Abelson Seminar Showcases Promising Efforts to Combat Stress-Related Conditions

In wealthy nations, Robert Sapolsky said, most people are lucky enough to "slowly succumb to stress-related death." Fortunately, emerging scientific insights are now suggesting new tools for fighting the negative health effects of stress, according to Sapolsky and nine other leading experts at the 2008 Philip Hauge Abelson Advancing Science Seminar.

"Here we have a collection of normal Westernized humans," Sapolsky dead-panned 24 October as he addressed some 175 attendees in the AAAS auditorium. "Which is to say, [after birth] we will [each] spend the next 80 years with our body going to hell on us," and ultimately, "most of us will die of a stress-related disease."

Sapolsky, the John A. and Cynthia Fry Gunn Professor of Neurology and Neurological Sciences at Stanford University, explained as part of a keynote presentation that short-term stress triggers beneficial physiological responses in animals and people. Based on ancient evolutionary adaptations, stressful situations can prompt a surge of energy and hormones such as adrenaline, as well as a sharpening of cognitive processes, which may help us to evade and outsmart predators. Stress also can initially increase cardiovascular tone and temporarily suppress growth and reproduction. After all, "If there's a tornado due this afternoon, you don't spend the afternoon gardening," Sapolsky said, and similarly, if "there's a lion two steps behind you, ovulate some other time."

Problems arise, however, when stress continues for long periods of time because it can contribute to a host of stress-related disorders—from insulin resistance, to increased fat deposition, hypertension, and elevated platelet viscosity. Other physical effects of stress can occur in the brain's learning and memory center, the hippocampus, where damage may include "the possibility of dead neurons," and in the amygdala, resulting in increased fear, anxiety, and depression, Sapolsky said.

Individual differences in responding to stressful situations can exacerbate all such physiological effects, he added. Those who interpret a sluggish line at the supermarket as a personal insult, for instance, may tend to suffer more negative health impacts than their easy-going neighbors. Conversely, stress can be modified when individuals have social support and outlets for expressing frustration, and when they feel a sense of control and optimism.

Field studies of baboons in Kenya provide a useful analogy of stress effects among humans, Sapolsky said. "They spend three hours a day getting the calories they need. That means they have nine hours a day to be god-awful terrible to some other baboon," he explained. "They are just like us!"

Sapolsky's research team observes baboons in the wild. Researchers document the number of stressful situations that individuals encounter, then carefully tranquilize animals to measure biochemical stress indicators such as cortisol levels. Low-ranking male baboons tend to have elevated blood pressure, reduced "good cholesterol," testicular suppression, lower insulin-like growth factor 1 and lymphocyte counts, and other effects.

Higher-ranking male baboons suffer fewer stress-related health effects. "Low-stress hormone guys outlived their higher-stress cohorts by two to three years," Sapolsky reported. Further, among female baboons, researchers measured a direct dose-response effect of stress: If a female is attacked four times by a larger male, for example, her stress hormone levels will be two times higher than levels in another female who was attacked only twice.

But social instability within the baboons' community exacerbates the negative effects of stress on individuals, Sapolsky said. An individual's personal experience of his or her ranking also clearly plays a role in health outcomes, he added.

Other speakers at the 2008 Abelson Seminar described advances in understanding the stress response based on human, animal and cellular studies. Presenters described research that may lead to an array of breakthroughs, perhaps including new therapies for alcoholism, neurodegenerative disorders and anxiety; for improving the effectiveness of vaccine regimens; and for more effectively helping traumatized children and veterans.

Specifically, the seminar featured sessions on three broad topics: The Biology of Stress; Social Factors, Behavior, and Physical Impacts; and Psychology and Future Treatments.

During the day's first session on biology, Richard I. Morimoto, the Bill and Gayle Cook Professor of Biology and Director of the Rice Institute for Biomedical Research at Northwestern University, described stress effects at the cellular and molecular levels that might someday offer new hope for 6.5 million Americans and tens of millions of others worldwide with neurodegenerative diseases.

When cells encounter environmental stress such temperature changes, Morimoto explained, proteins inside those cells can respond by coiling and folding into the wrong positions. Just as unbuttered pasta will clump together, forming a starchy mess, misfolded proteins may form plaques associated with diseases such as Huntington's, Alzheimer's, and Amyotrophic Lateral Sclerosis. But certain "molecular chaperones" can help to prevent proteins from misfolding, at least in model systems.

