A series of scientific studies published a few years ago suggested that survivors of disasters or atrocities such as the Holocaust or the Dutch Famine of 1944-45 passed on their biological scars to their children.
These studies made headlines, earning them a BBC Horizon documentary and Time cover (I wrote about them for New Scientist). It was clear that DNA wasn't the only way to inherit biological traits. And that any trait a person acquires in their lifetime might be passed on. This information is thought to be transmitted through chemical tags called epigenetic marks, which dial up or down the output of genes. We are born with our entire genetic family and this information remains virtually unchanged until we die. This phenomenon is known as transgenerational epigenetic inherit. It was largely because it seemed to free us from the tyranny that DNA imposes on our lives. Genetic determinism was dead.
Despite being a decade old, transgenerational epigenetic inheritance has fallen apart. It is known that it occurs in plants and in certain mammals. It can't be ruled out in humans, as science is difficult to prove anything. However, there isn't any convincing evidence to support it and no physiological mechanism that could explain it. A well-documented finding seems to be a major obstacle: Except in rare genetic disorders, all epigenetic markings are removed from the human egg and sperm shortly after their nuclei fuse during fertilization. Bernhard Horsthemke, a geneticist at the University of Duisburg–Essen in Germany, states that [epigenetic] patterns become established in every generation.
Epigenetics appears to support the argument that it is not nature versus nurture but nature plus nurture.
Skeptics at the time pointed out that it was difficult to separate the environmental, genetic and epigenetic contributions to inheritable traits. One thing is that a person inherits her mother's environment starting at the womb. This means that an individual's epigenome can be influenced by her mother without information being passed via the germline or reproductive cells. The threads have become more complicated over the past decade as epigenetic marks themselves are largely under genetic control. Certain genes can influence how other genes are annotated. This is evident in twin studies where certain epigenetic patterns were found to be more similar between identical twins than in non-identical twins.
Researchers have come to see the epigenome as more than just a language that the environment commands, but as a mechanism by which genes adapt to a changing environment. Jonathan Mill, an epigeneticist from the University of Exeter, said that although epigenetics is sometimes portrayed as opposing genetics, they are actually intertwined. Although the relationship between them remains to be determined, Adrian Bird, a geneticist at the University of Edinburgh believes that the role of the environment has been overstated in shaping the epigenome. He says that cells actually go to great lengths to protect themselves from environmental damage.
Whatever the relationship, epigenetics seems like it is proving that it's not nature versus nurture but nature plus nurture (so that genetic determinism remains dead). It doesn't seem to transfer across generations, regardless of how important the epigenome is.
The fact that transgenerational epigenetic inheritance remains what most people associate with epigenetics is a regrettable fact for all the researchers mentioned. However, the past decade has seen many exciting developments in the field in terms of how it has affected human health and disease. These marks, which are all cells in the body except those that are reproductive, can be extremely informative and have been made easier by new technologies.
An example of DNA methylation, the process by which genes are modified. This process is currently being studied to determine the influence of lifestyle and environment. Photograph: Laguna Design/Science Photo Library
Different definitions of epigenetics exist, which is why it is often misunderstood. It can be defined as modifications to DNA, which is the package that contains the DNA within the nuclei of the human cell's nucleus. Others include modifications toRNA. The addition of chemical groups can modify DNA. The most common form of DNA modification is methylation. This is when a methyl team is added to DNA. However, DNA can also be tagged using hydroxymethyl groups and proteins can be modified in the chromatin complex.
Researchers can create genome-wide maps that map DNA methylation. These maps can be used to track biological ageing. This is, as we all know, not the same thing as chronological ageing. These epigenetic clocks first appeared for blood and were strongly associated with other measures of ageing like blood pressure and cholesterol levels. The epigenetic signatures of ageing are different in different tissues so they can't tell you much about brain and liver. In the past five years, many other tissue-specific epigenetic clocks have been described.
