AAAS Abelson Event: Translational Researchers Fight Rare Diseases, Spinal Cord Injuries and More

After creating microspheres to slowly release protective drops into the eyes of glaucoma patients, bioengineer Erin Lavik combined endothelial and neural stem cells with a polymer matrix to generate blood vessels and rebuild the blood-spinal cord barrier of injured animals. Now, she and her colleagues have improved the matrix by manufacturing it as a liquid that solidifies after being injected and exposed to light.

Lavik, who holds the Elmer Lindseth Chair of Biomedical Engineering at Case Western Reserve University, also is experimenting with a simple nanoparticle designed to activate blood platelets. If the strategy works, it might suggest a way to improve human trauma care. The goal is to stop the excessive bleeding that exacerbates spinal-cord damage immediately following an injury, Lavik explained at the AAAS Abelson Advancing Science event on 20 November.

Elias Zerhouni, M.D.

“I’m so impressed with your gutsy approach,” event moderator Elias Zerhouni, M.D., told Lavik as they discussed translational medicine and its promise for improving human health. The salon-style conversation, also featuring Howard Hughes Medical Investigator Hal Dietz, M.D., the Victor A. McKusick Professor of Genetics and Medicine at the Johns Hopkins University School of Medicine, honored the legacy of science icon Philip Hauge Abelson, long-time AAAS senior adviser and Science editor emeritus.

Projects described by Dietz and Lavik, who collaborates with pediatric oncologists, ophthalmologists, geneticists and other specialists, exemplify the intensely multidisciplinary approach that will be essential to speed basic advances into clinical practice, said Zerhouni, chief scientific advisor for Science Translational Medicine launched by AAAS in October.

Trained as a pediatrician and cardiologist, Dietz made a commitment early in his career to study Marfan syndrome, a disorder of the body’s connective tissues, because of his attachment to patients. But he also suspected that unraveling the mechanisms of the rare disease might offer broader insights to more common conditions such as aortic aneurysm, mitrovalve prolapse, emphysema and glaucoma.

Hal Dietz, M.D.
[Photo by Benjamin Somers]

Before 1990, Dietz noted, the outlook for children with Marfan syndrome was considered bleak because they are born with a mutated version of the gene that encodes a key connective tissue protein, fibrillin-1. Scientists believed that the disease simply reflected inherent weakness of the tissues, which would be difficult or impossible to address after birth. Then, further research showed that tissue microfibrils, composed of fibrillin-1, normally regulate the activity of a growth factor, TGFβ.

In mice, the widely used blood pressure medicine losartan blocked TGFβ activity and prevented aneurysm. Evidence of similar protection was seen in a small group of children with severe Marfan syndrome, resulting in the launch of an ongoing clinical trial. “To date, we’ve treated 19 such children,” Dietz reported. “On average, these children were growing their aortas by 4 millimeters per year, every year prior to this medication, and only 0.4 millimeters a year after starting losartan.”

Dietz and colleagues are now investigating a new class of disorders called TGFβ vasculopathies. He also has experimented with using losartan to treat mitral valve disease, which affects about 7% of all women, and he has applied a TGFβ blocker to normalize muscle performance in mice, which may hold promise for helping people with a particular form of muscular dystrophy called Duchenne. In a mouse model, he said: “TGFβ neutralizing antibody or losartan fully rescues both the early and late phases of muscle regeneration in a model of Duchenne muscular dystrophy.”

Most recently, Dietz and colleague Enid Neptune have explored the consequences of blocking TGFβ in common forms of lung disease, including emphysema induced by exposure to cigarette smoke. Although Dietz cautioned that the work is still in the early stages, he believes that it may evolve to be “an exciting example of how something we’ve learned about a rare disorder may prove relevant more broadly.”

Erin Lavik
[Photo by Benjamin Somers]

Commending the successes of Dietz and Lavik, Zerhouni, a senior fellow with the Bill & Melinda Gates Foundation and former director of the National Institutes of Health (NIH), said that such promising fundamental results unfortunately can get stuck in the laboratory.

Too often, Zerhouni said, the astonishing basic advances of the past 50 years have not translated into medical breakthroughs. A lack of funding may be part of the problem: The U.S. biotechnology and pharmaceuticals sectors spent more than $60 billion on research and development in 2008—an investment that was roughly twice the size of the NIH’s total budget, he noted. At the same time, research using model systems often cannot be extrapolated in a predictable, linear fashion to address human-scale problems.

Speeding the pace of medical advances will require rewarding and supporting a multidisciplinary community of scientists studying diseases in human populations, according to Zerhouni. “There is no magic solution,” he said. “But we’d better find a solution,” given the burden of disease on individuals and the health-care system. Zerhouni added that “more basic research and greater and more diverse multidisciplinary interactions will be key.”