The Gene: An Intimate History - Siddhartha Mukherjee Page 0,88

segment-identity genes activate and silence genetic subroutines that result in the creation of organs, structures, and parts.

The development of the human embryo is also likely achieved through three similar levels of organization. As with the fly, “maternal effect” genes organize the early embryo into its main axes—head versus tail, front versus back, and left versus right—using chemical gradients. Next, a series of genes analogous to the segmentation genes in the fly initiates the division of the embryo into its major structural parts—brain, spinal cord, skeleton, skin, guts, and so forth. Finally, organ-building genes authorize the construction of organs, parts, and structures—limbs, fingers, eyes, kidneys, liver, and lungs.

“Is it sin, which makes the worm a chrysalis, and the chrysalis a butterfly, and the butterfly dust?” the German theologian Max Müller asked in 1885. A century later, biology offered an answer. It wasn’t sin; it was a fusillade of genes.

In Leo Lionni’s classic children’s book Inch by Inch, a tiny worm is saved by a robin because it promises to “measure things” using its inch-long body as a metric. The worm measures the robin’s tail, the toucan’s beak, the flamingo’s neck, and the heron’s legs; the world of birds thus gets its first comparative anatomist.

Geneticists too had learned the usefulness of small organisms to measure, compare, and understand much larger things. Mendel had shelled bushels of peas. Morgan had measured mutation rates in flies. The seven hundred suspenseful minutes between the birth of a fly embryo and the creation of its first segments—arguably the most intensively scrutinized block of time in the history of biology—had partly solved one of the most important problems in biology: How can genes be orchestrated to create an exquisitely complex organism out of a single cell?

It took an even smaller organism—a worm of less than an inch—to solve the remaining half of the puzzle: How do cells arising in an embryo “know” what to become? Fly embryologists had produced a broad outline of organismal development as the serial deployment of three phases—axis determination, segment formation, and organ building—each governed by a cascade of genes. But to understand embryological development at the deepest level, geneticists needed to understand how genes could govern the destinies of individual cells.

In the mid-1960s, in Cambridge, Sydney Brenner began to hunt for an organism that could help solve the puzzle of cell-fate determination. Minuscule as it was, even the fly—“compound eyes, jointed legs, and elaborate behavior patterns”—was much too big for Brenner. To understand how genes instruct the fates of cells, Brenner needed an organism so small and simple that each cell arising from the embryo could be counted and followed in time and space (as a point of comparison, humans have about 37 trillion cells. A cell-fate map of humans would outstrip the computing powers of the most powerful computers).

Brenner became a connoisseur of tiny organisms, a god of small things. He pored through nineteenth-century zoology textbooks to find an animal that would satisfy his requirements. In the end, he settled on a minuscule soil-dwelling worm called Caenorhabditis elegans—C. elegans for short. Zoologists had noted that the worm was eutelic: once it reached adulthood, every worm had a fixed number of cells. To Brenner, the constancy of that number was like a latchkey to a new cosmos: if every worm had exactly the same number of cells, then genes must be capable of carrying instructions to specify the fate of every cell in a worm’s body. “We propose to identify every cell in the worm and trace lineages,” he wrote to Perutz. “We shall also investigate the constancy of development and study its genetic control by looking for mutants.”

The counting of cells began in earnest in the early 1970s. First, Brenner convinced John White, a researcher in his lab, to map the location of every cell in the worm’s nervous system—but Brenner soon broadened the scope to track the lineage of every cell in the worm’s body. John Sulston, a postdoctoral researcher, was conscripted to the cell-counting effort. In 1974, Brenner and Sulston were joined by a young biologist fresh from Harvard named Robert Horvitz.

It was exhausting, hallucination-inducing work, “like watching a bowl of hundreds of grapes” for hours at a time, Horvitz recalled, and then mapping each grape as it changed its position in time and space. Cell by cell, a comprehensive atlas of cellular fate fell into place. Adult worms come in two different types—hermaphrodites and males. Hermaphrodites had 959 cells. Males had 1,031. By the late 1970s, the lineage