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) the week of July 11, 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.
In March, Chen won the $30,000 Lemelson-MIT Student Prize for her research, including this work; she also won the 2010 Collegiate Inventors Competition in the graduate student category.
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 breakdown products, or 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.
Inder Verma, a professor of molecular biology at the Salk Institute, says the new technology is not only an improvement over existing humanized mouse livers, it could be a step toward creating artificial livers from induced pluripotent stem cells derived from a patient’s own tissues.
“What you really want is to be able to do this with cells from a patient, so you can put them back in,” says Verma, who was not involved in this research.
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) the week of July 11, 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.
In March, Chen won the $30,000 Lemelson-MIT Student Prize for her research, including this work; she also won the 2010 Collegiate Inventors Competition in the graduate student category.
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 breakdown products, or 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.
Inder Verma, a professor of molecular biology at the Salk Institute, says the new technology is not only an improvement over existing humanized mouse livers, it could be a step toward creating artificial livers from induced pluripotent stem cells derived from a patient’s own tissues.
“What you really want is to be able to do this with cells from a patient, so you can put them back in,” says Verma, who was not involved in this research.
