The Gene: An Intimate History - Siddhartha Mukherjee Page 0,78

the point. The letters A, C, and T convey very little meaning by themselves, but can be combined in ways to produce substantially different messages. It is, once again, the sequence that carries the message: the words act, tac, and cat, for instance, arise from the same letters, yet signal vastly different meanings. The key to solving the actual genetic code was to map the elements of a sequence in an RNA chain to the sequence of a protein chain. It was like deciphering the Rosetta Stone of genetics: Which combination of letters (in RNA) specified which combination of letters (in a protein)? Or, conceptually:

Through a series of ingenious experiments, Crick and Brenner realized that the genetic code had to occur in a “triplet” form—i.e., three bases of DNA (e.g., ACT) had to specify one amino acid in a protein.II

But which triplet specified which amino acid? By 1961, several laboratories around the world had joined the race to decipher the genetic code. At the National Institutes of Health in Bethesda, Marshall Nirenberg, Heinrich Matthaei, and Philip Leder used a biochemical approach to try to crack the cipher. An Indian-born chemist, Har Khorana, supplied crucial chemical reagents that made code breaking possible. And a Spanish biochemist in New York, Severo Ochoa, launched a parallel effort to map the triplet code to corresponding amino acids.

As with all code breaking, the work proceeded misstep by misstep. At first, one triplet seemed to overlap with another—making the prospect of a simple code impossible. Then, for a while, it seemed that some triplets did not work at all. But by 1965, all of these studies had successfully mapped every DNA triplet to a corresponding amino acid. ACT, for instance, specified the amino acid Threonine. CAT, in contrast, specified a different amino acid—Histidine. CGT specified Arginine. A particular sequence of DNA—ACT-GAC-CAC-GTG—was therefore used to build an RNA chain, and the RNA chain was translated into a chain of amino acids, ultimately leading to the construction of a protein. One triplet (ATG) was the code to start the building of a protein, and three triplets (TAA, TAG, TGA) represented codes to stop it. The basic alphabet of the genetic code was complete.

The flow of information could be visualized simply:

Or, at a conceptual level:

Or:

Francis Crick called this flow of information “the central dogma” of biological information. The word dogma was an odd choice (Crick later admitted that he never understood the linguistic implications of dogma, which implies a fixed, immutable belief)—but the central was an accurate description. Crick was referring to the striking universality of the flow of genetic information throughout biology. From bacteria to elephants—from red-eyed flies to blue-blooded princes—biological information flowed through living systems in a systematic, archetypal manner: DNA provided instructions to build RNA. RNA provided instructions to build proteins. Proteins ultimately enabled structure and function—bringing genes to life.

Perhaps no illness illustrates the nature of this information flow, and its penetrating effects on human physiology, as powerfully as sickle-cell anemia. As early as the sixth century BC, ayurvedic practitioners in India had recognized the general symptoms of anemia—the absence of adequate red cells in blood—by the characteristic pallor of the lips, skin, and fingers. Termed pandu roga in Sanskrit, anemias were further subdivided into categories. Some variants of the illness were known to be caused by nutritional deficiencies. Others were thought to be precipitated by episodes of blood loss. But sickle-cell anemia must have seemed the strangest—for it was hereditary, often appeared in fits and starts, and was accompanied by sudden, wrenching bouts of pain in the bones, joints, and chest. The Ga tribe in West Africa called the pain chwechweechwe (body beating). The Ewe named it nuiduidui (body twisting)—onomatopoeic words whose very sounds seemed to capture the relentless nature of a pain that felt like corkscrews driven into the marrow.

In 1904, a single image captured under a microscope provided a unifying cause for all these seemingly disparate symptoms. That year, a young dentistry student named Walter Noel presented to his doctor in Chicago with an acute anemic crisis, accompanied by the characteristic chest and bone pain. Noel was from the Caribbean, of West African descent, and had suffered several such episodes over the prior years. Having ruled out a heart attack, the cardiologist, James Herrick, assigned the case rather casually to a medical resident named Ernest Irons. Acting on a whim, Irons decided to look at Noel’s blood under the microscope.

Irons found a bewildering alteration. Normal red blood cells are shaped like flattened disks—a