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Humanized mouse livers offer numerous drug testing possibilities
CAMBRIDGE, Mass.—Big help may be coming for pharmaceutical companies in the form of some very small livers, as exemplified in a recent paper published by the Massachusetts Institute of Technology (MIT). In that paper, researchers detail a new technology that could help researchers know exactly how a drug will affect humans before it goes into clinical trials.
Clinical trials are a huge investment for pharmaceutical companies, one that banks on the drug or drugs being tested working exactly as hoped. However, some drugs end up displaying side effects that can be damaging or even fatal to study participants—side effects that developers couldn't predict before the trials. This can lead to a trial being scrapped early, costing millions of dollars and setting a drug back by years.
Now, though, Alice Chen, a graduate student in the MIT-Harvard Division of Health Sciences and Technology (HST), has come up with a way to grow human livers inside of mice to produce "humanized" mouse livers that process and metabolize drugs the same way human livers do. While mice have been used for years in research, they are less effective in pharmaceutical testing since mouse livers process drugs differently than human livers. The discovery offers the ability to study drugs that might harm the liver before they get into clinical studies, as well as the human liver's reaction to diseases such as malaria and hepatitis.
Chen works in the laboratory of Sangeeta Bhatia, the John and Dorothy Wilson Professor of HST and Electrical Engineering and Computer Science. Chen's findings were published in the Proceedings of the National Academy of Sciences (PNAS), and Bhatia, a member of MIT's David H. Koch Institute for Integrative Cancer Research, is senior author of the paper.
The idea of humanized livers, says Chen, came from her desire to help advance the field.
"It sort of dawned on us one day that this would be useful, just having human liver tissues," says Chen.
Chen and Bhatia 's method of creating the humanized mouse livers consists of a tissue scaffold that includes nutrients and supportive cells, which preserve liver cells after they are removed from the body. The scaffold is the size and shape of a contact lens, with a similar texture, and is implanted into a mouse's abdominal cavity. The gel that the scaffold is made of also doubles as a barrier, keeping the mouse's immune system from rejecting the implant.
"There are methods of humanizing a liver in mice that have been published before that are very different from what we did," explains Chen. "In previous methods, researchers have really elegantly injected liver cells into mice that have a genetic liver injury, so it causes the liver cells to travel to that injured mouse liver, and then it clamps there and starts growing."
The issue with that method, however, is that it drastically limits which mice can be used for testing, as researchers would have to breed additional generations to have enough subjects to use in testing. With Chen's method, up to 50 mice can be implanted with scaffolds in a day, and it takes only about a week for the implanted tissue to fully integrate itself into the mice. In the paper's abstract, the researchers detail how the implants, or human ectopic artificial livers (HEALs), "stabilize the function of cryopreserved primary human hepatocytes through juxtacrine and paracrine signals in polymeric scaffolds." Unlike the current method, the HEALs can be introduced in mice without compromised livers, and mice implanted with HEALs "exhibit humanized liver functions persistent for weeks, including synthesis of human proteins, human drug metabolism, drug-drug interaction and drug-induced liver injury."
"We worked really hard to make sure the human livers were just working outside of the mouse first, that was a really big, important first step that took actually several years," says Chen, adding that there were some surprises when they studied how well the implants integrated into the mice. "We had cell types in our device that we knew would secrete factors that would work through the mouse blood vessels in our samples. We didn't know that the vessels would go through the implant, we thought they might just come to the surface of the implant."
The liver tissue successfully integrates into the mouse's circulation system, allowing drugs to reach it and proteins produced by the liver to enter the bloodstream. Though the mice maintain their own livers, the researchers are able to distinguish between the responses of mouse and human liver tissue. Administering dosages of coumarin and debrisoquine proved that the mice metabolized the drugs into the byproducts generated by normal human livers.
Moving forward, Chen says researchers will be studying how the humanized livers process other drugs whose metabolites are known, which will help them gauge the implants' reliability in terms of testing new drugs in order to predict how they will be processed in humans. In addition, the researchers will also work towards replicating the implants at even smaller sizes in hopes that potentially hundreds could be implanted in one mouse. If it works, it could drastically reduce how many mice would be needed for studies.
"We're also interested in looking at drug pairs, being able to create a battery of mice that have human livers that you can start really testing different combinations of drugs," Chen adds. "We're interested in looking at drug interactions, potentially dangerous drug interactions that would be hard to test prior to clinical trials and marketing."
The paper, entitled "Humanized mice with ectopic artificial liver tissues," was published in the July 11 issue of PNAS. In addition to Chen and Bhatia, the paper had four other authors: David K. Thomas of the Broad Institute of MIT and Harvard and the Division of Adult Palliative Care, Dana-Farber Cancer Institute and Harvard Medical School; Luvena L. Ong of the Harvard-MIT Division of Health Sciences and Technology; Robert E. Schwartz of the David H. Koch Institute and the Division of Medicine at Brigham and Women's Hospital; and Todd R. Golub of the Broad Institute of MIT and Harvard and the Howard Hughes Medical Institute at MIT.