Authors: Carl Zimmer
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 childrenâwho 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 epigeneticsâstarting, wrongly of course, with Lamarckâand 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:
Experienceâ>Brain stateâ>Altered gene expression in some specific neurons (so far so good, all systems working normally)â>Transmission of information to germline (how? what signal?)â>Instantiation of epigenetic states in gametes (how?)â>Propagation of state through genomic epigenetic “rebooting,” embryogenesis and subsequent brain development (hmmÂ .Â .Â .)â>Translation of state into altered gene expression
in specific neurons
(ah now, c'mon)â>Altered sensitivity of specific neural circuits, as if the animal had had the same experience itselfâ>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
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 animalsâand people in particularâremained 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 activeâtriggering, among other things, new colors in corn kernels.
This strange inheritance has turned up in other crops as well as in wild plantsâincluding toadflax. Enrico Coen and his colleagues discovered that
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 timeâand plenty of cell divisionsâfor 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
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 possibleâbut, again, not provenâthat 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.