Dna: The Secret of Life

by Watson, James

  The next step toward the Human Genome Project also came from deep in left field: the U.S. Department of Energy (DOE). Though its brief naturally concentrated on the nation's energy needs, the DOE did have at least one biological mandate: to assess the health risks of nuclear energy. In this connection, it had funded monitoring of long-term genetic damage in survivors of the atomic blasts at Nagasaki and Hiroshima and their descendants. What could be more useful in identifying mutations caused by radiation than a full reference sequence of the human genome? In the fall of 1985, the DOE's Charles DeLisi called a meeting to discuss his agency's genome initiative. The biological establishment was skeptical at best: Stanford geneticist David Botstein condemned the project as "DOE's program for unemployed bomb-makers," and James Wyngaarden, then head of the National Institutes of Health (NIH), likened the idea to "the National Bureau of Standards proposing to build the B-2 bomber." Not surprisingly, the NIH itself was eventually to become the most prominent member of the Human Genome Project coalition; nevertheless, the DOE played a significant role throughout the project, and, in the final reckoning, would be responsible for some 11 percent of the sequencing.

  By 1986 the genome buzz was getting stronger. That June, I organized a special session to discuss the project during a major meeting on human genetics at Cold Spring Harbor Laboratory. Wally Gilbert, who had attended Sinsheimer's meeting the year before in California, took the lead by making a daunting cost projection: 3 billion base pairs, 3 billion dollars. This was big-money science for sure. It was an inconceivable sum to imagine without public funding, and some at the meeting were naturally concerned that the megaproject, whose success was hardly assured, would inevitably suck funds away from other critical research. The Human Genome Project, it was feared, would become scientific research's ultimate money pit. And at the level of the individual scientific ego, there was, even in the best case, relatively little career bang for the buck. While the HGP promised technical challenges aplenty, it failed to offer much in the way of intellectual thrill or fame to those who actually met them. Even an important breakthrough would be dwarfed by the size of the undertaking as a whole and who was going to dedicate his life to the endless tedium of sequencing, sequencing, sequencing? Stanford's David Botstein, in particular, demanded extreme caution: "It means changing the structure of science in such a way as to indenture us all, especially the young people, to this enormous thing like the Space Shuttle."

  Despite the less than overwhelming endorsement, that meeting at Cold Spring Harbor Laboratory convinced me that sequencing the human genome was destined soon to become an international scientific priority, and that, when it did, the NIH should be a major player. I persuaded the James S. McDonnell Foundation to fund an in-depth study of the relevant issues under the aegis of the National Academy of Sciences (NAS). With Bruce Alberts of UC San Francisco chairing the committee, I felt assured that all ideas would be subject to the fiercest scrutiny. Not long before, Alberts had published an article warning that the rise of "big science" threatened to swamp traditional research's vast archipelago of innovative contributions from individual labs the world over. Without knowing for sure what our group would find, I took my place, along with Wally Gilbert, Sydney Brenner, and David Botstein, on the fifteen-member committee that during 1987 would hammer out the details of a potential genome project.

  In those early days, Gilbert was the Human Genome Project's most forceful proponent. He rightly called it "an incomparable tool for the investigation of every aspect of human function." But having discovered the allure of the heady biotech mix of science and business at Biogen, the company he had helped found, Gilbert saw in the genome an extraordinary new business opportunity. And so, after serving briefly, he ceded his spot on the committee to Washington University's Maynard Olson to avoid any possible conflict of interest. Molecular biology had already proved its potential as big business, and Gilbert saw no need to go begging at the public trough. He reasoned that a private company with its own enormous sequencing laboratory could do the job and then sell genome information to pharmaceutical manufacturers and other interested parties. In spring 1987, Gilbert announced his plan to form Genome Corporation. Deaf to the howls of complaint at the prospect of genome data coming under private ownership (thus possibly limiting its application for the general good), Gilbert set about trying to raise venture capital. Unfortunately, he was handicapped at the outset by his own less-than-golden track record as a CEO. Following his resignation in 1982 from the Harvard faculty to take the reins of Biogen, the company promptly lost $11.6 million in 1983 and $13 million in 1984. Understandably, Gilbert took refuge behind ivy-covered walls, returning to Harvard in December 1984, but Biogen continued to lose money after his departure. It was hardly the stuff of a mouth-watering investment prospectus, but ultimately Gilbert's grand plan foundered owing more to circumstances beyond his control than to any managerial shortcoming: the stock market crash of October 1987 abruptly terminated Genome Corp.'s gestation.

  In fact, Gilbert was guilty of nothing as much as being ahead of his time. His plan was not so different from the one Celera Genomics would implement so successfully a full ten years after Genome Corp. was stillborn. And the concerns his venture provoked about the private ownership of DNA sequence data would come into ever sharper focus as the HGP progressed.

