Richard C. Francis' Epigenetics: How a new field has changed the way we think about genes.

Reading between the lines.
June 20 2011 9:52 AM

Goodbye, Genetic Blueprint

What the new field of epigenetics reveals about how DNA really works.

(Continued from Page 1)

The causes of epigenetic attachments are various, and the evidence so far indicates they range from pollution to stressful social interactions. Studies on the long-term effects of a pregnant woman's poor nutrition suggest that the food our mothers eat while we are in the womb can shape our gene expression. So, too, the food they don't eat. The best data on long-term genetic change come from the terrible Dutch famine of 1944, when the Nazis blockaded food supplies, disrupted transport, and flooded farmlands in western Holland. It has emerged as the classic case study in the field, thanks to the exemplary record-keeping of the Dutch, which gives researchers solid longitudinal data on the famine's many far-reaching effects. For children who were in utero at the time of the famine, the consequences include a higher risk of schizophrenia, antisocial personality disorder and other psychological disturbances, and even 50 years down the road, a greater likelihood of becoming obese. At first glance it may seem that the legacy is poor health in general. But that's not how it works. The impact depends on exactly when the fetus was exposed to the famine, Francis reports. Women whose mothers suffered the famine in the first trimester have a higher risk of breast cancer. Those whose mothers suffered in the second trimester have problems with lungs and kidneys.

Epi-Genetics by Richard C.Francis.

The first person to realize what a data trove the Dutch records were was Clement Smith, a U.S. doctor who was flown to the Netherlands in 1945 to help. He found that children born during the famine were much smaller than those born before. Numerous teams have revisited the data, which have been updated during the decades since, and they have discovered many ways the famine is still playing out in the lives of Dutch people, even those who weren't born at the time. The studies became epigenetic 20 years ago, when scientists began to look for altered genes in famine survivors to see whether changed DNA explains the ways in which the survivors differ.

In 2009, one team unearthed a tantalizing result: Examining the blood cells of adults who were in the womb at the time of the famine, researchers discovered unusual epigenetic attachments on the gene that codes for a hormone called insulin-like growth factor 2. The hormone is crucial for growth, particularly in fetuses. It turns out the IGF2 gene of the famine group is methylated to a different degree than the same gene in a non-famine group. Even though scientists haven't yet traced the specific causal chain between the epigenetic attachments, the genes, and people's lives, those attachments are a smoking gun for epigenetic change in the womb, and health issues many decades later.

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Even more fascinating, and unnerving, it appears that the consequences of epigenetic change may stretch over several lifetimes. In one Swedish village, which also has records of crop harvests that go back hundreds of years, the paternal grandsons of men who experienced famine were less likely to have cardiovascular disease than their peers whose paternal grandfathers did not experience famine. But, wait, conventional wisdom says only genes are supposed to be passed on to the next generation. Most epigenetic attachments are stripped away from genes in the creation of sperm and egg cells. Yet it seems that a record of some epigenetic attachments is passed on and then recreated in the genome of the embryo, too. That means that an event in your parent's life that occurred before you were conceived could affect how your genes work today. In other words, the sins of the fathers may be visited on the deoxyribose nucleic acids of the sons. How malleable are our sons and daughters? The mechanisms involved are extraordinarily subtle. Researchers are now only beginning to understand how and why this happens.

It's almost enough to make one nostalgic for the simplicity of old-style genetic determinism, which at least offered the sense that the genetic hand you were dealt at birth was the same one you would play your whole life—except that epigeneticists hold out the promise that the blessings of a single life, too, can be passed on. Disease researchers, Francis reports, have hopes that the effects of abnormal epigenesis may be reversed. For example, it's possible that the damage caused by many cancers is epigenetic. If those epigenetic attachments can be altered, then it's possible the cancer can be stopped. Still, even if we are discovering that an extraordinary range of conditions may be epigenetic, not all of them are. There are still specific diseases that follow a deterministic path. If you are unlucky enough to draw the Huntington's mutation in the genetic shuffle, you will develop the disease. Francis rightly emphasizes the wonder of epigenetics and the molecular rigor it brings to the idea that life is a creative process not preordained by our genome any more than it is preordained by God. Yet even as epigenetic research invites dreams of mastery—self-creation through environmental manipulation—it also underscores our malleability. There is no easy metaphor for this combination. But if we must have one, we should at least start with the cell, not the gene. The genome is no blueprint, but maybe the cell is a construction site, dynamic, changeable, and complicated. Genes are building materials that are shaped by the cell, and they in turn create materials used in the cell. Because the action at the site is ongoing, a small aberration can have a small effect, or it can cascade through the system, which may get stuck. Recall that your body is a moving collection of these building sites, piled in a relatively orderly way on top of another. Malleability? It's an ongoing dance with chaos, but, incredibly, it works.

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