with thumbs emerging from our noses?
To answer these questions, we need to turn the clock of embryological development backward. In 1979, one year after Lewis had published his paper on the genes that govern limb and wing development, two embryologists, Christiane Nüsslein-Volhard and Eric Wieschaus, working in Heidelberg, began to create fruit fly mutants to capture the very first steps that govern the formation of the embryo.
The mutants generated by Nüsslein-Volhard and Wieschaus were even more dramatic than the ones described by Lewis. In some mutants, whole segments of the embryo disappeared, or the thorax or abdominal compartments were drastically shortened—analogous to a human fetus born with no middle or with no hind segment. The genes altered in these mutants, Nüsslein-Volhard and Wieschaus reasoned, determine the basic architectural plan of the embryo. They are the mapmakers of the embryonic world. They divide the embryo into its basic subsegments. They then activate Lewis’s commander genes to start building organs and body parts in some (and only those) compartments—an antenna on the head, a wing in the fourth segment of the thorax, and so forth. Nüsslein-Volhard and Wieschaus termed these segmentation genes.
But even the segmentation genes have to have their masters: How does the second segment of the fly thorax “know” to be a thoracic segment, and not an abdominal segment? Or how does a head know not to be a tail? Every segment of an embryo can be defined on an axis that stretches from head to tail. The head functions like an internal GPS system, and the position relative to the head and the tail gives each segment a unique “address” in the embryo. But how does an embryo develop its basic, original asymmetry—i.e., its “headness” versus “tailness”?
In the late 1980s, Nüsslein-Volhard and her students began to characterize a final flock of fly mutants in which asymmetrical organization of the embryo had been abrogated. These mutants—often headless or tailless—were arrested in development long before segmentation (and certainly long before the growth of structures and organs). In some, the embryonic head was malformed. In others, the front and back of the embryo could not be distinguished, resulting in strange mirror-image embryos (the most notorious of the mutants was called bicoid—literally “two-tailed”). The mutants clearly lacked some factor—a chemical—that determines the front versus the back of the fly. In 1986, in an astonishing experiment, Nüsslein-Volhard’s students learned to prick a normal fly embryo with a minuscule needle, withdraw a droplet of liquid from its head, and transplant it into the headless mutants. Amazingly, the cellular surgery worked: the droplet of liquid from a normal head was sufficient to force an embryo to grow a head in the position of its tail.
In a volley of pathbreaking papers published between 1986 and 1990, Nüsslein-Volhard and her colleagues definitively identified several of the factors that provide the signal for “headness” and “tailness” in the embryo. We now know that about eight such chemicals—mostly proteins—are made by the fly during the development of the egg and deposited asymmetrically in the egg. These maternal factors are made and placed in the egg by the mother fly. The asymmetric deposition is only possible because the egg itself is placed asymmetrically in the mother fly’s body—thereby enabling her to deposit some of these maternal factors on the head end of the egg, and others on the tail end.
The proteins create a gradient within the egg. Like sugar diffusing out of a cube in a cup of coffee, they are present at high concentration on one end of the egg, and low concentration on the other. The diffusion of a chemical through a matrix of protein can even create distinct, three-dimensional patterns—like a pool of syrup ribboning into oatmeal. Specific genes are activated at the high-concentration end versus at the low-concentration end, thereby allowing the head-tail axis to be defined, or other patterns to be formed.
The process is infinitely recursive—the ultimate chicken-and-egg story. Flies with heads and tails make eggs with heads and tails, which make embryos with heads and tails, which grow into flies with heads and tails, and so forth, ad infinitum. Or at a molecular level: Proteins in the early embryo are deposited preferentially at one end by the mother. They activate and silence genes, thereby defining the embryo’s axis from head to tail. These genes, in turn, activate “mapmaker” genes that make segments and split the body into its broad domains. The mapmaker genes activate and silence genes that make organs and structures.I Finally, organ-formation and