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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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.
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Friedrich Miescher, working at a laboratory in Tuebingen Castle in
southwestern Germany, discovered DNA as early as 1871.
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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.
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In 1940, Nobel laureate Erwin Schrödinger
helped launch the new field of biophysics with a lecture engagingly titled
"What is Life?"
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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.
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