Despite the fact that mice are very commonly used in biomedical research, not much help has been gained by their use in the testing of new drugs. The reason for this is that a mouse’s liver reacts differently to drugs as compared to the liver of humans. This makes it difficult to predict whether or not the potential drug being tested will be toxic in humans. As a result, harmful drugs can easily make their way to clinical trials even before the scientists actually discover their potential risks.

To solve this problem, Alice Chen, a graduate student from MIT-Harvard Division of Health Sciences and Technology (HST) came up with a solution. She created “humanized” mouse livers, by growing human liver tissues inside them, which were found to respond to drugs just the same way as a human liver does.

As described in the Proceedings of the National Academy of Sciences (PNAS) in the week of July 11, the humanized mouse can also be used to examine the response of the liver against some infectious diseases, such as malaria and hepatitis.

Chen said:

“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.”

One of the major challenges faced by Chen during the creation of the humanized mouse livers was that the human liver cells after being removed from the body could lose their function immediately.

Another problem the researchers have come up against, is that they can only use mice with very low immunity for the creation of humanized mouse livers. This problem has the potential of limiting their requirement for the study of immune response against some infectious organisms like hepatitis C virus, as well as drugs used to kill these organisms. Chen says that breeding mice with compromised immune systems is a time-consuming process as it takes months to create a single mouse with the required characteristics.

In order to overcome these challenges, a tissue scaffold was developed by Chen and Bhatia that contained the nutrients and supportive cells required for preserving the liver cells soon after they are taken from the body. The size, shape and texture of the tissue scaffold resembles a contact lens and can directly be implanted with ease into the abdominal cavity of mice.

The investigators can implant this tissue scaffold in up to 50 mice per day and the implanted liver tissue would commonly take up to one week to integrate itself with the mice. The gel which forms the scaffold acts as a partial barrier and prevents rejection of the implant by the immune system of the mouse.

In the PNAS paper, the scientists were able to show that drugs easily reach the implanted human liver tissue as it seamlessly blends with the circulatory system of the mouse. It also allows for the proteins produced by the liver to enter the bloodstream. (Although mice retained their own livers, the investigators have developed a technique to differentiate the responses of the mouse liver from that of the human liver tissue.)

To test the function of the humanized liver, the team administered drugs, such as Coumarin and Debrisoquine in the humanized liver and found out that the mice, just like human livers, broke them down into byproducts.

A study is now being conducted by Chen and her fellow researchers to better understand how the humanized livers respond to other drugs whose breakdown products are already known. This will also form the foundation to understand the effects of untested drugs.

Chen states:

“The idea that you could take a humanized mouse and identify these metabolites before going to clinical trials is potentially very valuable.”

They are also trying to make the implants as small as possible so that hundreds or even thousands could be implanted in one mouse. If they manage to achieve this, the drug development process would become more efficient – they would also need fewer mice for their studies, Chen added.

Written by Anne Hudsmith