TIM OVER HERE has the original Linnaeus flower.”
I had come back to Cold Spring Harbor, this time for its plants. A transplanted Englishman named Robert Martienssen met me in front of his lab, and we spent the morning admiring his mats of duckweed and tall stands of experimental corn. We went to one of the laboratory greenhouses to meet the farm manager, Tim Mulligan. He brought with him a black plastic pot with a flower.
Mulligan set it down on a counter made of planks, and I leaned in to inspect it. The pot contained a single plant, sprouting a dozen or so bright yellow blossoms. The flowers looked to me like miniature herald trumpets. The petals wrapped around each other to create a long, closed tube. Each tube curled out at the end, forming a spiked, five-sided rim.
It was a lovely plant, but if I encountered it on a walk through a meadow, I might well have crushed it under my boot. To Martienssen, however, it was one of the most interesting organisms in the world. It represented an enduring mystery about heredity and the forms it can take.
The flower I was looking at has a clear-cut pedigree. It’s a direct ancestor of a plant that was discovered in 1742 by a Swedish university student named Magnus Zioberg. Zioberg was hiking on an island near Stockholm when he happened to notice a trumpet-flowered plant. It confused him, because—aside from the flowers—it looked like a familiar plant called toadflax. The flowers of normal toadflax plants have a mirrorlike symmetry. They grow a few small yellow petals, some sprouting off to the left and others to the right, and a spike develops at the base of these flowers, pointing toward the ground. The flowers on the plant that Zioberg stumbled across had a circular symmetry instead.
Zioberg plucked the flower out of the ground, pressed it in a book, and brought it back to Uppsala University to show to his professor Olof Celsius. Celsius was thunderstruck. He immediately brought the flower to his colleague—and one of the most important naturalists in history—Carl Linnaeus.
Linnaeus was working at the time on a new system for classifying all plants and animals. It’s the system we still use today. To classify plants, Linnaeus paid particular attention to the shape of their flowers. When he looked at Zioberg’s discovery, he thought Celsius was having a joke at his expense. Celsius must have glued flowers from another species onto a toadflax plant to fool him. But Celsius assured Linnaeus it was genuine.
Zioberg had found a monster, Linnaeus decided. But such monstrous flowers were supposed to be sterile, and Linnaeus discovered that Zioberg’s specimen was fertile, growing the structures it would need to produce viable seeds. Linnaeus became even more astonished the closer he studied the structure of the flowers. They were unlike anything that Linnaeus—or any botanist before him—had ever seen. He begged Zioberg to go back to the island and bring him back some plants that were still alive.
Zioberg did so, and returned to Uppsala with a living plant that still had intact roots and stems. It was planted in the university’s botanical garden, but it languished and died. Linnaeus desperately made the most of the flower’s brief existence, writing down a wealth of observations. He produced a long report on that single plant, his surprise radiating off each page.
“This is certainly no less remarkable than if a cow were to give birth to a calf with a wolf’s head,” Linneaus declared. He considered the trumpet-shaped flower a species of its own. He named it Peloria—from the Greek for “monster.”
To make sense of this “amazing creation of nature,” as he called it, Linnaeus speculated that it descended from ordinary toadflax. Pollen from another species had fertilized a toadflax plant, somehow triggering a sudden leap into a new form. To say such things in the 1740s—a century before Mendel’s and Darwin’s work—verged on heresy. Species were supposed to be fixed since creation. Heredity could not abruptly change course and make a new species.
“Your Peloria has upset everyone,” a bishop wrote in an angry letter to Linnaeus. “At least one should be wary of the dangerous sentence that this species had arisen after the Creation.”
In his later years, as he studied other specimens, Linnaeus became less sure of what the plants really were. He discovered that sometimes a single Peloria plant grew a mix of monstrous trumpet flowers and ordinary mirrorlike ones. He couldn’t decide whether they were indeed a species of their own or some kind of strange variant that defied botany’s rules.
