Mouse:Human Chimera One More Step

A Salk Institute research team has successfully engineered a mouse strain with a liver consisting of mostly human liver cells. The scientists then infected the mice with human hepatitis virus, and used the mice to test treatments for Hepatitis infection. Eventually, this strain of mouse will allow scientists to test the reaction of human liver cells to drugs, chemicals, viruses, and toxins without endangering human life.

Bissig says his group's mouse/human chimera improves on a similar model developed several years ago that was genetically engineered to give human liver cells a growth advantage when injected into a mouse liver. Researchers engineered the mouse with a gene that destroyed its own liver cells. This programmed death gave human liver cells an advantage, and when researchers injected human hepatocytes, they were able to take over and repopulate the mouse liver. However, scientists found that the genetically engineered mice tended to die off early, which required injecting human liver cells within the first few weeks after birth--a risky procedure that often resulted in fatal hemorrhaging.

Instead, Bissig and his colleagues, including Inder Verma of the Salk Institute, sought to engineer a mouse chimera in which the introduction of human liver cells could be easily controlled. The group first engineered mice with several genetic mutations, which eliminated production of immune cells so that the mice would not reject human liver cells as foreign. The researchers made another genetic mutation that interfered with the breakdown of the amino acid tyrosine. Normally, tyrosine is involved in building essential proteins. To keep a healthy balance, the liver clears out tyrosine, keeping it from accumulating to toxic levels. Bissig engineered a mutation in mice that prevents tyrosine from breaking down, instead causing tyrosine to build up in liver cells, eventually killing the mouse cells, giving the human cells an advantage.

To avoid killing mouse liver cells too early (or killing the mice entirely), Bissig's team administered a drug that blocks the toxic byproducts of tyrosine buildup from killing liver cells. By putting the mice on the drug, and taking them off the drug a little at a time, researchers found that they could control the rate at which rodent liver cells died off.

The team then injected mice with hepatocytes from various human donors, and found that the cells were able to take over 97 percent of the mouse liver. The "humanized" mice were then infected with hepatitis B and C, and researchers found high levels of the virus in the bloodstream--versus normal mice, which are impervious to the disease and are able to clear the virus out quickly.

Bissig and his colleagues went a step further and treated the infected mice with a drug typically used to treat humans with hepatitis C. They found that, after treatment, the mice exhibited a thousand-fold decrease in viral concentration in the blood, similar to drug reactions in human patients. _TechReview

This team is focused on hepatitis viruses, but clearly the application of this chimeric technology goes light years beyond testing treatments for a virus or two.

Scientific publications must have a narrow focus in order to be taken seriously. But the implications of particular studies may reverberate far beyond the narrow intent of the original study. That is the case here.

Bissig says that in the future, he and his team hope to add a human immune system to their mouse model, so they can see how hepatitis acts, not only in a human liver, but in the presence of a normal, healthy human immune system.

Why stop there? Chimeric technology will allow animal organs to be replaced by human organs, piece by piece, creating perfect animal models for the study of human disease. But why stop there? Scientists are replacing animal brain tissue with human neuronal stem cells that develop into human neurons. Why not give the little critters human brains too? We can do it. We have the technology . . . .

The fact is, the djinn is out of the bottle -- has been out of the bottle since the discoveries of Watson, Crick, and others who preceded them.

The only question is: How far will we take the idea? The answer is that "we" are no longer in control. Biotechnology is a lot easier to teach, transport, and conceal than nuclear weapons technology. And a lot more dangerous, if you want to hear the truth.

Time to wake up to the things we need to be preparing for.