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Samuel L. Pfaff, Ph.D.
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In March of 2009, the Christopher & Dana Reeve Foundation joined the scientific community in hailing President Obama's lifting of the restrictions on Federally-financed research on human embryonic stem cells. Yet long before the President acted, the Foundation had laid the groundwork for devoting more resources to stem cell studies. (Visit our Stem Cell Research Center)
The promise of human stem cells
Whether extracted from embryos, derived from adult cells, or awakened from dormancy in the body's depths, human stem cells promise to usher in an age of regenerative medicine. Because these primitive cells can differentiate into all 200 of the known cell types, scientists may one day be able to prod them to spin off the specialized cells that will become bone, a heart valve, or any other replacement for an injured or diseased body part. Indeed, for some serious conditions caused by a single type of missing or misbehaving cell-like insulin-secreting cells in Type I diabetes stem cell therapies already are on the horizon.
Yet huge challenges remain before these cells can be used safely and reliably in people with spinal cord injuries, which are among the most complicated traumas that the body can endure. In theory, these cells would be part of a series of treatments designed to contain and mop up the messy disaster scene that a spinal cord injury had left behind, to recreate the intricate chains of neurons and their support cells that comprise the spinal cord, and then to restore lost function.
The experts weight in
Recognizing both the enormous potential of stem cell therapies and the invaluable role the cells can play in research, the Reeve Foundation convened a panel of international experts on stem cell biology in 2007. Participants included prominent researchers from the public and private sectors as well as physician-scientists who treat people with spinal cord injuries.
"We asked the distinguished participants to help us clarify our priorities and to suggest the steps we should take to accomplish them," said Susan Howley, executive vice president for research at the Foundation.
"The white paper that emerged from the workshop guided our Board's strategic decisions about how best to invest more resources in stem cell research."
The Reeve Foundation stem cell initiative
Based on the workshop's recommendations, the Foundation launched a major stem cell initiative last year, building on the multi-disciplinary talents and cuttingedge laboratory facilities of its International Research Consortium on Spinal Cord Injury. The initiative has three components:
- Fred H. Gage, Ph.D., a veteran spinal cord researcher and a member of the Consortium who is based at the Salk Institute, in La Jolla, CA, agreed to redirect his work for the Consortium to focus more on stem cell research, particularly on experiments with human embryonic stem cells.
- Samuel L. Pfaff, Ph.D., an expert in stem-cell biology and neurodevelopment, became another member of the Consortium. The addition of Dr. Pfaff and his experienced staff, also at the Salk Institute, complements the work of other researchers, paving the way for collaborations involving stem cells.
- A core laboratory, dedicated to stem cell biology, was set up at the Salk Institute under Dr. Gage's direction. The new core supplies undifferentiated stem cells and stem cell expertise to Consortium scientists, and it is a training ground for the young researchers who work under them.
The Reeve Foundation initiative reflects the growing importance of human and animal embryonic stem cells in basic and applied research. In the spinal cord field, they enable scientists to study how the human cord is assembled in the first place and to identify and test potential treatments for injuries. Experts say that these investigations are likely to bear fruit before scientists learn how to use the actual cells, safely and with predictable results, at the bedside.
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Fred H. Gage, Ph.D.
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Stem cells to motor neurons
For example, Dr. Gage has been coaxing human embryonic stem cells in laboratory dishes to become motor neurons and their support cells and then to form working spinal circuits. In the body, these circuits transmit signals from the brain and spinal cord to the muscles involved in walking and other voluntary movements. Dr. Gage and his colleagues use these tiny in vitro models to observe precisely what happens when the axons are cut, and then these scientists can screen various drugs to see if they limit the severity of the damage. Such experiments would be impossible with human subjects. "We already have come up with compounds that decrease the highly damaging inflammatory response to injury," Dr. Gage explained, adding that, in a person, this response continues for weeks and amplifies the severity of the injury. "The next step is to share these findings with the researchers who use animal models to see if our potential treatments work in vivo. This is a whole new approach to science, going from human cells to animals, but it is a necessary step to test for effectiveness and safety."
Building better tools
Dr. Pfaff, who heads the Gene Expression Laboratory at the Salk Institute, describes his main role in the Consortium as "enhancing the tools, technologies, and experimentation" that are available with stem cells. "Our current interest is in how we might create useful cell types and how those cells might be reintroduced into the injured spinal cord," he says. "The good news is that we already know enough about the signaling and molecular mechanisms so that we can turn embryonic stem cells into motor neurons with high efficiency."
In his research, Dr. Pfaff uses mouse embryonic stem cells to study how neurons are generated, put out axons, and link up to one another. His goal is to apply the "same tricks" that occur during the embryonic stage to restore all the elements of the spinal cord. He notes that one advantage of working with mouse cells is the availability of several lines that have been engineered to have genetic markers, which makes it possible to track the cells as they differentiate. Moreover, mouse motor neurons mature in seven to eight days, compared to 35 days for human cells. This accelerated pace also reduces the number of variables that may alter the cells. Dr. Pfaff emphasizes, however, that what he gleans from mouse cells has direct parallels in human cells. "Our end game is to get this into a therapy using human cells."
Bridging the gap in the spinal cord
He already is collaborating with Aileen Anderson, Ph.D., who runs the Consortium's Injury Core Laboratory, located at the University of California-Irvine. Using Dr. Anderson's mouse models, they are transplanting Dr. Pfaff 's stem-cell derived motor neurons into the injured spinal cord. They are testing whether the long axons that motor neurons project will stay within the spinal cord — they normally head out for muscles —and bridge the gap the injury makes. The two scientists are hopeful that spinal neurons will latch onto the transplanted cells and extend along them to rewire lost spinal circuitry. The new stem cell core laboratory is designed to support such collaborations. It cultivates stem cells in a highly controlled environment, which is particularly important for human cells because their long incubation increases the chance that something may go awry. The staff is skilled in maintaining the cells in their undifferentiated state so they can be handed off to Consortium members to generate the cell types they want to study. The laboratory also supplies the growth medium for the cells, which has to be very carefully monitored, as well as the so-called feeder cells that nourish stem cells and act as a scaffold to support them while they develop.
President Obama's Executive Order will make it easier to accomplish exchanges among laboratories, whether they are in the same building or thousands of miles apart.
"Thanks to the President's action, all our communication and collaborations will be more efficient," said Dr. Gage. "We no longer will have to maintain completely separate facilities for our work on the limited number of stem cells lines that were approved for Federal research and others that could be used only in studies funded by private sources."
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