In the last days of July, the Food and Drug Administration gave the green light to a clinical trial that has been nearly a decade in the making. The federal agency approved a test of some of the first fruits of human-embryonic-stem-cell research, in a new therapy that could help patients recover from spinal-cord injury.
The trial will be the first to use embryonic stem cells in human beings. The plan was developed by the Geron Corporation, a drug company, which financed the development of the cells in a lab at the University of California at Irvine.
Such partnerships took on even more importance this week, after a federal judge temporarily stopped the National Institutes of Health from financing embryonic-stem-cell research because it is tied to the destruction of embryos. The decision sent shock waves through the scientific community. It also makes arrangements like the one between Hans S. Keirstead, the researcher at Irvine, and Geron an attractive alternative to relying on federal money.
Federal financing has proved to be extremely volatile, even before this week’s ruling. In 1996, a ban on research involving the creation or destruction of human embryos went into effect as part of the budget bill for the Department of Health and Human Services. In 2001, President George W. Bush limited federal financing to research on just a few cell lines. The Obama administration expanded the pool of embryonic-stem-cell lines that could be used in federally financed research in 2009, but the judge’s ruling on Monday overturned that policy.
Working with Geron, says Mr. Keirstead, an associate professor of anatomy and neurobiology at Irvine, has ensured that his research can go forward. And the FDA’s decision in July was a “tipping point” that moved the science from the bench to the bedside, he says.
With the approval of the trial, the FDA has now set standards for testing stem-cell therapies in humans, including delaying trials before they begin if pretrial safety studies hint at any ill effects. “Now there’s a highway through what was a jungle,” Mr. Keirstead says.
Company Support
Hopes for disease treatments have been tied to human embryonic stem cells because they can develop into any cell type, including ones that can repair or prevent certain illnesses. That potential was demonstrated in the first research lines, which were developed from embryos that were created through in vitro fertilization and isolated in James A. Thomson’s laboratory at the University of Wisconsin at Madison in 1998.
At the time, no federal dollars could be used for work that harmed or destroyed human embryos because of the ban on such research that Congress first enacted in 1996. Dr. Thomson, who now heads the university’s program in regenerative biology, says he saw seeking funds from a private company as the only way to do his research. The company that he turned to was Geron. “It was built out of necessity,” Dr. Thomson says.
After Dr. Thomson’s discovery, and around the time President Bush announced his research restrictions, Mr. Keirstead got an idea for using these cells to treat patients with spinal-cord injury. When the spinal cord suffers a blow, the protective sheath around the branches of neural cells is damaged. Without this sheath, made of a substance called myelin, nerve cells eventually die. Embryonic stem cells, Mr. Keirstead believed, could be grown into new myelin-making cells and prevent the neural death that sometimes leaves patients paralyzed.
The 43-year-old researcher and his team were able to find the right conditions to make embryonic cells into oligodendrocytes, cells that produce new myelin around neurons’ axons. They also hit upon the right formula to make cell populations composed mostly of those cells, which would make the therapy ideal for commercial production.
Next, they injected the cells into mice and rats with spinal-cord injuries to see if they helped the animals recover, says Gabriel I. Nistor, a postdoctoral researcher who has worked with Mr. Keirstead since the project’s first days.
And they did. Rats that had been injected with human oligodendrocytes regained the ability to support their own weight, hold up their tails, and urinate, Mr. Nistor says.
The Irvine scientists used three “presidential” lines in their work, so named because the lines were among those eligible for federal financing during the Bush administration. Even though federal dollars were not off-limits for Mr. Keirstead, the likelihood of receiving a grant from the National Institutes of Health for a project with no preliminary data backing it was low, says Oswald Steward, a professor of neurobiology and behavior at Irvine and the director of the university’s center of research on spinal-cord injury.
Like Dr. Thomson before him, Mr. Keirstead went to Geron. “If you want to develop a treatment, you work with companies,” he says. Geron was willing to finance the basic science necessary to develop the treatment, and equipped to shepherd Mr. Keirstead’s work toward a commercial application. Over the next seven years, the company poured a total of about $3.5-million into his research. The rest of the money for his work came from a program run by the University of California system that matched the private company’s contributions.
The company now plans to inject the myelin-producing cells into patients within days of the events that leave them with spinal-cord injuries. The study, which is a Phase I trial, is intended to test only whether the therapy is safe, not how effective it is.
As yet, scientists have little idea of what to expect. Human life spans are decades longer than rats’, and the long-term effects of transplanting oligodendrocytes are unknown, Mr. Nistor says. Geron plans to monitor the study’s subjects for 15 years after the injections.
Many people will be keeping tabs on the trial, says Debra J.H. Mathews, an assistant director of the Johns Hopkins University’s bioethics institute. She believes the study will be under intense public scrutiny. If there are negative side effects in the clinical trial, it could influence financing and public support for the entire field,
“They are going to have to be very thoughtful about how they release data,” says Ms. Mathews, comparing Geron’s trial to an incident in one of gene therapy’s first clinical tests. In 1999 a young man died because of complications in a trial testing the safety of a treatment for liver disease, and the fallout from the tragedy derailed further work in the field.
James M. Wilson, the professor of pathology and laboratory medicine at the University of Pennsylvania who oversaw the gene-therapy trial, wrote an essay in May 2009 in Science magazine warning against moving too quickly in stem-cell research. Premature testing in human subjects could ultimately undermine the field’s growth, he wrote.
At this point both Geron and the FDA appear to be moving slowly. The company first received approval for the trial in early 2009, but then the agency delayed its start after some of the animals injected with the cells in preclinical safety tests developed small cysts. The FDA lifted the hold this summer after Geron developed methods to minimize the chances that cysts would form.
Moving On
Mr. Keirstead is already moving in a new direction. He and his university have licensed the technology to Geron. He has been able to publish the basic research conducted in his own laboratory, including tests of the therapy’s effectiveness, but the future work belongs to the company. “My role will simply be to watch,” says Mr. Keirstead, who is now pursuing other research related to neuron preservation.
About four years ago, he began working on a project to develop motor neurons from human embryonic stem cells with California Stem Cell Inc., a private company that develops clinical applications for stem-cell research and whose scientific advisory board Mr. Keirstead chairs. The $2.5-million project is financed entirely by the California Institute for Regenerative Medicine, which uses state money and private donations to support stem-cell research, he says.
That project is following fast on Geron’s heels: Mr. Keirstead and California Stem Cell recently submitted an application to conduct a clinical trial to the FDA. Unlike Geron, Mr. Keirstead’s new partner has allowed him to submit the results of the preclinical safety studies for publication.
Working with California Stem Cell has come with fewer strings attached, but the scientist says he would not hesitate to work with Geron again. His mission is to treat degenerative diseases in the central nervous system, and working with biotech companies lets him develop the basic science, then turn it over to people with the resources to turn it into a commercially viable product. “I don’t need to be the one to develop the final successful treatment,” he says.
