What was it, then? It could be frozen and thawed. Alcohol precipitated it. It settled out of solution in a white “fibrous substance . . . that wraps itself about a glass rod like a thread on a spool.” Had Avery placed the fibrous spool on his tongue, he might have tasted the faint sourness of the acid, followed by the aftertaste of sugar and the metallic note of salt—like the taste of the “primordial sea,” as one writer described it. An enzyme that digested RNA had no effect. The only way to eradicate transformation was to digest the material with an enzyme that, of all things, degraded DNA.
DNA? Was DNA the carrier of genetic information? Could the “stupid molecule” be the carrier of the most complex information in biology? Avery, MacLeod, and McCarty unleashed a volley of experiments, testing the transforming principle using UV light, chemical analysis, electrophoresis. In every case, the answer was clear: the transforming material was indubitably DNA. “Who could have guessed it?” Avery wrote hesitantly to his brother in 1943. “If we are right—and of course that’s not yet proven—then nucleic acids are not merely structurally important but functionally active substances . . . that induce predictable and hereditary changes in cells [the underlined words are Avery’s].”
Avery wanted to be doubly sure before he published any results: “It is hazardous to go off half-cocked, and embarrassing to have to retract it later.” But he fully understood the consequences of his landmark experiment: “The problem bristles with implications. . . . This is something that has long been the dream of geneticists.” As one researcher would later describe it, Avery had discovered “the material substance of the gene”—the “cloth from which genes were cut.”
Oswald Avery’s paper on DNA was published in 1944—the very year that the Nazi exterminations ascended to their horrific crescendo in Germany. Each month, trains disgorged thousands of deported Jews into the camps. The numbers swelled: in 1944 alone, nearly 500,000 men, women, and children were transported to Auschwitz. Satellite camps were added, and new gas chambers and crematoria were constructed. Mass graves overflowed with the dead. That year, an estimated 450,000 were gassed to death. By 1945, 900,000 Jews, 74,000 Poles, 21,000 Gypsies (Roma), and 15,000 political prisoners had been killed.
In the early spring of 1945, as the soldiers of the Soviet Red Army approached Auschwitz and Birkenau through the frozen landscape, the Nazis attempted to evacuate nearly sixty thousand prisoners from the camps and their satellites. Exhausted, cold, and severely malnourished, many of these prisoners died during the evacuation. On the morning of January 27, 1945, Soviet troops entered the camps and liberated the remaining seven thousand prisoners—a minuscule remnant of the number killed and buried in the camp. By then the language of eugenics and genetics had long become subsidiary to the more malevolent language of racial hatred. The pretext of genetic cleansing had largely been subsumed by its progression into ethnic cleansing. Even so, the mark of Nazi genetics remained, like an indelible scar. Among the bewildered, emaciated prisoners to walk out of the camp that morning were one family of dwarfs and several twins—the few remaining survivors of Mengele’s genetic experiments.
This, perhaps, was the final contribution of Nazism to genetics: it placed the ultimate stamp of shame on eugenics. The horrors of Nazi eugenics inspired a cautionary tale, prompting a global reexamination of the ambitions that had spurred the effort. Around the world, eugenic programs came to a shamefaced halt. The Eugenics Record Office in America had lost much of its funding in 1939 and shrank drastically after 1945. Many of its most ardent supporters, having developed a convenient collective amnesia about their roles in encouraging the German eugenicists, renounced the movement altogether.
* * *
I. The “backbone” or spine of DNA and RNA is made of a chain of sugars and phosphates strung together. In RNA, the sugar is ribose—hence Ribo-Nucleic Acid (RNA). In DNA, the sugar is a slightly different chemical: deoxyribose—hence Deoxyribo-Nucleic Acid (DNA).
“Important Biological Objects Come in Pairs”
One could not be a successful scientist without realizing that, in contrast to the popular conception supported by newspapers and the mothers of scientists, a goodly number of scientists are not only narrow-minded and dull, but also just stupid.
—James Watson
It is the molecule that has the glamour, not the scientists.
—Francis Crick
Science [would be] ruined if—like sports—it were to put competition above everything else.
