The First Dna Revolutionaries

Posted: July 03, 2000

They seemed unlikely candidates to make one of the pivotal discoveries of the 20th century. Francis H.C. Crick was a 35-year-old Ph.D. candidate who had abandoned physics, hoping to find his niche in biology. James D. Watson was a gawky-looking 24-year-old who rarely bothered to tie his shoelaces.

Both scientists were supposed to be working on other things, but they believed fervently that the most important scientific problem of their time was the mystery of inheritance - how everything from diseases to hair color to the very instructions to make a human being was passed on from generation to generation. They believed, as a few others did, that this "genetic code" was carried in the structure of a molecule called DNA.

In 1953, within two years of working together, they cracked that code,which turned out to be written in DNA's graceful spiraling structure. (Less than a half-century later, the Human Genome Project - an international effort that Watson himself shaped as its early chairman in the mid-1980s - last week announced that it had completed a massive reading of the genetic code as it applies to human beings.)

"It's a marvelous story about timing and circumstance, chance and ability coming together," said Gregory Petsko, a biologist at Brandeis University whose work involves discovering the structures of other biological molecules.

Watson and Crick have been honored over and over for their discovery, most notably with the 1962 Nobel Prize for Physiology or Medicine. Tomorrow, Philadelphia's highest award will be added to their collection.

Mayor Street will present a Liberty Medal to Watson at 10 a.m. tomorrow in front of Independence Hall. Watson has asked that the $100,000 prize be divided between the Salk Institute in La Jolla, Calif., and Clare College in Cambridge, England, where he studied. Crick, who has not left Southern California in years, will deliver brief remarks on audiotape.

Before Watson and Crick looked into it, deoxyribonucleic acid (DNA) was thought of as just formless gunk within a cell. They revealed it to be a collection of long, threadlike strands of a double helix - a twisted ladder carrying the four-letter genetic alphabet on its rungs.

The finding changed the world in dozens of ways. It clinched Darwin's theory of evolution by showing the relationship between all living things, revolutionized forensics, showed for the first time how cancer worked, started an industry known as biotechnology, and banished old notions of race by showing that all humans sprang from a recent common origin in Africa.

"It set the tone for the research in the rest of biology from that time until last week, when they announced the end of the Human Genome Project," said Norton Zinder, a Rockefeller University biologist who chaired the international gene-mapping effort and knew Watson and Crick at the time of their original finding.

"These were two guys who didn't really know what to do with themselves - they really didn't work too hard," Zinder said.

The American Watson, by his own written account, had gone to England on a fellowship to do other kinds of biology, and the Briton Crick was supposed to study proteins, not DNA, to secure his doctorate. Unlike the stereotypical scientists slaving away till dawn in basement laboratories, both Watson and Crick enjoyed endless dinner parties and otherwise lived a rich social life in Cambridge, according to Watson's 1968 memoir, The Double Helix.

But they never stopped thinking and talking about DNA. It was Watson's belief in DNA that took him to Cavendish Laboratory in 1951. There he met Crick, who, to his delight, shared his belief that DNA held the genetic code, and that it could be cracked.

They bonded almost immediately. The two men developed a sort of "intellectual crush on each other," historian Horace Freeland Judson writes in his book about the discovery, The Eighth Day of Creation.

At that time, genes were just a hazy concept. People talked of them as objects that passed traits from parents to offspring, but no one knew where they were located, what they were made of, or how they performed this feat.

It was clear that genes somehow translated their code into the construction of living tissue - telling a fertilized egg how to turn into a full-fledged organism. To do this, genes had to be very good at making copies of themselves so they could be passed from parent to offspring, and copied throughout the cells of the body.

Early 20th-century biologists realized the genes must be carried by some microscopic entities inside individual cells, and they correctly zeroed in on structures called chromosomes. Chemical analysis showed these chromosomes were made of protein and two other substances - RNA and DNA. Most people thought the protein was the important part, not the DNA.

But then a group of scientists at Rockefeller University in New York performed an early version of genetic engineering, moving DNA from one bacteria to another. The researchers used two kinds of bacteria, a smooth-looking one and a wrinkly one. When they swapped DNA, they found they could make smooth bacteria reproduce as wrinkly and the wrinkly ones, smooth.

