The Gene: An Intimate History - Siddhartha Mukherjee Page 0,86

specify macroscopic anatomical features—limbs, organs, and structures—was the first to be deciphered. Then came the mechanism by which an organism determines where these structures are to be placed: front or back, left or right, above or below. The very earliest events in the specification of an embryo—the specification of the body axis, of front and back, and left versus right—were among the last to be understood.

The reason for this reversed order might be obvious. Mutations in genes that specified macroscopic structures, such as limbs and wings, were the easiest to spot and the first to be characterized. Mutations in genes that specified the basic elements of the body plan were more difficult to identify, since the mutations sharply decreased the survival of organisms. And mutants in the very first steps of embryogenesis were nearly impossible to capture alive since the embryos, with scrambled heads and tails, died instantly.

In the 1950s, Ed Lewis, a fruit fly geneticist at Caltech, began to reconstruct the formation of fruit fly embryos. Like an architectural historian obsessed with only one building, Lewis had been studying the construction of fruit flies for nearly two decades. Bean shaped and smaller than a speck of sand, the fruit fly embryo begins its life in a whir of activity. About ten hours after fertilization of the egg, the embryo divides into three broad segments, head, thorax, and abdomen, and each segment divides into further subcompartments. Each of these embryonic segments, Lewis knew, gives rise to a congruent segment found in the adult fly. One embryonic segment becomes the second section of the thorax and grows two wings. Three of the segments grow the fly’s six legs. Yet other segments sprout bristles or grow antennae. As with humans, the basic plan for the adult body is furled into an embryo. The maturation of a fly is the serial unfolding of these segments, like the stretching of a live accordion.

But how does a fly embryo “know” to grow a leg out of the second thoracic segment or an antenna out of its head (and not vice versa)? Lewis studied mutants in which the organization of these segments was disrupted. The peculiar feature of the mutants, he discovered, was that the essential plan of macroscopic structures was often maintained—only the segment switched its position or identity in the body of the fly. In one mutant, for instance, an extra thoracic segment—fully intact and nearly functional—appeared in a fly, resulting in a four-winged insect (one set of wings from the normal thoracic segment, and a new set from the extra thoracic segment). It was as if the build-a-thorax gene had incorrectly been commanded in the wrong compartment—and had sanguinely launched its command. In another mutant, two legs sprouted out of the antenna in a fly’s head—as if the build-a-leg command had mistakenly been launched in the head.

The building of organs and structures, Lewis concluded, is encoded by master-regulatory “effector” genes that work like autonomous units or subroutines. During the normal genesis of a fly (or any other organism), these effector genes kick into action at specified sites and at specified times and determine the identities of segments and organs. These master-regulatory genes work by turning other genes on and off; they can be likened to circuits in a microprocessor. Mutations in the genes thus result in malformed, ectopic segments and organs. Like the Red Queen’s bewildered servants in Alice in Wonderland, the genes scurry about to enact the instructions—build a thorax, make a wing—but in the wrong places or at the wrong times. If a master regulator shouts, “ON with an antenna,” then the antenna-building subroutine is turned on and an antenna is built—even if that structure happens to be growing out of the thorax or abdomen of a fly.

But who commands the commanders? Ed Lewis’s discovery of master-regulatory genes that controlled the development of segments, organs, and structures solved the problem of the final stage of embryogenesis, but it raised a seemingly infinite recursive conundrum. If the embryo is built, segment upon segment and organ by organ, by genes that command the identity of each segment and organ, then how does a segment know its own identity in the first place? How, for instance, does a wing-making master gene “know” to build a wing in the second thoracic segment, and not, say, the first or third segment? If genetic modules are so autonomous, then why—to turn Morgan’s riddle on its head—are legs not growing out of fly’s heads, or humans not born