By Nicola Shepheard
The growing knowledge of how experiences get written onto our DNA, influencing development and disease, opens new avenues for personalised medicine. More broadly, evidence from animals that epigenetic marks can be inherited is challenging the standard view of evolution and fomenting a radical rethink of social disadvantage that crosses generations.
Beyond DNA: The post-genomic age
Last year, researchers from the University’s Liggins Institute and the Faculty of Medical and Health Sciences made headlines with the discovery of a potential blood marker for premature birth.
“This is exciting, as it could enable the targeting of therapies to delay or even prevent preterm birth,” said Professor Mark Vickers from the Liggins Institute, who co-led the research.
A pilot study had identified a unique molecular fingerprint in blood taken from women at 20 weeks of pregnancy who all went on to have their babies early (the fingerprint was not found in the blood of women who went to term). The team is now testing a bigger pool of samples.
The fingerprint found in the women who gave birth early was derived from micro-RNA (miRNA) analysis. MiRNAs are small, non-coding RNA molecules that influence the action of genes. They are part of the machinery of epigenetics – the way experience switches genes on and off.
Different miRNAs have been implicated in the development of – and protection from – a slew of diseases, including osteoporosis, Parkinson’s disease and certain cancers.
Scientists believe miRNAs are affected by environmental influences. Details are still unclear but knowledge is advancing.
Epigenetics’ roots go back at least to the 1930s, but it has re-emerged recently as one of the hottest fields in the life sciences, sending waves through the social sciences. Its boldest proponents say it demolishes the line between nature and nurture, revolutionising genetic identity and inheritance. Others are more cautious, arguing the hype has outpaced the evidence.
Dr Tatjana Buklijas, a trained physician and historian of science at the University’s Liggins Institute, has a Marsden grant to write a history of epigenetics.
“For all the excitement and publicity, there is no consensus on the scope, significance or even the definition of epigenetics,” she says. “But it is at least clear that genes are only part of the puzzle.
“The Human Genome was published in 2003. Through the eighties and nineties, people believed that once the genetic sequence was known we’d have all the answers to development and disease. But we don’t. We are not our genotypes, we are our phenotypes – what we come to be via our development in the world.”
In this “post-genomic age”, scientists are coming to understand how extra physical information layered on top of DNA in response to certain experiences can change how that code is read by cells – how your genes function in real time to create and recreate you. Dubbed the “epigenetic code”, it is composed of epigenetic markers – traces left by experience, molecular memories overwritten onto our DNA (see Molecular Memory box).
There are also other layers of information at play – one involves the way the DNA strand is folded tightly into the cell nucleus, bringing far-flung regions into contact and altering the functioning of genes; yet another involves the mysterious interactions between your genome and microbiome – the trillions of bacteria that live on and in you. Both are areas of intense study at the Institute.
“We are a walking talking ecosystem,” says associate professor, Dr Justin O’Sullivan. But that’s another story.
Nature and nurture: the interface
In the 1980s, English epidemiologist David Barker noticed something curious in disease and mortality maps of England.
Areas with high infant mortality and very low birth weight in the 1910s and 1920s were the same areas showing high death rates from heart disease 60 to 70 years later.
“Back then,” says Tatjana Buklijas, “heart disease was believed to be linked with an overly-rich Western lifestyle. Barker showed it was also linked with babies being born small.”
He realised that chronic, so-called “lifestyle” illnesses, such as heart disease, cancers and diabetes, arise not always from “bad” genes and unhealthy adult lifestyle, but from our earliest environments – in the womb and during infancy. Once controversial but now mainstream, this insight lies at the heart of a field called the developmental origins of health and disease.
Epigenetic processes are thought to underlie the many links that have since been identified between experiences during development, and health and disease in adult life. The Liggins Institute has a strong record of research in this area.
Very prominent in this field is its founding director Sir Peter Gluckman, who retains research links with the institute. The multifaceted view of obesity he advances is informed by epigenetics. Sir Peter was part of a collaboration with researchers at the University of Southampton (where Barker had his map Eureka moment) that showed the methylation (an epigenetic process) of a certain gene (RXRA) at birth is linked to the child’s later obesity.
Here’s another example of the environment re-tuning genes in obesity: a high-fat diet early in life is now known to increase the activity of genes that cause chronic, low-grade inflammation. This can be harmful to cells and tissues, increasing the risk of later chronic illnesses.
Sir Peter co-authored the 2012 book Fat, Fate and Disease: Why exercise and diet are not enough with long-time collaborator Professor Mark Hanson from the University of Southampton. Current scientific efforts, they argue, ignore the reality of the social, cultural, and biological factors make different populations and people respond differently – through epigenetic and other mechanisms – to living in the modern nutritionally-rich world.
They say that ultimately the food industry must be co-opted to turn the obesity tide.
Can epigenetic markers be passed down across generations?
This question is profound. If “yes”, then it would overturn the standard genecentric view of evolution.
“In this view,” says Tatjana Buklijas, “the idea is that you start from a blank slate. You have a sperm cell and an egg cell, and to form this embryo that contains the possibilities for all kinds of tissues, you have to delete all the epigenetic marks that the parents’ genes had. The argument has long been that epigenetic marks can’t survive – in less complex organisms like plants they can, but not in humans.”
A recent German study provided evidence for epigenetic inheritance in mice passed down in a father’s sperm. Mice that are raised in an environment “enriched” with exercise and cognitive training have their learning ability enhanced. The researchers found the same cognitive improvements in the offspring of these enriched mice.
