For more than 15 years now, Alzheimer's researcher David Bennett has been preserving his deceased subjects' brains, both frozen and fixed (or "pickled"), believing they would someday reveal why certain individuals hurtled down the path to dementia and others, some with a genetic predisposition toward the disease and with its characteristic plaques and tangles in their brains, showed no cognitive decline. Bennett, director of the Rush Alzheimer's Disease Center at Rush University Medical Center in Chicago, is among a growing number of researchers in the new field of epigenetics who are homing in on the place where our genes and environmental factors—from tobacco, viruses, and psychological trauma to diet, exercise, and stress—may intersect to promote or protect against disease. Through years of taking detailed histories while his subjects are alive, Bennett has helped suss out some of the life elements, from education to social isolation, that affect dementia's development. The working hypothesis, Bennett explains, is that "a lot of the plaques and tangles are probably genetically determined. And a lot of whether [they] express themselves as memory loss is determined by your experiences."
Exactly how that might happen is harder to pin down. But an emerging understanding that our genes are actually directed by some other source or code has entered the scene, and Bennett's preserved brain specimens are getting their big chance to contribute. Turns out, the DNA we are born with—the blueprint that underlies our very existence, from the color of our eyes to a predisposition for developing cancer—is not the whole story. What has begun to materialize as a potentially critical piece of the disease puzzle is that our genes seem to be instructed, in part, by a driver that can manipulate which of them are switched on and off, and when. Genome, meet your boss, the epigenome, which is what scientists are calling the chemical changes that can alter gene expression. "What happens when you age could be that genes are becoming switched on or switched off in an inappropriate fashion" to result in disease, says Peter Jones, researcher and director of the Norris Comprehensive Cancer Center at the University of Southern California. This discovery is more than an academic exercise: Though we cannot change our genes, experts say these chemical changes can be altered.
And some intriguing research in men with prostate cancer further supports the notion that altering gene expression may have real implications for health. A pilot study published in 2008 and led by Dean Ornish, president of the Preventive Medicine Research Institute and professor of clinical medicine at the University of California-San Francisco, found that men were able to alter the expression of cancer-relevant genes with intensive lifestyle changes. Prior to joining the study, the 30 subjects had independently chosen not to get conventional treatment and to instead employ "watchful waiting." Ornish found the men were able to lower their prostate-specific antigen scores and diminish the activity of their tumors by exercising 30 minutes daily, doing yoga or meditating for an hour daily, boosting their social support networks, and eating a low-fat diet based primarily on fruits, vegetables, beans, and soy protein. The 500-odd genes that were favorably affected were oncogenes that help drive prostate cancer and breast cancer as well as genes that spur oxidative stress and inflammation, which are components not only of common cancers but also of heart disease, says Ornish. "In every case where we could identify the gene change, it went in a healthy direction," he explains.
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Ornish's study didn't look at what mechanism might be actually tripping the genes' regulation switches, but there are two known chemical instruments of epigenetic action. A process called DNA methylation sets down "marks" on bits of DNA and is typically thought to squelch gene expression. Another, known as histone modification, effectively loosens pieces of the nearly 6-foot-long strand of DNA that is spooled and crammed into each cell, enabling portions of its genetic instructions to play out. Bennett's brain specimens, some 800 and counting, will be inspected for signs of these activities, and that information will be cross-referenced with the details of his subjects' lives, from the richness of social networks and frequency of mental challenges to their response to stress, to see which outside factors seem to prompt these chemical changes.
[Read more on how healthful habits might protect you against Alzheimer's.]
Glitches. Deciphering how these chemical processes might work in diseases including heart disease, autism, cancer, schizophrenia, diabetes, and asthma is a focus of the Roadmap Epigenomics Program, a $190 million National Institutes of Health initiative begun in 2008. "A critical part of understanding how DNA works is going to be this [question]: How does a cell know which genes to use and which genes to turn off?" explains Francis Collins, director of NIH and the leader of the Human Genome Project, which successfully mapped the genome. "It's the epigenetic control of how the genome is utilized that's critical for understanding how humans develop from a single cell, and we are increasingly aware that things can go wrong with that epigenetic programming, glitches in the software, and those can result in diseases," he says. An international consortium of researchers is also working to map the epigenomes of various cell and tissue types (unlike the single genome, there are multiple epigenomes) in normal and disease states, explains Jones.
