Around 10 years ago, several scientific studies were published that suggested survivors of traumatic events and atrocities like the Holocaust or Dutch famine of 1944-45 passed down the biological stress of those experiences to their children.
The studies created quite a stir. The BBC produced a documentary and Time magazine featured the subject on their cover. The stunning implications were that DNA wasn’t the only mode of biological inheritance. Characteristics acquired through life experiences could be passed on down the generations.
We receive our complete complement of genes at conception, and this does not change throughout our lifetime. Scientists hypothesized that traumatic experiences were transmitted by chemical tags on genes called epigenetic marks. The phenomenon was labeled transgenerational epigenetic inheritance, and it suggested that our fates were determined by more than just our DNA.
Now that over 10 years have passed, scientists now know that transgenerational epigenetic inheritance in humans does not exist. It is found in plants and some mammals. It cannot be ruled out in humans primarily because it is difficult to rule out anything in science. However, no convincing evidence or physiological mechanism has been found.
One well-documented finding alone seems to present a towering obstacle to it: except in very rare genetic disorders, all epigenetic marks are erased from the genetic material of a human egg and sperm soon after their nuclei fuse during fertilization. “The [epigenetic] patterns are established anew in each generation,” says geneticist Bernhard Horsthemke of the University of Duisburg-Essen in Germany.
Even so, the genetic, epigenetic, and environmental conditions that contribute to inherited traits are entwined. A baby shares its mother’s environment beginning in the womb. That baby’s epigenome could resemble her mother’s without the transmission of information via the germline or reproductive cells. In addition, epigenetic marks are influenced by other genes as shown in twin studies. Certain epigenetic patterns have been found to be more similar in identical twins than in non-identical ones.
This has led scientists to think of the epigenome as a way in which the genes adjust themselves to respond better to an unpredictable environment. “Epigenetics is often presented as being in opposition to genetics, but actually the two things are intertwined,” says Jonathan Mill, an epigeneticist at the University of Exeter. The relationship between them is still being worked out, but for geneticist Adrian Bird of the University of Edinburgh, the role of the environment in shaping the epigenome has been exaggerated. “In fact, cells go to quite a lot of trouble to insulate themselves from environmental insults,” he says.
As researchers conduct more studies, epigenetics seems to reinforce the notion that its nature plus nurture rather than nature versus nurture. And, the contribution of the epigenome doesn’t transmit across generations.
Still, the general public still thinks of epigenetics as transgenerational epigenetic inheritance. But the last 10 years has seen some exciting advances in the field including new insights into human health and disease. The marks that accumulate on somatic cells turn out to be very informative about these, and new technologies have made it easier to read them.
Plus, epigenetics has several definitions depending on the researcher, which is another reason the field is misunderstood. Some define it as modifications to chromatin, the package that contains DNA inside the nuclei of human cells, while others include modifications to RNA. DNA is modified by the addition of chemical groups. Methylation, when a methyl group is added, is the form of DNA modification that has been studied most, but DNA can also be tagged with hydroxymethyl groups, and proteins in the chromatin complex can be modified too.
Researchers can generate genome-wide maps of DNA methylation and use these to track biological aging, which is different from chronological aging. The first such “epigenetic clocks” were established for blood, and showed strong associations with other measures of blood aging such as blood pressure and lipid levels. But the epigenetic signature of aging is different in different tissues. The past five years have seen the description of many more tissue-specific epigenetic clocks.
Mill’s researchers are examining the brain clock, which may correlate with other indicators of aging in the cortex. The group has identified a potential epigenetic signature of neurodegenerative disease. “We’re able to show robust differences in DNA methylation between individuals with and without dementia that are very strongly related to the amount of pathology they have in their brains,” Mill says.
Scientists are still determining whether those differences are a cause or result of the pathology. However, they provide information about the genes and mechanisms that are disrupted due to the disease. This could lead to the development of novel diagnostic tests or treatments. For instance, if a signal in the blood correlates with a brain signal, it may lead to a predictive blood test for dementia.
Some scientists posit that the epigenome is primarily under genetic control while others are interested in the trace that certain environmental insults leave there. Smoking, for example, has a clear epigenetic signature. “I could tell you quite accurately, based on their DNA methylation profile, if someone was a smoker or not, and probably how much they smoked and how long they had smoked for,” says Mill.
James Flanagan of Imperial College London is examining this aspect of the epigenome to try to understand how lifestyle factors such as smoking, alcohol and obesity shape cancer risk. In fact, cancer is a key area in which clinical applications of epigenetics may have an impact. One idea, Flanagan says, is that once informed of their risk a person could make lifestyle adjustments to reduce it.
Drugs that remodel the epigenome have been used therapeutically in people with cancer, although they tend to have bad side effects due to the broad epigenetic impact. Other commonly prescribed drugs that have few side effects might turn out to work at least partly via the epigenome too. For instance, the risk of developing breast cancer is cut in half in diabetes patients taking metformin for lengthy periods of time. Flanagan’s group is investigating whether this protective effect is mediated by altered epigenetic patterns.
Meanwhile, the US-based company Grail has developed a test for over 50 cancers that detects altered methylation patterns in DNA circulating freely in the blood. Based on publicly available data on its false-positive and false-negative rates, the Grail test looks very promising, says Tomasz K Wojdacz, who studies clinical epigenetics at the Pomeranian Medical University in Szczecin, Poland.
Still, more studies are necessary. But if proven effective, the test could screen populations and pinpoint individuals at risk who would benefit from conventional diagnostic procedures like tissue biopsies. It could be a gamechanger in cancer, Wojdacz thinks, but it also raises ethical dilemmas that will have to be addressed before it is rolled out. “Imagine that someone got a positive result but further investigations revealed nothing,” he says. “You can’t put that kind of psychological burden on a patient.”
One concern is whether the general population will catch up on the advances rather than continue to believe the early promises that didn’t pan out. Science has only scratched the surface of the epigenome, says Flanagan. “The speed at which these things happen and the speed at which they might change back is not known.”
Sequencing the epigenome
Until recently, sequencing the epigenome was relatively slow and costly. Identifying all the methyl tags on the genome required two distinct sequencing efforts and a chemical manipulation in between. In the past few years, it has become possible to sequence the genome and its methylation pattern simultaneously, cutting the cost in half and increasing the speed.
Oxford Nanopore Technologies, the British company responsible for much of the tracking of the global spread of Covid-19 variants, offers such a technology. It works by pushing DNA through a nanoscale hole while the current passes either side. DNA consists of four bases or letters – A, C, G, and T – and because each one has a unique shape in the nanopore it distorts the current in a unique and measurable way. A methylated base has its own distinctive shape, meaning it can be detected as a fifth letter.
The US firm Illumina, which leads the global DNA sequencing market, is developing a different technique. Cambridge Epigenetix will soon announce its own epigenetic sequencing technology that could add a sixth letter in the form of hydroxymethyl tags.
Protein modifications still have to be sequenced separately, but some people include RNA modifications in their definition of epigenetics and at least some of these technologies can detect those too. This has the power to generate enormous amounts of new information about how our genetic material is modified in our lifetime. That’s why Ewan Birney who co-directs the European Bioinformatics Institute in Hinxton, Cambridgeshire says that epigenetic sequencing stands poised to revolutionize science: “We’re opening up an entirely new world.”