Chimera mice will help to find cures for hepatitis and cancer

Geneticists got a mouse with a human liverMembrane based on Technology Review: Mice Get Human Livers
To study a disease and study the effectiveness of the effects of drugs, biologists need to either grow a colony of cells of an organ in the laboratory, or find a model animal whose body will react to the effects in the same way as a human one.

In the case of hepatocytes, it is difficult to do both. Outside of the human body, they change properties and almost do not grow, and standard model animals – mice and rats – do not suffer from viral hepatitis, for example. The virus affects the liver of humans and chimpanzees (but it is difficult and unethical to grow and infect the latter, scientists believe).

In addition, the existing differences between our species lead to the fact that sometimes an effective medicine that was not toxic in the case of a model animal turns out to be unsuitable for humans. "That's why we decided to create a chimera mouse," says Karl-Dimiter Bissig, one of the authors of the current study.

A few years ago, Bissig's group created a genetically modified mouse in which its own liver cells were rapidly destroyed. Biologists put human hepatocytes in their place, filling the vacated space. However, this approach turned out to be, if not a failure, then at least not the best: the "modified" mice died quickly, which means that they had to implant human hepatocytes at the age of several weeks. To learn how to choose the time of introduction of human liver cells, scientists corrected the previous procedure.

Initially, they carried out modifications of the rodent genome, which changed the number of immune cells so that they would not attack "strangers". Next, Bissig and his colleagues forced the liver cells of mice to accumulate the amino acid tyrosine. In the body, it contributes to the creation of necessary proteins, but hepatocytes get rid of it, since tyrosine becomes toxic in large quantities.

As a result, the amino acid collects in liver cells and destroys them, giving an advantage to human hepatocytes. In order not to kill the liver (and rodents with it) ahead of schedule, researchers began to give mice a drug that for the time being restrained the toxic effect of tyrosine. This is how scientists gained control over the extinction of mouse hepatocytes.

Next, the rodents were injected with liver cells from human donors. It turned out that these hepatocytes were able to fill almost 97% of the mouse liver. Then the chimeras were infected with hepatitis B and C viruses . Soon, researchers discovered a large amount of the pathogen in the blood of animals.

"In the future, our model can be used to study liver cancer," says the head of the study, Professor Inder M. Verma, in a press release (The mouse with a human liver: a new model for the treatment of liver disease). Other applications: the treatment of malaria and the creation of drugs that activate the independent regeneration of liver cells.

Now it was necessary to try to cure the mouse with a "human" medicine, which Bissig and his comrades did. Several standard drugs that save from hepatitis C helped rodents cope with the disease (the concentration of the virus in the blood significantly decreased). This finally convinced American experts that chimera liver cells behave exactly the same as human ones.

However, this model is still not perfect. So, Professor Charles Rice from Rockefeller University notes that in addition to hepatocytes in the human liver, there are also other types of cells that probably interact with the bulk and are also involved in repelling a viral attack.

Raymond Chung from Harvard Medical School believes that it is also necessary to add the human immune system. "We cannot predict with certainty the response of our immunity to the effects of an antiviral drug that will be tested on such mice," he explains.

To this, Bissig replies that in the future his group plans to "attach" the human immune system to its current model as well. The method of Karl-Dimiter and his colleagues is described in detail in an open article in the Journal of Clinical Investigation (Karl-Dimiter Bissig et al., Human liver chimeric mice provide a model for hepatitis B and C virus infection and treatment).

Portal "Eternal youth" http://vechnayamolodost.ru25.02.2010