Facing the limits of stem cell research

How will Bush's recent decision affect universities' pursuit of embryonic stem cells?

BY KATE MORAN

Dr. Diane Krause, an associate professor of laboratory medicine and pathology at the Yale School of Medicine (YSM), grapples with issues of semantics. She chafes if one describes her work as "adult" stem cell research, a label she insists is not scientifically precise.

"The public seems to have invented this term," she said. "We've been working on adult-derived stem cells for years and never called them that—we called them what they were. If we got them from the bone marrow, they were bone-marrow-derived stem cells; if we got them from the liver, they were liver stem cells."

Endorsed by scientists or not, the term "adult" stem cell does have a specific meaning. It is the ethically innocuous cousin of the embryonic stem cell, a controversial new re-search tool that has provoked reproach from anti-abortion and religious groups.

Stem cells, embryonic or otherwise, are the body's chameleons, able to transform into multiple kinds of tissue. Researchers have proven, for example, that bone marrow stem cells in adults can transform into heart and liver cells, while those in the skin can differentiate into brain, muscle, and fat cells. This versatility could prove invaluable for treating chronic conditions such as Parkinson's disease, diabetes, and osteoporosis.

Embryonic stem cells are coveted by scientists because they are even more plastic—or adaptable—than those culled from adults. Yet until this summer, the government withheld federal funds from embryonic stem cell research because the process of harvesting the cells causes the embryos to die. Then on Thurs., Aug. 9, after months of consultation with researchers and ethicists alike, President George W. Bush, DC '68, lifted restrictions on federal dollars—but only for research on stem cell lines that had been created by the time of his decision. The National Institutes of Health (NIH), which distribute the funds, have estimated that some 60 stem cell lines around the world are available to federally financed researchers.

From the perspective of the last two decades, when federal money was entirely proscribed from research on human embryos, Bush's decision seems permissive. Daniel Kevles, Yale's Stanley Woodward Professor of History, called it "a step in a more liberal or more moderate direction. What he did was open the door—he opened it a crack." Still, Bush's position is decidedly more conservative than that of President Bill Clinton, LAW '73, who had proposed allowing federal dollars for embryonic stem cell research, as long as the actual extraction of the cells was not performed with government funds.

The decision "was politically savvy," Margaret Farley, the Gilbert L. Stark Professor of Christian Ethics at the Divinity School and co-chair of the Interdisciplinary Bioethics Project, said. "He tried to walk a thin line and not close [all research] off, but he also seemed not to change from what he promised his more conservative supporters. My own hunch is that he got lucky when he found out there were 60 or more cell lines—there's his solution."

But many scientists are skeptical that all of the 60-odd stem cell lines are viable. Some of the cell lines are owned by private firms, which have the power to restrict access or charge costly fees, and others have not been submitted to peer review and could be contaminated.

At the present time, no Yale researchers are conducting studies on embryonic stem cells, though work is happening at other major research universities such as Harvard, Johns Hopkins, and the University of Wisconsin, where Dr. James Thomson first isolated embryonic stem cells in 1998. Will scientists at Yale, who are often funded with federal dollars, soon begin to undertake embryonic stem cell work—or does Bush's plan present too many hurdles?

KRAUSE, FOR ONE, HAS NO INTENTION OF PURSUING RESEARCH with human embryonic stem cells, although she has been experimenting with plasticity in mouse and bone marrow stem cells for some time.

This year, she and Dr. Neil Theise of the New York University School of Medicine proved that stem cells in bone marrow can manufacture blood as well as a variety of other cells. They transplanted a single male-derived bone marrow stem cell into a female mouse and traced it through its Y chromosome, which is not found in females. They later found Y chromosomes in the blood—and the liver, skin, and lungs. "That was the first proof that there is a population of cells in the bone marrow that can make blood and other stuff," Krause said. "That's where you get the idea of plasticity—they can do so many different things." Her research group later demonstrated the same was possible in humans.

Anti-abortion groups have suggested that research like Krause's, which shows "adult" stem cells are versatile, could obviate the need for work on human embryos. But Krause said embryonic stem cells provide essential clues to help shape her own research. In fact, she appeared before a Senate subcommittee, led by stem cell advocates Tom Harkin (D-IA) and Arlen

Specter (R-PA) on Wed., Jul. 18, in support of federally funded stem cell research.

"Human embryonic stem cells hold promise, and that's why they should be funded," Krause told the Herald. "They teach us so much about development, which we can apply to other cells."

Dr. Jeffery Kocsis, a professor of neurobiology at YSM, harvests "stem-like cells" from a particular zone of the brain to repair myelin, the insulation that wraps around nerve fibers. Like Krause, he does not use embryonic stem cells directly, but he agreed, "If we limit research on embryonic stem cells, we may miss opportunities with adult stem cells for further development of potential therapies. We still don't know the potential of these cells."

Although researchers have offered sanguine predictions, embryonic stem cell research remains at an early stage of development; clinical applications will not be available for years. But Kevles, who co-teaches Introduction to the History of Medicine and Science, predicts that Bush will feel a hearty push to make more federal funds available as studies begin to progress. "A lot of people think [Bush] didn't go far enough, but the pressure isn't really there for him to go much further since we're only talking potential now," Kevles said. "But the first time scientists in some laboratory, whether public or private, develop an effective therapy, there will be public pressure for opening the door much more widely. It's almost impossible to halt."

