Mon. Aug 8th, 2022

ONE a little over a decade ago, a link of scientific studies was published that seemed to show that survivors of atrocities or disasters such as the Holocaust and the Dutch famine of 1944-45 had passed on the biological scars of the traumatic experiences to their children.

The investigations caused a sensation and earned their own BBC Horizon documentary and the front page of Time (I also wrote about them, too New researcher) – and no wonder. The astonishing consequences were that DNA was not the only form of biological inheritance, and that traits that a person acquired during their lifetime could be hereditary. Since we received our full complement of genes at conception, and it remains largely unchanged until our death, this information is believed to be transmitted via chemical tags on genes called “epigenetic tags” that dial the output of these genes up or down. The phenomenon, known as transgenerational epigenetic inheritance, captured the public imagination, in part because it seemed to free us from the tyranny of DNA. Genetic determinism was dead.

A decade later, the issue of transgenerational epigenetic inheritance in humans has crumbled. Researchers know that it occurs in plants and – weakly – in some mammals. They cannot exclude it in humans because it is difficult to exclude anything in science, but there is no convincing evidence for it to date and no known physiological mechanism by which it can function. A well-documented finding alone seems to constitute a towering obstacle to it: except in the case of very rare genetic disorders, all epigenetic markers are deleted from the genetic material in a human egg and a sperm shortly after their nuclei melt during fertilization. “That [epigenetic] patterns are re-established in each generation, ”says geneticist Bernhard Horsthemke from the University of Duisburg-Essen in Germany.

Even then, skeptics pointed out that it was terribly difficult to separate the genetic, epigenetic, and environmental contributions to hereditary traits. First, a person divides his mother’s environment from the womb onwards, so that the person’s epigenome can resemble her mother’s without being transmitted information via the germ line or reproductive cells. In the last decade, the threads have become even more tangled because it turns out that epigenetic markers are largely themselves under genetic control. Some genes affect the degree to which other genes are annotated — and this is shown in twin studies, where certain epigenetic patterns have been shown to be more similar in identical twins than in non-identical ones.

This has led researchers to think of the epigenome less as the language in which the environment controls the genes, and more as a way in which the genes adjust themselves to respond better to an unpredictable environment. “Epigenetics is often presented as being opposed to genetics, but in fact the two things are related,” says Jonathan Mill, an epigenetician at the University of Exeter. The relationship between them is still being worked out, but for geneticist Adrian Bird at the University of Edinburgh, the role of the environment in shaping the epigenome has been exaggerated. “In fact, cells go to a lot of trouble isolating themselves from environmental insult,” he says.

Whatever the relationship turns out to be, the study of epigenetics seems to reinforce the case that it is not nature versus care, but nature plus nutrition (so genetic determinism is still dead). And regardless of the epigenome’s contribution, it does not seem to translate across generations.

All of the aforementioned researchers judge the fact that transgenerational epigenetic inheritance is still what most people think of when they hear the word epigenetics, because the last decade has also seen exciting advances in the field in terms of the light it has shed on humans. health and disease. The labels that accumulate on somatic cells – that is, all the cells of the body except the reproductive ones – are proving to be very informative about these, and new technologies have made them easier to read.

A model for DNA methylation - the process that modulates genes.  The influence of the environment or lifestyle on this process is investigated.
A model for DNA methylation – the process that modulates genes. The influence of the environment or lifestyle on this process is investigated. Photo: Laguna Design / Science Photo Library

Different people define epigenetics differently, which is another reason why the field is misunderstood. Some define it as modifications of chromatin, the package that contains DNA inside the nuclei of human cells, while others include changes in 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 the most, but DNA can also be labeled with hydroxymethyl groups, and proteins in the chromatin complex can also be modified.

Researchers can generate genome-wide maps of DNA methylation and use these to track biological aging, which as everyone knows is not the same as chronological aging. The first such “epigenetic clocks” were established for blood and showed strong associations with other measurements of blood aging, such as blood pressure and lipid levels. But the epigenetic aging signature is different in different tissues, so these could not tell you much about e.g. Brain or liver. The last five years have seen a description of many more tissue-specific epigenetic clocks.