Peloria would continue to intrigue later generations of botanists. Reared in botanical gardens across Europe, the plant went on passing down trumpet flowers to later generations. Goethe, who was just as interested in flowers as he was in poetry, made sketches of Peloria alongside toadflax flowers. Hugo de Vries thought for a time he might discover proof for his mutation theory in Peloria. The monstrous flower must have arisen through a mutation to an ordinary toadflax, he believed, creating a new species in a single jump.
Peloria refused to surrender to such an easy explanation. If a mutation really had produced the plant’s trumpet flowers, it would have rewritten a piece of toadflax DNA. Later generations of Peloria would have inherited that mutation. Instead, the descendants of the original Peloria plants sometimes grew ordinary mirror flowers and sometimes monstrous trumpet ones, displaying no clear pattern that Mendel would have recognized.
In the late 1990s, a group of English scientists turned their attention to Peloria, using the tools of molecular biology. Enrico Coen of the John Innes Centre in England and his colleagues examined a gene involved in making flowers, called L-CYC. In order for ordinary toadflax plants to develop flowers, they must switch on the L-CYC gene in the tips of their stems. In Peloria, Coen discovered, L-CYC stays silent.
This difference is not due to a mutation that altered the gene for L-CYC in Peloria. Coen and his colleagues found that the gene is identical in toadflax and Peloria. The difference between them was not in their DNA but around it.
Coen found a different pattern of methylation around the L-CYC gene in Peloria and in normal toadflax. In Peloria, L-CYC had a heavy coating of methyl groups, preventing the flower’s gene-reading molecules from reading it. Coen and her colleagues noticed that as they bred new Peloria plants, they sometimes produced flowers that looked more like those of regular toadflax. When the scientists inspected the L-CYC gene in these throwbacks, they found that the gene had lost some of its methylation, allowing it to become more active again.
In Peloria, it seems, heredity has traveled down two channels. The flower has passed down copies of its genes, which guided the development of toadflax-shaped plants. But these plants also inherited a peculiar pattern of methylation that was not encoded in their genes. At some point before Zioberg stumbled across it in 1742, a toadflax plant accidentally added on methyl groups to its L-CYC gene. By silencing the gene, this methylation caused the flower to develop into a new shape. This newly altered flower then produced seeds, which inherited the same epigenetic mark. They fell to the ground, sprouted, and produced the same monstrously lovely flowers. Over the centuries that followed, some of their descendants lost the epigenetic mark, blooming into ordinary toadflax flowers once more. But other Peloria plants continued to inherit the wolf’s head of botany.
When I visited Martienssen, he was starting an experiment on Peloria. No one knew exactly how these plants kept inheriting the epigenetic marks for their monstrous flowers for so many generations. Martienssen had an idea for how to find out, but his experiment almost didn’t happen. When he asked Coen where he could get a supply of Peloria, Coen told him the flower had vanished. As far as Coen could tell, no one in the world had any Peloria left.
“They lost it at Kew Gardens,” Martienssen told me. “They lost it at Oxford Botanic Gardens, where they had it for two hundred years.”
After months of searching, Coen finally discovered a cache of the historically important flowers. He found it not in a botanical garden or in a scientific laboratory. A California nursery offered to ship Peloria anywhere in the world. Martienssen put in a big order, and once the plants arrived in Cold Spring Harbor, he and Mulligan started building up a supply of their own.
“We’re trying our best to make sure we don’t lose it,” Mulligan said.
In the late 1800s, Charles Darwin and Francis Galton first turned heredity into a scientific question. Scientists such as Hugo de Vries and William Bateson believed that in genes they had found an answer. They found a way by which living things today could be correlated with their biological past. But in the process, they didn’t just look for evidence in favor of genes as a vehicle for heredity. They also sought to refute any other alternative.
When August Weismann argued that the germ line carried heredity, walled off from somatic cells, he singled out Jean-Baptiste Lamarck as his opponent. Chopping off mouse tails was his way of refuting Lamarck’s claim that acquired characters could be passed down. “If acquired characters cannot be transmitted, the Lamarckian theory completely collapses and we must entirely abandon the principle by which alone Lamarck sought to explain the transformation of species,” Weismann said in 1889.
