The laboratory mouse—resilient, easy to breed and ideally suited to the genetic manipulations that form the basis of much of modern biomedical research—has been invaluable to immunologists such as Richard A. Flavell, Ph.D., chair and Sterling Professor of Immunobiology. But there are limits to the usefulness of this most versatile of research animals in immunology, because the mouse immune system has been tailored over evolutionary time to deal with pathogens different from those that infect humans. To compensate, scientists like Flavell supplement their work in mice with studies of human immune cells in culture, but here, too, there are inherent compromises. The immune system, a multifaceted mechanism distributed throughout the body, is difficult to emulate in a petri dish, and the behavior of cells in culture can be a poor predictor of how a drug will work in the living human body.
Since ethical considerations prohibit testing drugs in humans before they’ve been proven safe and effective, these intrinsic limitations of the tools available to immunologists mean that bringing vaccines and other cures from the laboratory to the clinic often requires a leap across an unavoidable knowledge gap.
“You don’t really want to be studying mouse cells; you want to study human cells, and ultimately you study humans in clinical trials,” said Flavell, who is also a Howard Hughes Medical Institute investigator. “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 colleagues at the Institute for Research in Biomedicine created a rudimentary 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 lack immune systems.
Manz’s paper appeared just as the Grand Challenges in Global Health initiative was accepting final proposals for grants. The initiative, funded by the Bill & Melinda Gates Foundation, the Canadian Institutes of Health Research and the Wellcome Trust, and administered by the Gates Foundation, planned to distribute more than $436 million to support innovative research on diseases that afflict the world’s poorest people. Flavell 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 for testing vaccines. In late June, Flavell learned that the initiative would award $17 million to 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 said.
A mouse model of human immunity, for example, would allow scientists to test a vaccine for HIV, which has heretofore been impossible because mice are normally not susceptible to the virus. But Flavell said 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 said.
Elizabeth E. Eynon, Ph.D., a research scientist in Flavell’s lab, said 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 said, “but the likelihood of failure at those stages would be reduced if we can show safety and efficacy beforehand.”