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.

Richard C. Francis. Click image to expand.

There are almost as many metaphors for genes as there are genes. One of the most familiar, and the hardest to let go of, is the tidy blueprint, at once reassuringly clear and oppressively deterministic: Our genome is the architectural plan for who we are. It tells our body how to build itself, setting our height, our health, and even our moods since before we are born. Small wonder that we imagine if we can read our genome, we will discover not just the truth of ourselves but perhaps our future, too. Remember the high hopes that spurred on the Human Genome Project in the 1990s? Though the genetic catalog is now largely complete, we still await many of the anticipated insights, and in Epigenetics: The Ultimate Mystery of Inheritance, Richard Francis, a writer with a biology Ph.D., traces the emergence of a different genetic paradigm. Our DNA shapes who we are, Francis reports from the research forefront, but it is far from a static plan or an inflexible oracle; DNA gets shaped, too. For good or ill, the forces that determine our fate can't be captured by anything so neat as a blueprint.

Francis's primer introduces a new field, whose roots predate the rise of pure genetic determinism. How is DNA itself shaped? The search for answers begins in the late-19th-century work of scientists such as Hans Driesch, whose study of sea urchin embryos revealed that the cell plays a key administrative role in an organism's development. He discovered that if you take cells from one location in the embryo—the area that will become, say, the spines--and plant them in another—the mouth area--their function changes: You don't get spines growing out of the mouth, you get a normal mouth. A cell's identity doesn't arise from a preordained genetic recipe inside it. Crucially, it is the cues that a cell gets from neighboring cells that affect how the genes inside it behave.

Epigenetics has taken its cue from this process, and sets out to explore not just how cells control the genes inside them but also how altered genes are passed on when cells reproduce—both within an organism's lifetime and, more fantastically, across generations. If you detect another historical antecedent, you're right. Looming over this new field is the once-derided Lamarck, who proposed in the 18th century that if a giraffe, for example, consistently stretches its neck to reach leaves, its children will be born with longer necks. Lamarck's ideas about how traits are acquired and passed down were mostly wrong. But the basic notion that an event in a parent's life can sculpt fundamental traits in a child, once consigned to the dustbin of biology, has been revived. The epigenetic quest is to discover how chemical attachments to genes shape the fate of an animal by altering the genes' long-term expression.

If cellular regulation of genetic expression sounds complicated, it is, which is one reason—aside from our allegiance to the idea of some foreordained pattern to our lives—the epigenetic field has been slow to develop. The research that has been accumulating for decades upends the conception of "controller" genes that are either "on" or "off." Francis is a thorough guide to the many ways in which personality and health can play out through our genes but not be coded for in DNA. He proceeds step-by-step. After all, this is unsettling terrain: The notion of environmental forces that can be genetically determining does not fit our deeply etched nature vs. nurture categories. Francis begins by explaining what he calls "garden variety," or short term—rather than epigenetic—gene regulation, by way of androgens, like testosterone. This happens in normal development, but also in abnormal situations, such as when athletes abuse steroids. Where normal testosterone changes gene expression, extra testosterone causes a frantically altered gene expression, which leads to strong muscles, shrunken testes, and out-of-control aggression. The changes are direct. You take the steroids, they affect some of the cells in your body, the gene activity inside those cells changes, and then your body changes. The changes in garden-variety gene regulation end with the affected cells, and with you. When cells divide they do not pass along the abnormal genetic activation. The children of a steroid abuser inherit their parent's genes, but they do not inherit the synthetic steroid-induced changes to gene expression.

But gene expression doesn't change merely when you put chemicals in your body. The connections between people may shape it, too. In the 1990s, scientists began to explore how social status can influence biology. In one kind of African cichlid fish, for example, the males are either "territory-owning" tough guys who have vividly bright colors, huge testes, larger neurons, and lots of testosterone. Or they are nonterritorial and much less striking. The low-testosterone males do not get to breed. Scientists discovered they could manipulate the social status of fish, their testosterone level and all the hoopla that accompanies it, by changing only the fish's "friends." If they put big, territorial fish in a tank with much bigger, territorial males, the former-breeders lost color, their testes and neurons shrank, and they literally transformed into nondominant fish. When they put nonterritorial wallflowers in a tank with females and smaller males, they too were transformed, but in the other direction. As Francis points out, we obviously can't run this kind of experiment with humans. It nevertheless shows how context can change the way genes work.

Changes that arise from normal gene regulation happen in the short term, but epigenetic changes alter the way that genes react to the world for a very long time—even when the original cause has vanished. It is this rather shocking long-term influence that makes epigenetics one of most alluring—and terrifying—shifts in how we think about our genes. Epigenetic changes can occur in adulthood, in childhood, even in utero (a phenomenon explained in Origins by Annie Murphy Paul), with the consequence that an event you experienced as a child could dictate the ways your genes behave in a different situation as an adult. It may have been simple-minded to assume that we are programmed by our genes, but there was a weird egalitarianism in that: Even if we get different genes to begin with, we are under their sway in the same way. Epigenetic change means that not only do we start out as unwitting participants in a genetic lottery, but environmental forces we cannot see or control can mess with our genetic hardware and change our destiny. At the level of DNA, epigenetic change occurs when particular chemicals become attached to the gene, and stay there, altering how the gene behaves. The first of these attachments to be discovered, and still the best known, is from the methyl group. In 1980, it was shown that different degrees of methylation can alter gene expression in different ways. Demethylation can cause problems, too. Depending on the genes involved, one consequence can be unconstrained cell division, otherwise known as cancer.

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.

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.

Christine Kenneally is the author of The First Word: The Search for the Origins of Language. Her writings can be found on the blog www.christinekenneally.com.

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