Weismann cleared a scientific path for geneticists to follow in the early 1900s, and they, like him, fashioned themselves as opponents of Lamarck and the so-called Lamarckians of their own day. In 1925, Thomas Hunt Morgan declared that genetic studies “furnish, in my judgment, convincing disproof of the loose and vague arguments of the Lamarckians.” Any Lamarckian who did not abandon those loose and vague arguments in the face of all the evidence had to be confusing wishful thinking for science. “The willingness to listen to every new tale that furnishes evidence of the inheritance of acquired characters arises perhaps from a human longing to pass on to our offspring the fruits of our bodily gains and mental accumulations,” Morgan sniffed.
Lamarck has remained an icon of pre-genetic thinking ever since. It’s a role that’s unfair both to him and to history. The inheritance of acquired traits had been widely accepted for thousands of years before Lamarck was born. In Europe, scholars from the Middle Ages to the Enlightenment treated it as fact. When Lamarck developed his theory of evolution from the inheritance of acquired traits, he felt no need to argue that it was true, because the matter had been settled so long ago. “The law of nature by which new individuals receive all that has been acquired in organization during the lifetime of their parents is so true, so striking, so much attested by the facts,” he once said, “that there is no observer who has been unable to convince himself of its reality.”
Regardless of whose name should be put on the idea, it continued to fall out of favor over the course of the twentieth century. As genetics explained more and more about life—with the discovery of the structure of DNA, with the fine details of its inheritance charted in thousands of experiments—the evidence for other forms of heredity remained weak: an odd frog or a stray stalk of wheat that seemed to pass down acquired traits. But some scientists continued to fight for conceptual room for more than one form of heredity. If we simply redefine heredity as genetics, they argued, we will never even look for those other channels.
Toward the end of the twentieth century, a few cases came to light that looked an awful lot like the inheritance of acquired traits.
In 1984, a Swedish nutrition researcher named Lars Olov Bygren launched a study of people in Överkalix, a remote region of Sweden where he had grown up. For centuries, Bygren’s relatives had eked out a difficult existence along the banks of the Kalix River, fishing salmon, raising livestock, and growing barley and rye. Every few years, they suffered devastating crop failures, leaving them with little food to eat during the six-month-long winters. In other years, the weather would swing far in their favor, bringing bumper crops.
Bygren wondered what sort of long-term effects these drastic changes had on the people of Överkalix. He picked ninety-four men to study. Studying church records, he charted their genealogies and discovered a correlation between their own health and the experiences of their grandfathers. Men whose paternal grandfathers lived through a feast season just before puberty died years sooner than the men whose grandfathers had endured a famine at that same point in their life. Women, Bygren found in a later study, also experienced an influence across the generations. If a woman’s paternal grandmother was born during or just after a famine, she ended up with a greater risk of dying of heart disease. It had long been known that a woman’s health while she was pregnant could influence a fetus, but Bygren’s research suggested the effects could stretch even further, to grandchildren or beyond.
Experiments on animals produced some similar results. In the early 2000s, Michael Skinner, a biologist at Washington State University, and his colleagues stumbled across one while they were investigating a fungus-killing chemical called vinclozolin. It’s used by farmers to protect fruits and vegetables from mold, despite some evidence it can interfere with sex hormones.
Skinner and his colleagues gave vinclozolin to pregnant rats, and their offspring developed deformed sperm and other kinds of sexual abnormalities. Later, one of Skinner’s postdoctoral researchers mistakenly bred these offspring and produced a new generation of rats. That error allowed Skinner to discover something he would not have expected: The grandsons of the poisoned rats also produced defective sperm, despite having no direct exposure to vinclozolin.
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.”
