The Gene: An Intimate History - Siddhartha Mukherjee Page 0,79

shape that allows them to be stacked atop each other, and thus move smoothly through networks of arteries and capillaries and veins, bringing oxygen to the liver, heart, and brain. In Noel’s blood, the cells had morphed, mysteriously, into shriveled, scythe-shaped crescents—“sickle cells,” as Irons later described them.

But what made a red blood cell acquire a sickle shape? And why was the illness hereditary? The natural culprit was an abnormality in the gene for hemoglobin—the protein that carries oxygen and is present abundantly in red cells. In 1951, working with Harvey Itano at Caltech, Linus Pauling demonstrated that the variant of hemoglobin found in sickle cells was different from the hemoglobin in normal cells. Five years later, scientists in Cambridge pinpointed the difference between the protein chain of normal hemoglobin and “sickled” hemoglobin to a change in a single amino acid.III

But if the protein chain was altered by exactly one amino acid, then its gene had to be different by precisely one triplet (“one triplet encodes one amino acid”). Indeed, as predicted, when the gene encoding the hemoglobin B chain was later identified and sequenced in sickle-cell patients, there was a single change: one triplet in DNA—GAG—had changed to another—GTG. This resulted in the substitution of one amino acid for another: glutamate was switched to valine. That switch altered the folding of the hemoglobin chain: rather than twisting into its neatly articulated, clasplike structure, the mutant hemoglobin protein accumulated in stringlike clumps within red cells. These clumps grew so large, particularly in the absence of oxygen, that they tugged the membrane of the red cell until the normal disk was warped into a crescent-shaped, dysmorphic “sickle cell.” Unable to glide smoothly through capillaries and veins, sickled red cells jammed into microscopic clots throughout the body, interrupting blood flow and precipitating the excruciating pain of a sickling crisis.

It was a Rube Goldberg disease. A change in the sequence of a gene caused the change in the sequence of a protein; that warped its shape; that shrank a cell; that clogged a vein; that jammed the flow; that racked the body (that genes built). Gene, protein, function, and fate were strung in a chain: one chemical alteration in one base pair in DNA was sufficient to “encode” a radical change in human fate.

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I. A team led by James Watson and Walter Gilbert at Harvard also discovered the “RNA intermediate” in 1960. The Watson/Gilbert and Brenner/Jacob papers were published back to back in Nature.

II. This “triplet code” hypothesis was also supported by elementary mathematics. If a two-letter code was used—i.e., two bases in a sequence (AC or TC) encoded an amino acid in a protein—you could only achieve 16 combinations, obviously insufficient to specify all twenty amino acids. A triplet-based code had 64 combinations—enough for all twenty amino acids, with extra ones still left over to specify other coding functions, such as “stopping” or “starting” a protein chain. A quadruplet code would have 256 permutations—far more than needed to encode twenty amino acids. Nature was degenerate, but not that degenerate.

III. The alteration of the single amino acid was discovered by Vernon Ingram, a former student of Max Perutz’s.

Regulation, Replication, Recombination

Nécessité absolue trouver origine de cet emmerdement [It is absolutely necessary to find the origin of this pain in the ass].

—Jacques Monod

Just as the formation of a giant crystal can be seeded by the formal arrangement of a few critical atoms at its core, the birth of a great body of science can be nucleated by the interlocking of a few crucial concepts. Before Newton, generations of physicists had thought about phenomena such as force, acceleration, mass, and velocity. But Newton’s genius involved defining these terms rigorously and linking them to each other via a nest of equations—thereby launching the science of mechanics.

By similar logic, the interlocking of just a few crucial concepts—

—relaunched the science of genetics. In time, as with Newtonian mechanics, the “central dogma” of genetics would be vastly refined, modified, and reformulated. But its effect on the nascent science was profound: it locked a system of thinking into place. In 1909, Johannsen, coining the word gene, had declared it “free of any hypothesis.” By the early 1960s, however, the gene had vastly exceeded a “hypothesis.” Genetics had found a means to describe the flow of information from organism to organism, and—within an organism—from encryption to form. A mechanism of heredity had emerged.

But how did this flow of biological information achieve the observed complexity of living systems? Take sickle-cell anemia