All progress in biomedicine is made on the horns of a dilemma. The testing of drugs or other therapies in humans before they are shown likely to be safe and therapeutically promising in preclinical studies is prohibited by ethical considerations. But the tools available for preclinical work—laboratory animals or isolated cells in a dish—are no substitute for testing in the living human body.
Bringing a potential cure from laboratory science to human clinical trials often requires an unsettling leap across an unavoidable gap in knowledge, and only a small fraction of the drugs that enter clinical testing are eventually approved for use in medicine.
This state of affairs has presented particular challenges in immunology research, says Richard A. Flavell, Ph.D., chair and Sterling Professor of Immunobiology. Mice, the most commonly used research animal, have immune systems that are tailored to deal with the bacteria and viruses that the species has been subjected to over evolutionary time, not the same set of pathogens that infect humans. And, as its name implies, the immune system isn’t a unitary organ like the liver, but a multifaceted mechanism distributed throughout the body, which is difficult to emulate faithfully in a petri dish.
“You don’t really want to be studying mouse cells; you want to study human cells, and ultimately you study humans, in clinical trials,” says Flavell, who is also a Howard Hughes Medical Institute investigator. “But most of the studies needed are really invasive, and therefore cannot safely be performed in people. There are enormous difficulties making sure that what you do in clinical trials is safe and isn’t going to adversely affect the patient.”
But a remarkable advance in a Swiss laboratory may provide a long-sought bridge between the bench and the bedside for immunologists. In 2004, Markus G. Manz, M.D., and his colleagues at the Institute for Research in Biomedicine managed to create a rudimentary but functional human immune system in mice by injecting human umbilical-cord blood containing stem cells and other progenitor cells into a mutant strain of mice that are born without immune systems of their own.
Manz’s paper appeared just as the Grand Challenges in Global Health initiative began accepting grant proposals. Flavell, seeing the vast potential of combining Manz’s technique with his own molecular genetic approaches in the mouse to streamline the development of new vaccines, proposed that his team join forces with Manz and with Tarrytown, N.Y.-based biotech company Regeneron Pharmaceuticals to perfect a mouse model of human immunity.
In late June, Flavell received the happy news that the Grand Challenges initiative had offered him a $17 million grant to oversee the project.
“It’s akin to a ‘Manhattan Project,’ to make this work like a true human immune system, so you could really do experimentation that is predictive of the human response,” Flavell says. “The present system doesn’t work exactly like human immunity, but we think we have an understanding of the deficiencies, and we’re going to make it work.”
A mouse model of human immunity would allow scientists to test many human vaccines in mice, including experimental HIV vaccines, which has heretofore been impossible because mice are normally not susceptible to the virus.
But Flavell says that the technique will have any number of applications. “This system, once it’s up and running, could be used to study all kinds of things,” he says. “It will be a big step forward.”
Elizabeth E. Eynon, Ph.D., a research scientist in Flavell’s lab, says that the model could make clinical trials much more efficient. “The FDA will require people to do just as many Phase I and Phase II trials as they do now,” she says, “but the likelihood of failure at those stages would be reduced if we can show safety and efficacy beforehand.”
Flavell and Eynon are gearing up to hire a dozen new scientists to begin the mouse project in earnest, but the magnitude of the Grand Challenges grant, the largest foundation grant in the history of the School of Medicine, is only slowly sinking in.
“Our heads are still spinning,” Flavell says.