Wednesday, November 26, 2014
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The Age of Epigenetics

LONDON – Fifty-one years ago, James Watson, Maurice Wilkins, and Francis Crick were awarded the Nobel Prize in Medicine for their discovery of DNA’s structure – a breakthrough that heralded the age of the gene. Since then, the field of genetics has advanced significantly, particularly as a result of the global Human Genome Project, which in 2003 identified all of the roughly 23,000 genes and three billion chemical base pairs in human DNA in order to screen for many rare diseases.

But, despite evidence that most diseases have a clear genetic component, only a fraction of the genes that explain them have been found. And scientists in the field remain puzzled by the fact that most identical twins (who share 100% of their genes) do not die from the same diseases. As a result, many in the scientific community are beginning to predict a decline in the role of the gene in pinpointing the root causes of diseases.

It is too soon to discount genetics, however, because the science of “epigenetics” – the study of mechanisms for turning genes on and off, thus changing the way a cell develops without altering the genetic code – is gaining traction. Indeed, the 2012 Nobel Prize in Medicine was awarded to John Gurdon and Shinya Yamanaka for revolutionizing scientists’ understanding of how cells develop by reprogramming DNA and cells without altering their genetic structure.

In 1962, Gurdon’s finding that almost any cell in the body contains the complete DNA code enabled him to create a tadpole by cloning an adult frog. More than four decades later, in 2006, Yamanaka discovered a way to trick complex adult cells in mice into regressing to their immature state, forming stem cells. Before this, stem cells – which can potentially be reprogrammed to develop into replacements for lost or damaged tissue – could be taken only from early-stage embryos, a practice that fueled ethical controversy.

The true promise of epigenetics has become apparent only in the last few years, as scientists’ ability to assess the epigenetic mechanisms in DNA – which can now be measured at roughly 30 million points across the human genome – has dramatically improved. Epigenetics can potentially be used to explain the root causes of many diseases that scientists have so far struggled to understand, from asthma to allergies to autism.

Consider lung cancer. Six decades ago, when most men smoked, British doctors linked smoking to lung cancer, making it the first disease to be causally linked to smoking. (In fact, lung cancer kills one in ten smokers.) But the incidence of certain kinds of lung cancer continues to rise – particularly in women – making it one of the most prolific killers worldwide, despite the general decline of smoking over the last 30 years.

Indeed, nowadays, many lung cancer patients have no history of smoking. These “blameless” patients seem to develop a different kind of lung cancer from those who report a history of smoking – one that is more responsive to new medications and has better, albeit still poor, outcomes.

Epigenetic processes that cause key anti-cancer genes, such as the tumor suppressor P16, to be switched off could explain the increased prevalence of lung cancer. A recent study showed that a few years of smoking can have this effect, making smokers more susceptible to a variety of cancers.

My team and I recently studied 36 pairs of identical twins, of which only one twin had breast cancer. These “genetic clones” had a few crucial differences. In the twin who developed the breast cancer, several hundred genes had been switched off. In a few genes, this had occurred five years before diagnosis. Such findings unlock the possibility of a diagnostic test well before the disease manifests itself, and of developing drugs that prevent – or even reverse – the cancer’s development.

Moreover, animal studies have shown that changes in stress or diet can alter the behavior and genes of future generations. As a result, it is likely that epigenetic changes can be inherited.

For example, smoking could have caused epigenetic changes in a grandparent’s DNA, effectively switching off certain anti-cancer genes. The genes would then be passed down to descendants in this switched-off state. Thus, the toxins that people ingest may not be the only relevant factor should cancer strike; the toxins that their parents or grandparents ingested could also be to blame.

Physical experiments revealing such trans-generational effects are impossible to conduct on humans, so historical or observational data must be used. One study of children in Bristol showed differences in growth depending on whether their grandfathers had smoked before the age of 11. Their bodies probably reacted defensively, adapting in the short term by changing the genes for the next few generations, or until the “danger” had passed, a so-called “soft inheritance” running in parallel to slower-acting evolutionary forces.

Fortunately, these epigenetic changes are potentially reversible. Four epigenetic leukemia drugs, which aim to switch the natural protective genes back on, are now on the market in the United States. More than 40 other epigenetic drugs are being developed, not only for cancer, but also for obesity and even dementia. In the future, regular epigenetic health check-ups could become standard practice.

More than 50 years on, genes remain crucial to understanding complex diseases – especially given scientists’ ever-improving ability to alter them. The age of the gene is far from over; it has simply progressed into the age of epigenetics.

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    1. CommentedNathan Coppedge

      "For example, smoking could have caused epigenetic changes in a grandparent’s DNA, effectively switching off certain anti-cancer genes. The genes would then be passed down to descendants in this switched-off state." I had been looking for evidence like this. There is even potential to develop visual or environmental stimulus which triggers a chemical response; some things which were once coincidences are now understood to have causal relationships. I think this could be encouraging when science applies a broad technical discernment, based on theories such as situationism and the study of natural kinds.

    2. CommentedAnatoli Scholz

      This is a terrifying, yet also importat thought, that we are indeed more directly responsible than previously assumed of our behaviour and habits. It apparently goes on to affect not only us and our immediate surroundings, but also our following generations. Terrifying in a way...

    3. CommentedPaul Jefferson

      The influence of epigenetics on an individual's behavior should also be of interest.

      For example, if urban youth who were exposed to leaded gasoline pollution in the 1960s tended to be more violent as adults, will their grandchildren also be more violent in adulthood -- because one or more lead-exposure epigenetic traits are inherited?

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