Morimoto's research team is using the nematode, C. elegans, as well as genetic analysis to better understand how heat shock transcription factor mediates the heat shock response, producing proteins that could potentially be harnessed to protect against cell damage and death. "We have identified 400 genes, 375 of which are conserved in humans that protect, and in some cases put us at risk," he said. "They are genes involved in making and getting rid of proteins."

Firdaus Dhabhar, from the Department of Psychiatry and the Institute for Immunity, Transplantation and Infection at Stanford University, focused on the positive effects of short-term stress. He described the fight-or-flight stress response as nature's fundamental survival system that could be harnessed clinically to enhance immunity during vaccination and surgery.

The body responds to stress such as a sudden danger or an exciting event by releasing a flood of hormones. Dhabhar explained that just as short-term stress prepares the heart and muscles for fight or flight, it also enhances immune function in key body systems such as the skin that may be most vulnerable to attacks. He showed that short-term stress experienced during immunization induces a long-lasting increase in immunity. He also showed that an adaptive fight-or-flight stress response during knee surgery predicts enhanced recovery. He and his colleagues identified an "up, then down" pattern of change in blood immune cell numbers during the stress of surgery: Early during surgery, immune cells—the body's "soldiers"—leave their "barracks" and enter the bloodstream, which increases their circulating numbers. Later during surgery, cells leave the bloodstream and move to potential "battle stations" such as the skin and lymph nodes, including the site of surgery. These changes in stress-induced immune cell distribution are related to enhanced recovery, measured for almost a year after surgery.

These findings, confirmed in rodents and people, suggest that short-term stress may stimulate an enhanced immune-system response. Dhabhar's team hopes to identify behavioral and/or pharmacological interventions that might help to strengthen immunity, by mimicking and harnessing the mind and body's protective fight or flight survival systems.

Another speaker, Darlene Francis of the University of California, Berkeley, noted that a wealth of data have confirmed a relationship between socioeconomic status and health. Francis, a former social worker who is now an assistant professor of neuroscience, psychology and public health, said that the world's poor suffer the greatest stress-related health effects.

But inherited or genetic risk factors are only one piece of the puzzle, she said. Within rat families, for example, the offspring of mothers who provided poorer quality of care (or, less stimulation to their newborns) tended to have more active hypothalamic-pituitary-adrenal or "stress-reactivity" levels as adults. Further, when rats born to less active mothers were placed in a more stimulating maternal environment, their stress-reactivity profiles became much more efficient.

"We're talking about an epigenomic difference that's actually being induced through parenting," Francis said. "Early experiences are calibrating the stress-axis. Differences in the stress-axis may then render populations more vulnerable (or resilient) to the slings and arrows of life."

As part of a second panel on social factors, behavior and physical impacts, Martha J. Farah of the University of Pennsylvania presented research demonstrating a link between childhood poverty and negative health effects of stress. Farah, the director of the Center for Cognitive Neuroscience who serves as the Walter H. Annenberg Professor of Natural Sciences, noted that stress can affect the development and functioning of brain systems necessary for learning and memory, as well as self-regulation.

In several studies, researchers have assessed five key brain regions among children in kindergarten, first grade and middle school. Children from both low- and middle-income families were asked to complete age-appropriate tasks requiring a response by different brain regions, she explained. Among poor children, language, memory and "executive functioning" seemed to be most significantly affected, Farah said, adding that "these are big honking effects—a standard deviation effect in language, for example."

With graduate student Daniel A. Hackman, colleague Hallam Hurt and others, Farah conducted home studies with children when they were 4 and then 8 years old. The goal, she said, was to learn whether children in more nurturing homes would be better equipped to learn in middle school. Language skills seemed to improve in homes offering the most enriching environment for children. Curiously, however, parental nurturance did not appear to significantly alter the development of language, Farah said. Conversely, however, parental nurturance and not environmental enrichment affected memory. Children raised in stressful circumstances by nurturing parents were more able to form new memories, consistent with animal studies of parenting and memory development. Unlike the findings with animals, however, the children in Farah's study had reduced hippocampal volume—a riddle that Farah has yet to unravel. "It's a work in progress that is not all neat and tidy," she acknowledged.

David M. Diamond, director of the Center for Preclinical and Clinical Research on Post-Traumatic Stress Syndrome and professor of psychology and molecular pharmacology and physiology at the University of South Florida discussed the role of the hippocampus in traumatic memory formation. Diamond, who also serves as a research career scientist in the Medical Research Division of the Tampa Veterans Affairs Hospital, described how stress can produce powerful "flashbulb" memories. He is exploring the apparent paradox that stress, which clearly impairs hippocampal functioning, can stimulate the long-term storage of information.

