The Gene: An Intimate History - Siddhartha Mukherjee Page 0,82

among other things, independently regulated modules. Some words are gathered into sentences; others are separated by semicolons, commas, and dashes.”

Pardee, Jacob, and Monod published their monumental study on the lactose operon in 1959, six years after the Watson and Crick paper on the structure of DNA. Called the Pa-Ja-Mo—or, colloquially, the Pajama—paper, after the initials of the three authors, the study was instantly a classic, with vast implications for biology. Genes, the Pajama paper argued, were not just passive blueprints. Even though every cell contains the same set of genes—an identical genome—the selective activation or repression of particular subsets of genes allows an individual cell to respond to its environments. The genome was an active blueprint—capable of deploying selected parts of its code at different times and in different circumstances.

Proteins act as regulatory sensors, or master switches, in this process—turning on and turning off genes, or even combinations of genes, in a coordinate manner. Like the master score of a bewitchingly complex symphonic work, the genome contains the instructions for the development and maintenance of organisms. But the genomic “score” is inert without proteins. Proteins actualize this information. They conduct the genome, thereby playing out its music—activating the viola at the fourteenth minute, a crash of cymbals during the arpeggio, a roll of drums at the crescendo. Or conceptually:

The Pa-Ja-Mo paper laid a central question of genetics to bed: How can an organism have a fixed set of genes, yet respond so acutely to changes in the environment? But it also suggested a solution to the central question in embryogenesis: How can thousands of cell types arise from an embryo out of the same set of genes? The regulation of genes—the selective turning on and off of certain genes in certain cells, and at certain times—must interpose a crucial layer of complexity on the unblinking nature of biological information.

It was through gene regulation, Monod argued, that cells could achieve their unique functions in time and space. “The genome contains not only a series of blue-prints [i.e., genes], but a co-ordinated program . . . and a means of controlling its execution,” Monod and Jacob concluded. Walter Noel’s red blood cells and liver cells contained the same genetic information—but gene regulation ensured that the hemoglobin protein was only present in red blood cells, and not in the liver. The caterpillar and the butterfly carry precisely the same genome—but gene regulation enables the metamorphosis of one into the other.

Embryogenesis could be reimagined as the gradual unfurling of gene regulation from a single-celled embryo. This was the “movement” that Aristotle had so vividly imagined centuries before. In a famous story, a medieval cosmologist is asked what holds the earth up.

“Turtles,” he says.

“And what holds up the turtles?” he is asked.

“More turtles.”

“And those turtles?”

“You don’t understand.” The cosmologist stamps his foot. “It’s turtles all the way.”

To a geneticist, the development of an organism could be described as the sequential induction (or repression) of genes and genetic circuits. Genes specified proteins that switched on genes that specified proteins that switched on genes—and so forth, all the way to the very first embryological cell. It was genes, all the way.III

Gene regulation—the turning on and off of genes by proteins—described the mechanism by which combinatorial complexity could be generated from the one hard copy of genetic information in a cell. But it could not explain the copying of genes themselves: How are genes replicated when a cell divides into two cells, or when a sperm or egg is generated?

To Watson and Crick, the double-helix model of DNA—with two complementary “yin-yang” strands counterposed against each other—instantly suggested a mechanism for replication. In the last sentence of the 1953 paper, they noted: “It has not escaped our notice that the specific pairing [of DNA] we have postulated immediately suggests a possible copying mechanism for the genetic material.” Their model of DNA was not just a pretty picture; the structure predicted the most important features of the function. Watson and Crick proposed that each DNA strand was used to generate a copy of itself—thereby generating two double helices from the original double helix. During replication, the yin-yang strands of DNA were peeled apart. The yin was used as a template to create a yang, and the yang to make a yin—and this resulted in two yin-yang pairs.

But a DNA double helix cannot autonomously make a copy of itself; otherwise, it might replicate without self-control. An enzyme was likely dedicated to copying DNA—a replicator protein. In 1957, the biochemist Arthur Kornberg