The Day DNA Met Its Match

On a dull winter day, a young, gangly American and an older Briton with a booming voice strolled into the Eagle pub in Cambridge, England. The older man flamboyantly proclaimed to the patrons that he and his friend had just uncovered the secret of life.

It wasn’t the demon drink talking: It was the sheer euphoria of discovery. That day -- 50 years ago today -- 24-year-old James Watson and 36-year-old Francis Crick realized they had solved one of the greatest mysteries of biology: the chemical structure of DNA, the blueprint of genetic inheritance.

Their finding was momentous, a leap forward that science needed desperately. By the early 1950s, biologists had begun to suspect that DNA, long viewed as a rather humdrum molecule, might actually be the stuff that genes were made of.

But no one knew what DNA looked like chemically -- and so, they had no clue how the stringy substance could harbor instructions for building blue eyes and brown skin, sunflowers and snapdragons, all the floridly varied items that evolution has shaped.

Watson and Crick figured out that structure on Feb. 28, 1953, after months of fervid discussion and chemical model-building. Informed by gorgeous images of DNA crystals from their colleagues and fueled by endless cups of tea and pints of bitter, they beat out their more seasoned rivals.

Fifty years on, the biological community is kicking up its collective heels in a worldwide anniversary jamboree, clinking glasses at galas, mulling the past and future at myriad scientific meetings, rolling out the TV retrospectives and pensively rubbing their chins at exhibitions of DNA-inspired art.

Crick, a distinguished research professor at the Salk Institute for Biological Studies, is in frail health and is remaining quietly at home in La Jolla. Watson, president of the Cold Spring Harbor Laboratory on Long Island, is touring the world.

Last week saw him in Monterey at a glitzy symposium sponsored by Time magazine, reminiscing on a stage adorned with giant atomic models and movies of swirling DNA strands. Tonight, he will be in New York, dining at a celebratory gala at the Waldorf-Astoria. In April -- the month when the pair’s spare, one-page paper was published in the prestigious scientific journal Nature -- he will be celebrating in England and unveiling a plaque at his old watering hole, the Eagle.

The over-the-top hoopla is excusable. Watson and Crick’s discovery has transformed practically every branch of medicine, biology, agriculture and pharmaceuticals.

Without understanding the structure of DNA, known in long form as deoxyribonucleic acid, there would be no biotech industry, no Human Genome Project, not a whisper of a chance for stem-cell therapy, and oceans of ignorance about the workings of our bodies in sickness and in health.

The genetic revolution that followed the finding was rapid. The structure that Watson and Crick unearthed was so elegant, so suggestive, that in less than a decade -- as a direct consequence of their work -- a string of deep mysteries about genes fell like dominoes.

Scientists deftly laid bare details of how DNA gets faithfully copied, how it mutates and evolves, how it carries a code, and how that code gets turned into proteins that build life and sustain it.

The discovery “was a complete watershed -- the great change of the last century in biology,� recalled Nobel-prize-winner Sidney Brenner of the Salk Institute, who played a key role in cracking the genetic code in the years that followed.

“I know that when I saw their model for the first time ... it was like turning over a page. It was, ‘Well, you can forget about everything else. Let’s get on with this.’ �

The story of Watson, Crick and the double helix that is DNA is about more than just a seminal leap in science -- it is also a gripping tale with a soap opera feel. The story has it all: warring colleagues, a precious prize, rivalries, secrecy, subterfuge and even a wronged woman: chemist Rosalind Franklin, whose X-ray pictures of DNA crystals were key to unraveling the mystery, but who some felt was cheated of the credit she deserved.

The setting for the discovery was the Cavendish Laboratory at Cambridge University, a drab, drafty building where (as Watson recalls) one needed those endless drinks of hot tea to stay warm.

Crick had arrived there in 1949 to get his doctorate in protein structure. The American whiz kid Watson arrived in 1951, also ostensibly to study proteins.

But not really.

In truth, Watson wanted to unearth the nature of genes. He was convinced that DNA, not proteins, held the key to that ultimate mystery.

Scientists had known about genes since 1900, the year long-ignored pea-breeding studies by Austrian monk Gregor Mendel were rediscovered, launching the field of genetics.

They had known about DNA even longer -- since 1869, when Swiss biochemist Johann Friedrich Miescher, while studying the chemistry of the cell nucleus, discovered it in pus drawn from bandages used on Crimean War wounded.

But it was hard for scientists to imagine that DNA and genes had much to do with each other. DNA contained nothing but sugars and phosphates and four chemicals known as “bases� -- adenine, thymine, guanine and cytosine. It was deemed far too stupid and simple to encode the complexities of life.

Proteins, on the other hand, were the movers and shakers in cells, able to chop things up and stick them together in myriad ways. They were top candidates for the brainy jobs of information storage and transmission.

