By Marian Turner of Nature magazine
The unique physiology of the human liver means that the toxicity of some candidate drugs is not picked up during preclinical tests in animals. But mice implanted with miniature human livers can mimic the ways in which the human body breaks down chemical compounds, to help spot potential problems before drugs are tested in humans.
A team led by Sangeeta Bhatia, a biomedical engineer at the Massachusetts Institute of Technology in Cambridge, made 20-millimetre-long artificial human livers and implanted them into otherwise normal mice. The researchers report today in Proceedings of the National Academy of Sciences, that the mice showed metabolism characteristic of the human liver for weeks after implantation.
"The key technique is that we make stable liver implants in the laboratory first," says biomedical engineer Alice Chen, an author on the study. The researchers combined human liver cells (hepatocytes) that carry out the liver's metabolic functions, with mouse fibroblast cells and human liver endothelial cells, which provide chemical signals the hepatocytes need to function. They encased the cell packages in a plastic scaffold and implanted them into mice.
When they gave the mice drugs that humans and mice break down differently, the mice produced the same breakdown products (metabolites) and showed the same metabolic interactions between drugs as a human would. The authors hope that the new technology will make drug development safer and less costly, by spotting toxicities before a drug gets to clinical trials.
"The implants are still a long way from being a liver, so the human metabolism is remarkable," says immunologist James Di Santo at the Pasteur Institute in Paris, who was not involved in the study. But he says these humanized mice might be limited to assessing certain classes of drugs--such as those that are only, or very differently, metabolized by human hepatocytes. The new implants only contain half a million human liver cells, compared to the tens of millions of cells in a mouse liver, so in some cases the mouse cell metabolism might mask the human metabolites that the system is designed to reveal.
Scientists have previously made mice with a greater proportion of human liver cells by injecting human cells into mice with damaged livers and waiting for the human cells to repair the injury. But it takes months for these 'chimeric' livers to form, compared with the 1-2 weeks Bhatia's team need to make their artificial livers. "Chimeras are also highly variable, and it's hard to tell how many of the human cells have proper liver metabolism," says Chen.
Another feature of the implants is that they are not immediately attacked by the mouse immune system. "We can tune the pore size of the polymer so that the mouse immune cells don't have easy access to the human cells inside the implant," says Chen. Because the artificial livers aren't rapidly rejected, scientists can implant them into any mouse strain, and still have weeks to follow their function, whereas chimeric livers can only be made in immunodeficient mice.
For Alexander Ploss, a virologist at Rockefeller University in New York, this means that the implants might be useful not only for drug testing but for studying human diseases. He sees the implanted mice as a toolbox--one into which he wants to add the nuts and bolts of the human immune system. His team recently generated the first non-primate animal model of infection by hepatitis C virus, which infects liver cells, by making mice with humanized immune systems. "By implanting humanized livers into humanized immune system mice, we could follow hepatitis viruses or malaria parasites interacting with immune cells and the liver at the same time," Ploss says.
This article is reproduced with permission from the magazine Nature. The article was first published on July 11, 2011.