Rats that were briefly stressed by being exposed to cats were able to retain new information about a water maze, Diamond reported, presumably because stress hormones had stimulated the learning and memory center in their brains. Longer stressful exposures impaired memory in the rats, however.

Stress, addiction and relapse behaviors were the focus of a presentation by Markus Heilig, M.D., chief of the Laboratory of Clinical and Translational Studies at the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health. Although some people may claim that stress drives them to drink alcohol, in fact, alcohol dependence increases an individual's sensitivity to stress. Heilig said that this may explain why his patients often tell him: "`Doc, little things can throw me off.'" Stress only makes rats drink if they have a history of alcohol dependence, he emphasized.

Heilig's team is pursuing a range of anti-stress mechanisms that might show promise as new alcoholism medications. Systems under investigation include, for example, corticotropin-releasing hormone, neurokinin, nociceptin, and neuropeptide Y. In a 12 February 2008 paper in Science, Heilig, David George, and colleagues reported that the neurokinin 1 receptor—a mediator of the brain's stress response—seemed to alleviate symptoms of alcohol dependence among mice and in a small, controlled study of recently detoxified alcoholic inpatients.

A third panel on psychology and future treatments opened with a presentation by Joseph LeDoux, University Professor and Henry and Lucy Moses Professor of Science at the Center for Neural Science at New York University. Some 40 million Americans suffer from fear and anxiety disorders, which can occur in tandem and tend to exacerbate a host of mental problems ranging from depression and addiction to schizophrenia and even autism, LeDoux noted. He estimated that fear and anxiety disorders may be related to $50 billion in costs per year, and he stressed that these conditions may be "low-hanging fruit"—promising more attainable solutions based on studies of the amygdala.

For instance, recent studies have shown that people may "reconsolidate" memories, so that they retrieve the last memory of an event that they had stored, rather than the original memory. This insight may have implications for treating post-traumatic stress disorder (PTSD), by pharmaceutically blocking the repetitive retrieval of disturbing memories, or by preventing certain short-term memories from being converted into longer-term flashbacks. Such questions will be pursued further by a new initiative called the Emotional Brain Institute, a collaboration of New York University and New York State University.

Bruce P. Dohrenwend, professor of epidemiology at the Mailman School of Public Health and Foundations' Fund for Research in Psychiatry Professor at the College of Physicians and Surgeons at Columbia University discussed how scientists' understanding of post-traumatic stress disorder has evolved since it was first officially diagnosed in 1980. Replacing earlier catch-all diagnoses such as "gross stress reactions," the modern definition of PTSD recognizes the profound impacts of primary exposure to traumatic events such as experiences in war and natural disasters, sexual assault and child abuse. Such circumstances—involving events far different from events like the loss of a job or divorce—when extreme and of long duration are known to produce persistent symptoms even in individuals with no predisposing conditions, Dohrenwend explained. As one of several illustrations of this point, he cited a study of 56 male U.S. prisoners of war captured by the Japanese. The study found that 84% of those POWs developed PTSD during their lives. Among 262 less harshly treated prisoners captured in Germany, 44% suffered from the disorder over their lifetimes.

Providing the Abelson Seminar's capstone lecture, Steven E. Hyman, M.D., provost of Harvard University and professor of neurobiology within the Harvard Medical School, quoted René Descartes, whose famous statement, "cogito ergo sum" ("I think, therefore, I am") reminds us of the uniquely human vulnerability to worry and stress. "We think of our minds but not our brains as part of our bodies," he said. Too often, he said, policy-makers have tended to believe that mental health disorders were somehow less real than conditions such as broken legs or cancer.

Hyman pointed out, however, that the recent $700 billion U.S. federal bailout of the financial sector was attached to a Mental Health Parity bill that should soon provide better insurance coverage for mental illnesses. He described the legislation as an important advancement because life's negative experiences—combined with genetic, behavioral, environmental and random factors—can "get under our skin," affecting our health. New research promises innovative strategies for intervening to improve human welfare.

The annual Abelson Seminar at AAAS honors the legacy of Philip Abelson, who served as editor of the journal Science for 22 years, and then as senior adviser to AAAS until shortly before his death at the age of 91. Abelson "had almost no interest in the past," said AAAS Chief Executive Officer Alan I. Leshner, executive publisher of Science, who moderated the 24 October event. "He was a man who was only interested in where science was going."

Ginger Pinholster

5 November 2008