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Honey, I shrunk the liver
CAMBRIDGE, Mass.—With liver toxicity looming as one of the main reasons pharmaceutical companies pull drugs off the market, the development of a technology to create tiny colonies of living human liver cells that model the full-sized organ should be welcome news to drug discovery and development professionals. MIT researchers recently reported that they had devised just such a technology, and believe their work could allow better screening of new drugs that are potentially harmful to the liver and may reduce the costs associated with their development.
A key reason potentially liver-toxic drugs slip through approval processes is because of the limitations of liver toxicity tests. Existing tests often use rat liver cells, which don't always respond to toxins like human cells do, notes Sangeeta Bhatia, associate professor in the Harvard-MIT Division of Health Sciences and Technology (HST) and MIT's Department of Electrical Engineering and Computer Science. Or the tests use dying human cells that survive for only a few days in the lab.
The new technology—that Bhatia and HST postdoctoral associate Salman Khetani describe in the Nov. 18 online issue of Nature Biotechnology—arranges human liver cells into tiny colonies only 500 micrometers in diameter that act much like a real liver and reportedly survive as long as six weeks.
To predict how close their model tissue comes to real liver tissue, the researchers evaluated gene expression profiles and found that these profiles are very similar to those of fresh liver cells, "giving us confidence that other [liver] functions are preserved," Khetani says.
For drug testing purposes, this allows each colony to provide a view into human liver response to a drug without requiring human exposure to the drug in a clinical trial, explains Bhatia. She adds that because the engineered tissue lasts so much longer than human tissues used in traditional tests, this opens the door to testing the effects of long-term drug use and will allow more extensive testing of drug-drug interactions.
In tests of drugs with a range of well-known toxicity levels, assays on the "micro-liver" models showed that the MIT-developed platform could predict the relative toxicity of these drugs as seen in the clinic, Khetani reports. For example, troglitazone, a drug withdrawn from the market by the FDA due to liver toxicity, showed toxicity levels much higher than its FDA-approved analogues, rosiglitazone and pioglitazone, when applied to the micro-liver model.
As good as the micro-liver model is, Khetani says there is still plenty of work to do.
"We have to further scale it down to a 384-well format for high-throughput screening in automated systems, and get the cultures to survive for several months [to further improve ability to do long-term drug tests]," Khetani says. "Other challenges include infecting these cultures with infectious diseases and producing a platform that allows pathogens to grow to enable study of pathogen lifecycle and for drug discovery purposes."
To build these model livers, the researchers use micropatterning technology—the same technology used to place tiny copper wires on computer chips—to precisely arrange human liver cells and other supporting cells on a plate. Khetani adapted this method from Bhatia's early work as an HST graduate student building micropatterned co-cultures of rat liver cells and supporting cells.
Bhatia notes that each model liver secretes the blood protein albumin, synthesizes urea and produces the enzymes necessary to break down drugs and toxins.
A startup company called Hepregen has licensed the technology and is working to introduce it into the pharmaceutical marketplace. Hepregen is a MIT spinout—incorporated this past summer—to commercialize the micro-liver platform and related technologies from Bhatia's patent portfolio in the tissue engineering space.
Hepregen is exploring investor funding to establish its facilities as well as collaborative research agreements with major pharmaceutical companies for the development, validation and evaluation of microscale liver cultures. Hepregen has been in talks with Merck and Novartis so far and seeks to be operational around spring 2008 and start collaborative research shortly thereafter.