Epigenetics, a word that seems to have stirred up disagreement between scientists for so long, is currently experiencing a rebirth and may have applications for the prevention of many different human diseases.
Starting at the beginning, the word ‘epigenesis’ was coined by the Greek philosopher Aristotle over 2,200 years ago because he was sick of the theory current at the time that we all start out as microscopic versions of our adult selves. He believed that all complex creatures grow from a simple fertilised egg or seed though to a mature organism through stages of development and differentiation: out of the simple comes the complex. This idea is widely accepted as true today.
Jump forward just over 2,100 years and we come across a man with possibly the longest name in scientific history: Jean-Baptiste Pierre Antoine de Monet, Chevalier de Lamarck. Let’s just call him Lamarck. He proposed that the way an organism adapted to its environment would somehow be passed down the generations. Two generations later, Charles Darwin liked Lamarck’s idea and went further, proposing an idea of his own – ‘gemmules’ – minute granules that are ‘thrown off’ by our tissues. Gemmules, he proposed, could multiply and travel to our eggs or sperm sex cells through which they could be passed on to future generations.
Step forward another 75 years and followers of Darwin thought they knew it all – evolution occurs by natural selection through random changes in our DNA that have enabled us evolve and adapt over millennia. And that’s that. Then Conrad ‘Hal’ Waddington came along and stirred things up by turning ‘epigenesis’ to ‘epigenetics’, which he used to describe the way in which our genes interact with their environment to make us what we are. In this sense, epigenetics means literally ‘the factors on top of our genes’. Waddington was a man before his time. Between then and now, arguments have raged about whether nature (genes) or nurture (environment) are more likely to influence our health and behaviour. The truth, exemplified by a recent book by Matt Ridley entitled ‘Nature via Nurture: Genes, experience and what makes us human’ is, like Waddington suggested, a combination of the two.
Today, epigenetics now describes the set of small molecules that sit ‘on top of our genes’ and choreograph when and how they act. This in turn directs our development from the zygote to the grave. Epigenetic molecules can be encoded by our DNA and they can be added or removed in response to our environment. Nature via nurture. Another way of looking at it is that in the symphony of life, epigenetic molecules are the musicians that play the genes as instruments and together they make up a huge orchestra of thousands of working genes. Alone, genes are silent; they need musicians to play them.
However, controversy still exists about what we can actually label as ‘epigenetic’. Some say that epigenetic changes need to be long-term, lasting for many cell generations, while others have shown that some epigenetic marks can change within a single cell’s lifetime. Some geeks say that the epigenetics should be tightly linked with its molecular definition and others that it should be loosely applied to how an organism adapts to its environment.
Arguments aside, epigenetic changes are most likely lie behind a recently recognised phenomenon call the Developmental Origins of Health and Disease. Known in short as ‘DOHaD’, the idea is that our experiences in the womb and early childhood can ‘program’ our future health. It is likely that epigenetics is part of the programming language involved. An oft-cited example of this in humans is that sixty-year-olds who were in their mother’s womb at the time of the Dutch Famine in the Second World War, not only had poorer heart health than their siblings but also had an epigenetic imprint of this experience stamped on a handful of their genes.
Animal studies reveal a similar story. In rats, a mother’s licking and grooming behaviour influenced subsequent stress levels in the offspring, mediated by an epigenetic change to a gene involved in stress response. Newborn rat pups whose mothers spend time licking and grooming them grow into calmer adults, whilst pups who receive little maternal attention tended to grow into more anxious adults. Grooming altered the pattern of epigenetic marks, which in turn altered gene activity of the stress regulator gene. Critically, when neglected rats were treated with a drug that alters these epigenetic marks, both their anxiety and the accompanying epigenetic changes could be reversed.
Such findings have huge implications for medicine, the largest being that if we can reliably detect epigenetic changes that in early childhood signal a risk for diseases such as cancer, heart disease, autism or diabetes, we can start to prevent these diseases by intervening early. This is the area I find most exciting, but we have a long way to go to the clinic for most of these. However, we can take heart from cancer research, which has already supplied a small number of epigenetic tests that can predict severity or response to treatment in some cancers.
Finally, it seems that in principle, Lamarck and Darwin may also have been on the right track after all. There is accumulating evidence that the environment our mothers and even our fathers encountered before we were a twinkling in their eye may be passed onto us in the form of a risk for conditions such as obesity, diabetes or anxiety. Studies of a remote Swedish village have shown that food abundance in grandparents correlate with the health of their grandchildren. Another found that sons of men who smoked just before puberty were more likely to become obese. However, neither of these has yet been linked with an epigenetic change. Could it be that epigenetic marks can ‘leak though’ to us via eggs and sperm? There is recent evidence that this can happen in animals that has people in some very high places invoking Lamarck.
We still need to discover how such factors could pass into the eggs and sperm and how these changes would survive two major life stages at which the epigenetic ‘whiteboard’ is wiped almost clean. This usually occurs just after fertilisation when a newly-formed zygote wants to shed its sexual origins and become a new human being and when the opposite happens, when a group of cells early on in development want to put on the sexual cloak and become eggs and sperm. However, I said ‘almost clean’, which leaves the door open in principle for these barriers to be breached. An attractive, emerging idea borrowed originally from plants is that small epigenetic molecules, in form of the “messenger” genetic material – ribonucleic acid (RNA) – can be shuttled into eggs or sperm and be inherited by the next generation, and survive the epigenetic cleaning. Watch this space.
‘Epigenetics explained‘ by Scientific American
Awesome animations and short documentaries
‘Lick your rats‘ interactive game from the Epigenetics Genetic Science Learning Center, University of Utah (takes about 5 mins to lick a couple of rats)
‘Epigenetics Overview‘ by Cell Signaling Technologies (02:14)
‘Epigenetics‘ – a short documentary from the Science Show on DNATube (09:26)
Articles – basic
‘Epigenetics’ by Brona McVittie (2006)
Articles aimed more at undergraduates