Same but Different : How epigenetics can blur the line between nature and nurture. (SIDDHARTHA MUKHERJEE, 5/02/16, The New Yorker)

The Minnesota twin study raised questions about the depth and pervasiveness of qualities specified by genes: Where in the genome, exactly, might one find the locus of recurrent nightmares or of fake sneezes? Yet it provoked an equally puzzling converse question: Why are identical twins different? Because, you might answer, fate impinges differently on their bodies. One twin falls down the crumbling stairs of her Calcutta house and breaks her ankle; the other scalds her thigh on a tipped cup of coffee in a European station. Each acquires the wounds, calluses, and memories of chance and fate. But how are these changes recorded, so that they persist over the years? We know that the genome can manufacture identity; the trickier question is how it gives rise to difference.

David Allis, who has been studying the genome's face for identity and difference for three decades, runs a laboratory at Rockefeller University, in New York. For a scientist who has won virtually all of science's most important prizes except the Nobel (and that has been predicted for years), Allis is ruthlessly self-effacing--the kind of person who offers to leave his name on a chit at the faculty lunchroom because he has forgotten his wallet in the office. ("We know who you are," the woman at the cash register says, laughing.)

As a child, Allis grew up in the leeward shadow of his sister, a fraternal twin, in Cincinnati, Ohio. She was the studious one, the straight-A student; he was the popular kid, the high-school fraternity president casual about his schoolwork. "We were similar but different," Allis said. At some point in college, though, Allis's studies became a calling rather than a chore. In 1978, having obtained a Ph.D. in biology at Indiana University, Allis began to tackle a problem that had long troubled geneticists and cell biologists: if all the cells in the body have the same genome, how does one become a nerve cell, say, and another a blood cell, which looks and functions very differently?

In the nineteen-forties, Conrad Waddington, an English embryologist, had proposed an ingenious answer: cells acquired their identities just as humans do--by letting nurture (environmental signals) modify nature (genes). For that to happen, Waddington concluded, an additional layer of information must exist within a cell--a layer that hovered, ghostlike, above the genome. This layer would carry the "memory" of the cell, recording its past and establishing its future, marking its identity and its destiny but permitting that identity to be changed, if needed. He termed the phenomenon "epigenetics"--"above genetics." Waddington, ardently anti-Nazi and fervently Marxist, may have had more than a biological stake in this theory. The Nazis had turned a belief in absolute genetic immutability ("a Jew is a Jew") into a state-mandated program of sterilization and mass murder. By affirming the plasticity of nature ("everyone can be anyone"), a Marxist could hope to eradicate such innate distinctions and achieve a radical collective good.

Waddington's hypothesis was perhaps a little too inspired. No one had visualized a gene in the nineteen-forties, and the notion of a layer of information levitating above the genome was an abstraction built atop an abstraction, impossible to test experimentally. "By the time I began graduate school, it had largely been forgotten," Allis said.

Had Allis started his experiments in the nineteen-eighties trying to pin down words like "identity" and "memory," he might have found himself lost in a maze of metaphysics. But part of his scientific genius lies in radical simplification: he has a knack for boiling problems down to their tar. What allows a cell to maintain its specialized identity? A neuron in the brain is a neuron (and not a lymphocyte) because a specific set of genes is turned "on" and another set of genes is turned "off." The genome is not a passive blueprint: the selective activation or repression of genes allows an individual cell to acquire its identity and to perform its function. When one twin breaks an ankle and acquires a gash in the skin, wound-healing and bone-repairing genes are turned on, thereby recording a scar in one body but not the other.

But what turns those genes on and off, and keeps them turned on or off? Why doesn't a liver cell wake up one morning and find itself transformed into a neuron? Allis unpacked the problem further: suppose he could find an organism with two distinct sets of genes--an active set and an inactive set--between which it regularly toggled. If he could identify the molecular switches that maintain one state, or toggle between the two states, he might be able to identify the mechanism responsible for cellular memory. "What I really needed, then, was a cell with these properties," he recalled when we spoke at his office a few weeks ago. "Two sets of genes, turned 'on' or 'off' by some signal."