Mills' group is currently working on a brain clock that, he believes, will correlate with other indicators for ageing in the cortex. Mills believes he has identified an epigenetic sign of neurodegenerative diseases. Mill states that there were strong differences in DNA methylation in individuals with and without dementia. These differences are strongly related to brain pathology. Although it is not possible to determine if these differences are caused or a consequence of the disease process itself, they do provide valuable information that can be used to develop new diagnostic and treatment methods. A predictive blood test for dementia could be developed if a signal is detected in the blood that correlates with the brain signal.
The epigenome can reveal details about your smoking habits. Researchers are currently working on a clinical application to these findings. Photograph by Chris Rout/Alamy
Bird and others believe that the epigenome is largely under genetic control. However, some researchers are curious about the effects of environmental insults on it. For example, smoking has an obvious epigenetic signature. Mill says that I can tell you very accurately based on someone's DNA methylation profile whether they were smokers and also how often they smoked.
James Flanagan, Imperial College London, is one of those who exploits this aspect of epigenome to study how lifestyle factors like smoking, alcohol and obesity affect cancer risk. Cancer is where epigenetics is at its most exciting in clinical applications. Flanagan suggests that people could be informed about their risk and make lifestyle changes to lower it.
Although drugs that alter the epigenome can be used to treat cancer patients, they are often associated with side-effects. This is because their epigenetic effect is so wide. Others that are widely prescribed and have few side effects might also work partially via the epigenome. Flanagans group has discovered that metformin can reduce breast cancer risk by more than half in patients with diabetes who have been taking it for a prolonged period of time.
Grail, a US-based company, has developed a test that detects DNA changes in blood.
The NHS started a trial of the Grails Galleri blood tests last month. This test is designed to detect epigenetic changes that can identify more than 50 types and forms of cancer. Grail
Tomasz K. Wojdacz studies clinical epigenetics at Pomeranian Medical University, Szczecin. He says that the Grail test is very promising based on publicly available data about its false-positive as well as false-negative rates. However, more data is required and is currently being collected in a major clinical study in the NHS. It is hoped that the test could be used to screen individuals and identify those at high risk. Then, they would be directed towards more traditional diagnostic procedures like tissue-specific biopsies. Wojdacz believes it could make a significant difference in the fight against cancer. However, it raises ethical questions that must be resolved before it can be implemented. He says that if someone gets a positive result, but further investigation uncovers nothing, it is not a good sign. That kind of burden psychologically on a patient is not possible.
It is not clear whether it is possible to turn back the epigenetic clock. Although this question is being investigated seriously, many researchers are concerned that people will be buying epigenetic cosmetics based on unsupported scientific claims. Flanagan says science has only scratched this surface. Flanagan says that scientists are still unsure of the speed with which these events occur and how they might change. This is still true for epidenetics. But it may be changing.
Sequencing of the epigenome
Sequencing the epigenome used to be a slow and costly process. For example, to identify all the methyl tags in the genome, it would take two separate sequencing efforts with a chemical manipulation. It has been possible to simultaneously sequence the genome and the methylation pattern over the past few years. This has halved the cost and doubled the speed.
Oxford Nanopore Technologies, a British company that tracks the spread of Covid-19 variants worldwide, has such a technology. It was listed on the London Stock Exchange last Wednesday. It works by pushing DNA through the nanoscale hole, while current flows on either side. Each base, or letter A, C, G, and T, makes up DNA. Because each one is unique in its shape in the nanopore, it distorts current in a unique, measurable manner. A methylated base is a unique shape that can be recognized as a fifth letter.
Illumina, the US company that leads the global DNA sequencing market offers a new technique. Shankar Balasubramanian, a chemist at the University of Cambridge, has stated that Cambridge Epigenetix will soon announce its own epigenetic sequence technology that could add a sixth letter, in the form of hydromethyl tags.
Although protein modifications must still be sequenced separately from each other, some people include RNA modification in their definitions of epigenetics. At least some of these technologies are able to detect them too. This means they can generate huge amounts of information about how our genetic material has been modified over our lifetime. Ewan Birney, who co-directs Hinxton's European Bioinformatics Institute, Cambridgeshire and is also a consultant to Oxford Nanopore says epigenetic sequencing has the potential to transform science.
