“We really thought it was the most important problem” – DNA 30 years on

I’ve seen quite a few DNA anniversaries now – 25, 30, 40, 50 and (this month!) 60. Seems a good time to revisit the first one I saw at first hand, as it were. I’m struggling a bit here – trying to be a good reporter while frankly star struck. (James Watson! Sidney Brenner!) And what that intro actually means is anybody’s guess, although the thread it starts does carry on through the piece. This one takes me back to features bashed out at speed on weekday afternoons in the 1980s . More interestingly, you can – with hindsight – discern the first stirrings of the human genome project, perhaps? Wish I still had the notes from this meeting…

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If science progresses, the end of one problem is the start of another – and the importance of the problem solved can be gauged by the complexity of its successors. On this score, the problem solved in Cambridge  30 years ago by Francis Crick and JamesWatson must rank near the top. The solution, reported in their classic Nature paper of April 25, 1953, was “a structure for the salt of deoxyribose nucleic acid (DNA)”.

The structure they proposed, with the two polymer strands of DNA winding round one another in the famous double helix, seemed like “a final solution to the problem – not, as we now see it, a beginning”, Watson said last week. But as he and Crick also wrote in 1953, the structure had “novel features which are of considerable biological interest”.

That interest has been sustained throughout the last 30 years because the structure Watson and Crick found identified DNA unequivocally as the carrier of information from one generation of an organism to the next – the genetic material. The double helix became the icon of the new science of molecular biology.

Many of the leading figures in that science gathered in Churchill College, Cambridge, last week to mark the anniversary of the double helix. And it was characteristic of the field that the conference they came to address – organised by Nature – was called “Molecular Biology Now and Tomorrow”. For after 30 years, the future still looks as productive as the past. As the biological revolution of the 1960s gives way to the biotechnological revolution of the 1980s the fruits of the double helix will finally be gathered in industry, health care and agriculture. And if not all the fruits of genetic manipulation may prove palatable, that was not the concern of this gathering, whose main purpose was to reflect the scientific excitement of the field today.

By the same token, historical reminiscence was also kept to a minimum – confined to an amiable ramble from Watson, before he took to his bed with flu. And although many lamented the absence of Francis Crick – now resident in California – that too seemed appropriate in some ways as he is no longer an active participant in the field, having abandoned molecular genetics to work on the brain. This was a good thing, Watson said, “because most people who think about the brain aren’t as bright as Francis”, but the lunchtime comment of one young gene-slicer that Crick was “into weird neurobiology these days” was probably a more typical view.

The celebration, then, was to mark these scientists’ confidence in their ability to tackle the key problems which remain as much as to honour past achievements. And if problems abound, so do analytic techniques for solving them. As Professor Bob Williamson of London’s St Mary’s Hospital Medical School put it, “It’s almost a continual intellectual and technical high to be in this field at this time.” It was one of the few moments in the history of science when technical resources outran intellectual resources – if an experiment could be conceived it could be carried out.

In Williamson’s own field of genetic disease, a time was approaching when all of the human genes would be available in chromosome specific libraries for anyone to dip into. The excitement now lay in moving on from the relatively simple afflictions like the blood disease thalassaemia to more complex conditions  – schizophrenia, depression, diabetes, high blood pressure.

The crucial techniques for this kind of work came together in the late 1970s, and enabled biologists to cut and join DNA pieces and transfer them from one cell to another. These recombinant DNA techniques were both a promise and a threat: a promise because they paved the way for enormously productive investigations of complex genetic systems; a threat because the power they offered for genetic manipulation led to calls for regulation of the science. But Watson now saw the debate about whether work with such powerful techniques should go ahead as “a black comedy – a piece from the theatre of the absurd”. Now it was over, and scientists could do pretty well whatever they wanted. This was the sole reminder that Williamson’s intellectual high rested in political as well as technical freedom.

The other scientific presentations made it clear how the edifice built on the foundation of the double helix depends on a whole battery of techniques. Recombinant DNA technology meant getting a handle on some of the tools the living cell uses for controlling DNA alteration – notably the so-called restriction enzymes which recognise specific sequences of DNA and cut the molecule. These in turn gave biologists the power to manipulate genes in experiments to unravel genetic regulation and evolution – which often disclose new controls and hence new tools to use in later experiments.

But the molecular biologists’ armoury also includes a range of subtle physical techniques. The X-ray crystallography which Crick learnt from Max Perutz in the 1950s is still being refined to give new insights into molecular structure. Perutz himself told the conference dinner that a separate celebration had been held in Cambridge only the previous day to mark the completion of a detailed X-ray map of the protein-DNA package which serves as the basic genetic store on higher organisms – a map later described by last year’s Nobel Prize winner Aaron Klug. And Mark Ptashne from Harvard showed how X-ray studies of the proteins controlling gene action in a tiny bacterial virus, together with volumes of other experimental results, have given his group the first detailed three-dimensional view of how proteins and base sequences in DNA interact. He predicted that: “Within the next year I’m going to make a lot of money by making proteins which will recognise any given base sequence”.

But even the combined power of those techniques is not enough for the most ambitious molecular biologists. Leroy Hood of CalTech described his group’s programme for developing new instruments for sequencing DNA and proteins much faster, and using smaller quantities of material. And more, they will soon add machines for making specified DNA strands reliably and efficiently. I began to believe the researcher who told me over lunch that it was as important to keep up with the instrument catalogues these days as to read papers reporting new experiments. Hood held that recombinant DNA only enabled researchers to do the easy things – new devices were now needed to unravel very complex systems like the genes controlling cellular recognition, which code for large numbers of proteins made in tiny amounts. “Soon, in fact, if you don’t have these machines, you won’t be able to compete”, he said. “I’ve been talking to a post-doctoral student here in Cambridge who has to take six weeks off to make a piece of DNA that my lab will turn out in four hours”.

So, there is no end in sight yet to the extension of the molecular biologist’s approach to more and more problems. But will the growth of the subject yield any new solutions as elegant and productive as the double helix? Very probably not, according to Sidney Brenner, who shared an office with Crick for many years at the Cambridge Laboratory for Molecular Biology. At the end of the meeting he gave a strong statement of the classic reductionist position that biological mechanisms are best understood by patient dissection, preferably molecule by molecule. Some felt that developmental and neural biology still awaited their Watson and Crick, but they might never be needed. Instead, we would see the steady decomposition of very complicated problems into sub-problems, which would be solved individually.

It was this confidence in simple solutions which Brenner earlier remarked distinguished the thinking of Watson and Crick and the rest in the beginning. Watson summarised the DNA discovery thus: “We really thought it was the most important problem – and we did something about it”. It is no more than molecular biologists have been doing ever since. (1983)

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