The Gene
Galton proposed piggybacking on a natural experiment. Since twins share identical genetic material, he reasoned, any substantial similarities between them could be attributed to genes, while any differences were the consequence of environment. By studying twins, and comparing and contrasting similarities and differences, a geneticist could determine the precise contributions of nature versus nurture to important traits.
Galton was on the right track—except for a crucial flaw: he had not distinguished between identical twins, who are truly genetically identical, and fraternal twins, who are merely genetic siblings (identical twins are derived from the splitting of a single fertilized egg, thereby resulting in twins with identical genomes, while fraternal twins are derived from the simultaneous fertilization of two eggs by two sperm, thereby resulting in twins with nonidentical genomes). Early twin studies were thus confounded by this confusion, leading to inconclusive results. In 1924, Hermann Werner Siemens, the German eugenicist and Nazi sympathizer, proposed a twin study that advanced Galton’s proposal by meticulously separating identical twins from fraternal twins.III
A dermatologist by training, Siemens was a student of Ploetz’s and a vociferous early proponent of racial hygiene. Like Ploetz, Siemens realized that genetic cleansing could be justified only if scientists could first establish heredity: you could justify sterilizing a blind man only if you could establish that his blindness was inherited. For traits such as hemophilia, this was straightforward: one hardly needed twin studies to establish heredity. But for more complex traits, such as intelligence or mental illness, the establishment of heredity was vastly more complex. To deconvolute the effects of heredity and environment, Siemens suggested comparing fraternal twins to identical twins. The key test of heredity would be concordance. The term concordance refers to the fraction of twins who possess a trait in common. If twins share eye color 100 percent of the time, then the concordance is 1. If they share it 50 percent of the time, then the concordance is 0.5. Concordance is a convenient measure for whether genes influence a trait. If identical twins possess a strong concordance for schizophrenia, say, while fraternal twins—born and bred in an identical environment—show little concordance, then the roots of that illness can be firmly attributed to genetics.
For Nazi geneticists, these early studies provided the fuel for more drastic experiments. The most vigorous proponent of such experiments was Josef Mengele—the anthropologist-turned-physician-turned-SS-officer who, sheathed in a white coat, haunted the concentration camps at Auschwitz and Birkenau. Morbidly interested in genetics and medical research, Mengele rose to become physician in chief at Auschwitz, where he unleashed a series of monstrous experiments on twins. Between 1943 and 1945, more than a thousand twins were subjected to Mengele’s experiments.IV Egged on by his mentor, Otmar von Verschuer from Berlin, Mengele sought out twins for his studies by trawling through the ranks of incoming camp prisoners and shouting a phrase that would become etched into the memories of the camp dwellers: Zwillinge heraus (“Twins out”) or Zwillinge heraustreten (“Twins step out”).
Yanked off the ramps, the twins were marked by special tattoos, housed in separate blocks, and systematically victimized by Mengele and his assistants (ironically, as experimental subjects, twins were also more likely to survive the camp than nontwin children, who were more casually exterminated). Mengele obsessively measured their body parts to compare genetic influences on growth. “There isn’t a piece of body that wasn’t measured and compared,” one twin recalled. “We were always sitting together—always nude.” Other twins were murdered by gassing and their bodies dissected to compare the sizes of internal organs. Yet others were killed by the injection of chloroform into the heart. Some were subjected to unmatched blood transfusions, limb amputations, or operations without anesthesia. Twins were infected with typhus to determine genetic variations in the responses to bacterial infections. In a particularly horrific example, a pair of twins—one with a hunched back—were sewn together surgically to determine if a shared spine would correct the disability. The surgical site turned gangrenous, and both twins died shortly after.
Despite the ersatz patina of science, Mengele’s work was of the poorest scientific quality. Having subjected hundreds of victims to experiments, he produced no more than a scratched, poorly annotated notebook with no noteworthy results. One researcher, examining the disjointed notes at the Auschwitz museum, concluded, “No scientist could take [them] seriously.” Indeed, whatever early advances in twin studies were achieved in Germany, Mengele’s experiments putrefied twin research so effectively, pickling the entire field in such hatred, that it would take decades for the world to take it seriously.
