). Letters carved on gravestones become unreadable in mere hundreds of years.

  In a way the conservation of the histone-H4 DNA document is even more impressive because, unlike tablets of stone, it is not the same physical structure that lasts and preserves the text. It is repeatedly being copied and recopied as the generations go by, like the Hebrew scriptures which were ritually copied by scribes every 80 years to forestall their wearing-out. It is hard to estimate exactly how many times the histone H4 document has been recopied in the lineage leading to cows from the common ancestor with peas, but it is probably as many as 20 billion times. It is also hard to find a yardstick with which to compare the preservation of more than 99 per cent of information in 20 billion successive copyings. We can try using a version of the game of grandmothers’ whispers. Imagine 20 billion typists sitting in a row. The line of typists would reach right round the Earth 500 times. The first typist writes a page of a document and hands it to his neighbour. He copies it and hands his copy to the next one. He copies it again and hands it on to the next, and so on. Eventually, the message reaches the end of the line, and we read it (or rather our 12,000th great grandchildren do, assuming that all the typists have a speed typical of a good secretary). How faithful a rendering of the original message would it be?

  To answer this we have to make some assumption about the accuracy of the typists. Let’s twist the question round the
other way. How good would each typist have to be, in order to match the DNA’s performance? The answer is almost too ludicrous to express. For what it is worth, every typist would have to have an error rate of about one in a trillion; that is, he would have to be accurate enough to make only a single error in typing the Bible 250,000 times at a stretch. A good secretary in real life has an error rate of about one per page. This is about half a billion times the error rate of the histone H4 gene. A line of real-life secretaries would degrade a text to 99 per cent of its original letters by the 20th member of the line of 20 billion. By the 10,000th member of the line, less than 1 per cent of the original text would survive. This point of near total degradation would be reached before 99.9995 per cent of the typists had even seen it.

  This whole comparison has been a bit of a cheat, but in an interesting and revealing respect. I gave the impression that what we are measuring is copying errors. But the histone H4 document hasn’t just been copied, it has been subjected to natural selection. Histone is vitally important for survival. It is used in the structural engineering of chromosomes. Maybe lots more mistakes in copying the histone H4 gene occurred, but the mutant organisms did not survive, or at least did not reproduce. To make the comparison fair, we should have to assume that built into each typist’s chair is a gun, wired up so that if he makes a mistake he is summarily shot, his place being taken by a reserve typist (squeamish readers may prefer to imagine a spring-loaded ejector seat gently catapulting miscreant typists out of the line, but the gun gives a more realistic picture of natural selection).

  So, this method of measuring the conservatism of DNA, by looking at the number of changes that have actually occurred during geological time, compounds genuine copying fidelity with the filtering effects of natural selection. We see only the descendants of successful DNA changes. The ones that led to death are obviously not with us. Can we measure the actual copying fidelity on the ground, before natural selection gets to work on each new generation of genes? Yes, this is the inverse of what is known as the mutation rate, and it can be measured. The probability of any particular letter being miscopied on any one copying occasion turns out to be a little more than one in a billion. The difference between this, the mutation rate, and the lower rate at which change has actually been incorporated in the histone gene during evolution, is a measure of the effectiveness of natural selection in preserving this ancient document.

  The histone gene’s conservatism over the aeons is exceptional by genetic standards. Other genes change at a higher rate, presumably because natural selection is more tolerant of variations in them. For instance, genes coding the proteins known as fibrinopeptides change in evolution at a rate that closely approximates the basic mutation rate. This probably means that mistakes in the details of these proteins (they are produced during the clotting of blood) don’t matter much for the organism. Haemoglobin genes have a rate of changing that is intermediate betwen histones and fibrinopeptides. Presumably natural selection’s tolerance of their errors is intermediate. Haemoglobin is doing an important job in the blood, and its details really matter; but several alternative variants of it seem capable of doing the job equally well.

  Here we have something that seems a little paradoxical, until we think about it further. The slowest-evolving molecules, like histones, turn out to be the ones that have been most subject to natural selection. Fibrinopeptides are the fastest-evolving molecules because natural selection almost completely ignores them. They are free to evolve at the mutation rate. The reason this seems paradoxical is that we place so much emphasis on natural selection as the driving force of evolution. If there is no natural selection, therefore, we might expect that there would be no evolution. Conversely, strong ‘selection pressure’, we could be forgiven for thinking, might be expected to lead to rapid evolution. Instead, what we find is that natural selection exerts a braking effect on evolution. The baseline rate of evolution, in the absence of natural selection, is the maximum possible rate. That is synonymous with the mutation rate.

