Importantly, when exposed to low doses of particular drugs over periods of weeks, the cells displayed chronic toxicity. Such toxicity is clinically significant given the way that people actually take drugs–every day for long periods of time–but it’s not possible to detect chronic effects in conventional liver cultures because they die too soon.
“These cells by many criteria look extremely [liver]-like,” says Charles Rice, who directs the Center for the Study of Hepatitis C at Rockefeller University. Bhatia’s liver cultures are “closer to in vivo” than traditional tissues used to study the liver in the lab, Rice says, be they liver-cancer cell lines or fast-deteriorating slices of liver tissue. “The scale and precision is really breathtaking. Pharmaceutical companies will be pretty interested.” Rice is collaborating with Bhatia to use the liver models to grow hepatitis C, with good preliminary results. The virus, which infects 3 percent of the worldwide population and is the leading cause of liver transplants in the United States, is difficult to study in the lab.
These better-functioning culture systems may also help detect drugs that are toxic to the heart. Knowing how these compounds are processed in the liver is critical. A drug that is harmless in its original state may be turned into a heart-toxic compound after passing through the liver, says Cornell’s Shuler. New ways of studying the liver are making it practical to test the toxicity of not only the drug itself, but also its metabolites. Shuler is developing what he calls a “body on a chip,” a microfluidic system that connects multiple tissue types to mimic the interaction of organs in the body. He says that Bhatia’s cultures could be plugged into such a system to provide the liver compartment. (Shuler’s work has been commercialized by Hμrel of Beverly Hills, CA. Last year, Hµrel announced a collaboration with the drug company Schering-Plough.)
Another possibility that these new liver models opens up is that of testing the effects of drug combinations. Patients often take more than one drug at a time, and drugs that are safe when taken alone may have unexpected toxic interactions with each other. The new liver models can be used to do studies at high throughput, and they should make it more practical to test drug combinations for potential toxicity, says Shuler.
“This will revolutionize the way drug testing is done,” predicts Tannenbaum. Hepregen will begin beta testing with pharmaceutical companies in the coming year; company cofounder Salman Khetani says that he and his colleagues are about a year from shipping their products.