The second contribution of the Nazis to genetics was never intended as a contribution. By the mid-1930s, as Hitler ascended to power in Germany, droves of scientists sensed the rising menace of the Nazi political agenda and left the country. Germany had dominated science in the early twentieth century: it had been the crucible of atomic physics, quantum mechanics, nuclear chemistry, physiology, and biochemistry. Of the one hundred Nobel Prizes awarded in physics, chemistry, and medicine between 1901 and 1932, thirty-three were awarded to German scientists (the British received eighteen; the Americans only six). When Hermann Muller arrived in Berlin in 1932, the city was home to the world’s preeminent scientific minds. Einstein was writing equations on the chalkboards of the Kaiser Wilhelm Institute of Physics. Otto Hahn, the chemist, was breaking apart atoms to understand their constituent subatomic particles. Hans Krebs, the biochemist, was breaking open cells to identify their constituent chemical components.
But the ascent of Nazism sent an immediate chill through the German scientific establishment. In April 1933, Jewish professors were abruptly evicted from their positions in state-funded universities. Sensing imminent danger, thousands of Jewish scientists migrated to foreign countries. Einstein left for a conference in 1933 and wisely declined to return. Krebs fled that same year, as did the biochemist Ernest Chain and physiologist Wilhelm Feldburg. Max Perutz, the physicist, moved to Cambridge University in 1937. For some non-Jews, such as Erwin Schrödinger and nuclear chemist Max Delbrück, the situation was morally untenable. Many resigned out of disgust and moved to foreign countries. Hermann Muller—disappointed by another false utopia—left Berlin for the Soviet Union, on yet another quest to unite science and socialism. (Lest we misconstrue the response of scientists to Nazi ascendency, let it be known that many German scientists maintained a deadly silence in response to Nazism. “Hitler may have ruined the long term prospects of German science,” George Orwell wrote in 1945, but there was no dearth of “gifted [German] men to do necessary research on such things as synthetic oil, jet planes, rocket projectiles and the atomic bomb.”)
Germany’s loss was genetics’ gain. The exodus from Germany allowed scientists to travel not just between nations, but also between disciplines. Finding themselves in new countries, they also found an opportunity to turn their attention to novel problems. Atomic physicists were particularly interested in biology; it was the unexplored frontier of scientific inquiry. Having reduced matter into its fundamental units, they sought to reduce life to similar material units. The ethos of atomic physics—the relentless drive to find irreducible particles, universal mechanisms, and systematic explanations—would soon permeate biology and drive the discipline toward new methods and new questions. The reverberations of this ethos would be felt for decades to come: as physicists and chemists drifted toward biology, they attempted to understand living beings in chemical and physical terms—through molecules, forces, structures, actions, and reactions. In time, these émigrés to the new continent would redraw its maps.
Genes drew the most attention. What were genes made of, and how did they function? Morgan’s work had pinpointed their location on chromosomes, where they were supposedly strung like beads on a wire. Griffith’s and Muller’s experiments had pointed to a material substance, a chemical that could move between organisms and was qui
te easily altered by X-rays.
Biologists might have blanched at trying to describe the “gene molecule” on purely hypothetical grounds—but what physicist could resist taking a ramble in weird, risky territory? In 1944, speaking in Dublin, the quantum theorist Erwin Schrödinger audaciously attempted to describe the molecular nature of the gene based on purely theoretical principles (a lecture later published as the book What Is Life?). The gene, Schrödinger posited, had to be made of a peculiar kind of chemical; it had to be a molecule of contradictions. It had to possess chemical regularity—otherwise, routine processes such a copying and transmission would not work—but it also had to be capable of extraordinary irregularity—or else, the enormous diversity of inheritance could not be explained. The molecule had to be able to carry vast amounts of information, yet be compact enough to be packaged into cells.
Schrödinger imagined a chemical with multiple chemical bonds stretching out along the length of the “chromosome fiber.” Perhaps the sequence of bonds encoded the code script—a “variety of contents compressed into [some] miniature code.” Perhaps the order of beads on the string carried the secret code of life.
