The code breaker

November 18, 1994

Sometimes a scientist's career lifts like a surfer catching a wave. A combination of ripe problems and apt techniques appears at just the right time, and someone who was drifting is off, riding the crest of discovery.

Kay Davies had that experience in the late 1970s, and she is still going. It was then that she discovered genes. The talk was of genetic diagnosis, of gene mapping, perhaps even gene therapy. And for a frankly uninspired protein chemist, the world changed: "I realised that there was something exciting to do in science".

It is hard to credit that this businesslike woman, with her 26-page CV listing nearly 200 papers, her newly confirmed chair in genetics at Oxford, secure in her accomplishments but still only in mid-career, ever had doubts about science. But that is how she tells the story.

She read chemistry as an Oxford undergraduate, won prizes, and was prevailed upon to stay on for a PhD. She did it, as much as anything, in order to avoid regretting not doing it. "I can't have been completely bored or else I wouldn't have done it, but I was not a fired-up PhD student." And she enjoyed the fact that it was tough going, moving towards biochemistry, setting up techniques, making them work. "I worked quite hard at it -- if you are going to do it, you might as well do it well."

She did it well enough to earn a Royal Society postdoctoral fellowship, which took her to a lab on the outskirts of Paris, "to learn something about proteins". But having proved herself, the motivation began to flag. "I spent more time skiing and playing tennis, I have to say."

Fortunately for her career, she also took the opportunity to look beyond the bench to the rest of science. "That was the great advantage of those days," she says, as if 1979 was an age ago, "you could actually try different things. You never felt there was any urgency to get a tenured position. You could actually explore bits of science and see what really interested you."

Her chemical education had not brought any contact with genetics. Now, with the "new genetics" just taking shape, that was what caught her interest. Genes were being manipulated in new ways, cut up with enzymes, patched together, and grown in bacteria. At the same time, the principles of the new mapping techniques which would ultimately lead to the human genome programme were emerging, and there was the promise of the discovery of many genes involved in human disease.

The young Davies learnt the techniques of "cloning", or making copies of pieces of DNA of interest, at the Pasteur Institute, then quickly moved back to London to join the group led by Bob Williamson at St Mary's Hospital. It was 1980 and, as she recalls, "not only did my interest explode; the whole field exploded".

A decade and a half on, and she has a central role in the British contribution to applying the new genetics. An explosion in knowledge needs strategists and entrepreneurs, and people who try and channel the flow. Inevitably, they get drawn into the politics of science, as Davies has in writing reports for the Academia Europea and the Office of Science and Technology. The trick is to balance this with the research, and she recently took a crucial decision to stick with the science, after a plum Medical Research Council job threatened to become more politics than research.

The job was to direct the council's new Clinical Sciences Centre at the Royal Postgraduate Medical School in Hammersmith, a flagship for its efforts to marry basic science with clinical research. Davies, who is interested above all in genetic disease, was invited to lead this effort, and build the new institute around the new genetics. But the venture fell foul of Government restructuring of London's health service. She spent many hours in meetings thrashing out the implications: "I was having to spend an enormous amount of time, turning up at meetings trying to persuade people that, you know, the muscle clinic needed to stay at the Hammersmith because the muscle research depended on it, and the department of haematology needed to be protected". This was not what she was there for: "I felt that as leader of that institution I needed to be leading from the front with the science, not the politics". So she quit last May and went back to Oxford. "If the best way of protecting the science base is for me to go back and do pure basic research, then I'll go back and do pure basic research for five years. What I won't do is stay in London and try to do that when I know I can't if I have all those other responsibilities."

The extra responsibilities she is keen on are ones which make the research more effective, like editing the new journal Human Molecular Genetics. She admits ruefully that this "nearly kills me", but journal editing is, of course, a superb way to keep abreast of other work in the field. "If you are trying to clone a gene for a particular disease, as we are for example in spinal muscular atrophy, I know what is going on in every other neuromuscular disease. If you are reviewing papers in related fields, they review the literature for you, so it's very easy to spot whether there is anything really significant coming through -- there is an enormous benefit from editing that journal at the moment."

She says that finding the gene for spinal muscular atrophy, known as "floppy baby syndrome", by what is called "positional cloning" will be her last such project. What was once a triumph for any gene is now boring, because the techniques are well-proven -- "it's just a turning of the wheel".

Once, it was far from boring, of course. The famous early successes, like the identification of the gene that carries the mutations for cystic fibrosis which Williamson worked on, or muscular dystrophy, Davies's special study, are among the most remarkable developments in biology of the past 30 years. That work, always stretching the limits of technique, has the curious double aspect of appearing inspiring but already a little quaint that defines landmarks in very fast moving fields. Along with the expansion of knowledge has come a fantastic proliferation of techniques, molecular tricks for doing almost anything the geneticists can think of. Davies's science has been transformed in just a few years.

