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Secret of Photo 51

Before Watson and Crick
by Brenda Maddox

Secret of Photo 51 homepage

The first half of 20th-century science belonged to physics, with the general theory of relativity, quantum mechanics, and nuclear fission. The second half would belong to biology. In the post-war world, the secret of the gene—how hereditary characteristics pass from one generation to another—was the hottest topic in science.

For a number of physicists who had worked on the Manhattan Project to develop the atomic bomb, the post-war shift into biology was a stark exchange of the science of death for the science of life. But their conversion was as much intellectual as ideological. Biology was now where the action lay. The war had interrupted a line of investigation leading towards understanding the chemical basis of heredity.

Seeking the genetic messenger

That physical features are passed on by discrete units (later called genes) had been discovered in 1865 by the Austrian monk Gregor Mendel in his experiments with garden peas. Each gene determined a single characteristic, such as height or color, in the next generation of plant. By 1905 it had been learned that within living cells the genes are strung together like beads on the chromosomes, which copy themselves and separate. But how does the genetic information get from the old chromosome to the new?

Protein was the obvious candidate. By the 1920s it was thought that genes were made of protein. The other main ingredient in the chromosome is deoxyribonucleic acid, or DNA. DNA, a substance of high molecular weight, was identified in 1871 by a young Swiss scientist, Friedrich Miescher. (There is, in fact, a second kind of nucleic acid in the cell, called RNA, with a slightly different chemical composition.) The "D" in DNA stands for "deoxy"—a prefix often spelled as "des" in Rosalind's day, a usage now obsolete—which identifies it as the ribonucleic acid with one fewer hydroxyl group. But as RNA exists in cells mainly outside the nucleus, it was unlikely to be the genetic vehicle.

Protein was far more interesting to geneticists than DNA because there was a lot more of it and also because each protein molecule is a long chain of chemicals, of which 20 kinds occur in living things. DNA, in contrast, contains only four kinds of the repeating units called nucleotides. Hence it seemed too simple to carry the complex instructions required to specify the distinct form of each of the infinite variety of cells that constitute living matter.

In 1936, at the Rockefeller Institute on the Upper East Side of Manhattan, a microbiologist called Oswald Avery wondered aloud if the "transforming principle"—that is, the carrier of the genetic information from old chromosomes to new—might not be the nucleic acid, DNA. No one took much notice. DNA seemed just a boring binding agent for the protein in the cell.

During the pre-war years, in Britain, J.D. Bernal at Cambridge and William Astbury at Leeds, both crystallographers, began using X-rays to determine the structure of molecules in crystals. Astbury, interested in very large biological molecules, had taken hundreds of X-ray diffraction pictures of fibers prepared from DNA. From the diffraction patterns obtained, Astbury tried building a model of DNA. With metal plates and rods, he put together a Meccano-like model suggesting how DNA's components—bases, sugars, phosphates—might fit together. Astbury concluded—correctly, as it turned out—that the bases lay flat, stacked on each other like a pile of pennies spaced 3.4 Ångströms apart. [An Ångström equals one ten-billionth of a meter.] This "3.4 Å" was no gratuituous detail. Published with other measurements in an Astbury paper in Nature in 1938, it was to remain constant throughout all the attempts to solve DNA's structure that were to come.

Avery’s discovery has been called worth two Nobel Prizes, but he never got even one.

But Astbury made serious errors, his work was tentative, and he had no clear idea of the way forward. By the time of the Second World War, no one knew that genes were composed entirely of DNA.

The gene's genie

In 1943, Avery, at 67, was too old for military service. Still working at the Rockefeller Institute and building on an experiment with pneumococcus (bacteria that cause pneumonia) done by the English physician Frederick Griffith in 1928, he made a revolutionary discovery. He found that when DNA was transferred from a dead strain of pneumoccocus to a living strain, it brought with it the hereditary attributes of the donor.

Was the "transforming principle" so simple then—purely DNA? In science, where many grab for glory, there are some who thrust glory from them. Avery, a shy bachelor who wore a pince-nez, was one of those too modest for his own good. His discovery has been called worth two Nobel Prizes, but he never got even one—perhaps because, rather than rushing into print, he put his findings in a letter to his brother Roy, a medical bacteriologist at Vanderbilt University Medical School in Nashville. "I have not published anything about it—indeed have discussed it only with a few," he said, "because I am not yet convinced that we have (as yet) sufficient evidence."

A year later, however, Avery, with two colleagues, wrote out their research. In what became a classic paper, they described an intricate series of experiments using the two forms of pneumococcus, virulent and nonvirulent. When they freed a purified form of DNA from heat-killed virulent pneumococcus bacteria and injected it into a live, nonvirulent strain, they found that it produced a permanent heritable change in the DNA of the recipient cells. Thus the fact was established—at least for the readers of The Journal of Experimental Medicine—that the nucleic acid DNA and not the protein was the genetic message-carrier.

The essential mystery remained. How could a monotonous substance such as DNA, like an alphabet with only four letters, convey enough specific information to produce the enormous variety of living things, from daisies to dinosaurs? The answer must lie in the way the molecule was put together. Avery and his co-authors, Colin MacLeod and Maclyn McCarty, could say no more than that "nucleic acids must be regarded as possessing biological specificity the chemical basis of which is as yet undetermined."

