The Sins of the Father

When Brian Dias became a father last October, he was, like any new parent, mindful of the enormous responsibility that lay before him. From that moment on, every choice he made could affect his newborn son's physical and psychological development. But, unlike most new parents, Dias was also aware of the influence of his past experiences — not to mention those of his parents, his grandparents and beyond.Where one's ancestors lived, or how much they valued education, can clearly have effects that pass down through the generations. But what about the legacy of their health: whether they smoked, endured famine or fought in a war?As a postdoc in Kerry Ressler's laboratory at Emory University in Atlanta, Georgia, Dias had spent much of the two years before his son's birth studying these kinds of questions in mice. Specifically, he looked at how fear associated with a particular smell affects the animals and leaves an imprint on the brains of their descendants.Dias had been exposing male mice to acetophenone — a chemical with a sweet, almond-like smell — and then giving them a mild foot shock. After being exposed to this treatment five times a day for three days, the mice became reliably fearful, freezing in the presence of acetophenone even when they received no shock.Ten days later, Dias allowed the mice to mate with unexposed females. When their young grew up, many of the animals were more sensitive to acetophenone than to other odours, and more likely to be startled by an unexpected noise during exposure to the smell. Their offspring — the 'grandchildren' of the mice trained to fear the smell — were also jumpier in the presence of acetophenone. What's more, all three generations had larger-than-normal 'M71 glomeruli', structures where acetophenone-sensitive neurons in the nose connect with neurons in the olfactory bulb. In the January issue ofNature Neuroscience, Dias and Ressler suggested that this hereditary transmission of environmental information was the result of epigenetics — chemical changes to the genome that affect how DNA is packaged and expressed without altering its sequence.Biologists first observed this 'transgenerational epigenetic inheritance' in plants. Tomatoes, for example, pass along chemical markings that control an important ripening gene. But, over the past few years, evidence has been accumulating that the phenomenon occurs in rodents and humans as well. The subject remains controversial, in part because it harks back to the discredited theories of Jean-Baptiste Lamarck, a nineteenth-century French biologist who proposed that organisms pass down acquired traits to future generations. To many modern biologists, that's “scary-sounding”, says Oliver Rando, a molecular biologist at the University of Massachusetts Medical School in Worcester, whose work suggests that such inheritance does indeed happen in animals. If it is true, he says, “Why hasn't this been obvious to all the brilliant researchers in the past hundred years of genetics?”.One reason why many remain sceptical is that the mechanism by which such inheritance might work is mysterious. Explaining it will require a deep dive into reproductive biology to demonstrate how the relevant signals might be formed in the germ line, the cells that develop into sperm and eggs and carry on, at a minimum, a person's genetic legacy.A mother might pass on effects of environmental exposures to a fetus during pregnancy. So, to study the phenomenon of transgenerational epigenetics cleanly, biologists are focusing on fathers, and have been looking at how sperm might gain and lose epigenetic marks. “In the past two to three years there's been a lot of new information,” says Michelle Lane, a reproductive biologist at the University of Adelaide in Australia. But proposals for how it all works are themselves embryonic. “It's a huge black box,” Lane says.Read more in...Nature, March 2014.