The Gene: An Intimate History - Siddhartha Mukherjee Page 0,183

usually they are brought up in very similar environments. When we consider this, it doesn’t seem surprising that if one of the twins develops schizophrenia, the chance that his or her twin will also develop the illness is very high. In fact, we have to start wondering why it isn’t higher. Why isn’t the figure 100 percent?

—Nessa Carey, The Epigenetics Revolution

Genes have had a glorious run in the 20th century. . . . They have carried us to the edge of a new era in biology, one that holds out the promise of even more astonishing advances. But these very advances will necessitate the introduction of other concepts, other terms and other ways of thinking about biological organization, thereby loosening the grip that genes have had on the imagination of the life sciences.

—Evelyn Fox Keller, An Anthropology of Biomedicine

A question implicit in the last chapter must be answered: If the “self” is created through the chance interactions among events and genes, then how are these interactions actually recorded? One twin falls on ice, fractures a knee, and develops a callus, while the other does not. One sister marries a rising executive in Delhi, while the other moves to a crumbling household in Calcutta. Through what mechanism are these “acts of fate” registered within a cell or a body?

The answer had been standard for decades: through genes. Or to be more precise, by turning genes on and off. In Paris, in the 1950s, Monod and Jacob had demonstrated that when bacteria switch their diet from glucose to lactose, they turn glucose-metabolizing genes off and turn lactose-metabolizing genes on. Nearly thirty years later, biologists working on the worm had found that signals from neighboring cells—events of fate, as far as an individual cell is concerned—are also registered by the turning on and off of master-regulatory genes, leading to alterations in cell lineages. When one twin falls on ice, wound-healing genes are turned on. These genes enable the wound to harden into the callus that marks the site of the fracture. Even when a complex memory is recorded in the brain, genes must be turned on and off. When a songbird encounters a new song from another bird, a gene called ZENK is turned up in the brain. If the song isn’t right—if it’s a song from a different species, or a flat note—then ZENK is not turned on at the same level, and the song is not released.

But if fate is recorded in the body by the transient turning on and off of genes, then why is it irreversible? The question, seemingly absurd at first glance, has long been a biologist’s conundrum: If there is no mechanism to “lock” fate forward, there should be no mechanism to lock it backward. If genetic switches are transient, then why isn’t fate or memory transient? Why don’t we age backward?

This question bothered Conrad Waddington, an English embryologist working in the 1950s. When Waddington considered the development of an animal embryo, he saw the genesis of thousands of diverse cell types—neurons, muscle cells, blood, sperm—out of a single fertilized cell. Each cell, arising from the original embryonic cell, had the same set of genes. But if genetic circuits could be turned on and off transiently, and if every cell carried the same gene sequence, then why was the identity of any of these cells fixed in time and place? Why couldn’t a liver cell wake up one morning and find itself transformed into a neuron?

In embryonic development, Waddington saw transience hardening into permanence—wounds turning into calluses. In an inspired analogy, Waddington likened embryonic differentiation to a thousand marbles sent tumbling down a sloping landscape full of crags, nooks, and crevices. As every cell charted its unique path down the “Waddington landscape,” he proposed, it got trapped in some particular crag or cranny—thereby determining its identity.

But a cell’s identity, Waddington realized, has to be recorded in some manner beyond its genome; otherwise the landscape of development would be inherently unstable. Some feature of a cell’s interior or exterior environment must be altering the use of a cell’s genes, he surmised, enabling each cell to stamp the marks of its identity on its genome. He termed the phenomenon “epi-genetics”—or “above genetics.” Epigenetics, Waddington wrote, concerns “the interaction of genes with their environment [ . . .] that brings their phenotype into being.”

A macabre human experiment provided evidence for Waddington’s theory, although its denouement would not be obvious for generations. In September 1944, amid the most vengeful phase of