Some data pointed toward DNA: A few years earlier, Rockefeller University bacteriologist Oswald Avery had shown that DNA could genetically alter bacteria. Most scientists refused to believe his results.

Watson and Crick were both believers; they were drawn to each other.

“We immediately discovered that we thought alike,� Watson said, reminiscing in Monterey last week. “He was the first person [that I met] who just accepted the Avery experiments. It was going to be DNA -- and [we decided] ‘Let’s go for it.’ �

“Go for it� they did -- although, as depicted by Watson, the effort was squeezed in between leisurely lunches, strolls through town and long chats about the charms of young ladies -- “popsies,� as Watson termed them.

They had rivals in the race. In England, Franklin and Maurice Wilkins at King’s College London were trying to solve DNA using a technique known as X-ray crystallography to create an image of the molecule. Franklin had been led to believe that DNA was her project alone. Wilkins thought Franklin was just his assistant. The two were barely speaking.

In America, the formidable Linus Pauling of Caltech, who had just solved a key structure of proteins for which he would later win a Nobel Prize -- was also working hard on solving DNA.

Unfazed by the competition, Watson and Crick jumped into the fray, aided by the few facts known about the molecule, and Franklin’s beautiful X-ray crystallography pictures, some of which had been presented publicly. They adopted a strategy of building experimental models out of Tinkertoy-like balls and rods to test which structures fit the data.

The months that followed were a herky-jerky mix of exuberance, false starts and several stomach-churning moments when they thought that they, or someone else, had found the answer.

In November 1951, after attending a presentation by Franklin, Watson and Crick believed they had the structure in their pocket -- a three-strand coil with the long backbones of phosphates and sugars on the inside and the four bases sticking out into space.

Wilkins and Franklin traveled up to Cambridge to take a look -- and were unimpressed.

“Awful,� is how Watson recently described the effort.

Pauling’s model -- shown to Watson and Crick by Pauling’s son, who happened to work in the same Cambridge department -- was no better: another triple helix with those bases again sticking outward.

“We’ll never understand how such an intelligent man did something so misguided,� Watson said.

The key came in January 1953. Wilkins -- without Franklin’s knowledge -- showed Watson Franklin’s new, clearer picture of a type of DNA known as the “B� form. The helical structure leaped from the dark blobs and swirls of the image.

“The instant I saw the picture, my mouth fell open and my pulse began to race,� Watson wrote in his 1968 book, “The Double Helix.�

Riding back to Cambridge on the train, he sketched everything he could remember of the image on a piece of newspaper.

A month later, the pair had the answer -- a double helix with strands running in opposite directions to each other. The backbones of sugars and phosphates were on the outside and the bases pointed into the center -- adenine on one strand always linked to thymine on the other, and cytosine always to guanine.

The beauty of the model, said Brenner, was that it showed how DNA could be accurately copied and inherited. First, the two strands could be pulled apart from each other. Then, for each, the second strand could be faithfully rebuilt -- directed by the specificity of the pairing of the bases.

Watson and Crick’s paper, less than a page in length, was published on April 25, 1953, followed a month later by a longer paper laying out the implications of the structure.

Crick, Watson and Wilkins were awarded the Nobel in 1962. Franklin tragically had died of ovarian cancer in 1958 at age 37, and so was denied the prize, which cannot be awarded after death. Had she lived, it is not clear what would have happened, because only three people can be awarded a Nobel.

With their discovery, Watson and Crick became two of the most famous biologists in the world. The very strands of the helix are often termed “Watson� and “Crick� in salute of them.

Thereafter, they trod very different paths, Crick as a researcher and thinker who played key roles in the cracking of the genetic code and later in the study of consciousness; Watson as a facilitator of science, who cheered on such giant projects as the Human Genome Project.

If the pair had not met or had kept their heads down, studying those proteins, what would have happened?

“If Beethoven hadn’t written the 9th Symphony, nobody else would have done it. But DNA was like America. It was waiting there to be discovered,� said Brenda Maddox, a London-based biographer who wrote a 2002 biography of Franklin.

Clearly, in a matter of months or years, the structure of the double helix would have been figured out. The molecular revolution would still have taken place.

Some believe the answer would have come to Pauling, who had solved other important molecular structures.

Others believe the discoverer would have been Franklin. Examining her notes after her death, a close colleague, Aaron Klug, penciled in the margin: “Nearly home.�

Yet Watson and Crick’s triumph, say scholars, lies in the subtle, intangible psychology of science. It lies in their rivals’ isolation, their own close collaboration and their complementary personalities, as well-matched as the strands of the helix that won them fame.

“Crick is absolutely top class. He has tremendous imagination, tremendous powers of intellectual capacity and capacity for hard work,� said Klug, a Nobel Prize winner and former president of Britain’s Royal Society. “But if it hadn’t been for Watson, it’s unlikely that Crick would have been drawn into it.

“Watson is the one who made it all happen. He pursued it, he set his sights on it, the most golden of molecules.