A step down the road to the origin of our species

The achievement of the Human Genome Project is just the beginning of the real work, says John Maddox

The near-completion of the Human Genome Project, announced this week, is and will remain a conspicuous landmark on the helter-skelter rush of genetics since the importance of the structure of DNA was recognised, after its discovery in 1953. But it is less of an end-point than a beginning. The hard grind starts now.

Although the complete sequence of the four chemical components of human (and all other) DNA has been called "The Book of Life", the trouble is that much of it remains in code. Even now those at the centre of this huge and triumphant project cannot say how many human genes there are: is it 40,000 or more like 120,000? The ambiguity hinges on the definition of a gene, but it is perplexing that it has come to light only in the past year or so.

The task ahead is to understand how the genome functions as it does. The essence of that process is simple, and now amply recorded in elementary textbooks. The genes, which are stretches along the length of each individual's DNA in every cell (except red blood cells), determine the production of proteins, the workhorses of the chemical reactions that sustain life and the chief structural materials in cells.

One puzzle is to know how particular genes, or groups of them, are active at particular stages in the life of a cell. In single-celled organisms such as bacteria, the textbook story seems to hold: protein molecules (made by genes) stick to DNA near the genes they control, turning them on and off. Much the same seems to happen in human cells, except that there may be several places in the DNA where controlling protein molecules stick. Until it is cleared up, this uncertainty will cloud attempts at gene therapy and transplanting genes from one species to another.

The great medical promise of the Human Genome Project will thus depend on the outcome of the research that lies ahead. But the hope that it will in future be possible to diagnose or even treat important partly inherited diseases will depend on the unravelling of yet another conundrum. As things are, diseases such as haemophilia or cystic fibrosis, caused by a false sequence in a single gene, can be (and are) dealt with in the clinic.

On the other hand, schizophrenia and diabetes, which run in families but may develop only when the environment is suitable, are much more complicated. Perhaps they involve several genes. Perhaps they involve the inheritance of patterns of folded DNA. But what the Human Genome Project will have done is to make the search for genes much more deliberate.

This recitation of the hurdles that lie ahead is not meant to decry the potential for new medicines and new treatments in the years ahead. Moreover, all of us will have to come to terms with the notion that our inherited endowment is susceptible to analysis, perhaps (in the very long run) even to improvement. This potential of the outcome of the project will be the focus of intensifying ethical argument and debate.

Meanwhile, there is one feature of the Human Genome Project that seems entirely benign: hidden in the DNA now recorded in the databases are data with a direct bearing on the history of evolution and, in particular, on the short history of the human race, which seems to span a mere 4.5 million years. Already much has been learned by comparing human genes with those of other animals.

Notoriously, human genes differ hardly at all from those in the chimpanzee that perform similar functions. An understanding of the human genome may therefore throw light on the question of why we differ so much from our nearest relatives. Is the physical arrangement of the genes a sufficient explanation?

In time, it should also be possible to guess at the genetic changes that accompanied the landmarks in human evolution - standing upright (as Homo erectus) just over two million years ago and learning to speak, perhaps as recently as 125,000 years ago. Then we shall have an authentic history of the human race that turns the fossil record into a vivid history.

The grander history of evolution in general will be pieced together more slowly, although there are already good estimates in the literature of the likely date of important events, such as the time when single-celled organisms developed the trick of living together as multi-cellular animals and plants. In due course, the sequence of the human genome will guide the search for an understanding of how life began on the surface of the earth.

Meanwhile, it is only proper that those involved with the project should give themselves an occasion to celebrate. That will be especially so if they have been able to strike an equitable and seemly arrangement between the public project and the private initiative of Craig Venter, whose upstartism has been wrongly scorned in the past few years.

Sir John Maddox is editor emeritus of Nature.

Research, pages 32-33