A new industry has grown from the science of DNA. Tony Durham talks to the man who started it all - and about the woman who nearly did
In the lobby of the Sanger Centre near Cambridge there is an illuminated sign which counts, not the number of Coca-Cola bottles sold, but the number of base-pairs of the human genome that the centre has mapped in sequence. With the data obtained from worms, puffer fish and other species, the count is well past 100 million. Within a few years this and other laboratories will have chemically analysed the entire complement of human genetic material, leaving only the question: what does it all mean?
James D. Watson, who with Francis Crick discovered DNA's twisted-ladder structure in the first place, directed the human genome project in Washington DC for four years. In Oxford for the summer, he is adamant that any doubts about the value of the project can finally be laid to rest. The researchers always hoped to find genes that cause disease. "That has gone better than we expected: four genes behind Alzheimer's, two behind breast cancer, and so on," he says.
A bigger surprise, however, was the extraordinary similarity between parts of the human genome and those of the worms and flies that were sequenced as a warm-up for the main project. It turns out we share key developmental pathways with insects. "A fruit-fly gene is the major gene behind basal cell carcinoma. These sorts of things we did not anticipate. Now we see it, we can see it's the way evolution will occur."
It was over the issue of patents that Watson parted with the human genome project and with his employer, the National Institutes of Health. He fell out with NIH director Bernadine Healy who was keen to patent gene sequences without waiting to find out what they meant or how they might be used. In the United States, everyone was doing it. "The US patent office has been very permissive and we think has given very broad patents. They gave a patent for any form of genetic engineering of cotton, which might mean that one person would own the cotton. To me that is pretty bad." Watson prefers the European position, which is that the application of a gene can be patented but not the gene itself.
While Crick branched off into neurobiology, Watson has stayed with the new discipline of molecular genetics that they jointly founded. Their story, or Watson's version of it, is famous. Thirty years after its publication The Double Helix is still regarded as a shocking book, a manual of anti-feminism or a primer in scientific gamesmanship. And, of course, a terrific read.
"He has mellowed a bit," counselled Max Perutz, a fellow Nobelist who may or may not have helped Watson and Crick win the race for DNA's structure when he showed them their rival scientist Rosalind Franklin's X-ray data. But Watson is still combative and plain-speaking, whether discussing fox-hunting (the state should not interfere), genetically modified food or the pittance on which professors are expected to live in pricey Oxford.
Franklin, who died in 1958, took beautiful X-ray pictures. But she was an inorganic chemist, not a crystallographer. Her experimental work at King's College, London helped Watson and Crick solve the DNA structure. But with a little crystallographic advice, Watson believes she could have solved it herself. He believes her poor grasp of the space groups or three-dimensional symmetries of crystals cost her the help of the great crystallographer Dorothy Hodgkin, whom she visited in Oxford. "The meeting went badly because Rosalind said there were three possible space groups. And Dorothy said two of those involve mirror symmetry and there is no mirror symmetry in DNA, and more or less made some remark which Rosalind took as an insult.
"Dorothy was a charmer but pretty tough. Rosalind and Dorothy, it wasn't two women bonding, it went the wrong way. Rosalind never came back to Oxford and never talked to someone who might have given her crystallographic advice."
Watson is still proud of The Double Helix but admits that the unflattering portrait of "Rosy" was based mainly on talks with her King's College colleague Maurice Wilkins, whose relationship with Franklin was notoriously frosty.
After the double helix breakthrough, one thing had to happen before the new discipline of molecular biology could flourish. The "protein people", who had backed protein against DNA as the genetic material, had to be dislodged from their powerful positions in the research community.
The key position of head of the National Institutes of Health was held, Watson says, by a series of people trained in the study of protein. "Not that they didn't appreciate genetics, but they were protein people. Most people said DNA is too boring to do all things a gene had to do."
But the double helix was the clincher. "It said DNA was the gene, because in seeing the complementary structure you could see how the information was copied." The complementary structure required that each base on one strand faced a matching (not identical) base on the other strand. Separate the strands, and each could serve as the template for a new molecule of DNA. Self-replication is the most basic requirement of a genetic material.
After leaving Cambridge Watson was appointed director of the Cold Spring Harbor Laboratory on Long Island, near New York, where he seemingly had the money and the staff to explore the new field. But the problems were tough, the tools rudimentary, and there was still surprisingly little that molecular biologists could actually do. "You could not sequence DNA. You could not isolate the gene."
But that soon changed. The gene-splicing techniques developed by scientists like Watson's student Walter Gilbert opened vistas of designer drugs, designer crops and even designer people. Dollar signs gleamed in investors' eyes. Scientists launched companies and became paper millionaires overnight.
The nucleic acid people have had four decades of success and expect their winning run to continue well into the new millennium. But, astonishingly, the protein people are back, and they are winning Nobel prizes. Stanley Prusiner, who took the medicine prize in 1997, has challenged the dogma that any infectious agent must be based on nucleic acid. Prusiner's prion theory, now the leading explanation of BSE and similar brain diseases, says the infection is carried by normal protein molecules that happen to fold up in an abnormal shape.
"It still bothers people that a disease could be caused by just a wrongly folded protein," says Watson. "It bothers us in the sense of understanding at a molecular level what really happens." A younger Watson would not have been merely bothered. He would have seized the problem, made it his own, lived it day and night, carried off the prize. But he has been there. He has done that.