As with so much in science, this story owes a lot to mice. The tale begins with a pregnant mouse in a laboratory in Boston, Massachusetts. Such is the unfortunate lot of a lab rodent that she was kept on a near-starvation diet when she was close to giving birth. As scientists expected, her babies were born smaller than usual. When they were raised normally, they later developed diabetes.
Now comes the twist. Even though these mice were fed well, their own young were also born unusually small and with a higher risk of diabetes. This was strange, because nothing had changed genetically and they had not suffered any problems in the womb or after they were born. They should have been perfectly healthy.
This puzzling study, published last month, echoes many performed on mice, worms and plants in the past few years in the name of a relatively young branch of science called epigenetics. In seeking to answer that eternal question of nature versus nurture — Does our upbringing shape us or do our genes? — this field has radically introduced a mysterious third element into the mix: the life experience of previous generations.
Illustration: Mountain People
There are many definitions of epigenetics, but simply put, it is a change in our genetic activity without changing our genetic code, University College London and the University of Bristol geneticist Marcus Pembrey says.
It is a process that happens throughout our lives and is normal to development. Chemical tags get attached to our genetic code, like bookmarks in the pages of a book, signaling to our bodies which genes to ignore and which to use, he added.
For decades, people have thought of our offspring as blank slates. Now, epigeneticists are asking whether in fact our environment, from smoking and diet to pollution and war, can leave “epigenetic marks” on our DNA that could get passed on to subsequent generations. They call the phenomenon epigenetic inheritance.
Until recently, most scientists assumed that whatever epigenetic marks we accrued during our lives were erased in our children. Embryos are known to be reprogrammed in the womb.
“For something to be transmitted epigenetically from one generation to the next, it would have to resist this reprogramming,” says Anne Ferguson-Smith, a geneticist at the University of Cambridge who ran the pregnant mouse study with her colleagues in Boston.
The notion that infants may retain some parental baggage has enormous repercussions for child development and evolution. Parents could suddenly find themselves responsible for passing on not only their poor genes, but also their poor lifestyles. Also, instead of adapting to our environments slowly over many generations, humans may be doing it much, much faster. Some have even breathlessly suggested that Charles Darwin’s theories will need to be rewritten.
However, before you throw out your biology textbooks, Ferguson-Smith counters that transgenerational epigenetic experiments are difficult to perform and can be misinterpreted.
“Journals are very excited about this. They want to publish this stuff, but we must be more cautious,” she says.
The basic problem is that researchers, including herself, still do not understand the scientific mechanism behind epigenetic inheritance, which would explain exactly how it happens.
Azim Surani, a leading developmental biologist and geneticist at the University of Cambridge, adds that while there is good evidence that epigenetic inheritance happens in plants and worms, mammals have very different biology. Surani’s lab carried out thorough studies on how epigenetic information was erased in developing mouse embryos and found that “surprisingly little gets through” the reprogramming process.
Timothy Bestor, a geneticist at Columbia University in New York, is far more damning, claiming that the entire field has been grossly over-hyped.
“It’s an extremely fashionable topic right now. It’s very easy to get studies on transgenerational epigenetic inheritance published,” he says, adding that all this excitement has lowered critical standards.
Although many epigeneticists insist that they are slowly building up solid evidence in mice, when it comes to humans, the case is even more unclear. Among the very few sources of data are long-term medical studies over multiple generations. One that is often quoted tracked families following the Dutch famine of 1944, showing that starvation in one generation had health repercussions on grandchildren.
More recently, Pembrey, who has spent the last 15 years looking for proof of epigenetic inheritance in people, mined the Avon Longitudinal Study, which has monitored 14,000 new mothers and their children since the early 1990s. Pembrey and his colleagues found that men who had started smoking before they were 11 had sons who were more likely to be obese by the time they were teenagers. Meanwhile, the grandsons of grandmothers who smoked, even if their mothers did not, were bigger.
Some epidemiologists have questioned these correlations, but Pembrey is convinced that epigenetic inheritance is well-placed to explain his observations.
“The remarkable thing is, whatever study we’ve planned so far, we have seen results,” he adds. “This is a phenomenon.”
Psychiatrists have also pinpointed anomalies that might be explained by epigenetics.