—Benoit Mandelbrot
Oswald Avery’s experiment achieved another “transformation.” DNA, once the underdog of all biological molecules, was thrust into the limelight. Although some scientists initially resisted the idea that genes were made of DNA, Avery’s evidence was hard to shrug off (despite three nominations, however, Avery was still denied the Nobel Prize because Einar Hammarsten, the influential Swedish chemist, refused to believe that DNA could carry genetic information). As additional proof from other laboratories and experiments accumulated in the 1950s,I even the most hidebound skeptics had to convert into believers. The allegiances shifted: the handmaiden of chromatin was suddenly its queen.
Among the early converts to the religion of DNA was a young physicist from New Zealand, Maurice Wilkins. The son of a country doctor, Wilkins had studied physics at Cambridge in the 1930s. The gritty frontier of New Zealand—far away and upside down—had already produced a force that had turned twentieth-century physics on its head: Ernest Rutherford, another young man who had traveled to Cambridge on scholarship in 1895, and torn through atomic physics like a neutron beam on the loose. In a blaze of unrivaled experimental frenzy, Rutherford had deduced the properties of radioactivity, built a convincing conceptual model of the atom, shredded the atom into its constituent subatomic pieces, and launched the new frontier of subatomic physics. In 1919, Rutherford had become the first scientist to achieve the medieval fantasy of chemical transmutation: by bombarding nitrogen with radioactivity, he had converted it into oxygen. Even elements, Rutherford had proved, were not particularly elemental. The atom—the fundamental unit of matter—was actually made of even more fundamental units of matter: electrons, protons, and neutrons.
Wilkins had followed in Rutherford’s wake, studying atomic physics and radiation. He had moved to Berkeley in the 1940s, briefly joining scientists to separate and purify isotopes for the Manhattan Project. But on returning to England, Wilkins—following the trend among many physicists—had edged away from physics toward biology. He had read Schrödinger’s What Is Life? and become instantly entranced. The gene—the fundamental unit of heredity—must also be made of subunits, he reasoned, and the structure of DNA should illuminate these subunits. Here was a chance for a physicist to solve the most seductive mystery of biology. In 1946, Wilkins was appointed assistant director of the new Biophysics Unit at King’s College in London.
Biophysics. Even that odd word, the mishmash of two disciplines, was a sign of new times. The nineteenth-century realization that the living cell was no more than a bag of interconnected chemical reactions had launched a powerful discipline fusing biology and chemistry—biochemistry. “Life . . . is a chemical incident,” Paul Ehrlich, the chemist, had once said, and biochemists, true to form, had begun to break open cells and characterize the constituent “living chemicals” into classes and functions. Sugars provided energy. Fats stored it. Proteins enabled chemical reactions, speeding and controlling the pace of biochemical processes, thereby acting as the switchboards of the biological world.
But how did proteins make physiological reactions possible? Hemoglobin, the oxygen carrier in blood, for instance, performs one of the simplest and yet most vital reactions in physiology. When exposed to high levels of oxygen, hemoglobin binds oxygen. Relocated to a site with low oxygen levels, it willingly releases the bound oxygen. This property allows hemoglobin to shuttle oxygen from the lung to the heart and the brain. But what feature of hemoglobin allows it to act as such an effective molecular shuttle?<
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The answer lies in the structure of the molecule. Hemoglobin A, the most intensively studied version of the molecule, is shaped like a four-leaf clover. Two of its “leaves” are formed by a protein called alpha-globin; the other two are created by a related protein, beta-globin.II Each of these leaves clasps, at its center, an iron-containing chemical named heme that can bind oxygen—a reaction distantly akin to a controlled form of rusting. Once all the oxygen molecules have been loaded onto heme, the four leaves of hemoglobin tighten around the oxygen like a saddle clasp. When unloading oxygen, the same saddle-clasp mechanism loosens. The unbinding of one molecule of oxygen coordinately relaxes all the other clasps, like the crucial pin-piece pulled out from a child’s puzzle. The four leaves of the clover now twist open, and hemoglobin yields its cargo of oxygen. The controlled binding and unbinding of iron and oxygen—the cyclical rusting and unrusting of blood—allows effective oxygen delivery into tissues. Hemoglobin allows blood to carry seventyfold more oxygen than what could be dissolved in liquid blood alone. The body plans of vertebrates depend on this property: if hemoglobin’s capacity to deliver oxygen to distant sites was disrupted, our bodies would be forced to be small and cold. We might wake up and find ourselves transformed into insects.