  The plan our Gilbert-less NAS committee devised under Alberts made sense at the time – and indeed the Human Genome Project has been carried out more or less according to its prescriptions. Our cost and timing projections have also proved respectably close to the mark. Knowing, as any PC owner has learned, that over time technology gets both better and cheaper, we recommended that the lion's share of actual sequencing work be put off until the techniques reached a sensibly cost-effective level. In the meanwhile, the improvement of sequencing technologies should have high priority. In part toward this end, we recommended that the (smaller) genomes of simpler organisms be sequenced as well. The knowledge gained thereby would be valuable both intrinsically (as a basis for enlightening comparisons with the eventual human sequence) and as a means for honing our methods before attacking the big enchilada. (Of course the obvious nonhuman candidates were the geneticists' old flames: E. coli, baker's yeast, C. elegans [the nematode worm popularized for research by Sydney Brenner], and the fruit fly.)

  1. 1953: Francis Crick (right) and me with our model of the double helix

  2. The key to Mendel's triumph: genetic variation in pea plants

  3. Notoriously camera shy T. H. Morgan was photographed surreptitiously white at work the fly room.

  4. Eugenics as it was perceived during the first part of the twentieth century: an opportunity for humans to control their own evolutionary destiny

  5. "Large family" winner, Fitter Families Contest, Texas State Fair (1925)

  6. Scientific racism: social inadequacy in the United States analyzed by national group (1922). "Social inadequacy" is used here by Harry Laughlin as an umbrella term for a host of sins ranging from feeblemindedness to tuberculosis. Laughlin computed an institutional "quota" for each group on the basis of the proportion of that group in the U.S. population as a whole. Shown, as a percentage, is the number of institutionalized individuals from a particular group divided by the group's quota. Groups scoring over 100 percent are overrepresented in institutions.

  7. The physicist Erwin Schrödinger, whose hook What Is Life? turned me on to the gene

  8. Erwin Schrödinger's What Is Life? published in 1944.

  9. A view through the microscope of blood cells treated with a chemical that stains DNA. In order to maximize their oxygen-transporting capacity, red blood cells have no nucleus and therefore no DNA. But white blood cells, which patrol the bloodstream in search of intruders, have a nucleus containing chromosomes.

  10. Lawrence Bragg (left) with Linus Pauling, who is carrying a model of the α-helix

  11. Maurice Wilkins in his lab at King's College, London

  12. Rosalind Franklin on o
ne of the mountain hiking vacations she loved

  13. X-ray photos of the A and B forms of DNA from, respectively, Maurice Wilkins and Rosalind Franklin. The differences in molecular structure are caused by differences in the amount of water associated with each DNA molecule.

  14. The chemical backbone of DNA

  15. The insight that made it all come together: complementary pairing of the bases

  16. Bases and backbone in flace: the double helix. (A) is a schematic showing the system of base-fairing that binds the two strands together (B) is a "sp ace-filling" model showing, to scale, the atomic detail of the molecule.

  17. Short and sweet: our Nature paper announcing the discovery. The same issue also carried longer articles by Rosalind Franklin and Maurice Wilkins.

  18. Matt Meselson beside an ultra-centrifuge, the hardware at the heart of "the most beautiful experiment in biology"

  19. The Meselson-Stahl experiment

  20. Arthur Kornberg at the time of winning his Nobel Prize

  21. The impact of mutation. A single base change in the DNA sequence of the human beta hemoglobin gene results in the incorporation of the amino acid valine rather than glutamic acid into the protein. This single difference causes sickle-cell disease, in which the red blood cells become distorted into a characteristic sickle shape.

  22. The genetic code, showing the triplet sequences for messenger RNA. An important difference between DNA and RNA is that DNA uses thymine and RNA uracil. Both bases are complementary to adenine. Stop codons do what their name suggests: they mark the end of the coding part of a gene.

  23. From DNA to protein. DNA is transcribed in the nucleus into messenger RNA, which is then exported to the cytoplasm for translation into protein. Translation occurs in ribosomes: transfer RNAs complementary to each base pair triplet codon in the messenger RNA deliver amino acids, which are bonded together to form a protein chain.

  24. François Jacob, Jacques Monody, and André Lwoff

  25. The cell's protein factory, the ribosome, in all its 3-D glory as revealed by X-ray analysis. (For simplicity, this computer-generated image does not show individual atoms.) There are.millioms of ribosomes in every cell. It is here that the information encoded in DNA is used to produce proteins, the actors in life's molecular drama. The ribosome consists of two subunits (orange and yellow), each composed of RNA, plus some sixty proteins (blue and green) plastered over the outside. Here the ribosome is caught in the act of producing a protein. Specialized small RNA molecules (purple, white, and red) transport amino acids to the ribosome for incorporation into the growing protein chain.

