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While the bioethical debate over stem-cell research rages on, Penn scientists are making progress using adult-human and animal stem cells—and hoping for broader future support for studies using embryonic stem cells.

By Joan Capuzzi Giresi | Illustration by Anastasia Vasilakis

“Only one in every million cells in the human body—the stem cells—really matter. Everything else is just a product of these,” said Dr. Stephen Emerson, the Francis C. Wood Professor of Medicine, chief of the Division of Hematology-Oncology, and associate director of clinical research for the Abramson Cancer Center.

A passionate advocate of stem-cell research, Emerson testified at a legistlative hearing held on Penn’s campus last September at which he called stem-cell biology the “Rosetta Stone” of modern health and disease treatment. “Discovering the language of stem cells, and the secrets of its translation, will make clear much that has been previously undecipherable,” he said. “How do you repair heart muscle damaged by heart attacks? Deliver the right stem-cell population to the damaged tissue, at the right time, with the right hormones to instruct the cells to form heart muscle. How do we prevent the crippling blindness of diabetes? Prevent blood-vessel stem cells from rushing headlong into the diabetic eye, forming new, chaotic blood vessels that bleed and clog.

“Cardiology, diabetes, obesity, cancer, blindness, osteoporosis, Alzheimer’s disease, even aging itself, are fundamentally all stem-cell processes.”

Residing in every tissue, from bone marrow to brain, pancreas to skin, plant to fungus, stem cells are the conductors in the complex orchestra that is the body—of fruit flies, humans, and every species in between. They direct the fate of every other cell, spawning new healthy cells to replenish organisms or flipping the “on” switch to diseases like cancers, autoimmune disorders, Alzheimer’s, and osteoporosis—and, perhaps, holding the key to treatments or cures for these and other now intractable conditions.

They are also, of course, the subject of one of the most intense ongoing bioethical and political debates in the United States, over the regulation of research using embryonic stem cells. First isolated in 1998 [“James Thomson and the Holy Grail,” Jan/Feb 2002], embryonic stem cells are harvested from the inner cell mass of the early-stage embryo, or blastocyst, at about five days old in a process that destroys the embryo.

Opponents of embryonic stem-cell research liken this to abortion and favor research focused on adult stem cells (which refers to cells isolated from any post-fetal tissue). However, while adult stem cells generally give rise to cells characteristic of their respective host tissues, embryonic stem cells are what is known as pluripotent—able to develop into any type of tissue and therefore of much greater potential to understand and treat a wide range of diseases. “Adult stem cells are already committed, and we cannot easily twist them into different images,” says Dr. Meenhard Herlyn, who leads the Molecular and Cellular Oncogenesis Program at the Wister Institute and has used embryonic stem cells to study the molecular mechanisms of malignant melanoma.

In August 2001, President Bush approved federal funding for biomedical investigation using embryonic stem cells—but only for studies involving cell lines that had already been established at the time. Many experts have argued that only a handful of these aging “approved” lines are actually viable, due to viruses and genetic mutations acquired over time.

“They’re too tired, not growing right, just burnt out!” says Dr. Arthur Caplan, the Emmanuel & Robert Hart Professor of Bioethics, chair of the Department of Medical Ethics, and director of the Center for Bioethics. Dr. John Wolfe, professor of pathobiology and pediatrics and director of Penn’s W.F. Goodman Center for Comparative Medical Genetics, considered using the established stem-cell lines for his research—aimed at correcting the genetic defects that cause certain inherited brain diseases in children—but later ruled them to be “inherently flawed.”

The federally sanctioned cell lines are, at best, a small group of mediocre selections to which every scientist has equal access. This is hardly inspiring for investigators, explains Dr. Glen Gaulton, professor of pathology/lab medicine and vice dean for research and research training at the medical school. “What’s the competitive advantage?” he asks. “As a researcher, you need to create a niche that separates you from others. That becomes difficult when you don’t have a unique tool to use in your work.”

