Toxicology on a chip

Researchers at Rensselaer Polytechnic Institute, University of California-Berkeley, and Solidus Biosciences have developed a biochip, called the MetaChip, which can analyse drug candidates for toxicity and eliminate harmful ones before they advance to pre-clinical stages.

Now beginning the second phase of funding for the US National Institutes of Health (NIH)-supported project, researchers are working to optimise the technology for pharmaceutical and biotechnology companies. The researchers are working to bring the MetaChip to market within a year.

“Compounds can be screened early, quickly, and effectively by the MetaChip to prevent toxic drugs from getting through the discovery process, being put on the market, and then getting recalled, such as we’ve seen with several high-profile cases recently,” says Jonathan Dordick, the Howard P. Isermann ’42 Professor of Chemical and Biological Engineering at Rensselaer.

“Weeding out toxic compounds earlier would also allow pharmaceutical companies to evaluate more compounds and more efficiently identify those that are most likely to become successful drugs,” adds Douglas Clark of the Chemical Engineering Department at the University of California-Berkeley.

The MetaChip (metabolising enzyme toxicology assay chip) mimics the effects of metabolism in the human liver where enzymes break down, neutralise, and excrete chemicals from food and pharmaceuticals. In many cases, the metabolised chemicals, called metabolites, are harmless or even beneficial. But some metabolites are toxic, and this toxicity can be difficult to predict or find at early stages of drug discovery with current testing methods.

“The relatively slow pace of technology development in toxicology and clinical safety evaluation that could be used in early phases of drug development continues to hinder the progression of lead compounds to pharmaceuticals,” Dordick says. “In addition to safety concerns, drug discovery is an extremely costly process with more than $1 billion invested in each approved drug. For the first time, the MetaChip can enable the initial and high-throughput analysis of metabolism-induced toxicology to be performed before significant resources are invested in the drug’s development.”

The MetaChip uses a culturing method by combining enzyme catalysis with cell-based screening on a single microscale chip. The drug candidates are added to a chip containing approximately 2,000 combinations of eight enzymes used in human liver metabolism and then sandwiched with a slide of human organ cells in order to detect toxic reactions to the compound.

When toxic reactions are detected, the toxic drug compounds are eliminated as potential candidates for further development as new pharmaceuticals. The researchers are also working to develop an automated MetaReader device to quickly analyse the results.

This slide includes approximately 2,000 combinations of eight enzymes used in human liver metabolism. To detect toxic drug compound reactions, the slide is “stamped” with a second slide of human organ cells. Photo by RPI/Moo-Yeal Lee and Jonathan Dordick