She Has Her Mother's Laugh: The Powers, Perversions, and Potential of Heredity (57 page)

Skinner and his colleagues launched a new study to see how far this effect could get passed down. They exposed more female rats to vinclozolin and then bred descendants for several generations. Even after four generations, they found, males kept on developing damaged sperm. Exposures to other chemicals, like DEET and jet fuel, could also alter the rats for generations.

Skinner's work inspired other researchers to look for other kinds of changes that could be inherited.
Brian Dias, a postdoctoral researcher at Emory University, wondered if mice might even pass down memories.

Each day, Dias put young male mice in a chamber into which he periodically pumped a chemical called acetophenone. It has an aroma that reminds some people of almonds, others of cherries. The mice sniffed the acetophenone for ten seconds, upon which Dias jolted their feet with a mild electric shock.

Five training sessions a day for three days was enough for the mice to associate the almond smell with the shock. When Dias gave the trained mice a whiff of acetophenone, they tended to freeze in their tracks. Dias also found that a whiff of acetophenone made the mice more prone to startle at a loud noise. In other trials, Dias would pump an alcohol-like scent called propanol into the chamber instead, without giving the mice a shock. They didn't learn to fear that odor.

Ten days after the training ended, researchers from Emory's animal resources department paid Dias a visit. They collected sperm from the trained mice and headed off to their own lab. There they injected the sperm into mouse eggs, which they then implanted into females. Later, after the pups had matured, Dias gave them a behavioral exam, too. Like their fathers, the new generation of mice was sensitive to acetophenone. Smelling it made them more likely to get startled by a loud sound, even though he had not trained the mice to make that association. When Dias allowed this new generation of mice to mate, the grandchildren of the original frightened males also turned out to be sensitive to acetophenone.

Dias then examined the nervous systems of these mice, hoping to find physical traces of the association. When a mouse smells acetophenone, the signal takes a precise path through its nervous system. The molecule latches onto only one type of nerve ending in the mouse's nose, and those nerves then send impulses to one small patch of neurons in the front of the mouse's brain. When mice learn to fear acetophenone, previous studies had shown, this patch gets enlarged.

The same patch of brain tissue that was enlarged in the trained mice was enlarged in their descendants as well. Yet the only link from the frightened fathers to their children and grandchildren was their sperm. Somehow, those cells had transmitted more than genes to their descendants. And somehow
the animals passed down information not carried in their genes but gained through experience.

Dias's work raised the possibility that
behaviors could be acquired and then inherited. Other researchers have come to a similar conclusion with their own experiments on mice. Stressful experiences when mice are young can change the way they cope with stress as adults. Young mice that are separated from their mothers for hours at a stretch act a lot like depressed people, for example. If they're put in water, they give up swimming quickly and just float helplessly. Male mice can pass down this helplessness to their offspring, and then on to their grandchildren.

The fact that fathers as well as mothers appear to influence future generations is especially intriguing. Unlike females, they have no direct link to developing embryos. In fact, males seem to be able to pass down behavioral traits by
in vitro fertilization alone. If these experiments are sound, there must be something inside sperm (and eggs, too, presumably) that can pass down these mysterious marks. And since it can be influenced by experience, it can't be genes.

—

To explain this eccentric heredity, some scientists looked toward the epigenome, that collection of molecules that envelops our genes and controls what they do. By the late 1900s, it had become clear that the epigenome is essential for the proper development of eggs into adults. Our cells coil up their DNA and alter their methylation as they divide. The distinctive combinations of genes they keep switched on help to commit them to becoming muscle, skin, or some other part of the body. These patterns can be remarkably durable, enduring through division after division. That's how little hearts grow into bigger hearts, instead of turning into kidneys.

Yet the epigenome is not simply a rigid program for turning genes on and off in a developing embryo. It is also sensitive to the outside world. Over the course of each day, for example, our epigenome helps drive our bodies through a biological cycle. We get sleepy and wakeful; we warm
and cool; our metabolic flame rises and falls. Our cycles stay on track with the twenty-four-hour rotation of our planet, thanks to the changing levels of light that enter our eyes over the course of each day. During the day, certain genes are active, making proteins important for waking life. As darkness falls, a growing number of proteins land around these genes, winding up their DNA and altering their methylation. The genes will stay silent through the night,
helpless until the morning's army of molecules wakes them again.

The epigenome can alter the workings of genes not only in response to reliable signals like dawn and dusk but to unpredictable ones as well.
When we develop an infection, immune cells bump into the pathogen and go into battle mode. They can start spewing out deadly chemicals or send signals to surrounding blood vessels to swell with inflammation. To undergo these changes, the cells reorganize their DNA, allowing certain genes to start making proteins while silencing others. And as the immune cells multiply, they pass down this battle-ready epigenome to their descendants as a kind of
cellular memory.

The memories we store in our brains may also endure thanks in part to changes we make to the epigenome. Starting in the mid-1900s, neuroscientists found that we sculpt the connections between neurons as new memories form. Some of the connections get pruned, while others get strengthened, and these patterns can endure for years. More recently, researchers have found that the formation of new memories is accompanied by some epigenetic changes. The coils of DNA in neurons get rearranged, for example, and new methylation patterns get laid down. These durable changes may ensure that neurons preserving long-term memories keep making the proteins they need to keep their connections strong.

Plants don't have brains, but they have a memory of their own—one that can respond to infections, deadly influxes of salt, or drought. Struggling against these challenges can prime a plant to prepare for more in the future. If a drought-stricken plant enjoys a shower of rain, it will still remember its lack of water. Even a week later,
it will respond to drought more strongly than a plant that has never faced such a threat to its existence. And
researchers have found that long-term changes to a plant's epigenome are essential for laying down these enduring responses.

