Although
scientists commonly use mice for biomedical research, they are not always
helpful for pharmaceutical testing. Because mouse livers react to drugs
differently than human livers, they often can’t be used to predict whether a
potential drug will be toxic to people. That means that a drug that harms the
liver could make it all the way to human clinical trials before researchers
discover its risks.
Now,
Alice Chen, a graduate student in the MIT-Harvard Division of Health Sciences
and Technology (HST), has developed a way to overcome that problem. By growing
human liver tissue inside mice, she has created “humanized” mouse livers that
respond to drugs the same way a human liver does.
The
humanized mice, described in Proceedings of the National Academy of Sciences
(PNAS), could also be used to study the liver’s response to infectious
diseases such as malaria and hepatitis.
“What’s
exciting to researchers is this idea that if we can create these mice with
human livers, we can basically create a slew of human-like patients to do drug development
screens, or to … develop new therapies,” says Chen, who works in the lab of
Sangeeta Bhatia, the John and Dorothy Wilson Professor of HST and electrical engineering
and computer science.
Bhatia,
who is a member of MIT’s David H. Koch Institute for Integrative Cancer
Research, is senior author of the PNAS paper.
A new scaffold
One obstacle to creating mice with human livers is that liver cells tend to
lose their function rapidly after being removed from the body. Another
challenge is that until now, creating mice with humanized livers required
starting with mice with severely compromised immune systems—which limits their
use for studying the immune response to infectious agents such as the hepatitis
C virus, or drugs to combat those agents. Furthermore, those approaches rely on
liver injury to create an environment in which implanted human liver cells can
proliferate.
The
process of breeding such mice is very time consuming: It can take months to
produce a single mouse with the right characteristics, Chen says.
To
overcome those issues, Chen and Bhatia developed a tissue scaffold that
includes nutrients and supportive cells, which preserve liver cells after they
are taken from the body. The tissue scaffold is the size, shape, and texture of
a contact lens, and can be implanted directly into the mouse abdominal cavity.
Using
this approach, the researchers can rapidly implant scaffolds in up to 50 mice
in a day; it takes about a week for the implanted liver tissue to integrate
itself into the mice. The gel that forms the scaffold also acts as a partial
barrier to the mouse’s immune system, preventing it from rejecting the implant.
In
the PNAS paper, the researchers demonstrated that the implanted liver
tissue integrates into the mouse’s circulation system, so drugs can reach it,
and proteins produced by the liver can enter the bloodstream. (The mice also
retain their own livers, but the researchers have developed a method to
distinguish the responses of mouse and human liver tissue.) Unlike existing
approaches, this technique can be used on mice with no liver injury and intact
immune systems.
To
test the function of the humanized livers, the team administered the drugs
coumarin and debrisoquine and found that the mice broke them down into
byproducts normally generated only by human livers.
Chen
and her colleagues are now studying how the humanized livers respond to other
drugs whose metabolites are already known. That will pave the way to exploring
the effects of untested drugs. “The idea that you could take a humanized mouse
and identify these metabolites before going to clinical trials is potentially
very valuable,” Chen says.
The
team is also working toward miniaturizing the implants to the point where
hundreds or thousands could be implanted in a single mouse. If successful, that
could make the drug development process more efficient and reduce the number of
mice needed for drug studies, Chen says.
