ON THE JOB FRONT

Although toxicology draws from fairly diverse disciplines, the consortium will provide a unique opportunity for card-carrying toxicologists to rub shoulders with molecular biologists who have expertise in microarray gene-expression profiling and proteomic technologies. It will also require people who have the ability to shuttle back and forth between molecular biology and bioinformatics.

In recent years, there has been a push in toxicology towards molecular biology. But the consortium creates a 'new nexus' for these groups to work together, says Helmut Zarbl of the Fred Hutchinson Cancer Research Center in Seattle, Washington. This institute, partnered with the University of Washington, is one of the five participating centres in the new consortium. Zarbl's research interests centre on chemical carcinogenesis and differential susceptibility — he is currently using a rat model to study environmental susceptibility to breast cancer.

Some recruiting for the centres is expected over the five-year period. But, when split five ways, the grant amount received by individual sites does not allow room for many new appointments, as the microarray technology that will be used for much of the work is still quite expensive.

Peter Spencer, who is leading the consortium team at the Oregon Health and Science University in Portland, expects to recruit a couple of staff over the next two years specifically for the consortium effort. He has plans for a new microarray core facility and will be looking for a director to run it.

MULTIFACETED ATTRACTION

David Schwartz (left) relishes the multifacted approach that the new toxicogenomics initiative offers.

The chance to take part in a multifaceted approach to disease development appealed to David Schwartz, head of pulmonary medicine at Duke University in Durham, North Carolina, and principal investigator for the Duke effort. The tendency until now, he says, has been to focus on either environmental exposures or genetic causes.

The consortium allows for a more complex view of disease aetiology. "We are all blinded to a certain extent by our own niche," he says. Schwartz's interest in getting beyond his own niche attracted him to Duke in the first place, because of its commitment to developing the area of genomics in general, through the newly established Institute for Genomics Sciences and Policy, and specifically environmental genetics, in which at least five additional recruitments are expected.

Having five centres working together, while also pursuing their own lines of inquiry, allows each to play to its existing strengths. For example, the University of North Carolina at Chapel Hill site will concentrate on susceptibility factors in the genomic response to toxicants, with a special emphasis on environmental carcinogenesis.

"We'd like to identify every gene that responds 'up' or 'down' in response to oxidative stress in at least three different kinds of human cells — epithelial, fibroblasts and lymphoblasts," says William Kaufmann, a professor of pathology and laboratory medicine. "And, moreover, to relate these patterns of response to biological responses monitored at the level of DNA damage/repair and cell-cycle checkpoints."

The Massachusetts Institute of Technology, the fifth participating centre, will use gene-expression profiling to study the effects of environmental alkylating agents on human health.

TOXICOGENOMICS TIMELINE

Searching for signatures: Helmut Zarbl (above) and Michael McClure (seated on the right, top).

Although each centre will have its own specialism, initial work will concentrate on setting standards for the technology that all the members will abide by, says Michael McClure, chief of the organs and systems toxicology branch in the NIEHS's division of extramural research and training. McClure anticipates that this phase-one 'harmonization' effort, which will establish clear definitions of standards and practices, precision of data and quality control, will take the better part of the first year to complete.

Phase two will focus on the development of a national microarray gene-expression database and the inclusion of data from a series of known toxicants in base-line species conducted in at least three of the five participating centres. Later phases will see an increase in the number of experiments, to include a series of unknowns, and an opening up of the database to data from investigators outside the consortium using some sort of clearing-house mechanism.

On the broader front, it is hoped that the initiative will lay some of the foundations for improved human risk assessment, as well as providing a clearer insight into the pathways and mechanisms of toxicity. It is also hoped that it will eventually lead to better exposure assessment and the development of biomarkers to detect exposures before symptoms arise.

By studying gene-expression patterns in individuals who are and are not susceptible, researchers hope to be able to elucidate the mechanisms of susceptibility to different environmental agents, which may in turn lead to improved treatments. Another potential spin-off of the research is that it could lead to a reduction in animal testing.

The consortium's ability to meet both short- and long-term goals will dictate whether it creates more research opportunities, both within the five member institutions and the NIEHS, and in establishing new collaborations beyond the existing framework.

"It's anticipated that there will be additional components added to this network," says McClure.