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First Base 

"It is simply not worth arguing with anyone so obtuse as not to realize that this complex of discoveries is the greatest achievement of science in the twentieth century."

— Sir Peter Medawar, The New York Review of Books, 1968

"Francis and I ... have been praised too often, just because DNA is so beautiful."

— James D. Watson, February 2003

Kevin Davies, Ph.D.Editor-in-ChiefApril 15, 2003 | Fifty years ago this month, James Watson and Francis Crick made history by publishing an extraordinary letter in Nature magazine. It was a family affair: Watson's sister, Elizabeth, typed the 900-word manuscript, while Odile, Crick's wife, sketched the classic curves of what would later become known universally as the double helix.

Two months earlier, Crick had impudently announced to the lunchtime crowd in The Eagle pub that they had discovered "the secret of life." In more subdued tones, Watson and Crick wrote, "This structure has novel features which are of considerable biological interest." The following pages contained two accounts of the X-ray analysis of DNA crystals from King's College, London: one by Maurice Wilkins, the other by Rosalind Franklin, the Sylvia Plath of biology, whose exquisite experimental data were critical to the discovery.

The doyens of DNA began building molecular models in 1951, but their first attempt was an unmitigated disaster. Franklin traveled up from London and was singularly unimpressed. "Rosalind's reaction to us was, we're jerks," Watson recalls, "and she was right!"

Six months later, Franklin captured a pristine X-ray image of DNA, logging it as Photograph 51. But she could not grasp the clues in front of her that suggested a helical structure. In her superb biography Rosalind Franklin, Brenda Maddox writes that Franklin would unknowingly provide "all the essential data for those who took the two brilliant leaps of intuition — antiparallel chains and base pairs — that cracked the problem."

Indeed, one glimpse of Photograph 51 in London, and Watson was electrified. Rushing back to Cambridge, clambering over the back wall of Clare College, he sensed that DNA must be a helix with just two chains. As he wrote in his classic memoir, The Double Helix: "Francis would have to agree. Even though he was a physicist, he knew that important biological objects come in pairs."

Base Pairs 
The race to deduce the structure of DNA wasn't so much Cambridge versus London, but England versus America. In January 1953, the great American chemist Linus Pauling sent a manuscript of his model of DNA to his son, who was working in Cambridge. One look, and Watson and Crick knew the author of The Chemical Bond had forgotten that the "A" in DNA stands for "acid." "The Pauling manuscript was so wrong, so bad," Watson recalls. "I had a sentence [in The Double Helix], 'Linus looking like an ass,' which Linus asked me to take out ... It was a bit vulgar, but that was actually the truth!"

Fearing that Pauling would quickly spot his blunder, Crick and Watson focused on the two outstanding questions. Having seen Franklin's raw data contained in a Medical Research Council (MRC) report, Crick advised Watson to run the two DNA backbone chains in opposite directions. The final piece of the puzzle was literally put together by Watson, who, using makeshift cardboard models of the four chemical bases, found two perfect pairings: A matching T, C with G. In true British style, they dashed off to the pub to celebrate.

Following Franklin's death of ovarian cancer in 1958, one obituary writer wrote: "Her photographs are among the most beautiful X-ray photographs of any substance ever taken." Photograph 51 was reproduced in Franklin's Nature paper, in which she graciously inserted on proofs: "Thus our general ideas are not inconsistent with the model proposed by Watson and Crick in the preceding communication." But she never appreciated how crucial her data had been.

By contrast, Watson and Crick only hinted at their profound debt to Franklin's "unpublished experimental results," and neither one mentioned her in his 1962 Nobel address. Fifty years later, Crick graciously credits Wilkins "and the wonderful work of Rosalind Franklin — without them we couldn't have done it."

But Watson stands his ground: "I didn't feel much sympathy for Rosalind, because she had the photographs ... It wasn't as if she had the data and we stole [them], she just didn't use her data! Rosalind should have talked to Francis, because he was interested in what she was doing. Francis would have told her ... to build two-chain [DNA] models, and she would probably have got the answer."

Double Celebration 
Coincidentally (or not), the anniversary of the outstanding scientific discovery of the 20th century coincides with another milestone that lays the foundation for science and medicine in the 21st. This month, the sequence of the human genome is declared "substantially complete." Just as the double helix proved the pinnacle of reductionism in biology, the human sequence sets the stage for a more holistic view of biology, in which the interaction of genes, proteins, metabolites, and pathways are evaluated at the level of the cell, organ, and entire organism.

Watson has been called the "Einstein of biology," which makes one wonder what to make of Crick, who most peers, including Watson, readily admit is the smarter of the pair. Immune to the anniversary brouhaha, Crick stays home in southern California, where he continues, even today, to publish important ideas on the subject of human consciousness.

Watson's role at Cold Spring Harbor Laboratory is largely ceremonial these days, but his seniority and stature give him great freedom of expression. He had delegates cheering during Time magazine's "Future of Life" conference in February, when he blasted the views of an opponent of embryonic stem cell research as "crap." As evidenced by his recent appearance in Miami (see "Genes, Girls, and Honest Jim," page 28), Watson can be disarmingly modest: "Through an accident of birth, and of several other people not claiming the structure when they could have, we've become very famous." But he has nothing to apologize for. "I think actually we deserved to get the answer, so I don't feel guilty at all."

Awarded the Nobel Prize in 1962, he was said by one reviewer of The Double Helix to deserve a second, this time for literature. Watson originally wanted to call the book Honest Jim, in the manner of a used-car salesman. Another potential title was Base Pairs, with the cover depicting "a picture of me looking at Francis, a picture of Maurice looking at Rosalind." Then there are those who feel his seminal textbook, The Molecular Biology of the Gene, was his most important literary effort. His more recent offering, Genes, Girls and Gamow, is a disappointment, although he can still turn a phrase. In 1954, he suggested that a talented American scientist continue his research in Sweden because "the ultracentrifuges had been pioneered there, and its women were said not to have sexual hangups."

Watson is clearly delighted with the progress in the Human Genome Project, which he launched in 1990. "DNA sequencing, assembly, and annotation now proceed beyond my wildest hope of the early 1990s," he says, singling out the sea squirt genome as one of his current favorites.

At age 75, Watson remains a controversial voice on issues such as genetic engineering, cloning, and stem cell research. Politically incorrect (and proud of it), at times his penchant for crassness masks his true genius. One wonders if, in this era of supercomputers and Big Biology, where the most profound scientific advances have not two but two hundred co-authors, we will ever see his like again. That would be science's loss.

And the Neal Goes to ...
Bio·IT World editors jubilantly celebrated the magazine's first anniversary by garnering two prestigious 2003 Neal Awards from American Business Media.

Mark Uehling won best single article for "Tortured by Paper," and Malorye Branca won best subject-related series of articles for "The New, New Pharmaco-genomics." Kudos also to Art Director Mark Gabrenya, for his contributions to both stories. Bio·IT World was also a finalist for best startup publication and, curiously, for best editorials.

Kevin Davies, Ph.D.
Bio·IT World 

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