"When I did a PhD you really had to make sure that you had the basic techniques at your fingertips. I don't think that's the case any more in molecular biology. The techniques come so thick and fast these days that you couldn't possibly keep up with them. There is a completely different way of looking at things."

One consequence is that the researchers work in larger teams, so that the full range of techniques is available. If the ultimate goal is clinical, the team has to be larger still. But their concerns are now no longer mainly with identifying genes. The new battery of techniques means that the initial gene tagging -- known as "reverse genetics" because it inverts the traditional logic of finding which protein does a particular job and then looking for its gene -- is becoming routine. That, after all, is the purpose of the human genome programme.

But, extraordinary though this ability is, it creates a much harder job: working out what each gene does. For because this is reverse genetics, when most genes are found no one has any idea which proteins they code for, let alone what those proteins are used for in the cell. "Of all the genes that have been cloned, there are still very few where we have a full understanding of the functions now. So there is a tremendous amount of biology involved in doing the rest of the reverse genetics." This, in a way, takes her back to her earlier research concerns, with proteins and how they work, and to an older research style. "There will be a gradual shift in my group, I expect, from using the reverse human genetics approach to more classical genetics, and using classical genetics means you have to use other organisms, to understand the function of genes by looking at mutations. So it's still very much genetics, but genetics of a very different, more basic type if you like."

The best current example is muscular dystrophy, a wholly mysterious disease until a few years ago. In 1987, after a seven-year effort by Davies's group and many others, the enormous gene which was linked to this progressive wasting disease was finally tracked down on the short arm of the X-chromosome. That was the key to a rush of discovery.

The gene identified a (very large) protein, dystrophin, which is defective in those who have the disease. Not suprisingly, this protein normally appears in muscle cells. Less predictably, it is also made, in a slightly modified form, in the brain, which is presumably linked to the mental retardation which afflicts a proportion of patients. Even more suprisingly, Davies discovered that human cells carry another, almost identical gene on a different chromosome. This gene, which codes for a protein dubbed utrophin, is active in most parts of the body. The different roles played by the two proteins have yet to be disentangled, but it is already clear that utrophin appears in fetal muscle, but disappears from some parts of muscle cells after dystrophin manufacture is turned on. So the existence of utrophin, whose description in a 1989 paper Davies reckons is her most important yet -- immediately raises speculation about treatment. This might be the simplest form of gene therapy. No need to fix a gene, or substitute new for old; simply turn back on one which is already there in the patient's cells.

"We have thought, well if you look at it theoretically, utrophin could replace dystrophin in DMD patients. There are also lots of reasons why it might not, but the best thing to do is to try and find something that will upregulate utrophin and then see if it works". From this point of view, the prospects for therapy look more promising than before. "There's an awful lot of redundancy in the genome that we never realised before. You knock something out and you find that the animal is pefectly OK. So there is a complexity which we didn't know about; there are ways in which different genes can compensate, in certain circumstances, for the absence of others."

Fast as all this is moving, she would still like to see progress speed up, for the sake of patients. "It is just a little disappointing that we are not moving to the therapy phase quite as fast as some of the families hoped we might."

She deals regularly with families coping with muscular dystrophy, or with spinal muscular atrophy. Many babies with this condition die very early on, but unlike muscular dystrophy, it is not progressive, and some survive. "They tend to be incredibly bright, so when you go to their meetings, and see them speeding around in their motorised wheelchairs, you don't feel any sort of real depression. The families know that what they're contributing to is unlikely to help their particular children, and they're quite happy to accept that."

Nevertheless, it is a constant reminder of the need to move beyond pre-natal diagnosis. "That's an enormous advance, but the next advance is therapy. It will come within the next decade, but that's still a long time compared to how long it took to get the linkages to these genes". Most often, pre-natal tests give the all-clear, as she knows from personal experience. Her own son is now six, and she admits that at times, working in this field, "you begin to wonder whether they are ever born normal. I certainly tested myself for everything I was working on, so you check that you aren't a cystic fibrosis carrier or a muscular dystrophy carrier as a matter of course". She was not, and the risks, she emphasises are still pretty low.

But when you work with the people who have fallen foul of the risk, the motivation for pressing on with the research is always clear. "Particularly now, as we discover more genes that have nothing to do with disease at all, the whole area is going to have an enormous impact on developmental biology. But my own specific interest has always been in muscular disease -- we always have part of the group concentrating on the applications."

Jon Turney is Wellcome fellow in the department of history, philosophy and communication of science, University College London.

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