Finally! Your Freedom to Travel...

 

I read this article on the train.  Great for all of you with health concerns.  It makes me want to relax and take another vacation!

Misery in the Genes

A professor finds DNA that can turn emotional stress into physical illness

 Noah Berger for The Chronicle

The research done by Steven W. Cole demonstrates the increasing sophistication of psychoneuroimmunology, the study of connections between mind and health.

By Helen Fields

Misery isn’t just depressing, it’s bad for your health. People going through stressful events, like divorce, are more likely to get sick. People who are HIV-positive see their condition worsen more quickly if they don’t have good social support. But nobody knows exactly how mental stress causes illness and death.

Now a study by researchers at the University of California at Los Angeles and several other institutions has come up with an actual biological pathway: a chain of molecules that connects stress to disease through genes. The scientists also learned that some people can get through tough times without ruining their health, thanks to a particular genetic variation that breaks the chain.

The study, published this spring in the Proceedings of the National Academy of Sciences, is wildly multidisciplinary, spanning psychology, molecular biology, immunology, and epidemiology. That posed challenges in lining up grants, says Steven W. Cole, an associate professor of medicine at UCLA, who led the research. But the study’s success signals the growth and increasing sophistication of Mr. Cole’s field, psychoneuroimmunology, the study of connections between mind and health.

Robert Ader, a professor of psychiatry at the University of Rochester, coined the discipline’s name around 1980, when he was studying animals that could be psychologically “tricked” into suppressing their immune systems. The animals were fed saccharin-flavored water and simultaneously dosed with a drug that suppressed the immune system. Later, just the taste of saccharin was enough to suppress their immune systems. Psychology appeared to affect biology.

“That was not received with open arms by the immunology community,” Mr. Ader says. Thirty years later, however, it is more established that the brain and immune system are linked. He says Mr. Cole’s study, which points to a specific biological connection between the two, should further convince doubtful scientists: “It takes it out of the area of all this psychological mumbo jumbo that they don’t understand and ties it down, physically, in a manner that is understood by the biomedical community.”

Widening the Genetic View

Until recently, most of the links found between psychology and health have been only correlations. It has been tough to figure out exactly how stress, or any other environmental factor, affects a gene. Scientists have tried to link genes to environment by pinpointing those that they know contribute to a disease. Then they looked to see whether environmental factors affect those genes, perhaps by increasing their activity. But scientists using this method limit themselves to only those genes they already think might be involved, because the entire pool of suspects—there are 20,000 to 25,000 human genes—is too large to examine.

Mr. Cole wanted to avoid making these narrow prejudgments. He took inspiration from scientists who scan the entire human genome looking for genes that can be linked to diseases. He developed a computer program with a specific goal: to find mutations in stretches of DNA that attract transcription factors, molecules in a cell that activate genes. Transcription factors can be pushed into action by environmental factors like stress. A mutation in the DNA regions that attract them, which are called binding sites, could disrupt this “on-off switch” and thus change the stress response.

The computer came up with thousands of such mutations. In the list of genes that were physically near the mutations, one stood out: interleukin 6, which makes an immune-system protein that is great if you cut yourself—it helps turn on the inflammatory response, which brings infection-fighting cells to the area—but a problem if you make it all the time. In the long term, it can lead to constant inflammation, which is bad for the body. “It’s almost like a generic fertilizer for the diseases that most often kill us,” Mr. Cole says. “Things like coronary heart disease, the most prevalent kinds of cancer, neurodegenerative diseases, probably Type 2 diabetes as well” are all linked to chronic inflammation.

Close to the interleukin 6 gene, the computer had turned up a binding site for GATA-1, a transcription factor. “But there was no guarantee that the whole thing the computer recognized took place in reality,” says Mr. Cole. So he did a series of experiments to figure out if GATA-1 was indeed the messenger that brings news of stress.

Stressing Out Genes

He started with cells in the lab. Cells, of course, cannot be exposed directly to, say, a death in the family, but there are other ways to stress them out. “If you squirt a stress hormone, norepinephrine, on some cells, you actually see activation of this GATA-1 transcription factor,” Mr. Cole says. And not only did the transcription factor spring into action, but the interleukin 6 gene was turned on, too—a good clue that he had the pathway right.

But that still wasn’t real life. If Mr. Cole was right about the connection between stress and disease, then a change in the GATA-1 binding site—the mutation noted by his computer program, a DNA difference that occurs in about 20 percent of the population—should keep the transcription factor from triggering so much inflammation. So people with that mutation might be healthier than those without it.

He went to a colleague who had DNA samples from a long-term study of older adults. That study had also surveyed people about their mental state, so researchers knew which ones were depressed—a good indicator that they’d been through stressful life events. People who were depressed at the beginning of the study and had the nonmutated sequence were twice as likely to die in the next 10 years as were others; those who had the mutation seemed to be protected. When Mr. Cole examined the data more closely, he saw that this was true only for deaths caused by diseases, such as cardiovascular disease, that are related to interleukin 6.

Because the connection held true for such inflammation-related diseases but not for deaths due to other causes, Mr. Cole became more convinced that he was on the right track. “I have to say, anytime things work out in the real world, frankly, it should be a surprise to those of us that do laboratory science. I assure you that there are many, many things that we discover that work fine in the test tube that don’t work out in the real world.”

Creative Techniques

Other researchers have been impressed by Mr. Cole’s results and by the combination of computer modeling, experimentation, and epidemiology he used to get there. “It’s a fine study,” says Gene E. Robinson, a neuroscientist, genome biologist, and professor of entomology at the University of Illinois at Urbana-Champaign, who studies how the environment affects honeybee behavior. “It’s a very creative coupling of different kinds of techniques and different perspectives to provide one of the most complete analyses of, basically, how does the social environment get under the skin.”

There are certainly other pathways that link stress to disease. But Mr. Cole’s method points to a new way to find links between environment and health.

The next question is whether happiness might balance out stress in the cells. “We all secretly hope there’s a pill,” Mr. Cole says—some way to give everyone the benefit of that mutated GATA-1 binding site. Of course, living a calmer life might have the same effect, but not many people manage that.

“If people cannot or will not give up stress, is there something we can do biologically to help?” Mr. Cole asks. It’s a big question, one that will probably take research wide enough to span many disciplines to answer.