The malleability of the epigenome is not an unalloyed good, though. Some studies suggest that stress and other negative influences can alter epigenetic patterns inside our cells, leading to long-term harm.

Some of the strongest evidence for this link has come from the laboratory of
Michael Meaney at McGill University. In the 1990s, Meaney and his colleagues started a study to see how rats experience stress. If they put rats in a small plastic box, the animals got anxious, producing hormones that raised their pulse. Some rats reacted more strongly than others to the stress, and, after some searching, Meaney and his colleagues found the source of the difference. It turned out that the rats that made more stress hormones had been licked less as pups by their mothers.

Working with Moshe Szyf, a McGill geneticist, Meaney investigated the physical differences that more licking or less licking produced in the animals. They knew that mammals control their stress response with the help of the hippocampus, that memory-forming region that keeps making new neurons through life. When stress hormones latch onto these neurons, the cells respond by pumping out a protein. Those proteins leave the brain and make their way to the adrenal glands, where they put a brake on the production of stress hormones.

Meaney and Szyf inspected the neurons in the hippocampus, looking closely at their methylation. In rats that get licked a lot, they found relatively little methylation around the gene for the stress-hormone receptor. In rats that get licked a little, the methylation is much greater. Meaney and Szyf proposed that when mothers lick their pups, the experience alters neurons in the hippocampus: Some of the methylation around their receptor gene gets stripped away. Freed from the methylation, the gene becomes more active, and the neurons make more receptors. In the well-licked pups, these neurons thus become more sensitive to stress, and rein it in more effectively. Rats that get little licking develop fewer receptors. They end up stressed-out.

Given that rats and humans are both mammals, it's possible that children may also undergo long-term changes to their stress levels from their
upbringing. In one small but provocative study, Meaney and his colleagues looked at brain tissue from human cadavers. They selected twelve who had died of natural causes, twelve people who had committed suicide, and another twelve who had committed suicide after a history of abuse as children. Meaney and his colleagues found that the brains of people who had experienced child abuse had relatively more methyl groups around their receptor gene, just as in the case of the under-licked rats. And just as those rats produced fewer receptors for stress hormones, the neurons of victims of child abuse had fewer receptors as well. It's conceivable that the child abuse led to epigenetic changes that altered emotions in adulthood, snowballing into suicidal tendencies.

Meaney and Szyf's work has inspired many other studies on how epigenetics may link the environment to chronic disorders. But even in the absence of trauma or poverty, the epigenome changes over our lifetime. In fact, a geneticist named Steve Horvath has proposed that our epigenome changes at a steady rate, like the ticking of a biological clock.

The idea of an
epigenetic clock came to Horvath in 2011 while he was studying spit. He and his colleagues had collected saliva from sixty-eight people and fished out some cells from the cheek lining that had been shed into the fluid. Initially, Horvath tried to find a difference in the methylation patterns between heterosexuals and homosexuals. But no clear pattern came to light. Hoping to salvage the study, he decided to compare the saliva according to the ages of the subjects.

Horvath and his colleagues found two spots along people's DNA where the methylation pattern tended to be the same in people of the same age. When they looked at other kinds of cells, they found other places where the methylation changed even more reliably as people got older. By 2012, Horvath was able to look at the methylation at sixteen sites in the DNA of nine different cell types. He could use those patterns to predict people's ages, with an accuracy of 96 percent.

When Horvath wrote up his experiments, two journals rejected them. It wasn't that his results were too weak. They were too good. The third time he got rejected, he drank three bottles of beer as fast as he could and
wrote a letter back to the editor, objecting to the reviews. It worked, and the paper appeared in October 2013 in the journal
Genome Biology.
When a team of researchers in the Netherlands read the study, they quickly tested out the epigenetic clock with samples of blood they had collected from Dutch soldiers. They could accurately guess the soldiers' ages to within a few months.

As provocative as such studies are, it's still far from clear whether the epigenetic clock matters much. The same uncertainty hovers over studies on how negative experiences can trigger epigenetic changes in the brain and the body. These studies tend to be small, and sometimes when other scientists replicate them, they fail to see the same results. It's even possible that the way scientists search for epigenetic change may trick them into seeing it where none exists. Perhaps the epigenetic clock is not produced by cells changing their epigenetic marks, for example. Perhaps some types of cells become more common as we get older, and those cells have different epigenetic marks than the cells more common in youth.

These uncertainties have not scared off scientists from studying epigenetics, however. The stakes are just too high. By cracking the epigenetic code, researchers may discover a link between nurture and nature. And if we can rewrite that code, we may be able to treat diseases by altering the way our genes work.

—

These studies raised the possibility that the mysterious kinds of heredity that Dias and others were observing were
the result of epigenetic changes getting passed down from one generation to the next. Within our bodies, it's clear that a cell can experience a change to its epigenetic pattern, and when it divides, its daughter cells will inherit that change. If those daughter cells happen to be germ cells, perhaps they could pass acquired traits on to later generations.

The prospect of this new kind of heredity made many people giddy. The mystery of missing heritability was solved, they claimed, because heredity was more than genes—it could be epigenetic, too. “
If the 20th century
belonged to Charles Darwin,” the epidemiologist Jay Kaufman declared in a 2014 commentary, “it is looking increasingly as if the 21st century will be handed back to Jean-Baptiste Lamarck, given the explosion of recent developments in epigenetics.”

A lot of people started talking about Lamarck again, making him the symbol of a more pliable kind of heredity. When
Nature Neuroscience
published Dias's study on memories of smells, they put a picture of Lamarck on the cover, complete with a thatch of gray hair and a high cravat.
New Scientist
covered the study in the same spirit, describing it in an editorial entitled “Mouse Memory Inheritance May Revitalise Lamarckism.”

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