New biochip mimics liver
Technology promises simplified toxicity testing of drug candidates
TROY, N.Y.—A team of researchers has developed a new type of biochip that emulates the metabolism of a human liver. The goal of the development is to eliminate the need to harvest and use liver cells from human cadavers to test the toxicity of potential new drugs candidates. Typically, this toxicity testing is conducted using human hepatocytes. “These cells, however, are known to be challenging to work with,” observes Dr. Jonathan S. Dordick, vice president for research and the Howard P. Isermann Professor at Rensselaer Polytechnic Institute, who helped lead the study. “Because they are harvested from the livers of cadavers, hepatocytes are expensive, delicate and vary significantly in their metabolic capacity and profile. This variability often results in loss of the predictive capacity of in-vitro tests to emulate what happens in the human body,” he tells DDNews.
The new biochip technology is the result of a collaboration between researchers from Rensselaer, the University of California, Berkeley, Samsung Electro-Mechanics and Solidus Biosciences Inc. The team’s research findings were published this week in the journal Nature Communications in a paper titled “High-throughput and combinatorial gene expression on a chip for metabolism-induced toxicology screening.”
The device—dubbed the TeamChip for Transfected Enzyme and Metabolism Chip—is prepared by delivering genes into miniaturized three-dimensional cellular microarrays on a micropillar chip using recombinant adenoviruses. The device enables users to manipulate the expression of individual and multiple human metabolizing-enzyme genes. To identify specific enzymes involved in drug detoxification, the team created 84 combinations of metabolic-gene expressions in a combinatorial fashion on a single microarray. Thus, the TeamChip platform can provide critical information necessary for evaluating metabolism-induced toxicity in a high-throughput manner. In addition, the TeamChip can be fine-tuned to mimic hepatocytes from an individual, which is critical in the development of more personalized drug toxicity assessment, Dordick notes.
“Drug discovery is a highly competitive enterprise that requires significant upfront investment and suffers a low success rate,” said Douglas S. Clark, dean of the College of Chemistry and the Gilbert Newton Lewis Professor at UC Berkeley, in the news release about the study (Clark co-led the study with Dordick). “A high-throughput alternative to using human hepatocytes would speed up the testing process and reduce costs, while alleviating the problems related to sourcing the cells from cadavers. The new TeamChip technology is a highly flexible platform that addresses these challenges directly.”
The researchers took immortalized liver cells that lacked the ability to perform metabolism and used an approach called viral transduction to “infect” these cells with viruses containing specific drug-metabolizing genes that lead to the expression of drug-metabolizing enzymes. Once expressed, these enzymes enable the liver cells to metabolize drugs and drug candidates. The cells can be engineered to express any number of enzymes, all in high-throughput mode
Each TeamChip features 532 individual assays that consist of these liver cells. The cells are “printed” onto the chip, each with different combinations and concentrations of viruses. The cells print as a liquid, but then quickly form gelatinous 3-D structures. These 3-D structures are likely to more accurately mimic the conditions within the human body than a flat, 2-D sample, according to Clark. Each sample is extremely small, with a volume of only 60 nanoliters.
Why 532 assays per chip? “Convenience, really,” says Dordick, “for spotting assays and replicates and follow-up analysis via fluorescent immunoassay.” Spotting six at a time, he notes, the process can be completed in minutes.
Once all of the samples have been printed, the chip is incubated for up to three days. Afterward, it is removed from incubation and then analyzed for cell viability. Cells that generate drug candidate metabolites that are toxic result in lower cell viability.
Traditionally, toxicity testing is conducted late in the preclinical phase of the drug discovery process. Dordick and Clark said the TeamChip could enable pharmaceutical companies to start doing quick, reliable, high-throughput toxicity testing significantly earlier in the process.
“This technology is a good way to determine, very early on, both the efficacy and the potential toxicity of a drug candidate,” according to Dordick. “Having this information as early in the process as possible enables pharma companies to focus their limited resources on pushing forward only the most promising candidates with good efficacy and low toxicity.”
Looking ahead, Dordick says this technology is a step toward the still-distant goal of developing a system that can be personalized to a specific patient. Such a system could mimic the liver of an individual and test the toxicity of different compounds to their unique physiology, he notes.
Dordick and Clark are the co-founders of Solidus Biosciences, which collaborated with Samsung to develop the new TeamChip. Solidus will commercialize the technology, a process that may begin with Solidus offering it as a service, Dordick says.
Along with Dordick and Clark, Moo-Yeal Lee, previously a researcher at Solidus and now a faculty member at Cleveland State University, served as a co-leader of the study. In addition, Rensselaer research scientist Seok Joon Kwon; Rensselaer postdoctoral researcher Kusum Solanki; Rensselaer chemical and biological engineering student Dhiral Shah, who has since graduated; Dong Woo Lee, Bosung Ku and Sang Youl Jeon of Samsung; and Jessica Ryan of Solidus Biosciences were also involved in the research.