The Future of Public Health Millennial Symposium Series resumed on December 6 when panelists discussed, "Genes and the Environment: The Origins of Asthma" in front of a large audience in Snyder Auditorium.

HSPH Dean Barry Bloom opened the symposium, describing the series’ purpose. Last year, 10 symposia organized by junior faculty members featured topics from each of the disciplines at HSPH. This year, the focus will be on interdisciplinary topics that address the interactions of fields.

JEFFREY DRAZEN: PURSUIT OF GENES

Jeffrey Drazen, editor-in-chief of The New England Journal of Medicine and a professor in the Department of Environmental Health, moderated the panel. He explained that the combination of genes and the environment in asthma makes the disease complex and hard to understand, but new technologies have made the pursuit of the genetic basis for the disease more plausible.

DUNCAN THOMAS: ASTHMA OVERVIEW

Duncan Thomas, professor of preventive medicine at the University of Southern California, provided a brief overview of what is currently known about asthma. The syndrome is the most common chronic disease in children and the incidence rates are climbing. Pets, tobacco and indoor allergens are suspected as triggers of asthmatic attacks, but other factors such as diet and genes most likely play a role.

The phenotype of asthma has been well-documented: airway hyper-reactivity, airway inflammation and airway obstruction that can be reversed.

What is less known are the genes involved in asthma. Scientists have identified regions on the chromosomes where genes implicated in asthma are thought to reside. They have also identified specific "candidate genes."

The problem with studying a disease such as asthma is that multiple genes and environmental exposures are associated with the syndrome, said Thomas. Variables must be compared while considering confounding items such as the effects of other genes.

One possible way to look at asthma, Thomas suggested, is through mathematical modeling, a technique that he uses for studying colorectal cancer. The model he outlined allows for the measurement of environmental factors and the interaction with genes and helps elucidate the biological pathways used by a disease such as asthma. At the very least, said Thomas, the model allows for comparison of variables, such as environmental factors, and helps researchers organize their thoughts.

FERNANDO MARTINEZ: ASTHMA AS AN IMMUNE SYSTEM DISEASE

Fernando Martinez, director of the Respiratory Sciences Center at the University of Arizona, said that he believes asthma is a disease of the immune system as it matures in early life.

Incidence of both asthma and allergies is on the rise, he said, and the two conditions are closely correlated. Between 40 and 50 percent of American children test positive for at least one local allergen in skin tests, said Martinez, while prevalence of asthma has nearly doubled to 20 percent in high-income countries.

When looking at asthma, researchers tend to look at factors that may have triggered an attack: for example, the pollutants in the air. Martinez said the triggers should not be confused with the origins. He said researchers should look at the environmental factors present when asthma first starts in a person, which can be when they are very young. More than two-thirds of asthmatics develop symptoms before the age of three. A leading hypothesis says that a main risk factor for asthma is allergen exposure, but the link is not so easy, said Martinez.

One study found that children exposed to other kids at home or in daycare within the first six months of life had half the risk of becoming asthmatic by age 13 than kids who did not have such exposure.

Pets may also have a protective effect. Studies have indicated that having a pet as a young child may halve the risk of that child becoming asthmatic.

A German study showed that children living in rural areas who were exposed to stabled animals and unpasteurized milk were less likely to become asthmatic than kids who were not.

What does exposure to other children, pets and stables have in common, asked Martinez–high levels of endotoxin, a component of the cell wall of a certain kind of bacteria. Children exposed to microbes when then are very young may actually be protected from developing asthma later, he said.

Martinez observed that humans are born with immature immune systems that grow with the children. Restricting exposure to certain microbes may lure the immune system into a false sense of security. Protective mechanisms fail to develop because the "danger signals" are missing, said Martinez. He said that a combination of genes and environmental factors may increase the likelihood of a Th-2 immune response, meaning the body becomes globally hyper-reactive to many allergens instead of specifically reactive to just a few.

CAROLE OBER: LINKAGE ANALYSES

Carole Ober, professor in the Department of Human Genetics at the University of Chicago, talked about the search for asthma genes. The identification of single genes in illnesses such as Huntington’s disease has become relatively straightforward, said Ober. Now, scientists are looking at complex trait mapping, she said.

Ober explained that scientists tend to use one of two approaches in identifying disease genes. "Positional cloning" has been described as a "needle in a haystack" approach because it does not start with a hypothesis. Genes are found, and then their functions are determined. Ober said she prefers this approach because it is the only way to potentially find all of the genes associated with a trait and to identify novel genes and pathways.

The second approach looks at "candidate genes." Scientists already know the function of a gene and match it to a disease. Ober said this approach assumes scientists know the pathophysiology of diseases and the biological function of all known genes, but these areas remain largely unknown when it comes to asthma.

Ober uses linkage studies to identify asthma genes. She matches the inheritance of approximately 400 specific pieces of DNA in the human genome, called markers, to the asthmatics in a family. Linked markers and asthma genes are inherited together, meaning that scientists may be able to find an asthma gene by looking in the area of the known marker.

Nine populations in the world have undergone genome-wide screening for asthma genes, said Ober. In at least three studies, 18 regions have been identified in the genome as possibly having asthma genes. In addition, between 20 and 30 asthma genes have been found whose effects are probably measurable, she said.

Ober is investigating both gene-gene interactions and gene-environment interactions related to asthma. She described the work of scientists in her lab who are using data from a Chicago-based study. They have identified two regions of the genome that are linked to an increased risk of becoming asthmatic in people who were exposed to cigarette smoking as infants: a gene-environment interaction. They also found two regions of the genome with linkage to asthma that became more apparent in asthmatics who had never been exposed to cigarette smoke as infants. How could a lack of exposure increase risk? Possibly because of the way genes interact with one another, said Ober. She added that the model is overly complex, but researchers can work through the complications if they consider more than one gene and environmental exposure at a time.

A web cast of "Genes and the Environment: The Origins of Asthma" can be viewed at www.hsph.harvard.edu. The next Future of Public Health symposium will be "The War on Cancer–30 Years On" with John Bailar, III, Department of Health Studies, University of Chicago; Edward Benz, Jr., president, Dana-Farber Cancer Institute; and Richard Klausner, former director, National Cancer Institute, on Thursday, February 7 at 3:30 p.m. in Snyder Auditorium.