  This isn’t really paradoxical. When we think about it carefully, we see that it couldn’t be otherwise. Evolution by natural selection could not be faster than the mutation rate, for mutation is, ultimately, the only way in which new variation enters the species. All that natural selection can do is accept certain new variations, and reject others. The mutation rate is bound to place an upper limit on the rate at which evolution can proceed. As a matter of fact, most of natural selection is concerned with preventing evolutionary change rather than with driving it. This doesn’t mean, I hasten to insist, that natural selection is a purely destructive process. It can construct too, in ways that Chapter 7 will explain.

  Even the mutation rate is pretty slow. This is another way of saying that, even without natural selection, the performance of the DNA code in accurately preserving its archive is very impressive. A conservative estimate is that, in the absence of natural selection, DNA replicates so accurately that it takes five million replication generations to miscopy 1 per cent of the characters. Our hypothetical typists are still hopelessly outclassed by DNA, even if there is no natural selection. To match DNA with no natural selection, the typists would each have to be able to type the whole of the New Testament with only one error. That is, they would each have to be about 450 times more accurate than a typical real-life secretary. This is obviously much less than the comparable figure of half a billion, which is the factor by which the histone H4 gene after natural selection is more accurate than a typical secretary; but it is still a very impressive figure.

  But I have been unfair to the typists. I assumed, in effect, that they are not capable of noticing their mistakes and correcting them. I have assumed a complete absence of proofreading. In reality, of course, they do proofread. My line of billions of typists wouldn’t, therefore, cause the original message to degenerate in quite the simple way that I portrayed. The DNA-copying mechanism does the same kind of error-correction automatically. If it didn’t, it wouldn’t achieve anything like the stupendous accuracy that I have described. The DNA-copying procedure incorporates various ‘proofreading’ drills. This is all the more necessary because the letters of the DNA code are by no means static, like hieroglyphs carved in granite. On the contrary, the molecules involved are so small — remember all those New Testaments fitting on a pin’s head — that they are under constant assault from the ordinary jostling of molecules that goes on due to heat. There is a constant flux, a turnover of letters in the message. About 5,000 DNA letters degenerate per day in every human cell, and are immediately replaced by repair mechanisms. If the repair mechanisms weren’t there and ceaselessly working, the message would steadily dissolve. Proofreading of newly copied text is just a special case of normal repair work. It is mainly proofreading that is responsible for DNA’s remarkable accuracy and fidelity of information storage.

  We have seen that DNA molecules are the centre of a spectacular information technology. They are capable of packing an immense amount of precise, digital information into a very small space; and they are capable of preserving this information — with astonishingly few errors, but still some errors — for a very long time, measured in millions of years. Where are these facts leading us? They are leading us in the direction of a central truth about life on Earth, the truth that I alluded to in my opening paragraph about willow seeds. This is that living organisms exist for the benefit of DNA rather than the other way around. This won’t be obvious yet, but I hope to persuade you of it. The messages that DNA molecules contain are all but eternal when seen against the time scale of individual lifetimes. The lifetimes of DNA messages (give or take a few mutations) are measured in units ranging from millions of years to hundreds of millions of years; or, in other words, ranging from 10,000 individual lifetimes to a trillion individual lifetimes. Each individual organism should be seen as a temporary vehicle, in which DNA messages spend a tiny fraction of their geological lifetimes.

  The world is full of things that exis
t … ! No disputing that, but is it going to get us anywhere? Things exist either because they have recently come into existence or because they have qualities that made them unlikely to be destroyed in the past. Rocks don’t come into existence at a high rate, but once they exist they are hard and durable. If they were not they wouldn’t be rocks, they would be sand. Indeed, some of them are, which is why we have beaches! It is the ones that happen to be durable that exist as rocks. Dewdrops, on the other hand, exist, not because they are durable, but because they have only just come into existence and have not yet had time to evaporate. We seem to have two kinds of ‘existenceworthiness’: the dewdrop kind, which can be summed up as ‘likely to come into existence but not very durable’; and the rock kind, which can be summed up as ‘not very likely to come into existence but likely to last for a long time once there’. Rocks have durability and dewdrops have ‘generatability’. (I’ve tried to think of a less ugly word but I can’t.)

  DNA gets the best of both worlds. DNA molecules themselves, as physical entities, are like dewdrops. Under the right conditions they come into existence at a great rate, but no one of them has existed for long, and all will be destroyed within a few months. They are not durable like rocks. But the patterns that they bear in their sequences are as durable as the hardest rocks. They have what it takes to exist for millions of years, and that is why they are still here today. The essential difference from dewdrops is that new dewdrops are not begotten by old dewdrops. Dewdrops doubtless resemble other dewdrops, but they don’t specifically resemble their own ‘parent’ dewdrops. Unlike DNA molecules, they don’t form lineages, and therefore can’t pass on messages. Dewdrops come into existence by spontaneous generation, DNA messages by replication.