The Gene: An Intimate History - Siddhartha Mukherjee Page 0,75

been clearly grasped.

—Francis Crick

The word code, I wrote before, comes from caudex—the pith of the tree that was used to scratch out early manuscripts. There is something evocative in the idea that the material used to write code gave rise to the word itself: form became function. With DNA too, Watson and Crick realized, the form of the molecule had to be intrinsically linked to function. The genetic code had to be written into the material of DNA—just as intimately as scratches are etched into pith.

But what was genetic code? How did four bases in a molecular string of DNA—A, C, G, and T (or A,C,G,U in RNA)—determine the consistency of hair, the color of an eye, or the quality of the coat of a bacterium (or, for that matter, the propensity for mental illness or a deadly bleeding disease in a family)? How did Mendel’s abstract “unit of heredity” become manifest as a physical trait?

In 1941, three years before Avery’s landmark experiment, two scientists, George Beadle and Edward Tatum, working in a basement tunnel at Stanford University, discovered the missing link between genes and physical traits. Beadle—or “Beets,” as his colleagues liked to call him—had been a student of Thomas Morgan’s at Caltech. The red-eyed flies and the white-eyed mutants puzzled Beadle. A “gene for redness,” Beets understood, is a unit of hereditary information, and it is carried from a parent to its children in an indivisible form in DNA—in genes, in chromosomes. “Redness,” the physical trait, in contrast, was the consequence of a chemical pigment in the eye. But how did a hereditary particle transmute into an eye pigment? What was the link between a “gene for redness” and “redness” itself—between information and its physical or anatomical form?

Fruit flies had transformed genetics by virtue of rare mutants. Precisely because they were rare, the mutants had acted like lamps in the darkness, allowing biologists to track “the action of a gene,” as Morgan had described it, across generations. But the “action” of a gene—still a vague, mystical concept—intrigued Beadle. In the late 1930s, Beadle and Tatum reasoned that isolating the actual eye pigment of a fruit fly might solve the riddle of gene action. But the work stalled; the connection between genes and pigments was far too complicated to yield a workable hypothesis. In 1937, at Stanford University, Beadle and Tatum switched to an even simpler organism called Neurospora crassa, a bread mold originally found as a contaminant in a Paris bakery, to try to solve the gene-to-trait connection.

Bread molds are scrappy, fierce creatures. They can be grown in petri dishes layered with nutrient-rich broth—but, in fact, they do not need much to survive. By systematically depleting nearly all the nutrients from the broth, Beadle found that the mold strains could still grow on a minimal broth containing nothing more than a sugar and a vitamin called biotin. Evidently, the cells of the mold could build all the molecules needed for survival from basic chemicals—lipids from glucose, DNA and RNA from precursor chemicals, and complex carbohydrates out of simple sugars: wonder from Wonder Bread.

This capacity, Beadle understood, was due to the presence of enzymes within the cell—proteins that acted as master builders and could synthesize complex biological macromolecules out of basic precursor chemicals. For a bread mold to grow successfully in minimal media, then, it needed all its metabolic, molecule-building functions to be intact. If a mutation inactivated even one function, the mold would be unable to grow—unless the missing ingredient was supplied back into the broth. Beadle and Tatum could thus use this technique to track the missing metabolic function in every mutant: if a mutant needed the substance X, say, to grow in minimal media, then it must lack the enzyme to synthesize that substance, X, from scratch. This approach was intensely laborious—but patience was a virtue that Beadle possessed in abundance: he had once spent an entire afternoon teaching a graduate student how to marinate a steak, adding one spice at a time, over precisely timed intervals.

The “missing ingredient” experiment propelled Beadle and Tatum toward a new understanding of genes. Every mutant, they noted, was missing a single metabolic function, corresponding to the activity of a single protein enzyme. And genetic crosses revealed that every mutant was defective in only one gene.

But if a mutation disrupts the function of an enzyme, then the normal gene must specify the information to make the normal enzyme. A unit of heredity must carry the code to build a metabolic