  Meanwhile, we should concentrate on mapping the genome as accurately as possible. Mapping would be both genetic and physical. Genetic mapping entails determining relative positions, the order of genetic landmarks along the chromosomes, just as Morgan's boys had originally done for the chromosomes of fruit flies. Physical mapping entails actually identifying the absolute positions of those genetic landmarks on the chromosome. (Genetic mapping tells you that gene 2, say, lies between genes 1 and 3; physical mapping tells you that gene 2 is 1 million base pairs from gene 1, and gene 3 is located 2 million base pairs further along the chromosome.) Genetic mapping would lay out the basic structure of the genome; physical mapping would provide the sequencers, when eventually they were let loose on the genome, with fixed positional anchors along the chromosomes. The location on a chromosome of each separate chunk of sequence could then be determined by reference to those anchors.

  We estimated that the entire project would take about fifteen years and cost about $200 million per year. We did a lot more fancy arithmetic, but there was no getting away from Gilbert's $1 per base pair estimate. Each space shuttle mission costs some $470 million. The Human Genome Project would cost six space shuttle launches.

  Our report was published in February 1988. The rough draft of the genome was published in 2001. The gaps continue to be filled in by sequencing labs around the world as I write, and in 2003 – the fiftieth anniversary of the discovery of the double helix and the fifteenth of the committee's report – we will have seen the completion of the sequence.

  While the NAS committee was still deliberating, I went to see key members of the House and Senate subcommittees on health that oversee the NIH's budget. James Wyngaarden, head of NIH, was in favor of the genome project "from the very start," as he put it, but less farsighted individuals at NIH were opposed. In my pitch for $30 million to get NIH on the genome track, I emphasized the medical implications of knowing the genome sequence. Lawmakers, like the rest of us, have all too often lost loved ones to diseases like cancer that have genetic roots, and could appreciate how knowing the sequence of the human genome would facilitate our fight against such diseases. In the end we got $18 million.

  Meanwhile the DOE was able to secure $12 million for its own effort, mainly by playing up the project as a technological feat. This, one must remember, was the era of Japanese dominance in manufacturing technology; Detroit was in peril of being run over by Japan's automobile industry, and many feared the American edge in high-tech would be the next domino to fall. Rumor had it that three giant Japanese conglomerates (Matsui, Fuji, and Seiko) had combined forces to produce a machine capable of sequencing 1 million base pairs a day. It turned out to be a false alarm, but such anxieties ensured that the U.S. genome initiative would be pursued with the sort of fervor that put Americans on the moon before the Soviets.

  In May 1988 Wyngaarden asked me to run NIH's side of the project. When I expressed reluctance to forsake the directorship of the Cold Spring Harbor Laboratory, he was able to arrange for me to do the NIH job on a part-time basis. I couldn't say no. Eighteen months later, with the HGP fast becoming an irresistible force, NIH's genome office was upgraded to the National Center for Human Genome Research; I was appointed its first director.

  It was my job both to pry the cash away from Congress and to ensure that it was wisely spent. A major concern of mine was that the HGP's budget be separate from that of the rest of NIH. I thought it vitally important that the Human Genome Project not jeopardize the livelihood of non-HGP science; we had no right to succeed if by our success other scientists could legitimately charge that their research was being sacrificed on the altar of the megaproject. At the same time, I felt that we, the scientists embarking on this unprecedented enterprise, ought to signal somehow our awareness of its profundity. The Human Genome Project is much more than a vast roll call of As, Ts, Gs, and Cs: it is as precious a body of knowledge as humankind will ever acquire, with a potential to speak to our most basic philosophical questions about human nature, for purposes of good and mischief alike. I decided that 3 percent of our total budget (a small proportion, but a large sum nevertheless) should be dedicated to exploring the ethical, legal, and social implications of the Human Genome Project. Later at Senator Al Gore's urging, this was increased to 5 percent.

  It was during these early days of the project that a pattern of international collaboration was established. The United States was directing the effort and carrying out more than half the work; the rest would be done mainly in the United Kingdom, France, Germany, and Japan. Despite a long tradition in genetics and molecular biology, the U.K.'s Medical Research Council was only a minor contributor. Like the whole of British science, it was suffering from Mrs. Thatcher's myopically stingy funding policies. Fortunately, the Wellcome Trust, a private biomedical charity, came to the rescue: in 1992 it established a purpose-built sequencing facility outside Cambridge – the Sanger Centre named, as we have seen, for Fred Sanger. In managing the international effort, I decided to assign distinct parts of the genome to different nations. In this way, I figured, a participating nation would feel that it was invested in something concrete, say, a particular chromosome arm, rather than laboring on a nameless collection of anonymous clones. The Japanese effort, for example, focused largely on chromosome 21. Sad to say, in the rush to finish, this tidy order broke down, and it proved to be not so easy after all
to superimpose the genome map on a map of the world.

  From the start I was certain that the Human Genome Project could not be accomplished through a large number of small efforts – a combination of many, many contributing labs. The logistics would be hopelessly messy, and the benefits of scale and automation would be lost. Early on, therefore, genome mapping centers were established at Washington University in St. Louis, Stanford and UCSF in California, the University of Michigan at Ann Arbor, MIT in Cambridge, and Baylor College of Medicine in Houston. The DOE's operations, first centered at their Los Alamos and Livermore National Laboratories, in time came to be centralized in Walnut Creek, California.