Harvard's Doug Melton conducts human embryonic stem cell research. COURTESY HARVARD UNIVERSITY

The promise of therapy has seduced public opinion in the past. In vitro fertilization, for example, would have been rejected several decades ago, Dr. Thomas Duffy, a professor of internal medicine at YSM who supports Bush's cautious approach, said. But now, he said, "not only has this allowed many people in society to have babies that would otherwise not have—it has also been a complete shift in how we perceive parenting. Once potential was realized, I think society was moved to accept the reality of what science offered."

For the public, said Dr. Dennis Cooper, clinical director of the medical school's blood stem cell transplant program, stem cells are an abstraction at this point. "But let's say someone shows they can fix a major medical problem," he said. "At that point, would the same barriers exist?" These days, he said, there seem to be few ethical objections to taking hearts for transplant from patients who are braindead but on life support—and thus technically alive.

But to expect a turnaround among anti-abortion voters if a treatment were found is to misunderstand the conservative mind, Gene Outka, the Dwight Professor of Philosophy and Christian Ethics and chair of a Yale working group on the ethics of stem cell research, said. "Clearheaded conservatives would still say we welcome these results, but we still wonder if embryos should be used. We're opposed to doing it in a certain way."

Outka identified himself as a conservative member of the working group, which formed two years ago under the auspices of the Interdisciplinary Bioethics Project. The 14-member working group, composed of representatives from the medical, law, divinity, and management schools, meets monthly to discuss moral questions but has no regulatory power over research projects in the University.

IF A RESEARCHER AT YALE
did want to conduct embryonic stem cell research, his project would be overseen by an institutional review board (IRB) to ensure that the cell lines were obtained in compliance with federal regulations, Dr. Maurice Ma-honey, the chairman of YSM's Human Investigation Committee, said.

And what is the likelihood that a Yale investigator will instigate embryonic stem cell research?

Theoretically, Yale researchers funded by the NIH could, for the first time ever, use government capital for embryonic stem cell research. Yet the cumbersome process of obtaining cell lines will likely impede new studies from beginning here anytime soon.

Diane Krause, an associate professor at the Yale Medical School, testifies before Congress about the benefits of stem cell research. COURTESY CNN.COM

Already, researchers are expressing doubts about the 60-plus stem cell lines pledged by Bush. Recent reports in newspapers suggest that fewer than 60 really exist, and those that do are of questionable quality.

"I don't know anything about these 60," Krause said. "They may or may not be legit and sterile and capable of making every cell in the body."

Kocsis said researchers are often skeptical of samples prepared outside of their own lab—which they always would be under Bush's proposal. "If one is limited in acquiring the cells from a particular source, you're not going to have full information on how they were handled or the way they were prepared," he said. "Scientists like to get close to the development of cells, so as things work and don't work, they have an idea why."

At Harvard University, Professor Doug Melton is investigating human embryonic stem cells that he obtained from a collaboration with researchers in Israel. In a visit to Washington, D.C. on Wed., Sept. 5, he told the Senate Committee on Health, Education, Labor, and Pensions, "The 60-plus cell lines will not be sufficient for the years of research required to investigate therapies with these cells. Looking ahead to clinical applications, including transplant and the problem of immunological rejection, there will certainly be a need for broader genetic diversity of cell lines." He also said mouse embryonic stem cells can mutate or lose their potential to differentiate with age.

For now, many scientists are unsure whether the owners of the 60 stem cell lines, many of which are private companies in foreign countries, will be willing to dispense them in the first place.

"One of the things that doesn't seem to get talked about is patents and whether [the holders] are obliged to share with researchers," Dr. Walter Robinson, an assistant professor of social medicine and pediatrics at Harvard Medical School, said.

In an editorial in the University of Pennsylvania's Center for Bioethics newsletter, published Sat., Sept. 1, Glenn McGee, an assistant professor of bioethics and the editor of the American Journal of Bioethics, likewise expressed concern that the owners of stem cells would "collect a royalty against both private and federal stem cell research that in my calculations could quickly amount to a weighty toll on stem cell research and therapy."

THUS FAR, HOWEVER, THE UNIVERSITY OF WISCON-
sin, which holds a patent on the embryonic stem cell, has resolved to make stem cell lines available for $5,000 in the U.S. through WiCell, its nonprofit subsidiary. Kevles called this sum "petty cash in the biomedical area" and said Wisconsin "is eager to make these lines available."

Melton has received funding from the Howard Hughes Medical Institute to derive new human embryonic stem cell lines, which he will distribute to other researchers at no cost. "We have no plans to sell these," Melton said. "When a chemist publishes a new chemical and people ask for it, he just gives it to them."

But Melton's cell lines, derived after Bush's decision, are not eligible for use by publicly funded researchers. These scientists must rely on the 60 cell lines cited by Bush, or flee to private biotech companies, which remain unfettered by the President's policy.

In the meantime, much uncertainty remains about the viability of the 60 lines. "We institutionally, and I personally, favored more extensive use of stem cells in research," University President Richard Levin, GRD '74, said. "I continue to have concerns about whether or not the solution reached is a sustainable one. Are there enough stem cell lines of quality that can sustain research? I think we are going to need another solution."

Front graphic by Shawn Cheng.

Info graphic by Erin I. Lewis and Justin Chen.

There are many potential uses for lab-grown stem cells. Muscle cells could be manufactured that might be used to repair the arteries and hearts of victims of atherosclerosis, while neuronal tissue could be harvested and used to treat diseases that debilitate the nervous system, such as Parkinson's and Alzheimer's. Furthermore, stem cells'ability to morph into pancreatic Islet of Langerhans cells, which manufacture insulin, suggest great promise for victims of late-onset diabetes.