Biophysics is born

In 1943, another scientist at one remove from the world conflict (because he had been offered a haven in neutral Ireland) gave a series of lectures in Dublin, called provocatively "What is Life?" An audience of 400 for every lecture suggested that his supposedly difficult subject was of great general interest.

Erwin Schrödinger, a Viennese, had shared the Nobel Prize in physics in 1933 for laying the foundations of wave mechanics. That same year he left Berlin, where he had been working, because, although not himself Jewish, he would not remain in Germany when persecution of the Jews became national policy. A long odyssey through Europe brought him, in 1940, to Dublin at the invitation of Eamon de Valera, Ireland's premier. De Valera had been a mathematician before he became a revolutionary, then a politician; in 1940 he set up the Dublin Institute of Advanced Studies. Schrödinger found Ireland "paradise," not least because it allowed him the detachment to think about a very big question.

In his Dublin lectures, Schrödinger addressed what puzzled many students—why biology was treated as a subject completely separate from physics and chemistry: frogs, fruit flies, and cells on one side, atoms and molecules, electricity and magnetism, on the other. The time had come, Schrödinger declared from his Irish platform, to think of living organisms in terms of their molecular and atomic structure. There was no great divide between the living and nonliving; they all obey the same laws of physics and chemistry.

He put a physicist's question to biology. If entropy is (according to the second law of thermodynamics) things falling apart, the natural disintegration of order into disorder, why don't genes decay? Why are they instead passed intact from generation to generation?

What Is Life? was the Uncle Tom’s Cabin of biology—a small book that started a revolution.

He gave his own answer. "Life" is matter that is doing something. The technical term is metabolism—"eating, drinking, breathing, assimilating, replicating, avoiding entropy." To Schrödinger, life could be defined as "negative entropy"—something not falling into chaos and approaching "the dangerous state of maximum entropy, which is death." Genes preserve their structure because the chromosome that carries them is an irregular crystal. The arrangement of units within the crystal constitutes the hereditary code.

The lectures were published as a book the following year, ready for physicists to read as the war ended and they looked for new frontiers to explore. To the molecular biologist and scientific historian Gunther Stent of the University of California at Berkeley, What Is Life? was the Uncle Tom's Cabin of biology—a small book that started a revolution. For post-war physicists, suffering from professional malaise, "When one of the inventors of quantum mechanics [could] ask 'What is life?,'" Stent declared, "they were confronted with a fundamental problem worthy of their mettle." Biological problems could now be tackled with their own language, physics.

Research into the new field of biophysics inched forward in the late 1940s. In 1949 another Austrian refugee scientist, Erwin Chargaff, working at the Columbia College of Physicians and Surgeons in New York, was one of the very few who took Avery's results to heart and changed his research program in consequence. He analyzed the proportions of the four bases of DNA and found a curious correspondence. The numbers of molecules present of the two bases, adenine and guanine, called purines, were always equal to the total amount of thymine and cytosine, the other two bases, called pyrimidines. This neat ratio, found in all forms of DNA, cried out for explanation, but Chargaff could not think what it might be.

That is where things stood when Rosalind Franklin arrived at King's College London on 5 January 1951. Leaving coal research to work on DNA, moving from the crystal structure of inanimate substances to that of biological molecules, she had crossed the border between nonliving and living. Coal does not make more coal, but genes make more genes.

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Watson and Crick

James Watson and Francis Crick stumbled upon the structure of DNA, but only by making use of the discoveries of many scientists who came before them, including Rosalind Franklin.


Friedrich Miescher, working at a laboratory in Tuebingen Castle in southwestern Germany, discovered DNA as early as 1871.


At a time when many scientists thought proteins must ferry heritable attributes to the next generation, microbiologist Oswald Avery discovered that the genetic carrier was in fact the humble nucleic acid DNA.


In 1940, Nobel laureate Erwin Schrödinger helped launch the new field of biophysics with a lecture engagingly titled "What is Life?"


Erwin Chargaff's discovery in 1949 that the total number of two of DNA's four base chemicals always equaled the total number of the other two helped set the stage for Watson and Crick's brilliant insight into DNA's structure just four years later.

Secret of Photo 51 Web Site Content
Before Watson & Crick

Before Watson and Crick
Brenda Maddox on how scientists came to focus on DNA as the secret of life.

Defending Franklin's Legacy

Defending Franklin's Legacy
One biologist's perspective on why Franklin deserved a Nobel Prize.

Picturing the Molecules of Life

Picturing the Molecules of Life
See how far imaging of DNA and other molecules has come in 50 years.

Anatomy of Photo 51

Anatomy of Photo 51
This shadowy X-ray photograph speaks volumes about the shape of DNA.

Journey into DNA

Journey into DNA
Take an animated journey into the tiny world of DNA.

Maddox Brenda Maddox is the author of Rosalind Franklin: The Dark Lady of DNA (HarperCollins, 2002), from which this article was excerpted with kind permission of the publisher.

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