Allis soon found his ideal subject: a bizarre single-celled microbe called Tetrahymena. Blob-shaped cells surrounded by dozens of tiny, whiskery projections called cilia, Tetrahymena are improbable-looking--each a hairy Barbapapa, or a Mr. Potato Head who fell into a vat of Rogaine. "Perhaps the strangest thing about this strange organism is that it carries two very distinct collections of genes," he told me. "One is completely shut off during its normal life cycle and another is completely turned on. It's really black-and-white." Then, during reproduction, an entirely different nucleus wakes up and goes into action. "So we could now ask, What signal, or mechanism, allows Tetrahymena to regulate one set of genes versus the next?"

By the mid-nineteen-nineties, Allis had found an important clue. Genes are typically carried in long, continuous chains of DNA: one such chain can carry hundreds of thousands of genes. But a chain of DNA does not typically sit naked in animal cells; it is wrapped tightly around a core of proteins called histones. To demonstrate, Allis stood up from his desk, navigated his way through stacks of books and papers, and pointed at a model. A long plastic tube, cerulean blue, twisted sinuously around a series of white disks, like a python coiled around a skewer of marshmallows.

"Histones had been known as part of the inner scaffold for DNA for decades," Allis went on. "But most biologists thought of these proteins merely as packaging, or stuffing, for genes." When Allis gave scientific seminars in the early nineties, he recalled, skeptics asked him why he was so obsessed with the packing material, the stuff in between the DNA. His protozoan studies supplied an answer. "In Tetrahymena, the histones did not seem passive at all," he said. "The genes that were turned 'on' were invariably associated with one form of histone, while the genes that were turned 'off' were invariably associated with a different form of histone." A skein of silk tangled into a ball has very different properties from that same skein extended; might the coiling or uncoiling of DNA change the activity of genes?

In 1996, Allis and his research group deepened this theory with a seminal discovery. "We became interested in the process of histone modification," he said. "What is the signal that changes the structure of the histone so that DNA can be packed into such radically different states? We finally found a protein that makes a specific chemical change in the histone, possibly forcing the DNA coil to open. And when we studied the properties of this protein it became quite clear that it was also changing the activity of genes." The coils of DNA seemed to open and close in response to histone modifications--inhaling, exhaling, inhaling, like life.

Allis walked me to his lab, a fluorescent-lit space overlooking the East River, divided by wide, polished-stone benches. A mechanical stirrer, whirring in a corner, clinked on the edge of a glass beaker. "Two features of histone modifications are notable," Allis said. "First, changing histones can change the activity of a gene without affecting the sequence of the DNA." It is, in short, formally epi-genetic, just as Waddington had imagined. "And, second, the histone modifications are passed from a parent cell to its daughter cells when cells divide. A cell can thus record 'memory,' and not just for itself but for all its daughter cells."

By 2000, Allis and his colleagues around the world had identified a gamut of proteins that could modify histones, and so modulate the activity of genes. Other systems, too, that could scratch different kinds of code on the genome were identified (some of these discoveries predating the identification of histone modifications). One involved the addition of a chemical side chain, called a methyl group, to DNA. The methyl groups hang off the DNA string like Christmas ornaments, and specific proteins add and remove the ornaments, in effect "decorating" the genome. The most heavily methylated parts of the genome tend to be dampened in their activity.

In the ensuing decade, Allis wrote enormous, magisterial papers in which a rich cast of histone-modifying proteins appear and reappear through various roles, mapping out a hatchwork of complexity. (His twin, Cathy Allis, is an ace crossword-puzzle constructor, having supplied Times readers with nearly a hundred puzzles--an activity that is similar but different.) These protein systems, overlaying information on the genome, interacted with one another, reinforcing or attenuating their signals. Together, they generated the bewildering intricacy necessary for a cell to build a constellation of other cells out of the same genes, and for the cells to add "memories" to their genomes and transmit these memories to their progeny. "There's an epigenetic code, just like there's a genetic code," Allis said. "There are codes to make parts of the genome more active, and codes to make them inactive."

And epigenetics could transform whole animals. "The idea that cells can acquire profoundly different properties by manipulating their epigenome was becoming known," Danny Reinberg told me. "But that you could create different forms of a creature out of the same genome using epigenetics? That was a real challenge."

Even putative Darwinists are Lamarckists.