Still, only a handful of scientists made the leap to the importance of DNA or thought it was possible to understand how it worked. The main exception was Linus Pauling, considered the world's greatest chemist and a man whom the young Watson and Crick admired, imitated and feared.

Watson was sure that Pauling, 6,000 miles away at the California Institute of Technology, was hot on the DNA trail.

The only way to beat Pauling, the pair realized, was to use his own method for understanding chemical structures. Pauling had pioneered the use of physical models, resembling Tinker Toys, that he built by figuring out the exact bonding tendencies of the various atoms involved in a large molecule. (Nowadays, such modeling would be done by computer.)

But Watson and Crick had one advantage over Pauling. Crick, with his physics background, had become interested in an analytical technique called X-ray crystallography, in which scientists passed X-rays through materials, creating patterns that reveal keys to the materials' crystalline structure. A few people were beginning to use X-rays to study complicated biological substances.

X-ray crystallography wasn't something a scientist could just pick up, however. It took years of training to learn to do it right. Recognizing this, Crick struck up a collaboration with a laboratory in nearby London, where two other scientists, Maurice Wilkins and Rosalind Franklin, were beginning to use the technique on DNA.

Combining X-ray crystallography and modeling, Watson and Crick still found the structure a puzzle. The easy thing was figuring out that DNA had a repetitive part, which they called the backbone, and a more irregular part - four chemicals called bases that might be carriers of a four-character code.

The hard thing was determining how they went together. The scientists thought the structure probably coiled into a "helix," as other large biological molecules tend to do. But they constructed their model of DNA as a triple helix, with the uniform backbone in the middle and the coding bases - dubbed A,C,T, and G - on the outsides.

They recognized that this structure wasn't quite right, but not so Pauling, who got his version of an erroneous triple helix published in the scientific journal Nature.

Meanwhile, Franklin, one of the X-ray crystallography experts with whom Watson and Crick had been working, had perfected her technique. One of her pictures showed that the backbone had to be on the outside, with the coding bases in the middle.

That, combined with clues from chemists about the bonding properties of the bases, quickly led them to the correct structure - the double helix in which each base pairs up with a counterpart: C (Cytosine) with G (Guanine), and A (Adenine) with T (Thymine).

Once others saw it (and Nature published it), acceptance by the worldwide scientific community was almost immediate. The structure was simple, elegant, and had the ability to do all the things that the previously mystical "genes" seemed to do.

"It looked so good . . . it was too pretty not to be true," Zinder said. "Things after that seemed sort of obvious."

Watson went on to teach at Harvard University before heading the molecular biology program at Cold Spring Harbor Laboratory on Long Island. He directed the Human Genome Project between 1989 and 1992.

Crick continued to piece together the genetic puzzle, helping to show how DNA's cousin, RNA, was used to transfer information to proteins, the building blocks of life. He moved to the Salk Institute in 1977, and in recent years has concentrated on another mysterious arena - the workings of the brain and the poorly understood phenomenon we call consciousness.

Faye Flam's e-mail address is fflam@phillynews.com

Liberty Medal

The medal: The Philadelphia Liberty Medal honors "an individual or organization from anywhere in the world that has demonstrated leadership and vision in the pursuit of liberty of conscience or freedom from oppression, ignorance or deprivation." It comes with a $100,000 prize.

Selection: Recipients are chosen by an international commission made up of leaders in government, world affairs, education, culture and business. The medal is administered by Greater Philadelphia First, comprising the chief executives of some of the region's largest companies.

Past winners: Lech Walesa (1989), former President Jimmy Carter (1990), Oscar Arias/Doctors Without Borders (1991), Thurgood Marshall (1992), F.W. de Klerk/Nelson Mandela (1993), Vaclav Havel (1994), Sadako Ogata (1995), King Hussein I/Shimon Peres (1996), CNN International (1997), George J. Mitchell (1998), Kim Dae Jung (1999).

If You Go: Mayor Street will present the medal to James D. Watson (Francis H.C. Crick will send taped remarks) tomorrow at 10 a.m. in front of Independence Hall, Chestnut Street between Fifth and Sixth Streets. The ceremony will go on rain or shine.

Broadcast: The event will be broadcast live by WPVI-TV (Channel 6) from 10 till around 11:15 a.m.

|
|
|
|
|