One of the most important of those disease-causing glitches is probably stress, says Moshe Szyf, an epigenetics researcher and professor in the department of pharmacology and therapeutics at McGill University in Montreal. Not only can stress hormones change gene expression for the worse, but they are pervasive, he explains, traveling to every organ and tissue in the body. While a stressful situation—say, losing a job or fighting in a war—may subside, the fascinating part is that through those epigenetic marks, "the exposure is memorized in our genome," even though the hormones have stopped churning, explains Szyf.
And that can have serious consequences. Szyf has done recent research showing that males who were abused as children and later committed suicide had epigenetic changes that inhibited stress-regulating genes. Those changes weren't seen in the brains of the control group, males who had died (though not by suicide) and hadn't been abused or neglected in childhood. The speculation is that the subjects' exposure to abuse, a known risk factor for suicide, was a life-altering factor that actually changed gene expression. Profound abuse and suicide are extreme examples, of course, but the implications of stress on health operate along a gradient of severity, says Szyf.
That connection appears to go the other, and happier, way, too, demonstrated by earlier work Szyf did with collaborators at McGill. That research showed that rats that were well nurtured by their mothers in infancy, which means they were licked and groomed, cranked out less of the stress hormone cortisol and had a better-developed hippocampus, a part of the brain involved in mood and the stress response. The rat pups that were not well licked and groomed showed epigenetic marks suppressing genes in the hippocampus that normally quell the release of stress hormones. "When the gene's function is reduced, control of stress is compromised," explains Szyf. "This could lead to both behavioral and physiological consequences." More fodder for the stress theory: Szyf points to "very convincing" 2009 research out of the University of Chicago that showed rats that were stressed and isolated had altered gene expression and tumor growth and were more likely to develop breast cancer.
In the case of cancer, researchers are looking at whether epigenetic changes may actually spark new tumors. For example, two malfunctions in tumor-suppressor genes had been thought to be culprits behind the disease: a mutation that crops up and stops their protective effects, and the loss of a copy of such a beneficial gene during cell division. Both fuel the runaway growth of cancerous cells. But there appears to be a third way, says Jones, one that has become apparent only in the past decade: A "perfectly good" tumor-suppressing gene can be muffled. "That has enormous potential for treatment because all you have to do is turn it back on again," Jones explains. By accidentally discovering in the 1980s that precancerous cells were turned into muscle cells by exposure to a certain chemical and then connecting the process to the undoing of DNA methylation, Jones and his team essentially launched the field of epigenetics. Since then, he has worked to harness this process for the benefit of patients with myelodysplastic syndrome, a preleukemia. And in 2004, the first new epigenetic cancer drug was approved by the Food and Drug Administration. The drug, marketed as Vidaza, works by removing the DNA methylation marks that are keeping protective genes from playing their usual role as safeguards against tumor development. Now Jones, along with a group led by Stephen Baylin at Johns Hopkins University, is in the midst of a three-year research project testing several epigenetic drugs in patients with late-stage lung, colon, and breast cancers.
Laboratory research is all well and good, but what is all this interest in epigenetics saying about how we should behave now? "Given that epigenetics is so new, we don't have a lot of experience in how you deal with that information and apply it clinically," explains Andrew Feinberg, director of the Johns Hopkins University Center for Epigenetics in Common Human Disease. Likewise, we cannot soon expect changes to public-health recommendations based on the notion of regulating our gene expression to prevent disease. And, he says, we can never ignore the basic blueprint of our hard-coded DNA. "It's a mistake to leave the genes out," he says. (And there's still much to be discovered about the human genome; now that it has been mapped, scientists have realized that most diseases don't come down to a single gene or even a handful. Instead, genes interact with one another with seemingly infinite complexity to cause illness.)
Indeed, the old rules of healthful living still apply, from getting regular physical activity to eating right and shunning tobacco. "Our work doesn't change those things," says Szyf. "It just provides an explanation" as to how they might provide a benefit. While Szyf suspects that critical epigenetic changes predisposing us to illness may occur in the womb and during early childhood, it's not clear whether it would be practical to reverse them. It's possible, he says, that some changes have accumulated in so many different places that it would be tough to reverse them all.
Yet some are optimistic that even though we will never be able to trump our own genes, we do have some control over how their influence plays out. The revelation from 30-odd years spent investigating what power an individual has over personal health, says Ornish, is that "our genes are a predisposition, but our genes are not our fate." In fact, he says, they "are much more dynamic than we'd once thought."
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