Transgenerational epigenetic inheritance, as this new flavor of Lamarckism came to be known, inspired giddiness far beyond scientific journals. It implied that our health and even our minds were shaped by an alternate form of heredity. If you let your imagination run wild through the possible implications, it can be hard to get it back on its leash. The fact that vinclozolin and DEET can have transgenerational effects is worrying when you consider that many other chemically similar compounds might as well, including some of the chemicals in plastics. In 2012, 280 million tons of plastics were produced worldwide, and much of it ended up in the environment. It’s bad enough to envision their potential to disrupt hormones in people and animals. It’s worse to picture a legacy of this pollution enduring through the generations.
Now imagine that poverty, abuse, and other assaults on parents also impress themselves epigenetically on their children—who might then pass down those marks to their own children. Think of all the social ills you might explain with Lamarck. In 2014, a journalist named Scott C. Johnson indulged in this speculation in a feature entitled “The New Theory That Could Explain Crime and Violence in America.” He wove the story of a black family in Oakland, California, beset by poverty, addiction, and crime into a scientific history of epigenetics—starting, wrongly of course, with Lamarck—and then running up to recent experiments on mice. “Forget what you’ve heard about guns and drugs,” Johnson exhorted us. “Scientists now believe the roots of crime may lie deep within our biology.”
If, on the other hand, you suffered from upper-middle-class anxieties, epigenetics could become your new yoga. A hypnotherapist named Mark Wolynn started running workshops around the United States where he rummaged back in the genealogy of his clients for hidden epigenetic troubles. “The newest research in epigenetics tells us that you and I can inherit gene changes from traumas that our parents and grandparents experienced,” Wolynn declared on his website. He promised to deprogram those inherited changes by helping build “new neural pathways in your brain, new experiences in your body, and new vitality in your relationship with yourself and others.” All for only $350 per workshop.
Coming out of an epigenetic workshop, your neural pathways rebuilt, you might be shocked to discover just how much skepticism there is in scientific circles about transgenerational epigenetic inheritance. Many critics see no basis for drawing huge lessons from the evidence gathered so far. They are suspicious of the small size of many of the most sensational studies. Results that look like evidence of transgenerational epigenetic inheritance may often be random flukes. In some cases, the results may be genuine, yet the causes may have nothing to do with inherited epigenetic marks.
But some of the most potent attacks on this form of inheritance have been directed at the molecular details. It’s hard to see how exactly the experiences of parents can reliably mark the genes of their descendants. While it’s true that the methylation pattern in cells can change during people’s lifetimes, it’s not at all clear that those changes can be inherited.
The trouble with this hypothesis is that it doesn’t fit what we know about fertilization. A sperm carries its own payload of DNA, which has its own distinct epigenome as well. For example, sperm have to tightly wind their DNA in order to fit it inside their tiny confines. During fertilization, the sperm’s genes enter the egg, where they encounter proteins that attack the father’s epigenome. As the embryo starts to grow, the epigenetic drama continues. The totipotent cells strip away much of the remaining methylation on their DNA. And then they reverse course and start putting a fresh batch of methyl groups back on.
This new methylation helps cells in an embryo take on new identities. Some cells commit to becoming the placenta. Others start giving rise to the three germ layers. And when the embryo is around three weeks old, a tiny wedge of cells receives a set of signals that tell them they have been picked for immortality. They will become germ cells. The newly formed primordial germ cells alter their epigenome yet again. They strip off much of the methylation from their DNA.
Many scientists doubt that inherited epigenetic marks can survive all this stripping and resetting. If heredity is a kind of memory, methylation suffers radical amnesia in every generation.
It’s concerns like these that led a number of scientists to question Brian Dias’s claim that mice can inherit memories. Kevin Mitchell, a neurogeneticist at Trinity College, Dublin, took to Twitter to express his skepticism. He delivered a rant worthy of August Weismann.
