Feature: Nature or Nurture? Neither!

This feature appeared in the November/December 2009 issue of Australian Life Scientist. To subscribe to the magazine, go here.

Professor Emma Whitelaw, from the Queensland Institute of Medical Research, doesn’t much look like a radical. But appearances can be deceiving. Whitelaw has struggled tirelessly for nearly two decades to have the wider scientific community appreciate the importance of the upstart field of epigenetics, beginning with a grassroots campaign in her own smaller departmental world. Her efforts have not been in vain.

Now that she has a bright new Australia Fellowship from the National Health and Medical Research Council, Whitelaw can take a short break from continually proving the significance of epigenetics and can finally start to address the really juicy questions posed by the field. Such as whether much of our phenotypic differences may be down to stochastic variables – AKA dumb luck - rather than genetic or environmental influences.

“For me personally, the Fellowship means that I have five years of funding to do some outlandish kinds of things and again ask the big questions, and that is always where I am happiest,” she says.

Whitelaw’s work has always centred on understanding the control of gene expression in higher eukaryotes, like us, humans. Following an undergraduate science degree at the Australian National University in Canberra, Whitehall spent almost 20 years in the UK, where she obtained a D.Phil at Oxford. She then developed her ongoing interest in genetics working there and in London. She relocated to Sydney in 1992 and finally migrated to the Sunshine State and QIMR three years ago.

It was when she arrived back in Australia that Whitelaw began to realise the phenomenon of epigenetics could provide some of the missing pieces to fill the gaps of knowledge in the world of gene transcription. Epigenetics is the study of changes in phenotype or gene expression in the absence of changes to the underlying DNA sequence itself. Landmark work on transcriptional silencing and epigenetic effects was to follow for Whitelaw and, now, epigeneticists are rapidly establishing whole new processes underlying the way that genes behave in different cells and different individuals.

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The first hurdle

That’s not to say epigenetics as a discipline was accepted by the broader science community straight away. “Fifteen years ago, people were not all that happy about the concept of epigenetics,” Whitelaw recalls. “This made it a hard area to get funded, with the work often seen as high risk.”

The first major struggle for Whitelaw was proving the importance of epigenetics in mammals, and this was particularly so within her own academic sphere. At that time, around 15 years ago, the concept of epigenetic change was accepted in the Drosophila model and in yeast, but not yet in the world of mammals. For example, the head of Whitelaw’s department in Sydney didn’t believe that two cells of the same type within the same tissue of a mammal could express the same gene in two different ways. This now well established concept went against the prevailing doctrine that every subset of genes in the same tissue was programmed by its genetic code to behave in exactly the same way. “What we now call epigenetic silencing or gene variegation was thought to be a result of some kind of genetic deletion that made the silencing happen.”

We now know that epigenetic gene silencing is the result of changes to either the chromatin proteins that package and regulate the genetic material (such as histones) or to the DNA itself, by biochemical processes such as methylation. But at that time, Whitelaw recalls: “I had to get an Honours student to clone out the gene that we thought was epigenetically silent and then activate it in a different system and sequence it to show it was still there to prove conclusively that there was not an underlying genetic change and to convince my boss.”

Whitelaw’s early efforts were rewarded with a series of significant publications in leading journals, including Nature Genetics, and has since been the subject of considerable review. In retrospect, Whitelaw feels that going through those extra few hoops was worth it to really address one of the crucial issues upfront. Satisfyingly, it was this work, and that of a few others around the world, that helped convince the broader scientific community that epigenetic gene silencing really does play a critical part in mammalian development.

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Dumb luck

So just what are these radical questions that Whitelaw wants to pursue? “At the moment I am most interested in the idea that a large contribution to our physical traits – our phenotype – is neither genetic nor environmental in the strictest sense of the words. Instead, it is another thing: the probabilistically based establishment of an epigenetic state in the genome.”

This means we can no longer blame all the bad things about us on our parents and/or on the fact that we grew up in Ipswich (substitute your preferred equivalent here). Instead, it seems that a string of random or pure chance events that occurred before we were even breathing have determined why and how we are unique, for better or worse. These so-called epigenetic changes have tweaked our pre-set genetic data at specific points.

“These events happening during embryonic development influence whether some populations of not particularly critical genes, but nevertheless genes that influence your phenotype, are on or off,” says Whitelaw. “It comes down to the luck of the draw.”

According to Whitelaw, the biological implications of epigenetics are immense. “I think it will turn out to explain a lot of our phenotype in health and disease. We are not just a product of the genes that we inherited from our parents, and researchers have now demonstrated this over and over in mice. In addition to the processes underlying Mendelian genetics, these random processes occur in development that switch some genes on in mammal A compared to genetically identical littermate mammal B, residing in the same womb. “Then, there is a time point in development when these random events are set for the rest of your life.”

Although not resting on her laurels just yet, Whitelaw candidly admits that the Australia Fellowship from the NHMRC awarded earlier this year was a huge bit of positive feedback for her personally. “I have worked on this one problem for a very long time and for a lot of that time we had to go against the grain, and that was tough. But we now seem to be at a stage where people are understanding the sorts of things we were talking about 10 years ago and are really quite excited about it all.”