Analysis of the fathers’ sperm identified several miRNA molecules that could explain the inherited characteristics, two of them known to influence activity in genes related to the formation of synapses. Other research with mice points to inheritance of epigenetic markers involved in a disease called cardiac hypertrophy.
For a trait to be considered transgenerational, though, it has to pass down to the great grandchild of the original parent. Professor Mark Vickers says most epigenetic effects wash out by the third generation in animal models.
But looking at this through a social science lens, it doesn’t matter so much whether epigenetic effects are passed on directly through egg and sperm or indirectly through similar environmental influences acting on each generation.
Medical student Helen Ker wrote an honours thesis, supervised by Tatjana Buklijas, looking at how whakapapa could provide a framework for this understanding of epigenetic inheritance.
“What’s been known for a long time in a Māori worldview is that we can’t simply separate people and their ira (gene or life principle) from their environments, and this is expressed within the Māori concept of inheritance or whakapapa,” explains Helen Ker.
“Whakapapa may be a natural and useful framework for understanding how multiple, interacting environmental influences such as land, water and food are connected to influence health outcomes.”
For example a whakapapa framework may help us work out how to tackle health disparities, as well as intergenerational poverty, that persist despite policy interventions and economic growth.
“The great thing about epigenetics is that most of these processes are reversible and temporary, so there are things we can do to address them, which come with a call for action.”
Australian medical anthropologist Emma Kowal has sounded a thoughtful warning to the many indigenous scholars who have embraced the socially progressive potential of epigenetics.
“Although breaking down the barrier between genes and environment sounds progressive, epigenetics may not necessarily translate to egalitarian social policy,” she wrote. Epigenetics could even be used for racist agendas, as its forerunner was in the eugenics movement.
“In the nineteenth and early twentieth century, many scholars believed that environmental effects on the body were inherited, and some groups experienced racial degeneration due to the ‘racially poisonous’ environment they lived in.”
Epigenetics also “has the potential to intensify the blame on parents, and mothers in particular, for children’s wellbeing, shifting responsibility away from societal factors that are far beyond maternal control [and this] could increase the already unrealistic pressure on indigenous parents to overcome the structural barriers their children face”.
Mother-blaming rings out in headlines like “Mother’s diet during pregnancy alters baby’s DNA”, “Pregnant 9/11 survivors transmitted trauma to their children”, and “Just one cup of coffee can harm unborn children, say researchers”.
In a Nature article called “Don’t blame the mothers”, Harvard historian Sarah Richardson writes that an understanding of how both parents’ experiences impact their children’s health and wellbeing would, ideally, guide policies that support parents and children. “But exaggerations and over-simplifications are making scapegoats of mothers, and could even increase surveillance and regulation of pregnant women.”
Take alcohol. After early research into fetal alcohol syndrome (a collection of physical and mental problems in children of women who drink heavily during pregnancy) drinking during pregnancy became stigmatised and, in some parts of the United States, criminalised. A large recent study has shown no adverse effects in children whose mothers drank moderately during pregnancy, but still women suffer social disapproval and agonise over a single sip.
Expect to hear much more about epigenetic inheritance in coming years. “What is very likely,” says Tatjana, “is there are multiple layers of heredity happening – genetics, epigenetics or genetic networks that come together spatially, and cultural heredity. I like the underlying idea that we’re not separate from our environment – it aligns with my politics. It’s about seeing the world in a much more interactive way.”
Epigenetics in action
Epigenetics explains how the environment alters or modulates gene expression. Here are some examples:
- Bisphenol A (BPA), a now widely banned additive in some plastics has been linked to cancer and other diseases. The “how” behind that link seems to involve epigenetic modification.
- Childhood abuse and other forms of early trauma seem to affect the methylation patterns in DNA, which may help to explain the poor health of many abuse victims throughout their adulthood.
- In some cancers, such as leukemias, malignant cells have strikingly aberrant patterns of epigenetic markers, though it is hard to distinguish cause and effect. Targeted epigenetic drugs are already in use and many others are being developed.
- One experiment suggested that by changing an ant’s epigenetic code you can change the nature of the creature: researchers injected a histone-altering chemical into the brains of carpenter ants at a sensitive moment in their development, and they switched castes: soldiers became foragers.
Bauble and highlighters: Molecular memory
You may remember learning about the double helix of a DNA molecule at school – the twisted ladder with rungs made of pairs of bases. A gene is a section of those rungs that codes for molecules with a function – varying in size from a few hundred to more than two million DNA bases in humans.
Every organism has a unique order, or sequence, of genes, and each cell (except red blood cells) contains a more or less identical copy of that DNA, tightly bundled in its nucleus.
If you think of a human DNA sequence as the text of an instruction manual for making a human body, as science writer Cath Ennis put it, epigenetic markers can be thought of as two colours of highlighter: one for marking text that needs to be read carefully, one for bits that are less important. The highlighting pattern varies across cell types – the same genes with different instructions make different cells.
One type of epigenetic mark is methylation – where tiny molecules called methyl groups stick to certain sections of the DNA. They tend to dampen the activity of affected genes. Imagine them as baubles dangling from the DNA Christmas tree, added and removed by special protein elves.
Another is histone modification, where methyl groups and other small molecular tags attach to histone proteins, which are the scaffolding core of proteins that DNA coils around. They can either turn up or turn down genes. These two kinds of markers work together as a system.
The new kid on the epigenetic marker block is micro-RNA (miRNA), molecules which normally help switch genes off once they’ve done their job.