The Gene: An Intimate History - Siddhartha Mukherjee Page 0,62

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.

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