Medical school researchers showcase findings at international meeting

The annual meeting of the American Association for the Advancement of Science, or AAAS, brings together the world’s foremost researchers in a wide-range of discussions, seminars and presentations. This year’s meeting took place Thursday through Monday in Seattle. Four School of Medicine researchers gave presentations in their areas of expertise.

Thorny tech issues in parenting

Advances in reproductive technologies have brought babies into the lives of thousands of yearning couples. But with those advances come some difficult questions: What is a parent? Who decides what a parent is? And will we, as a society, be satisfied with the answer?

Linda Giudice, MD, PhD, professor of obstetrics and gynecology, delved into these issues in a panel discussion called “Creating a World We Won’t Want to Inhabit?”

Giudice and the other panelists focused their comments on “Bloodlines: Technology Hits Home,” a PBS documentary that aired nationally in June 2003. “Noel Schwerin [writer, director and producer of the show] wanted people to think about what happens when technology is used in other situations besides traditional arrangements,” said Giudice, who is also chief of reproductive endocrinology and infertility at Stanford.

The documentary presented one scenario in which a baby was conceived by donor sperm and the egg of one woman and was carried by that woman’s lesbian partner. Who was the mother in this situation? “I would consider both women to be the mother, but legally I don’t know if there is an answer,” Giudice said.

The documentary makes it clear that current laws are inadequate when applied to questions raised by these technologies; one physician interviewed on the program said fertility specialists are often the ones setting policy. “There is so little precedent for unique arrangements – and the arrangements are still fairly rare – that a lot of policies are being made on the spot,” Giudice said. One of the biggest challenges is in the court, when such arrangements go awry, she added.

New technology can lead to concerns over far more provocative things than the creation of nontraditional families, however. Giudice and the panel addressed what she calls the “extremes of technology,” such as reproductive cloning. She said it’s important for people to realize that the worst-case scenarios are unlikely to occur and physicians and researchers need to ensure they do not.

“There are many options in reproductive technologies, but we’re not likely to see the ‘Brave New World’ that is associated with the extremes of this technology,” she said. Donald Kennedy, PhD, former Stanford president and editor-in-chief of Science, moderated. –Michelle L. Brandt

Insight into immunity development

With this season’s launch of FluMist, the first intranasal vaccine against influenza, U.S. health consumers could potentially have simple and painless protection from the sometimes deadly virus.

While the level of public acceptance remains unclear, the fact it has proven effective thus far provides not only a case study in live-vaccine development but also a tool for researching how influenza immunity develops following infection.

Harry Greenberg, MD, professor of microbiology and immunology, gave an overview of the hurdles encountered in the development of a live vaccine and the lessons that might apply to development of other important vaccines at a presentation called “Live Intranasal Influenza Vaccine: A New Era Begins.”

Greenberg was involved in the pre-licensing phases of FluMist while on a leave of absence from Stanford. “The time it takes to develop a vaccine, especially a live attenuated vaccine, can be extremely long,” he said. The first description of what became the FluMist vaccine initially was published in 1967, he noted.

When such a long development period is involved, Greenberg said, evaluation criteria can change. In the case of FluMist, the regulatory agencies increased the number of people it considered sufficient to demonstrate the product’s safety after the vaccine was already in late stages of development, prolonging the process.

Greenberg is also co-director of a large study at Stanford comparing the live attenuated vaccine delivered in the nose against its injected, inactivated counterpart. Researchers hope to observe differences in how the immune system reacts to the two routes of administration.

Because of its genetics, Greenberg said, the flu virus has the ability to outsmart the host immune system, which makes it a moving target for vaccine development. He explained that influenza has a highly efficient mechanism of mutating that allows it to re-infect people and cause severe acute respiratory illness annually, especially in young children and the elderly. It can be an extremely virulent pathogen that could be a target for misuse as an instrument of bioterrorism. In fact, the study was funded by a government bioterrorism grant.

“Understanding respiratory tract immunity has great relevance for biodefense,” Greenberg said. But he thinks a lot more is to be learned from this study beyond improving our ability to deal with the bioterrorism threat. “We hope to learn how best to enhance immunity in the respiratory tract for all pathogens,” he said. –Mitzi Baker

Mouth microbes and the immune system

The immune system may be shaped by some of the very agents it exists to fight, according to research by David Relman, MD, associate professor of medicine and of microbiology and immunology.

