by MERLIN CROSSLEY

Epigenetics is such a cool word. It’s a bit like the word “metaphysics.” Metaphysics  sounds like physics but is way more mysterious.

Epigenetics refers to processes that overlie genetic controls, and I think metaphysics aims to refer to the things that came after and are beyond physics. Metaphysics includes the supernatural and to many people both terms promise something a little spooky.

Indeed, when I was a student I heard a great talk where the presenter joked that all their experimental results that could be explained by conventional understandings of DNA, RNA and protein, were put in a folder marked GENETICS. All the results they couldn’t explain, they put into a second folder, called EPIGENETICS. Over time the second folder became very large and attracted a lot of attention.

The term genetics relates to understanding how characteristics are inherited. The term epigenetics has had, to be frank, many different meanings.

Sometimes it does refer to weird inheritance patterns, changes over generations that are unusual in that they are not related to expected mutations (misspellings or mistakes) in the DNA code. Instead, the observed changes result from the addition of chemical groups, such as carbon and three hydrogens (methyl groups) to Cytosine residues in DNA, or the sticking of proteins (which are big biological molecules) to DNA, or methyl groups to those proteins. On one level it’s simple – epigenetic marks on DNA are involved in turning some genes on, or even more often, turning particular genes off.

This is a massive area of research dating back to the beginnings of molecular biology, with the work done first in bacteria, and in yeast, plants and animals. In multi-cellular organisms, like humans, the reason that our blood cells look different from our muscle cells, is that they have turned on different subsets of our 20,000 or so genes. And that has been done via epigenetics, or more precisely by different DNA-binding proteins and/or chemical marks sticking to different genes in each cell type, and turning some genes on and others off. From one perspective the field of epigenetics really just entails studying gene regulation.

Some of the first experiments related to how stimuli, changes in the environment (things like sugar concentrations in bacteria, or diet, stress, or smoking or normal human development) could affect what DNA-binding proteins or chemical groups were stuck to different genes in our DNA.  But epigenetics reached celebrity status when it was proposed that the changes could persist across generations. That stimuli that affected your parents or grandparents might persist via marks on your DNA and end up influencing you very nature and being. Exciting as this was, its importance tended to be over-hyped by ideas like “you are what your grandparents ate.”

To some people this was attractive since epigenetics became a complicating factor that could save us from genetic determinism – our genome sequences will never dictate who we are because epigenetic additions can override our genes, by turning some off or on. Others felt we could learn from our environment and that perhaps Lamarckian inheritance was right after all. That is by stretching their necks successive generations of giraffes could grow longer necks! If we responded properly to our environment our future children might benefit.

But while the inheritance of epigenetic states through generations is well documented in bacteria and in plants, in animals, and particularly in humans, it appears that most marks and proteins are stripped off our DNA when we reproduce, and the data that epigenetic information can be inherited across generations is much more controversial. If anything is inherited it usually manifests itself as a slightly increased statistical risk of developing some chronic disease late in life, rather than as the inheritance of any clearly defined characteristics.

I’m not sure why epigenetic inheritance seems to be more prominent in plants than animals but the obvious idea is that it makes more sense to prepare plant offspring with clues as to which genes to turn on to survive in an environment because the apple doesn’t fall far from the tree and the offspring may end up inhabiting that same environment. In the case of animals they will just head off in new directions so epigenetic responses to past environments are less relevant. But that’s all just me speculating!

Nevertheless, although I remain uncertain about the trans-generational inheritance of epigenetically controlled characteristics in humans, I do think that the way epigenetic effects control different genes in different cell types within individual humans and other organisms remains one of the most exciting and most studied topics in biology. This is partly because if we could turn genes on and off at will, we would be able to treat a large number of diseases, including chronic conditions, cancer or viral diseases. For this reason my lab has been trying to get to the bottom of how epigenetic marks can operate at the molecular level for a long time now.

What I’ve observed in the field of epigenetics conforms to a general pattern in science.

The research begins with observations that are mysterious – why are all tortoiseshell cats female? Why do Dalmatians have odd patterns of spots, or why are some bacteria resistant to viral infections and others susceptible? Then the chemical components controlling these processes begin to be defined – biology morphs into chemistry. Then as understanding increases further biophysics and physics can be used to explain and predict outcomes. Ultimately, when more and more quantitative and bioinformatic data are known, the age of mathematical predictions arrives and the story is complete – biology has morphed through chemistry and physics to settle as mathematics.

I don’t think epigenetics has quite passed the chemical stage yet but it has certainly changed. The spookiness of unusual inheritance has been replaced with chemical knowledge of marks on DNA and on the proteins or sometimes small RNAs that operate like proteins and bind DNA.

I look forward to the days when we understand all these processes and can control gene expression but part of me is also a little sad that as the understanding dawns another haunting mystery fades and we have to look elsewhere for magic.

Merlin Crossley

Deputy Vice-Chancellor Academic

UNSW