Melding expertise, furthering research

By Beth Azar
Monitor staff

After virologist Ron Glaser, PhD, married clinical psychologist Janice Kiecolt, PhD, in 1980, he dreamed of combining his two passions by devising a research project they could collaborate on.

She was ready to move from assertiveness-training research to a more engaging line of investigation. So she suggested they examine whether psychological stress affects immune function. He was extremely skeptical that psychology had any relationship to biology, but wanted to work with his wife enough to try it. He figured they?d do one study together, it wouldn?t work, and that would be the end of it.

To his surprise, it did work. They found that exam stress adversely blunted immune function in medical students: Immune measures were less potent right before exams than during summer vacation.

That first study put the Glasers on the ground floor of what has developed into the thriving field of psychoneuroimmunology (PNI), the study of connections between behavior, the brain and the immune system. And, 16 years later, what Ron Glaser thought of as a sentimental side-line to his fully funded Epstein Barr virus research program has transformed him into the director of the Institute for Behavioral Medicine Research. And he?s moved from medical microbiology and immunology department chair to the overseer of one of Ohio State University?s most productive research programs.

The success of the Glasers, and PNI research in general, lies in the interdisciplinary nature of the work, says Norman B. Anderson, PhD, director of the National Institutes of Health Office of Behavioral and Social Sciences Research. It allows scientists to begin examining health from a more integrated standpoint than ever before.

Glaser, who boasts 13 seasoned researchers on his PNI team, agrees: 'With the diverse expertise of our group we can approach a problem from virtually any direction.'

'Before I could only look at one segment of a problem,' says Philip Marucha, PhD, DMD, another immunologist on the Ohio State team who is interested in the process of wound healing. 'As a team we can look at the whole system.'

With that whole-system approach, the Ohio State team and other groups of PNI researchers are finding a complex interaction between psychology, the central nervous system, the immune system and physical health.

Psychology and biology

During the past decade, scores of studies have documented a link between high stress levels and decreased immune-system activity. Now, researchers are trying to divine the mechanism by which stress may produce changes in immune function?and they are trying to determine whether the impact on immune function is clinically significant.

These next steps are crucial, says Glaser. As a virologist, he doesn?t 'buy statistically significant correlations,' he says. 'I want to see biological significance.'

Several PNI teams have begun building evidence for biological significance. For example, psychologist Sheldon Cohen, PhD, of Carnegie Mellon University, finds that people who are most stressed are most likely to get colds. And Stanford University psychiatrist David Spiegel, MD, has evidence connecting stress-reduction therapy with prolonged survival of breast cancer patients.

The Ohio State researchers have equally compelling results from a study of wound healing in 11 medical students. Marucha punched small wounds into the roof of students? mouths?once during summer vacation and once right before their immunology final exam when a perceived stress scale confirmed that they were more stressed. Wounds healed an average of three days, or 40 percent, faster during vacation than during exams for all 11 students, says Kiecolt-Glaser.

'It was only 11 students but the effect was so large, it?s whoppingly significant,' says Kiecolt-Glaser.

These studies support the hypothesis that stress causes immune function changes and that those changes lead to health and healing effects, says Glaser. But neither his lab nor any other PNI team has absolutely proven that causal relationship, he says.

Work by Ohio State?s John Sheridan, PhD, holds promise that the researchers may confirm a causal relationship. He recently replicated the wound-healing experiment in mice. He found that if he blocked the release of the stress-related hormone cortisol in these animals, he could restore the normal healing rate. This implies that cortisol release may inhibit immune function, which then hinders healing.

Needing each other

The ability to piece together the complex relationships between the varied biological and psychological systems relies on the expertise of each team member, says Kiecolt-Glaser. The immunologists, endocrinologists and neuroscientists rely on the behavioral scientists to design the studies.

'These studies have to be designed with the right controls, and the right analyses built in, and the psychologists know how to do that,' says Glaser. 'It?s relatively easy for them to gain a working understanding of

immunology, but it takes more work and a lot of time to understand behavioral issues and learn how to design these complex studies.'

At the same time, 'we couldn?t design good studies without the expertise of our [nonbehavioral] colleagues,' says Ohio State psychobiologist John Cacioppo, PhD, who began working with the Glasers five years ago. The psychologists rely on the immunologists and endocrinologists to determine which measures of immune function to use.

'As a psychologist, I didn?t appreciate how complicated immune function is?there?s no single measure, and different assays may make more sense depending on the study,' says Kiecolt-Glaser.

She and her behavioral colleagues also have to keep in mind other immunological factors as they design the studies. For example, because immune function fluctuates throughout the day, all blood samples must be collected on a strict schedule.

The psychologists also need input from their molecular colleagues before they begin to analyze the data, says psychologist Barbara Andersen, PhD. She?s leading a highly complex study designed to determine whether a behavioral intervention can prolong the lives of breast cancer patients and, if so, how.

'We have to learn the properties of the [immunological] data just like we have to learn how the scores work on the BDI,' she says. 'You have to make sure your statistical strategy makes biological sense.'

For example, in the most recent article out of the breast cancer study (Journal of the National Cancer Institute, Vol. 90, No. 1, p. 30?36), Andersen had to know something about natural killer cell lysis, or the ability of natural killer cells to destroy tumor cells. The responsiveness of these cells depends on the ratio of the killer cells to tumor cells. But the relationship isn?t necessarily a linear one. Often the response is lowest at both the highest and lowest cell ratios but strongest at the middle cell ratios.

'This is the type of information psychologists need to learn from their immunology colleagues,' says Andersen. 'If not, you might use a statistical technique that makes no sense biologically. We need to hone our statistical expertise to address important psychological questions in an accurate biological context.'

Minor costs

There are costs to cross-disciplinary research, admit the Ohio State PNI researchers. For one, PNI is expensive, the studies are time consuming and personnel intensive, and coordinating all the researchers involved can be difficult and inefficient.

'With this type of research you?ve got a lot of Indians and a lot of chiefs,' says Andersen.

But 'these costs are trivial when you take into account the clear gains from working with an interdisciplinary group,' says Cacioppo.

'You become a more well-rounded scientist,' adds Glaser, who, as associate vice president for health sciences research at Ohio State, tries to encourage researchers to try cross-disciplinary research. 'It forces you to think about what you?re studying from new angles, and it can double your opportunity for funding.'