designs. We have reinvented most of them ourselves in technological life.
But now we must leave such comfortable terrain behind and step into the unknown. One of the most remarkable, beautiful and bizarre things that Mother Nature achieves without apparent difficulty is something for which we have no human analogy at all: the 1 7 4 G E N O M E
development of a human body from an undifferentiated blob called a fertilised egg. Imagine trying to design a piece of hardware (or software, for that matter) that could do something analogous to this feat. The Pentagon probably tried it, for all I know: 'Good Morning, Mandrake. Your job is to make a bomb that grows itself from a large blob of raw steel and a heap of explosive. You have an unlimited budget and one thousand of the best brains at your disposal in the New Mexico desert. I want to see a prototype by August. Rabbits can do it ten times a month. So it cannot be that hard. Any questions?'
Without the handrail of analogy, it is difficult even to understand Mother Nature's feat. Something, somewhere must be imposing a pattern of increasing detail upon the egg as it grows and develops.
There must be a plan. But unless we are to invoke divine intervention, that imposer of detail must be within the egg itself. And how can the egg make a pattern without starting with one? Little wonder that, in past centuries, there was a natural preference for theories of prefor-mation, so that some people thought they saw within the human sperm a miniature homunculus of a man. Preformation, as even Aristotle spotted, merely postpones the problem, for how did the homunculus get its shape? Later theories were not much better, though our old friend William Bateson came surprisingly close to the right answer when he conjectured that all organisms are made from an orderly series of parts or segments, and coined the term homeosis for it. And there was a vogue in the 1970s for explaining embryology by reference to increasingly sophisticated mathematical geometries, standing waves and other such arcana. Alas for mathematicians, nature's answer turns out, as ever, to be both simpler and much more easily understood, though the details are ferociously intricate. It all revolves around genes, which do indeed contain the plan in digital form. One large cluster of these developmental genes lies close to the middle of chromosome 12. The discovery of these genes and the elucidation of how they work is probably the greatest intellectual prize that modern genetics has won since the code itself was cracked. It was a discovery with two stunning and lucky surprises at its heart.1
As the fertilised egg grows into an embryo, at first it is an undiffer-S E L F - A S S E M B L Y 1 7 5
entiated blob. Then gradually it develops two asymmetries - a head-tail axis and a front-back axis. In fruit flies and toads, these axes are established by the mother, whose cells instruct one end of the embryo to become the head and one part to become the back. But in mice and people the asymmetries develop later and nobody knows quite how. The moment of implantation into the womb seems to be critical.
In fruit flies and toads, these asymmetries are well understood: they consist of gradients in the chemical products of different maternal genes. In mammals, too, the asymmetries are almost certainly chemical. Each cell can, as it were, taste the soup inside itself, feed the information into its hand-held G P S microcomputer and get out a reading: 'you are in the rear half of the body, close to the underside.' Very nice to know where you are.
But knowing where you are is just the beginning. Knowing what you have to do once you are there is a wholly different problem.
Genes that control this process are known as 'homeotic' genes. For instance, our cell, on discovering where it is located, looks this location up in its guidebook and finds the instruction: 'grow a wing', or 'start to become a kidney cell' or something like that. It is not of course literally like this. There are no computers and no guidebooks, just a series of automatic steps in which gene switches on gene which switches on gene. But a guidebook is a handy analogy, none the less, because the great beauty of embryo development, the bit that human beings find so hard to grasp, is that it is a totally decentralised process. Since every cell in the body carries a complete copy of the genome, no cell need wait for instructions from authority; every cell can act on its own information and the signals it receives from its neighbours. We do not organise societies that way: we are obsessed with dragging as many decisions as possible to the centre to be taken by governments. Perhaps we should try.
Fruit flies have been a favourite object of geneticists' studies since the early years of the century, for they breed quickly and easily in the laboratory. It is the humble fruit fly we must thank for the elucidation of many of the basic principles of genetics: the idea that 1 7 6 G E N O M E
genes are linked on chromosomes, or Muller's discovery that genes can be mutated by X-rays. Among the mutant flies thus created, scientists began to find ones that had grown in unusual ways. They had legs where they should have antennae, or wings where they should have small stabilisers called halteres. A certain segment of the body, in other words, had done something appropriate to a different segment of the body. Something had gone wrong with the homeotic genes.
In the late 1970s, two scientists working in Germany named Jani Nusslein-Volhard and Eric Wieschaus set out to find and describe as many such mutant flies as possible. They dosed the flies with chemicals that cause mutations, bred them by the thousand and slowly sorted out all the ones with limbs or wings or other body parts that grew in the wrong places. Gradually they began to see a consistent pattern. There were 'gap' genes that had big effects, defining whole areas of the body, 'pair-rule' genes that subdivided these areas and defined finer details, and 'segment-polarity' genes that subdivided those details by affecting just the front or rear of a small section. The developmental genes seemed, in other words, to act hierarchically, parcelling up the embryo into smaller and smaller sections to create ever more detail.3
This came as a great surprise. Until then, it had been assumed that the parts of the body defined themselves according to their neighbouring parts, not according to some grand genetic plan. But when the fruit-fly genes that had been mutated were pinned down and their sequences read, a further surprise was in store. The result was the first of two almost incredible discoveries, which between them amount to one of the most wonderful additions to knowledge of the twentieth century. The scientists found a cluster of eight homeotic genes lying together on the same chromosome, genes which became known as Hox genes. Nothing strange about that.
What was truly strange was that each of the eight genes affected a different part of the fly and they were lined up
the fifth the thorax, the sixth the front half of the abdomen, the seventh the rear half of the abdomen, and the eighth various other parts of the abdomen. It was not just that the first genes defined the head end of the fly and the last genes made the rear end of the fly. They were all laid out in order along the chromosome - without exception.
To appreciate how odd this was, you must know how random the order of genes usually is. In this book, I have told the story of the genome in a sort of logical order, picking genes to suit my purpose chapter by chapter. But I have deceived you a little in doing this: there is very little rhyme or reason for where a gene lies.
Sometimes it needs to be close to certain other genes. But it is surely rather literal of Mother Nature to lay these homeotic genes out in the order of their use.