Public support for embryonic stem-cell research appears to be running high—a poll conducted this summer by the Opinion Research Council for the Coalition for the Advancement of Medical Research, a group that supports stem-cell research, found that 72 percent of respondents were in favor of allowing research on embryos that would otherwise be discarded. Another poll found 69 percent of Republican doctors favored expansion of federal funding to support research on such embryos.

Nevertheless, President Bush reaffirmed his position in July, exercising the first veto of his presidency to reject a bill that would have overturned his executive order and expanded federal support for embryonic stem-cell research involving the estimated 400,000 “spare” embyros in fertility clinics, the great majority of which will ultimately face destruction. Congress failed to override the veto—in the Senate, by just one vote—and so the situation for federal funding remains the same as it has been since 2001.

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 employed—via bone-marrow transplantation—to 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 myoblasts—muscle stem cells—into 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 cells—the signals that regulate their growth and differentiation—is 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 pursue—and the bulk of funding is federal for all biological research—people 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 law—the Pennsylvania Abortion Control Act—has 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 state—one such proposal was the subject of the hearing held on campus a year ago, at which both Caplan and Emerson testified—but they have so far failed to muster enough support to bring a vote to the floor.

Establishing a center for research on stem cells—included within the general field of regenerative medicine, which also encompasses gene therapy and other cell-based therapies—was 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 boundaries—including 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 building—the Hill Pavilion, set to open this year—will 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.’”

One critical step that may one day lead to developing therapies that employ stem cells is diagramming the journey the stem cells make once introduced into damaged tissue. At the medical school, Dr. Jerry Glickson, research professor in the Department of Radiology, tags molecules with substances visible by modern imaging techniques. Working with stem-cell researchers, Glickson labels myoblasts and bone-marrow stem cells with iron-oxide particles—“a glorified version of rust,” he says—prior to injecting them into diseased mouse hearts. Under MRI, he then follows the labeled particles to monitor their integration into damaged heart muscle, and their differentiation patterns.

Associate Professor of Radiology Harish Poptani uses a similar technique to observe the fate of stem cells injected into the brain tissue of animals with lysosomal storage disorders. He and the lead investigator, pediatric pathobiologist John Wolfe, hope that the procedure, which prolongs the lives of affected mice by about a year, can one day be used to help children, in whom these disorders are also lethal. An understanding of the mechanisms by which stem cells repair diseased neural tissue might one day lead to therapeutic cloning techniques using embryonic stem cells—which, Wolfe explains, are more likely than adult stem cells to propagate in sufficient numbers to benefit patients suffering from lysosomal storage disorders, and even strokes and tumors.

Dr. George Cotsarelis, the Albert M. Kligman Associate Professor of Dermatology at the medical school, who runs one of the world’s leading laboratories investigating epithelial (skin) stem cells, looks at the molecular signals responsible for the four major changes the skin undergoes: alopecia (baldness), wound healing, aging, and cancer formation. This, in hopes of eventually targeting pathways that regrow hair, repair wounds, rejuvenate old skin and prevent uncontrolled cell growth, or cancer.

“The stem cells really are the common denominator in all of these seemingly different processes,” he explains.

Cotsarelis showed that all cutaneous cell lines—from hair to the skin surface, or epidermis—are generated by special stem cells in the “bulge,” or outer layer, of the hair follicle. He also defined a group of genes expressed in follicular stem cells, including specialized receptors and signaling molecules, that are upregulated in the follicle. Cotsarelis hopes to unravel the convoluted cascade of molecular events responsible for hair follicle cycling, which is at the heart of most cases of hair loss. “What are the signals telling the stem cells which fate to take?” he asks.

