Not Waiting to Exhale
Initiatives Range from Lab to Community
This article originally appeared in GenomeLife, Issue 5.
Zebrafish embryo expressing green fluorescent proteinSome investigators are almost superstitious about their grants, not wishing to discuss or share them with anyone outside of the appropriate funding agency, sometimes even after they' ve been funded.
Then there' s David Schwartz.
Schwartz, Professor of Medicine and Genetics, Director of the Division of Pulmonary and Critical Care Medicine, and reigning environmental genomics czar on campus, responds to an inquiry about Duke' s initiatives in environmental genomics by handing this visitor not one, but three thick spiral-bound proposals. "Here," he says without irony, "I' ve made it easy for you."
Schwartz can be forgiven for not wanting to explain each of the National Institute of Environmental Health Sciences (NIEHS)-funded projects he' s overseeing in detail-he' s busy and will only get busier if he begins to manage (as is likely) a third multi-year, multimillion-dollar collaborative effort on top of the two that are already in full swing. Nevertheless, his excitement about the projects soon takes over as he graciously details each one, which together comprise Duke' s Program in Environmental Genomics.
For Schwartz, the fundamental issue in environmental genomics-and the principal mission of the Center for Environmental Genomics-is to understand why certain people develop disease when challenged with environmental agents while others remain healthy.
"It' s a pretty simple concept," he says. "Yet to do it right requires sophistication in terms of exposure assessment, toxin presentation, and the ability to assess phenotypes in humans and across model systems like mice, zebrafish and worms. And then on top of that, we need the ability to computationally understand how these genomic and biological responses relate to each other."
The main approach uses tiny microarrays to measure how environmental stresses alter gene expression and therefore, human health. The Center is casting its net over a wide area, studying genomic responses to environmental agents not only in multiple organisms, but in multiple human disease states as well, including asthma, pulmonary fibrosis, and several other diseases.
One example of the Center' s breadth can be found in the collaboration between Professor of Molecular Genetics and Microbiology Elwood Linney and Associate Professor of Medicine Marcy Speer. The two are trying to determine the genetic and environmental bases of relatively common neural tube defects (NTDs) such as spina bifida. Because studying neural tube development in vivo is impossible in humans and limited in rodents, Linney is using the highly visible zebrafish embryo to identify candidate genes on the basis of gene expression changes associated with neurodevelopmental abnormalities. These candidate genes can then be screened by Speer in human NTD families. Conversely, should Speer find candidate genes on the basis of her NTD family studies, Linney can test them in a zebrafish model.
Comparative genomics & neural tube defects Environmental Asthma: All I Need is the Air that I Breathe
The second initiative, The Pathogenesis and Genetics of Environmental Asthma, is a NIEHS-sponsored Program Project whose investigators ask the specific question: How do genes regulate the response to environmental toxins in such a way that some people develop asthma and others do not?
Within the Project are three scientific undertakings. The first, led by Schwartz and [Assistant Professor of Medicine] John Sundy, focuses on people with asthma and tries to understand their genomic responses to environmental stimuli. By examining how those stimuli alter gene expression, Schwartz hopes to find out which aberrantly expressed genes are important in genetic susceptibility to asthma.
"Our approach to studying asthma involves exposing patients to a variety of different things-endotoxin, dust mites, or saline as a control-and then seeing which genes are differentially expressed in those patients' airways," says Schwartz. "Those differentially expressed genes are potential targets for further study. When we compare responses, we see some genes that are upregulated in response to saline but downregulated in response to endotoxin and vice versa. We then examine those in larger susceptible populations and see whether those are truly genes that are involved in the pathogenesis of asthma."
Research Professor of Medicine W. Michael Foster heads up the second project, the goal of which is to determine why some people have toxic responses when they inhale ozone. Finally, Professor of Medicine and Biochemistry Jonathan Stamler is examining the biological importance of nitric oxide and its metabolites in the airway as well as immune and inflammatory responses to various stimuli.
The Center for Comparative Biology of Vulnerable Populations: Infrastructure, Policy and Community
The third initiative, funding of which is expected to be formally announced any day, is the Center for Comparative Biology of Vulnerable Populations and is what NIEHS calls an Environmental Health Sciences Research Center (EHSRC). The idea behind EHSRCs, says Schwartz, is to build scientific centers that are similar to cancer centers in scope. "A cancer center provides infrastructure so that scientists within a university can study cancer more efficiently and effectively," he says. "Similarly, an EHSRC provides infrastructure for the investigation of environmental health issues."
The Duke Center will focus on a range of neurodevelopmental and pulmonary diseases. In addition, it will be dedicated in large part to environmental policy issues. Supporting this will be a number of core facilities, much as the Duke Comprehensive Cancer Center relies on cores. These cores will include facilities dedicated to microarrays, proteomics, inhalation toxicology, and computational biology.
Defining "vulnerable populations" is a critical and potentially thorny task for the Center. According to Deputy Center Director and Associate Professor Marie Lynn Miranda, a population might be considered vulnerable for any number of reasons, including age, geography, disease, nutritional status, race and/or genetics. "Vulnerability may be physiological, biological, or social," she says. "When we' re looking at in utero exposures and exposures of young children to toxicants, we must also consider what the home environment is like. Do these kids live in an enriched home environment or do they live in a deprived one? Does a violent neighborhood, child abuse or any other factor exacerbate the effects of the exposure to the environmental toxicant?"
Miranda may be most energized by her duties as Director of the Community Outreach and Education Program (COEP). "The COEP is designed to ensure that the expertise that exists within the Center is made available to the community in meaningful ways. That can take a variety of different forms. One will be through workshops in the community, sometimes geared toward physicians, sometimes geared toward community groups. I think the COEP Core serves as kind of a natural bridge for people from the community to access the Center' s resources. And this group of investigators associated with the Center is genuinely excited about that community connection."
With regard to educating the community about genome sciences, Miranda thinks the COEP Core can play a role there, too. She envisions workshops and community discussions on the basics of genetics and genomics, their impact on the delivery of medical care, benefits and pitfalls, and relevant ethical questions. "I think that' s part of the bridge. It' s important for the investigators to know what the public ethos is regarding this type of research and how it' s proceeding, especially if we' re recruiting from local communities to participate in that research."
Opportunity and Convergence
Center for Genome Technology Director Joe Nevins is co-director of the Center for Environmental Genomics and believes that Duke'
s Program in Environmental Genomics has a chance to make a substantive contribution to a burgeoning field. "Those of us involved in genome research are always asking, 'Where are the opportunities?'
Clearly, some are in cardiovascular disease and cancer. But now, thanks to the efforts of David, there are also significant programmatic opportunities in the area of environmental health at Duke. It'
s also important to point out that these initiatives encompass the full breadth of genome sciences and policy: human genetics, mouse models, bioinformatics, microarray analysis, and, especially in the Vulnerable Populations project, community and policy issues."
Schwartz sees the NIEHS' strong commitment to environmental genomics as an appropriate recognition of the recent convergence between genomic information and environmental health sciences. "There has been a recognition in the field for a very long time that genetics plays a role in determining why certain individuals develop particular diseases. But it' s also abundantly clear that the environment plays an equally important role. In fact, in most cases, those environmental stresses on the human genome are what allow susceptibility genes to influence our health."