It is the form of hemoglobin, then, that permits its function. The physical structure of the molecule enables its chemical nature, the chemical nature enables its physiological function, and its physiology ultimately permits its biological activity. The complex workings of living beings can be perceived in terms of these layers: physics enabling chemistry, and chemistry enabling physiology. To Schrödinger’s “What is life?” a biochemist might answer, “If not chemicals.” And what are chemicals—a biophysicist might add—if not molecules of matter?
This description of physiology—as the exquisite matching of form and function, down to the molecular level—dates back to Aristotle. For Aristotle, living organisms were nothing more than exquisite assemblages of machines. Medieval biology had departed from that tradition, conjuring up “vital” forces and mystical fluids that were somehow unique to life—a last-minute deus ex machina to explain the mysterious workings of living organisms (and justify the existence of the deus). But biophysicists were intent on restoring a rigidly mechanistic description to biology. Living physiology should be explicable in terms of physics, biophysicists argued—forces, motions, actions, motors, engines, levers, pulleys, clasps. The laws that drove Newton’s apples to the ground should also apply to the growth of the apple tree. Invoking special vital forces or inventing mystical fluids to explain life was unnecessary. Biology was physics. Machina en deus.
Wilkins’s pet project at King’s was solving the three-dimensional structure of DNA. If DNA was truly the gene carrier, he reasoned, then its structure should illuminate the nature of the gene. Just as the terrifying economy of evolution had stretched the length of the giraffe’s neck and perfected the four-armed saddle clasp of hemoglobin, that same economy should have generated a DNA molecule whose form was exquisitely matched to its function. The gene molecule had to somehow look like a gene molecule.
To decipher the structure of DNA, Wilkins had decided to corral a set of biophysical techniques invented in nearby Cambridge—crystallography and X-ray diffraction. To understand the basic outline of this technique, imagine trying to deduce the shape of a minute three-dimensional object—a cube, say. You cannot “see” this cube nor feel its edges—but it shares the one property that all physical objects must possess: it generates shadows. Imagine that you can shine light at the cube from various angles and record the shadows that are formed. Placed directly in front of the light, a cube casts a square shadow. Illuminated obliquely, it forms a diamond. Move the light source again, and the shadow is a trapezoid. The process is almost absurdly laborious—like sculpting a face out of a million silhouettes—but it works: piece by piece, a set of two-dimensional images can be transmuted into a three-dimensional form.
X-ray diffraction arises out of analogous principles—the “shadows” are actually the scatters of X-rays generated by a crystal—except to illuminate molecules and generate scatters in the molecular world, one needs the most powerful source of light: X-rays. And there’s a subtler problem: molecules generally refuse to sit still for their portraits. In liquid or gas form, molecules whiz dizzily in space, moving randomly, like particles of dust. Shine light on a million moving cubes and you only get a hazy, moving shadow, a molecular version of television static. The only solution to the problem is ingenious: transform a molecule from a solution to a crystal—and its atoms are instantly locked into position. Now the shadows become regular; the lattices generate ordered and readable silhouettes. By shining X-rays at a crystal, a physicist can decipher its structure in three-dimensional space. At Caltech, two physical chemists, Linus Pauling and Robert Corey, had used this technique to solve the structures of several protein fragments—a feat that would win Pauling the Nobel Prize in 1954.
This, precisely, is what Wilkins hoped to do with DNA. Shining X-rays on DNA did not require much novelty or expertise. Wilkins found an X-ray diffraction machine in the chemistry department and housed it—“in solitary splendor”—in a lead-lined room under the embankment wing, just below the level of the neighboring river Thames. He had all the crucial material for his experiment. Now his main challenge was to make DNA sit still.