“Microbes not only provide functions that promote health but may actually guide the stages of our own immune system development,” said Relman. “It seems reasonable to propose that only until we have an idea of the make-up and variability of the microbial ecosystems living within us do we begin to get an idea of the mechanisms underlying the functions they perform, such as immune system maturation and defense against pathogens.”

Relman presented an overview of his lab’s work on this subject, along with some new findings, as part of the “Innate Immunity and Oral Health” program.

The mouth provides a thriving community of microbes and a unique field in which to study how these tiny creatures interact with their hosts. Relman’s group has concentrated efforts on the subgingival crevice – the deep gap between the gums and teeth – in their search for microbes. Even though almost 500 bacterial strains or species have been identified in this oral pocket, Relman believes there remains a substantial amount to be learned about their behavior and response to perturbation, such as brushing and flossing, and environmental insults such as being attacked by the immune system.

Some of the most basic questions remain unanswered in the microbial world, said Relman. While there is a general consensus that bacteria play a role in causing gum disease, no single microbe has been implicated as the culprit. “The details on how oral microbes cause disease is probably not a simple story,” said Relman. “One agent does not equal one disease. There are complex interactions between members of the oral flora.”

Relman’s group uses several unique approaches, one of which involves directly analyzing the microbes in plaque surrounding the tooth rather than growing the microbes in the lab. Previously, Relman said, the search for pathogens has been limited to things that could be cultivated, which may represent only half of the members of the oral microbial world.

By preparing DNA directly from the plaque and studying each bacterial genetic sequence, they have found microbes never before located in the mouth; some of these microbes hadn’t been seen anywhere. The group is also expecting to publish a study soon on organisms previously not known to play a role in human disease.

Relman’s lab is collaborating with biochemistry professor Patrick Brown, MD, PhD, on developing microarrays – glass slides carrying thousands of DNA spots, each representing a different gene – to screen samples for thousands of micro-organisms at once. The hope is to discover the relationship between human gene expression in subgingival tissue and the microbial life found at the same time and site. –Mitzi Baker

Sleep, cancer progression link

A good night’s sleep may be one weapon in the fight against cancer, according to medical school researchers. Their work pieces together a link between mental well-being and cancer recovery.

Previous studies have found that cancer patients who go through group therapy or have a strong social network fare better than those with weaker social support. The question has been how psychosocial factors exert their influence on cancer cells. David Spiegel, MD, professor in psychiatry and behavioral sciences, and Sandra Sephton, PhD, a former postdoctoral scholar, suggest that a person’s sleep/wake cycle might be the connection.

Spiegel presented this work in session titled “Biology and Behavior: New Pathways to Cancer Control?”

“Psychosocial factors affect your behavior patterns, such as exercise, what you eat and drink, and your sleep,” Spiegel said. Of these factors, how well you sleep can seriously alter the balance of hormones in your body. This makes the sleep/wake cycle, also called the circadian rhythm, a good candidate for study.

Spiegel suggested two possible ways in which the circadian rhythm may influence cancer progression. The first involves a hormone called melatonin, which the brain churns out during sleep. Melatonin belongs to a class of compounds called antioxidants that mop up damaging free-radical compounds. With a disrupted circadian rhythm, the body produces less melatonin.

Melatonin also slows the ovaries’ production of estrogen. For many ovarian and breast tumors, estrogen spurs the cancerous cells to continue dividing. Shift workers on duty through the night produce less melatonin and may therefore produce more cancer-activating estrogen.

The second link lies with a hormone called cortisol, which reaches peak levels at dawn then declines throughout the day. Cortisol helps regulate immune system activity, including the activity of a some immune cells.

One study found that people who are at high risk of breast cancer have a shifted cortisol rhythm, suggesting that people whose cortisol cycle is thrown off by troubled sleep also may be more cancer-prone.

In past work, Spiegel and his colleagues have found that women with breast cancer whose normal cortisol cycle is disrupted – with peak levels in the afternoon rather than at dawn – die earlier from the disease. Those women whose cortisol cycle was shifted also tended to sleep poorly, to have lost a spouse or partner and to have cancer-fighting branches of their immune system suppressed. –Amy Adams