Honey, I shrunk the liver

MIT researchers devise method to make tiny colonies of cells mimic a human liver

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CAMBRIDGE, Mass.—With liver toxicity looming as one of themain reasons pharmaceutical companies pull drugs off the market, the developmentof a technology to create tiny colonies of living human liver cells that modelthe full-sized organ should be welcome news to drug discovery and developmentprofessionals. MIT researchers recently reported that they had devised justsuch a technology, and believe their work could allow better screening of newdrugs that are potentially harmful to the liver and may reduce the costsassociated with their development.

A key reason potentially liver-toxic drugs slip throughapproval processes is because of the limitations of liver toxicity tests.Existing tests often use rat liver cells, which don't always respond to toxinslike human cells do, notes Sangeeta Bhatia, associate professor in theHarvard-MIT Division of Health Sciences and Technology (HST) and MIT'sDepartment of Electrical Engineering and Computer Science. Or the tests usedying human cells that survive for only a few days in the lab.

The new technology—that Bhatia and HST postdoctoralassociate Salman Khetani describe in the Nov. 18 online issue of NatureBiotechnology—arranges human liver cells into tiny colonies only 500micrometers in diameter that act much like a real liver and reportedly surviveas long as six weeks.

To predict how close their model tissue comes to real livertissue, the researchers evaluated gene expression profiles and found that theseprofiles are very similar to those of fresh liver cells, "giving us confidencethat other [liver] functions are preserved," Khetani says.

For drug testing purposes, this allows each colony toprovide a view into human liver response to a drug without requiring humanexposure to the drug in a clinical trial, explains Bhatia. She adds thatbecause the engineered tissue lasts so much longer than human tissues used intraditional tests, this opens the door to testing the effects of long-term druguse and will allow more extensive testing of drug-drug interactions.

In tests of drugs with a range of well-known toxicitylevels, assays on the "micro-liver" models showed that the MIT-developed platformcould predict the relative toxicity of these drugs as seen in the clinic,Khetani reports. For example, troglitazone, a drug withdrawn from the market bythe FDA due to liver toxicity, showed toxicity levels much higher than itsFDA-approved analogues, rosiglitazone and pioglitazone, when applied to themicro-liver model.

As good as the micro-liver model is, Khetani says there isstill plenty of work to do.

"We have to further scale it down to a 384-well format forhigh-throughput screening in automated systems, and get the cultures to survivefor several months [to further improve ability to do long-term drug tests],"Khetani says. "Other challenges include infecting these cultures withinfectious diseases and producing a platform that allows pathogens to grow toenable study of pathogen lifecycle and for drug discovery purposes."

To build these model livers, the researchers usemicropatterning technology—the same technology used to place tiny copper wireson computer chips—to precisely arrange human liver cells and other supportingcells on a plate. Khetani adapted this method from Bhatia's early work as anHST graduate student building micropatterned co-cultures of rat liver cells andsupporting cells.

Bhatia notes that each model liver secretes the bloodprotein albumin, synthesizes urea and produces the enzymes necessary to breakdown drugs and toxins.

A startup company called Hepregen has licensed thetechnology and is working to introduce it into the pharmaceutical marketplace.Hepregen is a MIT spinout—incorporated this past summer—to commercialize themicro-liver platform and related technologies from Bhatia's patent portfolio inthe tissue engineering space.
Hepregenis exploring investor funding to establish its facilities as well as collaborativeresearch agreements with major pharmaceutical companies for the development,validation and evaluation of microscale liver cultures. Hepregen has been intalks with Merck and Novartis so far and seeks to be operational around spring2008 and start collaborative research shortly thereafter.

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