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A paradigm shift in genetics

Amanda Gefter is an editor for New Scientist magazine Every day, it seems, we read about the discovery of a gene for this or a gene for that. "Researchers identify the fat gene!" the headlines scream. "Scientists pin down intelligence gene!" "Alcoholism gene found!" Even though

Amanda Gefter

is an editor for New Scientist magazine

Every day, it seems, we read about the discovery of a gene for this or a gene for that. "Researchers identify the fat gene!" the headlines scream. "Scientists pin down intelligence gene!" "Alcoholism gene found!" Even though the path from gene (a string of nucleotides) to phenotype (fat, intelligent, lush) is rarely straightforward, genetic determinism - the idea that our physical and behavioral traits are governed by the twisted sequences of DNA lurking inside our cells - permeates popular culture. From Watson and Crick's 1953 discovery of the DNA double helix to the sequencing of the human genome in 2003, the idea that our genes inform who we are and what we do has become integral to our understanding of what it is to be human.

This populist kind of genetic determinism is appealing because it undermines what seem to be unfair social judgments. Alcoholism is now a disease, and obesity is now chalked up to a chromosomal raw deal. At the same time, it lifts a certain burden of moral responsibility. You can't blame a criminal for his actions; it's "in his genes."

The struggle between determinism and free will is an ancient one, but genetics seems to have settled the score: "You can't be blamed for your faults," it seems (to some people) to say, "but you're also stuck with the cards you were dealt." Accountability is avoidable, but DNA is destiny.

Well, don't surrender yourself to your genome just yet. The more scientists learn about the complex relationships among genes, environment, disease and phenotype, the more they are realizing how restrictive the old biological paradigm is.

"Our understanding of genetics is currently undergoing a paradigm shift," says Melanie Ehrlich, a molecular biologist at the Tulane Cancer Center. "It is now commonly acknowledged among scientists that it is not enough to look to DNA as the sole determinant of heredity."

Ehrlich is referring to the emerging field known as epigenetics. The epigenome is the elaborate chemical switchboard that can turn genes on and off like flipping a light switch. Our genes encode instructions for the building of proteins. On its own, DNA is nothing but an inert biological handbook, but chemicals in each cell actively read and transcribe the instructions, then use them to build our bodies cell by cell. Every cell in your body contains an identical genome, and yet a brain cell is quite different from a skin cell.

How do the differences arise? Because different genes are


from one cell to the next. How does a cell know which genes to implement and which to ignore? That set of instructions is contained in the cell's


. Whereas the genome is static - its sequence of base pairs unchanging except in the rare and often detrimental case of a mutation - the epigenome is dynamic, busily deciding which genetic instructions should be put into action and which should be chemically strangled into silence.

Scientists are now learning that the epigenome is highly sensitive to its environment. The food you eat, the air you breathe, and the stress or happiness you feel can actually alter your genetic makeup - not by changing the sequence of your DNA, but by deciding which genes are expressed.

Biologists have long known that our bodies and behaviors are shaped in part by nature and in part by nurture, but the exact link between gene and environment had always been fuzzy. Now, it is coming into focus: The link is the epigenome.

Epigenetics is opening up a whole new window on the nature of disease. Many cancers, for instance, are not genetic in origin - caused by one or more mutations to our DNA - but epigenetic. "We finally understand that abnormal epigenetic changes are just as important for cancer formation and development as are genetic mutations," Ehrlich says. "Without epigenetic changes, human cancers would probably be rare." The same is believed to be true for autoimmune diseases, diabetes and depression.

Even more surprising has been the discovery that, like genes themselves, epigenetic effects can be passed down from generation to generation. That was first demonstrated in mammals by Randy Jirtle and colleagues in a groundbreaking experiment in 2000. Jirtle took mice that carried a gene called the agouti gene, which made their fur yellow and rendered them susceptible to particular diseases, and fed them a diet containing so-called methyl groups - molecules that can attach to a gene and block it from being used. The methyl molecules, commonly found in foods such as soy and leafy vegetables, attached to the agouti gene and switched it off.

The real surprise came when the mice became parents. Their offspring were born with the agouti gene still in their DNA but silenced. They had brown fur and were no longer susceptible to the same diseases. The parent mice had passed on not only their DNA, but also the epigenetic switches attached to it.

The moral of the story? What you eat today could affect your children's genes . . . even your grandchildren's.

"What you do now won't affect only you," Jirtle says. "That's not trivial."

Makes you rethink that doughnut, now doesn't it?

The National Institutes of Health recently announced that as part of their Roadmap Initiative they will commit more than $190 million in the next five years to epigenomics research. One of the goals is to develop a series of publicly available reference epigenome maps: a Human Epigenome Project analogous to the Human Genome Project. It's an ambitious undertaking, since every different type of cell has its own epigenome. Jirtle, however, is optimistic. "I don't think it will be as complicated as people think," he says. "It's a lot of data, but it's doable."

"The human epigenome remains largely uncharted scientific territory," says Nora Volkow, director of the National Institute of Drug Abuse. "Recent advances in tools and technologies make a human epigenome project a next logical step. It is likely that a human epigenome project . . . may be invaluable in enhancing our understanding of the epigenetic basis of human disease." It could even pave the way for novel cures. "Understanding the human epigenome at a deep level," Volkow says, "provides us with the incredibly exciting potential of learning new ways to 'debug' the epigenetic software regulating our DNA to reverse particular disease pathways."

The epigenetics revolution is in its infancy, but it promises big things - cures for disease, a better understanding of stem cells, even antidotes to aging. From a cultural perspective, it promises to shift the way we think about our own role in our health. Suddenly, free will can be heard shouting over the murmur of genetic determinism. Maybe we aren't stuck with the cards we were dealt after all. You can't un-mutate a gene, but you can potentially reverse an epigenetic effect. "Epigenetic effects are more flexible and less deterministic, but they require taking more responsibility for the health of your epigenome, for you and for your offspring, even for your grandchildren and great-grandchildren," Jirtle says. "Responsibility is the downside of free will."

To see the "Epigenomics" part of the NIH Roadmap Initiative: