While Emerson and others express frustration at the federal limits, he and most investigators at Penn are proceeding with studies using adult stem cells while they hope for a change in the status quo. Meanwhile, research involving animal embryonic stem cells in the School of Veterinary Medicine and elsewhere across the University, which might one day be adapted to humans, is progressing without the ethical and political obstacles that complicate human research.
However great their eventual promise in curing disease, stem cells offer little immediate gratification. “Some proponents of stem-cell research are saying, ‘If we can fund it, people will be out of their wheelchairs by next Christmas.’ This is simply not true,” says Caplan. “If you’re going to do research on stem cells, you have to be in there for the long haul. It’s going to take decades to understand them with precision.”
Adult stem cells have been studied since 1960, and have been routinely employedvia bone-marrow transplantationto treat leukemias for decades. (They are currently used in treatments for more than 100 diseases and conditions.) Yet the doctors performing the procedures were, in a sense, like drivers who operate a car without understanding what happens under the hood: They didn’t really know how the stem cells worked.
Things haven’t changed much, to hear Dr. Mark Oyama, associate professor of cardiology at Penn’s Ryan Veterinary Hospital. Oyama transfers myoblastsmuscle stem cellsinto canine hearts to determine whether they can repair damaged heart muscle. “You put the cells in, and no one actually knows what they’re going to do,” he says.
Stem cells work through thousands of time-dependent steps, all directed by genes. “Understanding the biology of stem cellsthe signals that regulate their growth and differentiationis astronomically complex,” explains Gaulton. “If we’re lucky, we grasp one percent of it. No, probably a tenth of a percent.”
When discoveries do eventually come, researchers in the United States may be reading about them rather than making them. Unlike most areas of biomedical research, in which America is the world leader, the field of stem-cell research has yet to be established in this country. This is at least partly due to the U.S.’s stance on embryonic stem-cell research, which contrasts starkly with the aggressive approaches taken by countries like China, Singapore, Korea, India, Australia, the Netherlands, the U.K., and Canada.
While a few U.S. institutions have clusters of stem-cell investigators, Gaulton says, “There isn’t any one single ‘Go to’ place for stem cells. Everybody is jogging. No one is running.”
The reason is the lack of federal funding, which makes it especially difficult to build a cadre of young researchers in a field, he adds. “Talented investigators become engaged in areas of research because, one, they are passionate about the area, and, two, they know that if they do their research well and their ideas are terrific, they will be funded to do that work. It’s a challenging and demanding life,” Gaulton says. “So if there’s no funding out there to pursueand the bulk of funding is federal for all biological researchpeople are just going to stay away from it. It’s difficult enough to get money for biological research now, period, in any area.”
Given the level of public support and the perceived long-term benefit to being a center for stem-cell discoveries, some of the states have stepped in to fill the gap in federal support with funding of their own to support embryonic stem-cell research. New Jersey, Maryland, Illinois, Connecticut, Massachusetts, and California, have passed initiatives, with California’s bond measure to provide $3 billion in support over the next 10 years garnering the most publicity. (After the measure passed in November 2004, opponents sued to stop the bond issue, charging that the agency created was unconstitutional. In July, California’s Republican Governor Arnold Schwarzenegger approved a state loan of $150 million to keep the agency afloat until the courts rule.)
Pennsylania ranks fifth in NIH funding among the states, and boasts, in addition to Penn (ranked No. 2 in the nation for grants), institutions like Thomas Jefferson University in Philadelphia and the University of Pittsburgh, among others, with strong biomedical expertise. However, not only is Pennsylvania not among the states vying for a leadership position in supporting embryonic stem-cell research, but an existing lawthe Pennsylvania Abortion Control Acthas clouded the prospects for such research even further. Passed in 1989, the act forbids fetal experimentation not intended to benefit the particular fetus in question; a fetus is defined as an organism from the point of conception to live birth. The law was passed before embryonic stem cells were discovered, and whether it would apply to such research has not been established. In the wake of President Bush’s 2001 order, then-Governor Ridge’s administration went on record as saying that Pennsylvania’s law does not prohibit research on existing stem cell lines harvested from embryos outside the state; however, there have been no court cases testing that interpretation. In the meantime, few dare cross the threshold.
Some Democratic legislators in Harrisburg have tried to pass a bill supporting embryonic stem-cell research in the stateone such proposal was the subject of the hearing held on campus a year ago, at which both Caplan and Emerson testifiedbut they have so far failed to muster enough support to bring a vote to the floor.
Establishing a center for research on stem cellsincluded within the general field of regenerative medicine, which also encompasses gene therapy and other cell-based therapieswas listed among the “upper tier” of goals in the School of Medicine’s strategic plan completed by early 2003, according to Gaulton. Based on strategic urgency, links to clinical needs and uses, and programmatic issues, the school decided to first develop institutes in cardiovascular biology; a program uniting diabetes, obesity, and metabolism; and translational medicine. “They’re now under way, we’ve established the funding for them, chosen the leaders, and now we’re moving towards the second wave of items. Stem cells are in that second wave.”
A research institute at Penn that would focus on stem cells and other areas of regenerative medicine could begin operating sometime in the next year, according to Dr. Perry Molinoff, the A.N. Richards Professor and emeritus chair of the Department of Pharmacology in the medical school, who stepped down as vice provost for research in July. The institute would focus initially on investigations with animal stem cells and human adult stem cells, and eventually would incorporate work on the human embryonic stem-cell lines established and approved by the federal government. Additional faculty would be recruited for the venture, which would cross multiple school boundariesincluding the School of Arts and Sciences, the School of Engineering and Applied Science (where bioengineering is an increasing focus) as well as the medical and veterinary schools, and possibly the dental school. (As of late summer, negotiations were under way with a candidate to lead the institute, according to Gaulton.)
“Given our established expertise in developmental biology and regenerative medicine, we hope we can be significant players in the field,” Molinoff says. Penn also possesses another unique asset in Dr. Ralph Brinster, the Richard King Mellon professor of reproductive physiology at the veterinary school, who pioneered the field of animal transgenesis, or cloning. “We will be building on his contributions,” Molinoff says.
This fall Brinster will receive the prestigious Gairdner Foundation International Award for his groundbreaking discoveries in mammalian germ-line modification. Early in his career, he established techniques for culturing and manipulating eggs. In 1994, he made international news when he transplanted the stem cells of one mouse into another. The resultant germ cells retained the genes of the donor mouse. More recently, he has developed a procedure for altering genes in spermatogonial stem cells, the cells that produce sperm [“Gazetteer,” May/June 2005].
The veterinary school is morphing into an active hub for stem-cell work. Its new research buildingthe Hill Pavilion, set to open this yearwill include a number of stem-cell labs for both current and newly recruited stem-cell researchers. And plans are in the works to expand the germ-cell center at the New Bolton Center to focus on animal embryonic stem cells. All told, the vet school will be investing some $2.5 million in its stem-cell initiative.
Other researchers at the vet school include Dr. Ina Dobrinski, the Marion Dilly and David George Jones Chair in Animal Reproduction and director of the school’s Center for Animal Transgenesis, who manipulates and transplants male germ cells in order to improve the health and productivity of farm animals. [“Gazetteer,” Nov/Dec 2002]. Veterinarian Susan Volk, who also holds faculty appointments at the medical and dental schools, prods bone-marrow stem cells into forming new bone. Her technique might eventually be used to enhance the repair of fractures and bone gaps.
Veterinary cardiologist Oyama hopes his work in dogs will someday be a boon to managing certain types of human heart disease. By tracking the migration of muscle stem cells injected into both normal dog hearts and hearts rendered flabby by dilated cardiomyopathy, a cardiac muscle-wasting disease, he aims to shed light on the mending mechanisms of myoblast-transfer in people with ischemic heart damage.
A newcomer from the University of Illinois, Oyama believes Penn uniquely complements his research, and vice versa. “We have access here to all the cutting-edge stuff in human medicine. And as long as we have signed consent forms from pet owners, we get to do research in animals that the regulations prohibit in people.”
Dr. Stephen DiNardo, professor of cell and developmental biology at the medical school, studies the activity of stem cells during spermatogenesis in fruit flies. Stem cells divide asymmetrically, generating new stem cells as well as daughter cells, which become end products like eggs and sperm. By marking the stem cells with pigment, DiNardo follows their developmental journey and analyzes the constellation of genes expressed therein. Understanding the molecular signals in the process provides insight into what can go wrong in producing sperm and other types of cells.
DiNardo says the fruit-fly model is applicable to other species because at their core, these mechanisms are quite comparable. “The kinds of molecular pathways that make a limb in a fruit fly are eerily similar to those in vertebrates,” he explains, “and it’s this amount of ‘identical’ that wows me.”
While animal, and even insect, models are ideal for developing what Dr. Phillip Scott, associate dean for research at the veterinary school, calls “a fundamental understanding of biology for all species,” interspecies variations in physiology do exist. Therefore, lessons learned from one organism cannot always be applied directly to treatment modalities for another.
Speaking to the legislators last September, Emerson made the case for studying human as well as non-human embryonic stem cells by paraphrasing Alexander Pope: “‘The only proper study of man is man himself.’”
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©2006 The Pennsylvania Gazette
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FEATURE: Promise and Politics