Wilkins was plowing methodically through his work in the early 1950s when he was interrupted by an unwelcome force. In the winter of 1950, the head of the Biophysics Unit, J. T. Randall, recruited an additional young scientist to work on crystallography. Randall was patrician, a small, genteel, cricket-loving dandy who nonetheless ran his unit with Napoleonic authority. The new recruit, Rosalind Franklin, had just finished studying coal crystals in Paris. In January 1951, she came up to London to visit Randall.
Wilkins was away on vacation with his fiancée—a decision he would later regret. It is not clear how much Randall had anticipated future collisions when he suggested a project to Franklin. “Wilkins has already found that fibers of [DNA] give remarkably good diagrams,” he told her. Perhaps Franklin would consider studying the diffraction patterns of these fibers and deduce a structure? He had offered her DNA.
When Wilkins returned from vacation, he expected Franklin to join him as his junior assistant; DNA had, after all, always been his project. But Franklin had no intention of assisting anyone. A dark-haired, dark-eyed daughter of a prominent English banker, with a gaze that bored through her listeners like X-rays, Franklin was a rare specimen in the lab—an independent female scientist in a world dominated by men. With a “dogmatic, pushy father,” as Wilkins would later write, Franklin grew up in a household where “her brothers and father resented R.F.’s greater intelligence.” She had little desire to work as anyone’s assistant—let alone for Maurice Wilkins, whose mild manner she disliked, whose values, she opined, were hopelessly “middle-class,” and whose project—deciphering DNA—was on a direct collision course with hers. It was, as one friend of Franklin’ s would later put it, “hate at first sight.”
Wilkins and Franklin worked cordially at first, meeting for occasional coffee at the Strand Palace Hotel, but the relationship soon froze into frank, glacial hostility. Intellectual familiarity bred a slow, glowering contempt; in a few months, they were barely on speaking terms. (She “barks often, doesn’t succeed in biting me,” Wilkins later wrote.) One morning, out with separate groups of friends, they found themselves punting on the Cam River. As Franklin charged down the river toward Wilkins, the boats came close enough to collide. “Now she’s trying to drown me,” he exclaimed in mock horror. There was nervous laughter—the kind when a joke cuts too close to the truth.
What she was trying to drown, really, was noise. The chink of beer mugs in pubs infested by men; the casual bonhomie of men discussing science in their male-only common room at King’s. Franklin found most of her male colleagues “positively repulsive.” It was not just sexism—but th
e innuendo of sexism that was exhausting: the energy spent parsing perceived slights or deciphering unintended puns. She would rather work on other codes—of nature, of crystals, of invisible structures. Unusually for his time, Randall was not averse to hiring women scientists; there were several women working with Franklin at King’s. And female trailblazers had come before her: severe, passionate Marie Curie, with her chapped palms and char-black dresses, who had distilled radium out of a cauldron of black sludge and won not one Nobel Prize but two; and matronly, ethereal Dorothy Hodgkin at Oxford, who had won her own Nobel for solving the crystal structure of penicillin (an “affable looking housewife,” as one newspaper described her). Yet Franklin fit neither model: she was neither affable housewife nor cauldron-stirrer in a boiled wool robe, neither Madonna nor witch.
The noise that bothered Franklin most was the fuzzy static in the DNA pictures. Wilkins had obtained some highly purified DNA from a Swiss lab and stretched it into thin, uniform fibers. By stringing the fiber along a gap in a stretch of wire—a bent paper clip worked marvelously—he hoped to diffract X-rays and obtain images. But the material had proved difficult to photograph; it generated scattered, fuzzy dots on film. What made a purified molecule so difficult to image? she wondered. Soon, she stumbled on the answer. In its pure state, DNA came in two forms. In the presence of water, the molecule was in one configuration, and as it dried out, it switched to another. As the experimental chamber lost its humidity, the DNA molecules relaxed and tensed—exhaling, inhaling, exhaling, like life itself. The switch between the two forms was partly responsible for the noise that Wilkins had been struggling to minimize.
The Gene Page 17