Cardboard cutouts, flash of insight set off DNA revolution

NEW YORK -- Fifty years ago this month, on a foggy Saturday morning in Cambridge, England, a 24-year-old beanpole of an American scientist sat down with a few white cardboard cutouts and set off a revolution in biology.

The cutouts, about the size of teacup saucers, looked basically like an elementary school geometry project: Some were hexagons, others looked like a hexagon with a pentagon attached.

But to James Watson, who'd created them the night before, they represented fragments of the mysterious molecule that obsessed him and his collaborator Francis Crick: deoxyribonucleic acid, better known as DNA.

It wasn't yet clear to scientists whether DNA was the stuff of genes. But Watson and Crick thought it was, and for about 18 months they had been trying to figure out the three-dimensional structure of the DNA molecule.

"It seemed to us it had to be the secret of life," Watson recalled recently. "We thought it was the most important problem to solve if you were a biologist."

Four bases

As he worked in the lab at Cambridge University, he knew he had to be close.

The cardboard cutouts represented the four kinds of "bases" found in the DNA molecule. Bases are part of the basic building blocks of DNA, and somehow they had to pair up in a way that would nestle smoothly in the overall structure. But how?

It wasn't just a matter of jamming the cardboard polygons together; the real bases would bond only via hydrogen atoms that Watson portrayed with little sticks protruding from the cutouts.

As he switched the shapes around on his desk, he suddenly saw the answer: a scheme that gave him two identically shaped pairs.

His first reaction: "It's so beautiful."

Nowadays, even high school biology students know what Watson and, soon thereafter, Crick realized on that day:

The DNA molecule is a double helix, resembling a ladder that's been twisted along its length. Each "rung" is made up of two bases, paired according to the rule that jumped out at Watson from his desktop. These bases provide the genetic code; just as a four-letter alphabet could spell out words, the sequence of the four kinds of bases along the length of the DNA molecule spells out the information stored in genes.

The finding unleashed a torrent of research into DNA that's still going on, both to understand how it works and to put it to use. Many of today's scientific headlines -- the deciphering of the DNA of humans and other species, the transplanting of genes into animals and crops to change their traits, the use of gene therapy to treat disease, the DNA evidence that exonerates people imprisoned unjustly -- ultimately came from the double helix discovery.

The 50th anniversary of the finding is being widely celebrated this year by high-profile scientific journals and conferences in the United States, Europe and Australia. There's even a black-tie dinner on Feb. 28 -- the actual anniversary date -- at New York's Waldorf-Astoria, hosted by several scientific institutions.

Polite critics

All in all, it's a heady legacy for a couple of researchers who knew little chemistry and never did an experiment to reach their goal. Instead, they used research from others to guide them in building models that resembled Tinker Toy creations.

Watson, a Chicago native who'd abandoned zoology in college after a book got him excited about genetics, arrived in Cambridge in 1951 at age 23. There he met Crick, 12 years older, an ebullient physicist by training with a booming laugh. Soon the two men were sharing lunch almost every day; their colleagues eventually gave them a room together so they could talk without disturbing anybody else.

"It was intellectual love at first sight," says Victor McElheny, author of the new book, "Watson and DNA: Making a Scientific Revolution."

As they pondered the riddle of DNA, they challenged each other. They could be each other's worst critic, but in a polite way, McElheny said.

"Neither of us had a big ego ... we just wanted to get the answer," recalled Watson, now 74 and president of the Cold Spring Harbor Laboratory in Cold Spring, N.Y.

In this drive to the goal, he said in an interview, "Francis was brains .... I was the emotion."

But both of them could learn from the experimental results of others. Crucially, they benefited from work by chemist Rosalind Franklin of King's College in London. She had investigated the shape of DNA molecules by bombarding them with X-rays and tracking how the rays scattered. She found strong evidence of a helix structure -- results that Watson said made his jaw drop and his pulse race during one visit to London.

But Franklin died of ovarian cancer in 1958 at age 37, before she could have shared in the Nobel Prize.

So why was there a Nobel Prize at all? Why was this discovery such a big deal?

"It was an astonishing revelation," said George Washington University historian Horace Freeland Judson, who is editing a collection of Crick's scientific papers. "It made brilliantly clear, instantly, how genes worked in principle."

What's more, says Yale historian Daniel Kevles, it made a strong case that DNA was indeed the stuff of genes, and it opened up huge avenues of research. In fact, the structure plainly suggested the answer to one basic question about genes: How do they copy themselves so they can be inherited?

When they announced their discovery to the world in April 1953, Watson and Crick acknowledged that implication with one of the most famous sentences in scientific literature: "It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material."

It sure does. The pairing scheme that Watson saw on his desktop was shown within a few years to be key to how genes replicate themselves. The ladder-like DNA molecule splits lengthwise, cutting each rung in half and exposing each base to the chemical soup. Then each exposed base pairs off with the same kind of partner as before. Result: two identical DNA molecules.

The structure also gave scientists a starting point to attack the other big question about genes: How do they direct the moment-to-moment production of proteins in cells?

Scientists eventually discovered that molecules of a DNA-like substance called RNA carry instructions from genes to the cell's protein-making machinery. By the mid-1960s, they'd identified the "words" in the DNA code that ordered specific building blocks for proteins.

At the time Watson and Crick revealed their discovery, however, its significance was largely overlooked.

"It was like a tree falling in the middle of the forest. It had no impact," recalled Alex Rich, who was studying DNA at the California Institute of Technology when he heard the news, and is now a biophysics professor at the Massachusetts Institute of Technology.

"Most places just ignored it," Rich said, in part for lack of interest in DNA and because of skepticism over what was, after all, just a hypothesis.

Excitement about the discovery didn't really build up until the late 1950s, after scientists showed that DNA replicates itself the way Watson and Crick suggested, and other experiments began to sketch out its involvement in making proteins.

The DNA story is far from over. Scientists are still working out the details of how DNA is replicated so quickly and accurately -- an astonishing feat, since each human cell contains billions of base pairs lined up along nearly six feet of DNA, all packed into a nucleus only one-twentieth the width of a human hair.

Scientists are also exploring the use of DNA as a building material for making vanishingly tiny devices and powerful computers.

Crick, now 86, is president emeritus and a professor at the Salk Institute for Biological Studies in San Diego. He has turned to exploring the biology of consciousness. He and a collaborator published a commentary on that topic just this month.

Watson, who served as an early leader of the massive government project to map all the human genes, says the biggest questions nowadays in molecular biology -- the field he and Crick helped found -- lie in the brain.

"How are instincts inherited? ... How is information stored in the brain, whether it's your memory of a face or some sort of instinctive act? How does the brain tell the lion to kill?

"No one knows enough about the organization of the brain to come up with an answer," Watson said. "Brain research doesn't yet have its double helix."

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On the Net:

Anniversary Web site: www.dna50.org/main.htm

Primer on DNA: www.dnaftb.org