Toxicogenomics elucidates human disease

A rapidly-developing field across the country and at Duke, toxicogenomics holds the key in identifying the genetic and environmental basis for many diseases.

With its inception in Sep. 2001, the Duke Center for Environmental Genomics, a division of the University's Institute for Genome Sciences and Policy, has been focusing its attention on toxicogenomics by effectively using genomic techniques as a tool for traditional toxicology studies.

This recently developed field has resulted from the completion of the mapping of the human genome. "Now that the Human Genome Project is concluded, we have a new tool," said Dr. David Schwartz, director of the center and professor of medicine. "We are using technology to make discoveries that were simply not possible before."

The novel field of toxicogenomics involves the exposure of simple laboratory organisms such as yeast, zebrafish and mice to environmental toxins and the analysis of the resulting gene expression and changes in physical appearance. These findings are then applied to humans through comparative genomics in order to determine how genes influence the ability of certain individuals to protect themselves against infection and bacterial stress.

"This approach is really promising and will provide the necessary clues to understanding Spina Bifida," Speer said. "It brings human and experimental systems together since humans will never be specimens in genomic testing and research. We've gotten a lot of results so far, but we're still trying to make sense of them."

Second to congenital heart failure, Spina Bifida is one of the most common birth defects. Studies have shown that genetics occupies a role in the occurrence of Spina Bifida, which is a failed closure of bones around the developing brain and spine of the fetus during the first month of pregnancy.

While it has a small incidence of one in 1,000 babies in the country, it is twice as common in North and South Carolina for babies to be born afflicted. Marcy Speer, genetic epidemiologist and associate professor of medicine, attributed this statistic to environmental influences.

Speer's team has established that an appropriate intake of folate, a B vitamin found in green leafy vegetables, before pregnancy can reduce the risk of the defect by 50 to 70 percent. Epileptic medicines, obesity and diabetes have also shown an impact on the incidence of Spina Bifida. Additionally, Speer pointed to the defoliant Agent Orange, a toxin that men in Vietnam were exposed to, as another potential factor in causing the defect.

Toxicogenomic research involves a process known as microarray analysis, which allows researchers to study thousands of genes at once. Since the human genome is massive and it is difficult to obtain human tissue for scientific research, this technique is used to quickly obtain substantial quantities of data.

The microarray analysis technique will also allow researchers at the center to ascertain the genetic basis of environmental asthma, a project recently sponsored by an $8 million National Institute of Health grant to Schwartz.

Results to date have shown that owning a pet is beneficial since it exposes a person's immune system to many allergens, allowing them to build up antibodies against the toxins. Duke scientists are also investigating links between asthma and the epidemiological role of cockroaches and dust mites.

The new technique also promises to reduce the costs associated with testing toxins for their harmful effects.

"It's really an extraordinarily useful process. Typical testing is very costly and can take several years to produce results," said Jonathan Freedman, director of the center's toxicology core and associate professor at the Nicholas School of the Environment. "Through toxicogenomics, it only takes a few months at a fraction of the cost and you don't have to use animals."

Until new tools to survey and store the potential toxins are created, however, it will be difficult to identify the specific role that environmental factors play in the causes of disease.

"In the study of disease, scientists face a barrier due to a lack of available information and data. It's imperative that we build databases to find diagnostic patterns to expedite research," said Dr. John Quackenbush of The Institute for Genomic Research at NIH.

Duke scientists are currently building these large databases of possible genomic responses to thousands of metals and chemicals in our environment and categorizing these toxins based upon their behavior. Chemical companies, for instance, can profile new compounds and look for similarities with previously established genomic responses. By predicting possible side effects due to chemical causes, animal testing may too be avoided.

Duke is one of six toxicogenomic centers around the country, collaborating with the University of North Carolina at Chapel Hill, MIT, the University of Washington, the University of Oregon and the National Institute for Environmental Health Sciences.