His research opens the door to new therapies that target the genes responsible for controlling follicular stem cells, “so they would make a hair where they normally would not have.” Cotsarelis might also one day be able to duplicate these molecular events in vitro in order to clone hair follicles for transplantation into patients suffering from hair loss. He thinks human trials using stem cells to treat alopecia will take place in the next five years, and he predicts that his team’s latest finding could lead to treatments aimed at enhancing the flow of cells from the hair follicle to the epidermis, thereby accelerating the mending of broken skin.

The field of oncology may be one of the biggest beneficiaries of stem-cell work. When doctors diagnose colon cancer or lymphoma, for instance, they are detecting what hematologist-oncologist Emerson calls “the tip of the lethal iceberg,” a minute population of stem cells gone awry.

Dr. Anil Rustgi, the T. Grier Miller Professor of Medicine and Genetics at the medical school and chief of the Gastroenterology Division, studies the molecular machinations of gastrointestinal (GI) cancers, with a special focus on esophageal cancer. One of the most prevalent malignancies in the world, esophageal cancer is also among the deadliest because it produces rapid growth yet subtle symptoms.

In the lab, Rustgi identifies and characterizes normal esophageal stem cells, and hunts down stem cells in diseased tissue from his patients’ surgical biopsies, aiming to formulate new treatment ideas by observing and manipulating the very stem cells that sicken his patients.

While the adult stem cells he studies help him piece together the mysteries of esophageal cancer, he says “the Holy Grail would be to figure out how human embryonic stem cells transdifferentiate into other tissue types, and then use these cells to develop new and exciting strategies to treat cancers.”

In his lab, Emerson studies the pathways for regulating the maturation and output of bone-marrow stem cells. “The bone marrow is the nursery school of blood cells,” he explains. These stem cells sometimes churn out progeny in abnormal proportions, resulting in leukemias. Emerson’s research team recently identified the protein NF-Ya as prime candidate for a master regulatory gene governing hematopoiesis, or blood-cell production. He wants to find a way of controlling the directives that NF-Ya issues to its stem cell subjects, forcing them either to self-renew or to differentiate into daughter cells.

But Emerson is growing impatient with bone-marrow stem cells because, he says, they don’t grow quickly enough, or infinitely. “Our 25 years of studying adult [bone-marrow] stem cells have still not given us these answers,” he laments.

In considering the future of medicine, Gaulton makes a distinction between the school’s priorities for attacking near-epidemic conditions like cardiovascular disease and diabetes and obesity, and research on stem cells. “The priorities in the other areas are imperative because we know more about those individual diseases. We have exciting things to target in those diseases. We have patients we can study directly and really make dramatic, short-term—meaning one-to-three year—differences,” he says. “Stem cells is a longer trajectory. We don’t know nearly enough about the basic biology as we need to, so basic biology is needed for both adult stem cells and embryonic stem cells. Therefore, the application of those stem cells to disease is also way behind other disease areas.”

But the view from 20 years on is likely to be different. “The upside future potential for stem-cell research and the application of that to a number of specific diseases, cancer maybe being the most clear-cut one, are enormous, absolutely enormous,” he says. “So it’s a little lower [priority] right now, but just a little.”

Funding remains the dominant factor impeding progress. “You’ve got to have the talented people who can identify great questions and propose great experiments; then you’ve got to have the money and the facilities to support them to do it. Otherwise, they’ll just migrate to other areas. Right now, it’s just very, very difficult.”

What little research money there is in the field is mostly in adult stem-cells, “which are technically very demanding,” he says. “There are very, very few talented stem-cell researchers, here at Penn and nationally. We’d love to recruit more.”

If, as seems at least plausible, the next presidential administration (Republican or Democratic) takes a more supportive position on federal funding for embryonic stem-cell research, then Penn and other institutions will be able to shift their attention and resources more in that direction, says Gaulton. Then the actual science—the hard intellectual business of unlocking the secrets of stem cells, and adapting that knowledge to help patients—can begin to overtake the politics and the promises.

Joan Capuzzi Giresi C’86 V’98 is a journalist and a veterinarian in the Philadelphia area.

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