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Turning our genes on and off

Turning our genes on and off

Recent discoveries in “epigenetics” are opening up profound questions about how humans develop, and how diseases might be treated

Aren’t our genes fixed?

From Mendel and Darwin in the 19th century, to Watson and Crick in the 20th, scientists have shown that genetic material passed from parent to child forms the blueprint for our development. But in a quiet scientific revolution, researchers in recent years have come to realise genes aren’t a fixed, predetermined programme simply duplicated from one generation to the next. Instead, genes can be turned on and off by our experiences and environment. The food we eat, the stress we undergo, the pollution we’re exposed to, all these can influence the genetic legacy we pass on to our children and even grandchildren. This, in turn, could fundamentally alter our understanding of conditions from autism to cancer. In October, scientists at the University of California, Los Angeles, raised a storm by presenting data that indicated a potential epigenetic basis for homosexuality.

And what is epigenetics?

Literally meaning “on top of” or “above” genetics, it’s the study of how our underlying genes are activated by the world around us. Think of the 20,000-25,000 genes in the human genome as songs stored on a computer. Epigenetics is about the albums, the playlists, the process of deciding which songs to play. A British embryologist, Conrad Waddington, coined the phrase in the 1940s after studying the impact of heat stress on fruit fly larvae. Larvae exposed to high temperatures developed unusual wings that in some cases were passed down through generations – even though the subsequent larvae weren’t exposed to heat themselves. Waddington called this process “genetic assimilation”, and in the decades since, geneticists have come to realise that our genes are continually activated/deactivated by life experiences and chemical signals, in a process involving various “switches” and “tags”.

How does this epigenetic activity affect who we are?

We’re only just finding out. The most obvious such activity takes place in the womb. Each one of an embryo’s cells contains exactly the same DNA, yet these cells go on to perform vastly different tasks, becoming skin cells, liver cells, brain cells, etc. That’s because various genes inside them are “tagged” to switch off, or on. Queen bees and worker bees, for example, have the same genes, but larvae fed royal jelly have certain genes switched off and become queens. In humans, studies have shown that during pregnancy, what the mother eats can have a major impact on how this tagging process unfolds. Prenatal diets low in folic acid, vitamin B12 and other nutrients containing “methyl groups” – sets of chemicals used to tag genes – have been linked to an increased risk of asthma and brain and spinal cord defects in children.

Can such changes occur later?

Absolutely. Young children who are abused have been found to be more likely to have epigenetic changes that make coping with stress much harder. Twins may both inherit a gene that pre-disposes them to cancer, but if only one goes on to develop habits (a bad diet, say, or smoking) that turn on the gene, that twin may develop the disease later in life while the other stays cancer free. The controversial UCLA study looked at 37 pairs of identical twins in which one twin was gay, and found five “epi-markers” that were more common among the gay men. This suggests a possible biological mechanism for what scientists have long suspected: that sexuality has roots in both our genes and life experiences.

Are epigenetic changes inheritable?

This is where epigenetics throws a real spanner in any strict Darwinian version of evolution (see box). Scientists used to think that epigenetic tags were erased from one generation to another. Now they know that about 1% stay in place, and can be passed on. A famous study of the Dutch Hunger winter of 1944-1945 (when the Nazis deprived the Dutch of food), showed that children conceived at the time themselves grew up to give birth to smaller-than-usual offspring. Traumatised mice have been shown to father generations of mice with blunted stress responses, a condition associated in humans with depression and schizophrenia. David Crews, a zoologist at the University of Texas, speculates that soaring obesity and autism rates could have roots in our grandparents’ exposure to “the chemical revolution of the 1940s”, which introduced new fertilisers, detergents and pesticides into the food chain.

Are these insights yielding medical therapies?

Yes. In the past five years, evidence showing that epigenetics has a major role in triggering certain cancers has become “rock solid” according to biologists, and big pharmaceutical firms are now intent on designing drugs that switch certain genes on and off. Two main types are being developed: those based on “HDAC inhibitors” (the same compounds found in royal jelly, which helps turn worker bees into queens), and “DNMT therapies”, which focus on the main chemicals that tag genes for activation/deactivation. Last month, GlaxoSmithKline, the British drugs giant, announced that it has epigenetic drugs in trials to treat solid tumours, leukaemia and small cell lung cancer for which it will seek regulatory approval by 2020.

What are the wider implications?

Epigenetics challenges the idea that we are hardwired by our genes, and underlines – in scientific terms – the importance of diet, housing, love, education and so forth, on how our bodies and minds develop. Mice born with a defective gene that can make them yellow, fat and prone to disease have been shown to suppress the gene if living on a methyl-rich diet (methyl-rich foods include soybeans and red grapes). But geneticists are keen to emphasise the complexity of this new field. The human genome contains a DNA sequence of three billion letters forming 20,000-plus genes: the “epigenome” refers to every possible modification of those genes.

Darwin vs. Lamarck

The idea that experiences, not just biological hardware, are passed down through generations has been around for a long time. “The fathers have eaten a sour grape, and the children’s teeth are set on edge,” said the prophet Jeremiah. In 1801, a French naturalist, Jean-Baptiste Lamarck, based his theory of evolution – the “inheritance of acquired characteristics”– on this very notion. Organisms, he believed, passed on traits and behaviours that they had developed over their lifetime. Giraffes, for example, had long necks because they were always stretching them to reach high leaves.

Lamarckism faced ridicule after Darwinism took hold later in the century; and in 1891, the German biologist August Weismann appeared to debunk the theory entirely by chopping off the tails of mice to prove their pups would not inherit their taillessness. Epigenetics now raises the possibility that Lamarck wasn’t 100% wrong, even though he did believe many things that clearly were – for example, that evolution was tending towards “perfection” and that species could not go extinct. According to Lamarck, they just morphed into better, more complex organisms. To scientists working in epigenetics, says Jonathan Mill, of Exeter University, the fear is that “it’s being used as an explanation for all sorts of things without any real direct evidence”.

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