“For transgeneration epigenetic transmission of behaviour to occur in mammals,” he wrote, “here’s what would have to happen:
Experience—>Brain state—>Altered gene expression in some specific neurons (so far so good, all systems working normally)—>Transmission of information to germline (how? what signal?)—>Instantiation of epigenetic states in gametes (how?)—>Propagation of state through genomic epigenetic “rebooting,” embryogenesis and subsequent brain development (hmm . . .)—>Translation of state into altered gene expression in specific neurons (ah now, c’mon)—>Altered sensitivity of specific neural circuits, as if the animal had had the same experience itself—>Altered behaviour now reflecting experience of parents, which somehow over-rides plasticity and epigenetic responsiveness of those same circuits to the behaviour of the animal itself (which supposedly kicked off the whole cascade in the first place)
For scientists like Mitchell, an epigenetic form of heredity suffers from more than just biological gaps. It demands rewriting entire fields of science that researchers already understand very well.
In 2014, Robert Martienssen coauthored the definitive cold-water bath for the new Lamarckism. He and Edith Heard, a biologist at the Curie Institute in Paris, looked over all the research to date and published a review in the journal Cell entitled “Transgenerational Epigenetic Inheritance: Myths and Mechanisms.”
“Might what we eat, the air we breathe, or even the emotions we feel influence not only our genes but those of descendants?” Heard and Martienssen asked. For all the attention that scientists and others had drawn to that question, they saw no reason to answer the question with a yes. “So far there is little support,” they wrote.
When I visited Martienssen at Cold Spring Harbor in 2017, he still didn’t see any reason to revise his judgment. The research on animals—and people in particular—remained too skimpy to get excited about. He saw no compelling evidence for a mechanism that could carry epigenetic traits across many generations of animals.
Yet Martienssen found it funny that he had gained a reputation as a naysayer. While he finds the evidence weak in the animal kingdom, he spends most of his time in the kingdom of plants. And there the evidence is actually overwhelming. “This sort of thing happens all the time in nature,” Martienssen told me.
Plant scientists got their first clues to this extra channel of heredity in the mid-1900s. Corn kernels took on new colors, but their offspring didn’t follow Mendel’s Law, and after a few generations the ancestral color sometimes returned. A careful inspection of corn DNA showed that these changes to their color were not the result of mutating genes. It was the pattern of methylation that was changing. Each time plant cells divide, they rebuild the same pattern of methylation on the new copies of DNA that they make. But every now and then, plant cells alter the pattern: They add an extra methyl group where none was before, or a methyl group falls away and isn’t restored. These changes can silence a gene in a plant or allow it to become active—triggering, among other things, new colors in corn kernels.
This strange inheritance has turned up in other crops as well as in wild plants—including toadflax. Enrico Coen and his colleagues discovered that Peloria reliably produced its trumpet flowers because it passed down a distinctive methylation of its L-CYC gene. Other researchers gathered other plants from the wild and found that some of them inherited epigenetic patterns that influenced their size, shape, and tolerance for harsh conditions. In experiments, they stripped off methyl groups from certain segments of DNA in plants and then bred them. The plants could reliably pass down these new epigenetic patterns for twenty generations or more.
It’s possible that plants make it easier for transgenerational epigenetic inheritance to occur than do animals. Unlike animals, plants don’t set aside germ cells early in development and reset their methylation. A red oak acorn will break open, and its cells will develop into roots and a stem, and over years its cells will multiply into a tree. After it has grown for about a quarter of a century, it will prepare to reproduce, reprogramming some of the cells on the tips of its branches into a botanical version of stem cells.
These cells swiftly divide, forming flowers, some with pollen (the plant equivalent of sperm) and some with ovules (the plant equivalent of eggs). The tree’s ovules may get fertilized by pollen from other trees, developing into acorns. The following year, the same oak will produce a new batch of stem cells at its branch tips that will grow into flowers and sex cells. It will keep doing so for centuries. In other words, there’s plenty of time—and plenty of cell divisions—for the epigenetic patterns in red oaks to change before their somatic cells turn into germ cells. And since plants don’t reset their epigenetic marks in germ cells the way animals do, there’s an opportunity for a new red oak tree to inherit new epigenetic marks from its parents.