Similarity and difference; order and diversity; message and matter. Schrödinger was trying to conjure up a chemical that would capture the divergent, contradictory qualities of heredity—a molecule to satisfy Aristotle. In his mind’s eye, it was almost as if he had seen DNA.
* * *
I. The quote has also been attributed to Rudolf Hess, Hitler’s deputy.
II. Ploetz would join the Nazis in the 1930s.
III. Curtis Merriman, an American psychologist, and Walter Jablonski, a German ophthalmologist, also performed similar twin studies in the 1920s.
IV. The exact number is hard to place. See Gerald L. Posner and John Ware, Mengele: The Complete Story, for the breadth of Mengele’s twin experiments.
“That Stupid Molecule”
Never underestimate the power of . . . stupidity.
—Robert Heinlein
Oswald Avery was fifty-five in 1933 when he heard of Frederick Griffith’s transformation experiment. His appearance made him seem even older than his years. Frail, small, bespectacled, balding, with a birdlike voice and limbs that hung like twigs in winter, Avery was a professor at the Rockefeller University in New York, where he had spent a lifetime studying bacteria—particularly pneumococcus. He was sure that Griffith had made some terrible mistake in his experiment. How could chemical debris carry genetic information from one cell to another?
Like musicians, like mathematicians—like elite athletes—scientists peak early and dwindle fast. It isn’t creativity that fades, but stamina: science is an endurance sport. To produce that single illuminating experiment, a thousand nonilluminating experiments have to be sent into the trash; it is battle between nature and nerve. Avery had established himself as a competent microbiologist, but had never imagined venturing into the new world of genes and chromosomes. “The Fess”—as his students affectionately called him (short for “professor”)—was a good scientist but unlikely to become a revolutionary one. Griffith’s experiment may have stuffed genetics into a one-way taxicab and sent it scuttling toward a strange future—but Avery was reluctant to climb on that bandwagon.
If the Fess was a reluctant geneticist, then DNA was a reluctant “gene molecule.” Griffith’s experiment had generated widespread speculations about the molecular identity of the gene. By the early 1940s, biochemists had broken cells apart to reveal their chemical constituents and identified various molecules in living systems—but the molecule that carried the code of heredity was still unknown.
Chromatin—the biological structure where genes resided—was known to be made of two types of chemicals: proteins and nucleic acids. No one knew or understood the chemical structure of chromatin, but of the two “intimately mixed” components, proteins were vastly more familiar to biologists, vastly more versatile, and vastly more likely to be gene carriers. Proteins were known to carry out the bulk of functions in the cell. Cells depend on chemical reactions to live: during respiration, for instance, sugar combines chemically with oxygen to make carbon dioxide and energy. None of these reactions occurs spontaneously (if they did, our bodies would be constantly ablaze with the smell of flambéed sugar). Proteins coax and control these fundamental chemical reactions in the cell—speeding some and slowing others, pacing the reactions just enough to be compatible with living. Life may be chemistry, but it’s a special circumstance of chemistry. Organisms exist not because of reactions that are possible, but because of reactions that are barely possible. Too much reactivity and we would spontaneously combust. Too little, and we would turn cold and die. Proteins enable these barely possible reactions, allowing us to live on the edges of chemical entropy—skating perilously, but never falling in.
Proteins also form the structural components of the cell: filaments of hair, nails, cartilage, or the matrices that trap and tether cells. Twisted into yet other shapes, they also form receptors, hormones, and signaling molecules, allowing cells to communicate with one another. Nearly every cellular function—metabolism, respiration, cell division, self-defense, waste disposal, secretion, signaling, growth, even cellular death—requires proteins. They are the workhorses of the biochemical world.
