DNA: more questions than answers

Gene therapy and designer babies? We might have sequenced the human genome, but we are far from being able to perform miracles. Steve Jones reports

In my first term at university (less than 50 years ago but closer to that magic figure than I might prefer) I was directed to the library and told to find the most important scientific paper of the past decade.

It was easy; one volume of the journal Nature, number 171, was uniquely battered, and two of its pages were darkened and torn by the impress of hundreds of fingers.

In just a few paragraphs, the Watson and Crick paper brought the double helix to an astonished world and provided one of the icons of the 20th century.

This week that icon has been polished with the finest rouge: the announcement that the genome has been sequenced with greater than 99.9 per cent accuracy brings to an end the greatest co-operative effort in biology.

It also raises a host of questions: just what is a gene, what turns them on and off - and, endlessly, does the double helix alter our view of the meaning of life and what it is to be human?

A glance over the past half century shows strange shifts in public attitudes, while a look to the future by some of the most eminent of today's geneticists reveals a certain scientific caution.

I once met a policeman who did not know the difference between DNA and DOA (dead on arrival), but that was in the Sixties and perhaps he was having me on. Nowadays, everyone recognises the famous image, most people have some idea how it works, and many see the double helix as a threat as dangerous as its twin symbol, the mushroom cloud.

The authors of the famous Nature paper that began it all were well aware of the importance of their work. They did not disguise the fact from their competitors (as his book The Double Helix shows, where Newton stood on the shoulders of giants, Watson preferred to stand on their toes).

In this anniversary year, every scientist agrees; Rosalind Franklin, who took the crucial X-ray but missed its significance, was wrong but romantic, while Crick and Watson were right but repulsive. Their discovery marked the beginning of modern biology.

Only one newspaper, the now extinct News Chronicle, mentioned it at the time ("Discovering how these chemical cards are shuffled and paired will keep the scientists busy for the next 50 years").

The media's failure mirrored that of the 19th-century president of the Linnean Society, who commented on Darwin's paper that his year had "not been marked by any of those striking discoveries which at once revolutionise, so to speak, the department of science on which they bear". In 1953, the world was much less stirred by the new genetics than it should have been.

Now it is shaken. The grand agitation began in the 1970s. A glance at a BBC Horizon of 20 years ago catches the flavour. Slippery slopes abound as scientists play God to the sound of doom-laden music.

Gene therapy, we were assured, was almost here - but how far should it go? In the film, two parents engineer a child to be artistic but outgoing (the ethics people balk at the ambition gene) as the presenter intones that "we are the cruelest and most ruthless species that has ever walked the earth" (try telling that to a malaria parasite).

The next step is to engineer out the gene for war and, failing that, science might, he says - in a nod to the dinner parties of the time - even insert an orange gene into a duck.

All this was silly then and looks even sillier now. Gene therapy is still little more than a hope, we know no genes for art, and as for controlling warfare, a decent system of international law (or even compulsory castration) would be easier.

Even so, science has moved on since that programme was made. The 1981 Horizon suggested it would take 6,000 scientists 40 years to sequence human DNA. That was too pessimistic; the job was done far faster and more cheaply than anyone expected.

Cloning is here, human genes work in sheep and - if it was not so unfashionable - citrus-enhanced poultry could soon be on the shelves.

Ethics, though, has stayed oddly unmoved. The most recent Horizon on the topic dealt with the late and lamented Dolly. It highlighted lots of good biology but, once again, felt impelled to make vague threats about the future ("Now, six pieces of Al's mother are frozen in a vat, somewhere in America!").

In the face of such relentless pessimism, it's worth reminding ourselves in this historic month for biology that the double helix has been bigger on promises than on delivery.

We do not have reliable gene therapy or designer babies (whatever they might be) and human cloning has not happened. Last week's reported failure to clone a monkey suggests that, for purely technical reasons, it probably never will.

Because it seems to be close to ancient questions about identity, about right and wrong, and about what it means to be human, many expect too much of genetics. In the end, though, it is just a science.

What do the experts think about its future, half a century on? They must be sick of being asked. Physics has brought us the bomb and chemistry the ozone hole, but chemists and physicists do not spend all their time predicting, or even apologising.

Undeterred, I asked three Nobel prize-winners about their hopes for the next half century. All were cautious; no designer babies or cancer cures, but a sober realisation, as knowledge increases, of how far we have to go.

The beautiful simplicity of 1953 has become clouded. Genetics looks rather like physics in 1900, when many assumed that the science was done and dusted. The atom, the solar system and the universe were the same things on different scales and all that remained was to tidy up the details and to invent some better steam engines.

Then came a discovery; certain elements glowed with definite colours when heated. That was the first step to quantum theory and, quite soon, the austere Newtonian edifice collapsed, to be replaced by a world of uncertainty (and, in the end, by the mushroom cloud).

Genetics has not quite come to that, but it might. The first hint came from the shortage of genes - not a million, as the 1982 Horizon predicted, but only about 30,000; little more than in a simple plant.

Worse, what once seemed like single genes can be cut and spliced to produce scores of products - but others can be knocked out altogether with no effect. Why, we know not; but it reminds us that we stand among questions and not answers.

Molecular biology is anatomy plus dollars. Watson and Crick were the intellectual successors of the 16th-century Italian Vesalius, who began the great dissection just completed by the human genome project.

The first heart transplant had to wait for 400 years from his day and even the circulation of the blood took a century. To understand the molecular machinery (let alone manipulate it) might not take as long - but it will not happen tomorrow.

Even so, it is fun to speculate. Sir Paul Nurse, 2001's Nobelist, hopes that soon we will discover how each cell receives a complete set of genes when it is formed and - a more daring prediction - that we will even know how cells (which, unlike DNA, can reproduce without help) actually work. That's a real ambition, as it might help to understand cancer.

Tim Hunt, who shared that year's award, hopes that "omics", whether gene-, or proteo-, will disappear (thoughtless hype, he says), while Sydney Brenner, a pioneer of the helix (and winner of the 2002 prize) feels that by 2053 we might even understand how genes co-operate to build complex creatures from a simple chemical - and that we will then be in the era of synthetic biology, when animals will be made to order.

Tim Hunt agrees. He hopes that one day there might be a computer program that will take any DNA sequence and calculate the size, shape and physiology of the creature involved. It would then, he says, be a short step to the resurrection of the Dodo.

However, Dr Hunt is of the Vesalian school, for he predicts that this will take not 50 years but 1,000. With luck, orange-flavoured ducks, if not dodos, will have come home to roost before then, we will be used to what genetics can and cannot do, and the human race will find something different to worry about.

Steve Jones is Professor of Genetics at University College London

16 April 2003