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CAAT Director Hartung Profiled in Nature Journal: Big Biology: The 'Omes Puzzle

Thomas Hartung wants to learn all the ways a small molecule can hurt you. To do so, he has organized the Human Toxome Project, funded with US$6 million over five years from the US National Institutes of Health, plus extra support from the Environmental Protection Agency and the Food and Drug Administration. The -ome suffix, Hartung says, suited the scale of his goal: a description of the entire set of cellular processes responsible for toxicity. “The toxome is very similar to the Human Genome Project because it establishes a point of reference,” says Hartung, a toxicologist at Johns Hopkins Bloomberg School of Public Health in Baltimore.

Toxicity testing in animal studies costs millions of dollars for every compound that enters human trials, yet animal tests sometimes fail to predict toxicity in humans. More than one in six drugs are pulled for safety problems that are discovered during human trials. Hartung says that the toxome could help to lay out a series of straightforward cell-based assays that could replace animal tests — and perhaps improve on them. Knowing which toxicity-related processes a compound triggers could also help scientists to tweak promising new drugs or industrial molecules into less-harmful versions.

The project is still in its early days — making sure that the same assay yields the same results in different labs. Eventually, however, those pathways could be used in cell-based assays to serve as bellwethers of toxicity. “We’d know if we triggered one of those pathways that something bad would happen, and we’d know what that adverse event would be,” says David Jacobson-Kram, who evaluates ways to predict toxicity at the Food and Drug Administration in Silver Spring, Maryland. He warns that a molecule that seemed harmless to cells in culture might behave differently in the body — for example if the liver converted it to a toxin. Nonetheless, he says, the toxome project could save time, money and animals. “Do I think this paradigm has promise?” he asks. “Absolutely.”To start with, Hartung wants to expose cells to toxic chemicalsand then monitor their metabolomes (the set of all small molecules in the cell) and their transcriptomes. He hopes to piece together the details of pathways in human cells that disrupt hormone signals, poison liver cells, break the heart’s rhythm or otherwise endanger people’s health. The total number of pathways, Hartung believes, will be perhaps a couple of hundred — a manageable amount for testing toxicities.

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