Mills group, for example, is working on a brain clock that he hopes will correlate with other indicators of aging in the cortex. He has already identified what he believes is an epigenetic signature of neurodegenerative disease. “We are able to show robust differences in DNA methylation between people with and without dementia that are very strongly related to the amount of pathology they have in their brains,” says Mill. It is not yet possible to say whether these differences are a cause or consequence of the pathology, but they do provide information on the mechanisms and genes that are disrupted in the disease process that may guide the development of new diagnostic tests and treatments. If, for example. If a signal could be found in the blood that correlated with the brain signal they have detected, it could form the basis of a predictable blood test for dementia.

A woman who smokes
Details of smoking habits can be demonstrated from the epigenome – researchers are working on a clinical application for these observations. Photo: Chris Rout / Alamy

While Bird and others argue that the epigenome is predominantly under genetic control, some researchers are interested in the trace that certain environmental insults leave there. For example, smoking has a clear epigenetic signature. “I could tell you quite accurately, based on their DNA methylation profile, whether someone was a smoker or not, and probably how much they smoked and how long they had been smoking,” Mill says.

James Flanagan of Imperial College London is among those taking advantage of 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 the area where there is the greatest tension regarding the clinical application of epigenetics. One idea, Flanagan says, is that once a person was informed of their risk, a person could make lifestyle adjustments to reduce it.

Drugs that remodel the epigenome have been used therapeutically for those already diagnosed with cancer, although they tend to have bad side effects because their epigenetic effect is so broad. Other highly prescribed drugs that have few side effects may also be shown to work at least in part via the epigenome. Based on the striking observation that the risk of breast cancer is more than halved in diabetic patients who have been taking the diabetes drug metformin for a long time, Flanagan’s group is investigating whether this protective effect is mediated by altered epigenetic patterns.

Meanwhile, the US-based company Grail – which has just been controversially acquired by DNA sequencing giant Illumina – has come up with a test for more than 50 cancers that detect altered methylation patterns in DNA circulating freely in the blood.

A Grail researcher at work
Last month, the NHS launched a trial of Grail’s Gallery blood test, designed to detect epigenetic changes that identify more than 50 types of cancer. Photo: Grail

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 Pomeranian Medical University in Szczecin, Poland. But more data is needed and is now being collected in a major clinical trial in the NHS. The idea is that the test would be used to screen populations and identify individuals at risk, who would then be guided toward more classical diagnostic procedures, such as tissue-specific biopsies. It may be a game changer in cancer, Wojdacz believes, but it also raises ethical dilemmas that need to be addressed before it rolls out. “Imagine someone got a positive result, but further research revealed nothing,” he says. “You can’t put that kind of psychological burden on a patient.”

The jury is aware of whether it is possible to turn back the epigenetic clock. This question is the subject of serious study, but many researchers are concerned that when a wave of epigenetic cosmetics hits the market, people differ with their money on the basis of scientifically unsupported claims. Science has only scratched the surface of the epigenome, Flanagan says. “The speed at which these things happen and the speed at which they can change back is not known.” It can be the fate of any young science to be misunderstood. This is still true for epidenetics, but it may be changing.

Sequencing of the epigenome

Until recently, sequencing the epigenome was a relatively slow and expensive affair. For example, identifying all the methyl labels on the genome would require two different sequence efforts and a chemical manipulation in between. In the last few years, however, it has become possible to sequence the genome and its methylation pattern simultaneously, halving the cost and doubling the rate.

Oxford Nanopore Technologies, the UK company responsible for much of the global spread of Covid-19 variants that floated on the London Stock Exchange last week, offers such technology. It works by pushing DNA through a nanoscale hole while current passes each 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 characteristic shape, which means that it can be detected as a fifth letter.

The US company Illumina, which leads the global DNA sequencing market, offers a different technique, and chemist Shankar Balasubramanian from the University of Cambridge has said that his company, Cambridge Epigenetix, will soon announce its own epigenetic sequencing technology – one that could add a sixth letter in the form of hydroxymethyl marks.

Protein modifications still need to be sequenced separately, but some people include RNA changes in their definition of epigenetics, and at least some of these technologies can detect them as well – meaning they have the power to generate vast amounts of new information about how our genetic material has changed in our lifetime. That’s why Ewan Birney, co-director of the European Bioinformatics Institute in Hinxton, Cambridgeshire, and a consultant for Oxford Nanopore, says epigenetic sequencing is poised to revolutionize science: “We’re opening up a whole new world.”

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