The Epigenetics Revolution

Nessa Carey

The Epigenetics Revolution

For Abi Reynolds, who reprogrammed my life

And in memory of Sean Carey, 1925 to 2011

Acknowledgements

Over the last few years I’ve had the privilege of working with some truly amazing scientists. There are too many to name here but special acknowledgements must go to Michelle Barton, Stephan Beck, Mark Bedford, Shelley Berger, Adrian Bird, Chris Boshoff, Sharon Dent, Didier Devys, Luciano Di Croce, Anne Ferguson-Smith, Jean-Pierre Issa, Peter Jones, Bob Kingston, Tony Kouzarides, Peter Laird, Jeannie Lee, Danesh Moazed, Steve McMahon, Wolf Reik, Ramin Shiekhattar, Irina Stancheva, Azim Surani, Laszlo Tora, Bryan Turner and Patrick Varga-Weisz.

Thanks go also to my former colleagues at CellCentric – Jonathan Best, Devanand Crease, Tim Fell, David Knowles, Neil Pegg, Thea Stanway and Will West.

As a first-time author I owe major gratitude to my agent, Andrew Lownie, for taking a risk on me and on this book.

Major thanks also to the lovely people at my publishers Icon, especially Simon Flynn, Najma Finlay, Andrew Furlow, Nick Halliday and Harry Scoble. Their unfailing patience with my complete ignorance of all aspects of publishing has been heroic.

I’ve had great support from family and friends and I hope they’ll forgive me for not mentioning them all by name. But for sheer entertainment and distraction during some stressy patches I have to thank Eleanor Flowerday, Willem Flowerday, Alex Gibbs, Ella Gibbs, Jessica Shayle O’Toole, Lili Sutton and Luke Sutton.

And for always resisting the temptation to roll her eyes every time I said, ‘I can’t meet friends/do the dishes/go away for the weekend because I’m working on my book’, I’ve got to thank my lovely partner Abi Reynolds. I promise I’ll take that ballroom dancing lesson now.

Introduction

DNA.

Sometimes, when we read about biology, we could be forgiven for thinking that those three letters explain everything. Here, for example, are just a few of the statements made on 26 June 2000, when researchers announced that the human genome had been sequenced[1]:

Today we are learning the language in which God created life.

US President Bill Clinton

We now have the possibility of achieving all we ever hoped for from medicine.

UK Science Minister Lord Sainsbury

Mapping the human genome has been compared with putting a man on the moon, but I believe it is more than that. This is the outstanding achievement not only of our lifetime, but in terms of human history.

Michael Dexter, The Wellcome Trust

From these quotations, and many others like them, we might well think that researchers could have relaxed a bit after June 2000 because most human health and disease problems could now be sorted out really easily. After all, we had the blueprint for humankind. All we needed to do was get a bit better at understanding this set of instructions, so we could fill in a few details.

Unfortunately, these statements have proved at best premature. The reality is rather different.

We talk about DNA as if it’s a template, like a mould for a car part in a factory. In the factory, molten metal or plastic gets poured into the mould thousands of times and, unless something goes wrong in the process, out pop thousands of identical car parts.

But DNA isn’t really like that. It’s more like a script. Think of Romeo and Juliet, for example. In 1936 George Cukor directed Leslie Howard and Norma Shearer in a film version. Sixty years later Baz Luhrmann directed Leonardo DiCaprio and Claire Danes in another movie version of this play. Both productions used Shakespeare’s script, yet the two movies are entirely different. Identical starting points, different outcomes.

That’s what happens when cells read the genetic code that’s in DNA. The same script can result in different productions. The implications of this for human health are very wide-ranging, as we will see from the case studies we are going to look at in a moment. In all these case studies it’s really important to remember that nothing happened to the DNA blueprint of the people in these case studies. Their DNA didn’t change (mutate), and yet their life histories altered irrevocably in response to their environments.

Audrey Hepburn was one of the 20th century’s greatest movie stars. Stylish, elegant and with a delicately lovely, almost fragile bone structure, her role as Holly Golightly in Breakfast at Tiffany’s has made her an icon, even to those who have never seen the movie. It’s startling to think that this wonderful beauty was created by terrible hardship. Audrey Hepburn was a survivor of an event in the Second World War known as the Dutch Hunger Winter. This ended when she was sixteen years old but the after-effects of this period, including poor physical health, stayed with her for the rest of her life.

The Dutch Hunger Winter lasted from the start of November 1944 to the late spring of 1945. This was a bitterly cold period in Western Europe, creating further hardship in a continent that had been devastated by four years of brutal war. Nowhere was this worse than in the Western Netherlands, which at this stage was still under German control. A German blockade resulted in a catastrophic drop in the availability of food to the Dutch population. At one point the population was trying to survive on only about 30 per cent of the normal daily calorie intake. People ate grass and tulip bulbs, and burned every scrap of furniture they could get their hands on, in a desperate effort to stay alive. Over 20,000 people had died by the time food supplies were restored in May 1945.

The dreadful privations of this time also created a remarkable scientific study population. The Dutch survivors were a well-defined group of individuals all of whom suffered just one period of malnutrition, all of them at exactly the same time. Because of the excellent healthcare infrastructure and record-keeping in the Netherlands, epidemiologists have been able to follow the long-term effects of the famine. Their findings were completely unexpected.

One of the first aspects they studied was the effect of the famine on the birth weights of children who had been in the womb during that terrible period. If a mother was well-fed around the time of conception and malnourished only for the last few months of the pregnancy, her baby was likely to be born small. If, on the other hand, the mother suffered malnutrition for the first three months of the pregnancy only (because the baby was conceived towards the end of this terrible episode), but then was well-fed, she was likely to have a baby with a normal body weight. The foetus ‘caught up’ in body weight.

That all seems quite straightforward, as we are all used to the idea that foetuses do most of their growing in the last few months of pregnancy. But epidemiologists were able to study these groups of babies for decades and what they found was really surprising. The babies who were born small stayed small all their lives, with lower obesity rates than the general population. For forty or more years, these people had access to as much food as they wanted, and yet their bodies never got over the early period of malnutrition. Why not? How did these early life experiences affect these individuals for decades? Why weren’t these people able to go back to normal, once their environment reverted to how it should be?

Even more unexpectedly, the children whose mothers had been malnourished only early in pregnancy, had higher obesity rates than normal. Recent reports have shown a greater incidence of other health problems as well, including certain tests of mental activity. Even though these individuals had seemed perfectly healthy at birth, something had happened to their development in the womb that affected them for decades after. And it wasn’t just the fact that something had happened that mattered, it was when it happened. Events that take place in the first three months of development, a stage when the foetus is really very small, can affect an individual for the rest of their life.

Even more extraordinarily, some of these effects seem to be present in the children of this group, i.e. in the grandchildren of the women who were malnourished during the first three months of their pregnancy. So something that happened in one pregnant population affected their children’s children. This raised the really puzzling question of how these effects were passed on to subsequent generations.

Let’s consider a different human story. Schizophrenia is a dreadful mental illness which, if untreated, can completely overwhelm and disable an affected person. Patients may present with a range of symptoms including delusions, hallucinations and enormous difficulties focusing mentally. People with schizophrenia may become completely incapable of distinguishing between the ‘real world’ and their own hallucinatory and delusional realm. Normal cognitive, emotional and societal responses are lost. There is a terrible misconception that people with schizophrenia are likely to be violent and dangerous. For the majority of patients this isn’t the case at all, and the people most likely to suffer harm because of this illness are the patients themselves. Individuals with schizophrenia are fifty times more likely to attempt suicid ...

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