There’s another important difference between animal epigenetics and plant epigenetics. Even though plants cover their genes with the same methyl groups, they use different molecules to apply them. Martienssen and other researchers have discovered that plants do so by producing small RNA molecules, each of which can home in on specific segments of DNA. Once they reach their target, the RNA molecules draw proteins around them, which add methyl groups to the DNA. When these cells divide, their daughter cells inherit these RNA molecules, which can continue to control how their genes work.
Something similar might have happened in Peloria. Now that Martienssen had tracked down the last source in the world, he could see if his hunch was right. His plan was to pull out RNA molecules from the strange flowers. “I’m hoping,” he said, “that we can finally close this chapter and explain the monster.”
The biology of animals may offer less of an opportunity for transgenerational epigenetic inheritance than that of plants. But that does not necessarily slam the door shut on the possibility. To a number of scientists, it remains ajar.
Our understanding of epigenetics depends on how well we can see it. When scientists began mapping the methylation that coats DNA, they could barely see it at all. In the 1990s, Enrico Coen could cut out a single gene and inspect it for methylation. Scientists then developed the tools for mapping the methylation across all the DNA in a cell. But they had to pull the DNA out of millions of cells at once to do so. If those cells belonged to subtly different types, each with a different pattern of methylation, the scientists could see only an epigenetic blur. By the 2010s, scientists were learning how to put cells on a kind of microscopic conveyor belt where they could inspect all the methylation in each cell, one at a time.
As our epigenetic focus has sharpened, old assumptions have turned out to be wrong. In 2015, for example, Azim Surani, a biologist at the Wellcome Institute in England, led one of the first studies on the epigenetics in human embryonic cells. In particular, he and his colleagues examined the cells that were on the path to becoming eggs or sperm. They observed these so-called primordial germ cells stripping away most of their methylation before applying a fresh coat. But a few percent of the methyl groups remained stubbornly stuck in place on the DNA.
A lot of the cells shared the same resistant stretches of DNA that held on to their old epigenetic pattern. These stretches contained virus-like pieces of DNA called retrotransposons. They can coax a cell to duplicate them and insert the new copy somewhere else in the cell’s DNA. Methylation can muzzle these genetic parasites.
Retrotransposons typically sit near protein-coding genes, and it is possible that those genes get muzzled, too. Surani and his colleagues found that some of the genes near the stubborn methylation sites have been linked to disorders ranging from obesity to multiple sclerosis to schizophrenia. Based on their experiments, the scientists concluded that these genes are promising candidates for transgenerational epigenetic inheritance.
It is also possible—but, again, not proven—that other molecules may carry out transgenerational epigenetic inheritance. Sperm cells, for example, deliver RNA molecules into the eggs they fertilize, along with their chromosomes. Some of those RNA molecules help orchestrate the earliest stages of an embryo’s development. Tracy Bale, a biologist at the University of Pennsylvania, has carried out experiments to see if the RNA molecules in sperm can allow experiences of fathers to influence their offspring.
In particular, Bale and her colleagues investigated the effect of stress that male mice experienced early in life. They found that when these stressed mice matured, they produced sperm with an unusual blend of RNA molecules. The scientists wondered what sort of effect these RNA molecules might have on offspring. They injected an RNA cocktail into the sperm of mice that had not experienced a lot of stress, and then fertilized eggs with the sperm. The pups that these eggs developed into handled stress badly. Bale’s research suggests that the RNA in a stressed father’s sperm can shut down certain genes in the cells of their offspring. And by silencing these genes, fathers can permanently alter their offspring’s behavior.
A few other researchers have also found tantalizing hints of the hereditary power of RNA in animals. Antony Jose, a biologist at the University of Maryland, tracks RNA molecules produced inside the body of a tiny worm called Caenorhabditis elegans. RNA molecules created in the worm’s brain can make their way across its body and end up inside its sperm, where it turns off a gene. Other researchers have found that RNA molecules in the worms can turn off the same gene in the next generation, and for several generations after that. It appears that the RNA molecules sustain themselves through the generations by spurring young worms to make more copies of themselves.
