Harvard’s Lee Rubin says the near-term promise of embryonic stem cells will be realized in drug screening rather than in therapeutics.
Alexandra Goho
Over the last 10 years, the prospect of turning embryonic stem cells into therapies for degenerative diseases or replacement tissues has generated enormous excitement within the scientific community and the public. However, “Using stem cells as therapeutics is not the easiest, most straightforward path to producing a therapy,” says Lee Rubin, director of translational medicine at the Harvard Stem Cell Institute. “I believe it will work and there will be breakthroughs involved, but those breakthrough therapies may be far off in time.”
Instead, Rubin predicts that using embryonic stem cells for drug screening—an application that has received much less attention—is more likely to have a near-term impact. Rubin joined the Harvard faculty this summer to launch a stem cell-based drug-screening program, bringing years of experience in drug development from the biotech industry with him (See related story, The two-way career path between academia and biotech, about Rubin’s career).
His group is using motor neurons derived from mouse embryonic stem cells to screen thousands of compounds to find new drugs for spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), also called Lou Gehrig’s disease. Both diseases result from the loss of motor neurons.
Rubin believes the first therapies to result from stem cells will not be cells but small molecule drugs selected from this screening process. Some of these drugs might target stem cells in the body and encourage tissue repair. Embryonic stem cells could also provide researchers with an unlimited supply of different cell types, such as pancreatic and cardiac cells, for screening drugs.
Find the medicine
In conventional drug discovery, researchers typically need millions to billions of cells to screen a library of hundreds of thousands of drug compounds. To obtain that many motor neurons, researchers would need to dissect thousands of mice. Since that’s not a feasible option, SMA researchers use the more abundant connective tissue cells called fibroblasts from patients with the disease. The problem is that these cells aren’t even affected by SMA, says Rubin. “It really may limit the kinds of drugs you could discover.”
Over the years, Rubin has become an expert in generating large numbers of motor neurons—billions in just a week—from mouse embryonic stem cells. The neurons come from stem cells isolated from mice that have the genetic mutation for either SMA or ALS. Using an automated screening system, the researchers test hundreds of thousands of drug compounds to see which ones might rescue the motor neurons from death.
Rubin and his colleagues have already identified one promising molecule—a known drug compound—from their SMA drug screen. In a preliminary experiment in mice, the compound increased levels of a particular motor neuron protein. “We don’t know if it’s going to promote survival [of motor neurons], but we know that it elevates the protein in the mouse,” says Rubin.
Discovery tool
The next step will be to test any drug candidates in human motor neurons. Kevin Eggan, Rubin’s colleague at the Harvard Stem Cell Institute, has developed a way of isolating stem cells from human embryos that bear the genetic mutation associated with SMA. Rubin explains that the embryos are derived from in vitro fertilization efforts in which embryos were screened for the disease but were not implanted.
Gabriela Cezar, a stem cell biologist at the University of Wisconsin, Madison, says human embryonic stem cells could also be invaluable for predicting the toxicity of compounds before they enter into clinical trials. Current toxicity tests rely on animals or human cells that have been immortalized through genetic mutations. “But these cells are completely artificial systems. They don’t behave like their in vivo counterparts,” says Cezar. Instead, testing drug toxicity on liver or heart cells derived from human embryonic stem cells could be much more predictive, she adds.
For now, only a handful of labs are investigating the use of embryonic stem cells for drug discovery. Cezar hopes that will change. “This is an under-looked area that could really benefit patients in the near future,” she says.
Related story: The two-way career path between academia and biotech. Lee Rubin says it’s becoming easier to move between careers in industrial drug development and academia.