Rachel Yehuda, a psychiatrist and neuroscientist at Mount Sinai Hospital in New York, discovered that pregnant survivors of the Sept. 11, 2001, World Trade Center attacks who suffered post-traumatic stress disorder had offspring with lower levels of cortisol. This is a hormone associated with a heightened state of alarm. Her research has shown that the same applies to the offspring of Holocaust survivors.
Epigenetics may even answer the question of why mental disorders, including autism and schizophrenia, run in families. Grainne McAlonan, clinical senior lecturer in neurodevelopmental disorders at King’s College London, says that studying the DNA of these patients has not provided enough answers.
“We’re not fully explaining autism as a fully genetic disorder,” she says.
Ultimately, the problem with all this is that human life is messy, critics say. Thousands of different factors could explain health patterns in generations of the same family. This is the main reason why, to understand our basic biology without being clouded by our genetics, complicated upbringings and varied environments, perfectly uniform lab mice are the next-best thing.
“You can’t experiment on humans as you do on animals,” Pembrey says.
Such is the rodent’s importance to epigenetics that the University of Utah even has an online game allowing you to “lick a rat pup” virtually to find out how this affects its epigenome.
Now we turn to another tale of mice, this time traumatized mice. In a widely covered study published at the end of last year, researchers Kerry Ressler and Brian Dias at Emory University in Atlanta, Georgia, gave male lab mice electric shocks every time they were exposed to the smell of acetophenone, a chemical used in perfumes because of its sweet fragrance, such as cherries and orange blossom. The eventual Pavlovian result was that the mice shuddered at the mere scent of acetophenone.
The surprise was that their children feared the smell, too, even though they had not received any shocks. So did their grandchildren.
“It was a beautifully controlled experiment,” says Pembrey.
The results suggest that the fear of the smell of acetophenone passes into the sperm of the mice through some kind of chemical process, leaving epigenetic marks that are not erased in the womb. Some reporters have likened it to a “memory” being passed down the generations.
Dias says they have since received e-mails from people who are convinced that they have experienced their own transgenerational “memories.”
Sometimes these are behaviors, such as abuse or addiction. Other times, they are phobias. One person told him: “I detest the smell of eggs and my great-great-grandmother did not like eggs.”
However, Ressler and Dias’ experiment has also raised eyebrows.
Ferguson-Smith says their work was “poorly presented,” with a lack of detail that makes it difficult to interpret the results. Bestor adds that they failed to explain how a response associated with the nose managed to pass all the way into sperm.
Like all other epigenetic inheritance studies that he finds problematic, Bestor says: “There is a total lack of plausible mechanism.”
The researchers acknowledge that, although they believe their mouse experiment is correct, the results remain largely a mystery.
“How are they escaping reprogramming?” Dias says. “This is beyond the expertise of a single individual, a single lab, a single field.”
The questions do not end there. Prime among them is how long possible epigenetic effects such as these might last.
Early findings hint that they may wear off within two generations, which would suggest that human evolution is not much affected. Surani says there is only a slight possibility that grandchildren are affected and that he has seen no evidence in generations beyond that.
More worryingly, Surani says that researchers who are not getting positive results are finding their work more difficult to publish, which is feeding hype around the field.
“There have been people who have tried to replicate some of this stuff and it doesn’t work,” he says.
Even different strains of mice can produce different results.
With so many opposing views, scientists have found themselves taking sides.
“The weight of evidence is building up,” Pembrey says.
Dias adds: “There’s a traditional dogma where this cannot occur, but this dogma is now being challenged.”
Indeed, Dias believes that people are yet to appreciate just how much human biology is affected by epigenetic inheritance.
“It’s more prevalent than we can actually wrap our heads around,” he says, adding that just as genetics promised to reveal so much about ourselves, the same could happen with epigenetics.
There may be medical benefits in knowing that epigenetic marks exist and how our lifestyles affect them, Dias says.
“You can imagine a scenario where the die is not completely cast… You could possibly mask the gene expression effects of your ancestral experiences,” he says.
Knowing that you may be at greater risk of obesity because your father smoked as a boy, for instance, may prompt you to change your diet. Similarly, parents may become more careful about their lifestyles to protect future generations.
The danger, until then, is that the enthusiasm around epigenetics outpaces what scientists actually know.
Bestor says that science can be as faddish as journalism.
In response to criticisms Dias agrees that epigenetic inheritance is a make-or-break idea: “It’s either going to come a cropper, or it’s going to revolutionize the way we think about inheritance.”
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