Nucleic acids, in contrast, were the dark horses of the biochemical world. In 1869—four years after Mendel had read his paper to the Brno Society—a Swiss biochemist, Friedrich Miescher, had discovered this new class of molecules in cells. Like most of his biochemist colleagues, Miescher was also trying to classify the molecular components of cells by breaking cells apart and separating the chemicals that were released. Of the various components, he was particularly intrigued by one kind of chemical. He had precipitated it in dense, swirling strands out of white blood cells that he had wrung out of human pus in surgical dressings. He had found the same white swirl of a chemical in salmon sperm. He called the molecule nuclein because it was concentrated in a cell’s nucleus. Since the chemical was acidic, its name was later modified to nucleic acids—but the cellular function of nuclein had remained mysterious.
By the early 1920s, biochemists had acquired a deeper understanding of the structure of nucleic acids. The chemical came in two forms—DNA and RNA, molecular cousins. Both were long chains made of four components, called bases, strung together along a stringlike chain or backbone. The four bases protruded out from the backbone, like leaves emerging out of the tendril of ivy. In DNA, the four “leaves” (or bases) were adenine, guanine, cytosine, and thymine—abbreviated A, G, C, and T. In RNA, the thymine was switched into uracil—hence A, C, G, and U.I Beyond these rudimentary details, nothing was known about the structure or function of DNA and RNA.
To the biochemist Phoebus Levene, one of Avery’s colleagues at Rockefeller University, the comically plain chemical composition of DNA—four bases strung along a chain—suggested an extremely “unsophisticated” structure. DNA must be a long, monotonous polymer, Levene reasoned. In Levene’s mind, the four bases were repeated in a defined order: AGCT-AGCT-AGCT-AGCT and so forth ad nauseam. Repetitive, rhythmic, regular, austere, this was a conveyer belt of a chemical, the nylon of the biochemical world. Levene called it a “stupid molecule.”
Even a cursory look at Levene’s proposed structure for DNA disqualified it as a carrier of genetic information. Stupid molecules could not carry clever messages. Monotonous to the extreme, DNA seemed to be quite the opposite of Schrödinger’s imagined chemical—not just a stupid molecule but worse: a boring one. In contrast, proteins—diverse, chatty, versatile, capable of assuming Zelig-like shapes and performing Zelig-like functions—were infinitely more attractive as gene carriers. If chromatin, as Morgan had suggested, was a string of beads, then proteins had to be the active component—the beads—while DNA was likely the string. The nucleic acid in a chromosome, as one biochemist put it, was merely the “structure-determining, supporting substance”—a glorified molecular scaffold for genes. Proteins
carried the real stuff of heredity. DNA was the stuffing.
In the spring of 1940, Avery confirmed the key result of Griffith’s experiment. He separated the crude bacterial debris from the virulent smooth strain, mixed it with the live bacteria of the nonvirulent rough strain, and injected the mix into mice. Smooth-coated, virulent bacteria emerged faithfully—and killed the mice. The “transforming principle” had worked. Like Griffith, Avery observed that the smooth-coated bacteria, once transformed, retained their virulence generation upon generation. In short, genetic information must have been transmitted between two organisms in a purely chemical form, allowing that transition from the rough-coated to the smooth-coated variant.
But what chemical? Avery fiddled with the experiment as only a microbiologist could, growing the bacteria in various cultures, adding beef-heart broth, removing contaminant sugars, and growing the colonies on plates. Two assistants, Colin MacLeod and Maclyn McCarty, joined his laboratory to help with the experiments. The early technical fussing was crucial; by early August, the three had achieved the transformation reaction in a flask and distilled the “transforming principle” into a highly concentrated form. By October 1940, they began to sift through the concentrated bacterial detritus, painstakingly separating each chemical component, and testing each fraction for its capacity to transmit genetic information.
First, they removed all the remaining fragments of the bacterial coat from the debris. The transforming activity remained intact. They dissolved the lipids in alcohol—but there was no change in transformation. They stripped away the proteins by dissolving the material in chloroform. The transforming principle was untouched. They digested the proteins with various enzymes; the activity remained unaltered. They heated the material to sixty-five degrees—hot enough to warp most proteins—then added acids to curdle the proteins, and the transmission of genes was still unaltered. The experiments were meticulous, exhaustive, and definitive. Whatever its chemical constituents, the transforming principle was not composed of sugars, lipids, or proteins.