Chronic infection with malaria and hepatitis B and C occurring in more than 800 million people worldwide leads to at least 1.5 million deaths yearly. Although significant strides have been made in treatment and vaccination for these liver-based diseases, shortfalls remain. Progress has been stymied for several reasons, chief among them is the lack of an effective research model. Now, advances in mouse model creation are conspiring to usher in a new era in the research and treatment of these life-threatening maladies, and possibly many others.

Scientists studying these diseases have sought a research animal with both human liver cells and a human immune system. But this raises a conundrum: Engineering mice with human liver cells requires annihilation of the mouse immune system so that the foreign cells are not rejected, but the detrimental effects of both hepatitis B and C (HBV and HCV)—cirrhosis, scarring and even liver cancer—stem from the immune response against the virus. Without an intact immune system, studying how viruses work and the potency of new therapies and vaccines is greatly hindered; new drugs can be explored, but the vital role that the immune system plays in enhancing efficacy will be lost. With chimpanzee research prohibited by ethical and financial concerns, and cell cultures providing an imperfect match to in vivo disease, the need for a way to devise a research mouse with humanized liver and immune cells has been clear.

Researchers at the Salk Institute for Biological Studies recently succeeded in overcoming two hurdles for a "humanized" model: engineering mice with livers housing enough human cells to properly study HBV and HCV, and creating enough of the animals. In addition to being immune-deficient, the mice also carried a genetic defect that leads to production of a liver toxin. From birth, the animals were given a drug to suppress the toxin, which was then slowly withdrawn, obliterating the mice's liver cells and leaving a space for human liver cells to engraft and expand within the architecture of the mice's livers. The approach led to mice with consistently high amounts of human liver cells. The animals also proved hardier than previous models, indicating that a population large enough to provide meaningful data could be obtained. The mice were susceptible to both HBV and HCV, and viral antigens present in the liver signaled that a humanlike process was at play.

As improvements in liver models have made headway, so have simultaneous efforts to improve mouse models with human immune systems. The most recent efforts have focused on injecting human immune system stem cells and/or blood cells into mice whose own immune development has been genetically switched off. The antiviral immune response, however, is not yet on par with that seen in humans. Current research is now focused on adding additional human immune components, obliterating more of the mouse immune system, and preventing the rejection of the foreign human cells. Although incremental, the advances in both the liver cell and immune system mouse models is bringing the ultimate goal—a single animal with both features humanized—within reach.

Still, significant barriers remain. As Charlie Rice, who together with Alex Ploss leads a research group at The Rockefeller University studying mouse models for hepatitis C, explains, the liver and immune components should ideally be from the same person, which would eliminate genetic variation as a potential factor in the mouse’s response to a virus or a new drug. In addition, human liver and immune cells required for transplantation are hard to come by: They are expensive, available in limited quantities, and acquiring them is surrounded by ethical concerns. One solution to both these problems is to start with stem cells that can differentiate into liver and immune components inside the mouse, an approach that is being investigated by Rice's group.

Understanding which parts of the immune system are essential to re-create inside the mouse is another challenge. Scientists need to be certain that any activity against a virus is triggered by the human components, not the mouse's own immunity. "You really need the human immune system to be working like a human immune system," Rice says.

Yet even growing more immune components might not be sufficient. "It's not only the physical interactions [that vary] but also the positioning, function and movement," says Ron Germain, an immunologist at the National Institutes of Health. "Is this going to look anything like a human system? The answer is, it's very hard to know."

Successfully melding these models could transform the future of HBV, HCV, malaria and other diseases, including HIV/HCV co-infection, a widespread problem with no viable treatment options. Even the most current best therapies are neither completely effective nor inexpensive, and treatment-resistant virus strains are an ongoing threat. Combining human immune and liver components in a single animal could lead to curative drugs and even virus-eradicating vaccines.

And the futuristic potential expands from there. Rice envisions an on-demand collection of animals housing human immune components combined with target organs and tissues beyond the liver in order to study other pathogens as well as for improved preclinical research of vaccines and new drugs. The ability to create a mouse with cells from a single person means that eventually patients could have their very own personalized animal models for studying the potential impact of a drug. At the very least, Rice says, the mouse will be a vast improvement for preclinical drug development for many pathogens, "where the results...would be much more predictive of what would happen in people."