We are not worms, of course, but a number of experiments have demonstrated that human cells can send RNA molecules to each other on a regular basis. Very often, they are delivered in tiny bubbles, called exosomes. Scientists have observed more and more types of cells releasing exosomes, and more and more taking them up. In some species, embryos may use exosomes to send signals between parts of the body to make sure they all develop in sync. Heart cells may release them after a heart attack to trigger the organ to repair itself. Cancer cells spew out exosomes with exceptional abandon—probably as a way to manipulate surrounding healthy cells into becoming their servants. In 2014, an Italian biologist named Cristina Cossetti observed that exosomes cast off by cancer cells in male mice could deliver their RNA into their sperm cells.
These studies are far from conclusive, but they’ve been provocative enough to send scientists back to reread The Variation of Animals and Plants Under Domestication. Darwin’s gemmules certainly don’t gather genes from around the body. But perhaps—just perhaps—exosomes are a modern incarnation of gemmules, ferrying the RNA molecules that allow the experiences of one generation to influence the next.
But even if there is a link from somatic cells to the germ line and to future generations, it won’t be enough to resurrect Lamarck. What made Lamarck’s theory so seductive in the nineteenth century was the idea that the acquired traits were adaptive. In other words, they helped animals and plants survive, enabling species to fit themselves to their environment. Lamarck believed his version of evolution could explain why species were so well matched to their surroundings. In Lamarck’s world, giraffes stretched their necks and ended up with the longer necks they needed to get food.
There is no solid evidence that transgenerational epigenetic inheritance is adaptive in the sense Lamarck intended. The few experiments that come closest to support have been carried out on plants. In one such study, researchers at Cornell University put caterpillars on a small flowering plant called Arabidopsis thaliana. The plants responded by making toxic chemicals that slowed down the onslaught. The researchers then bred the plants for two generations and then unleashed a new assault of caterpillars on the third-generation offspring. The plants still made high levels of toxins that stunted the growth of the insects.
Martienssen finds these experiments intriguing but doesn’t see them as solid proof of Lamarckism. Arabidopsis thaliana is the lab rat of the plant kingdom, for example, having been bred by scientists for many generations in caterpillar-free conditions. Their response to insect enemies may not reflect what happens outside, in the insect-infested world.
“Finding that is still a Holy Grail of epigenetics,” Martienssen said. “I mean, there are reports out there, but nothing has really, really stuck.”
It’s entirely possible that some inherited epigenetic changes are good for plants. But it’s also possible that others are bad, and still others indifferent. The flowers of Peloria grabbed Linnaeus’s attention, but no one has demonstrated that they do the plants any more good than the ordinary toadflax flower. An epigenetic flip simply swapped one flower for another.
Dandelions, scientists have found, can inherit epigenetic patterns that make them sprout early or late. Wild populations of Arabidopsis inherit some patterns that make some of their roots grow deep and others shallow. It’s possible—although it has yet to be proven—that this overall variety helps out plants. If a drought strikes a prairie, a population of flowers may avoid extinction because of the long roots that a few of them have, thanks to the lingering luck of the epigenetic draw.
Regardless of what transgenerational epigenetic inheritance does for plants, Martienssen told me, he saw them as a legitimate part of how their ancestors influence their descendants.
At one point in our conversation, Martienssen surprised me by asking if I had ever heard of Luther Burbank. I had indeed; just a few weeks before, I had made my own pilgrimage to his garden in Santa Rosa. But here at Cold Spring Harbor, at a modern shrine to genetics, I didn’t expect to hear his name. Martienssen said that Burbank fascinated him. Burbank might not have been a rigorous scientist, but he could perceive patterns that still matter to science today. Martienssen stared off and recited to me a line of Burbank’s that he drops whenever he can into his lectures and papers.
“Heredity,” Burbank declared, “is only the sum of all past environment.”