'Not-so-identical' twins may hold the key to disease

How understanding epigenetic switching could cast light on subtle differences that may give rise to illness.

"Growing up we were like two peas in a pod." "Even our best friends found it quite hard to tell us apart".

Dan and Scott Shillum are identical twins, genetic clones produced from the accidental division of a single fertilised egg into two embryos in their mother's womb some 40 years ago.

Which is quite surprising when you meet them because - apart from sounding the same, and finishing each others sentences like an old married couple - Dan and Scott don't look that similar at all. Brothers certainly, but not necessarily twins, and definitely not identical.

"I'm a couple of inches taller, and I've got a bigger frame" says Scott. "You mean fatter" laughs Dan. "We started to drift apart physically in our teens" Scott continues, rising to the challenge, "I played rugby because I was bigger, faster, stronger. Dan was more football."

While I'm listening to this fraternal trip down memory lane, dermatologist Dr Dan Glass is scrubbing-up for surgery. We're on a ward at St Thomas's Hospital, where Dan and Scott have agreed to undergo a battery of tests as part of the Epitwin Project. Today's procedure is a skin biopsy that will be used to study the genetic markers in their subcutaneous fat.

The Epitwin Project is the brainchild of Tim Spector, who heads the Twin Research Unit at St Thomas's and is Professor of Genetic Epidemiology at Kings College London. Rather than looking at the similarities between identical twins, as most of the research tends to do, Epitwin will look at the differences. Differences that explain why identical twins - who share exactly the same DNA and very similar environments - can sometimes look so different, and often develop and die from different diseases.

"We used to think the most interesting thing about identical twins was in the similarities" Professor Spector explains, "but it's the differences, the discordance, that tells you more."

Professor Spector is looking for the subtle effects of epigenetics - the chemical instruction manual that overwrites the genetic code, dictating when genes are switched on or switched off. "Epigenetic switching is like a dimmer switch for gene expression" he explains, "It's the third element in our make up alongside nature and nurture."

It's precisely because identical twins like the Shillums have exactly the same genetic code - and shared a very similar environment as they grew up - but have developed so differently as adults, that makes them an ideal case study. By comparing the patterns of epigenetic switching between them - and 5,000 other discordant identical twins enrolled in the project - Professor Spector hopes to identify the subtle differences that give rise to disease.

And this new approach is already paying dividends. The first of a series of papers produced by Professor Spector's team looking at epigenetic switching in breast cancer has identified one particular gene, DOK7, that - when stuck in the on position - appears to increase an individual's risk of developing the disease.

It's a finding that may offer both a new way to diagnose breast cancer, and a novel target for drug development that aims to turn down the dimmer switch on overactive gene expression.

The fact that genes may not be so immutable after all comes as no surprise to Scott Shillum. "It was always obvious to us that there must be something else there, because the DNA element is identical but we're very different people."