Stem Cell Pioneers

Despite federal opposition to embryonic stem cell research, academic freedom and profits in California is luring scientists to the field

As Irving Weissman drives past Cannery Row in Monterey, California, in a light rain, he waves an open palm like an impresario, showing off the picturesque bay and craggy coastline. "Spectacular," Weissman says as he pulls onto the grounds of the Hopkins Marine Station. He's a distinguished immunologist, best known for his studies of blood cells, but he's also a straight-shooting Montana native who sports the type of rugged beard you might expect on a fur trader, his father's profession. When he sees David Epel walking by, Weissman stops his black Lexus sedan and lowers a window.

"How can you sleep at night?" asks Epel, a marine biologist who investigates fertilization in sea urchins.

"Nobody can," smiles Weissman.

Epel and Weissman are marveling over the decision made by the voters of California in November 2004 to spend up to $3 billion in the state over the next ten years on human embryonic stem cell research. Known as Proposition 71, the initiative has created a gold rush fever that's caught the attention of stem cell scientists everywhere. Many prospectors envision rewards well beyond dollars: new treatments and possibly cures for a wide array of medical conditions, such as Alzheimer's, diabetes, Parkinson's, osteoporosis, multiple sclerosis, spinal cord injury, cancer and heart disease.


Weissman, who has a small lab at the Hopkins Marine Station and a much larger one 90 miles away at its parent institution, Stanford University, played a starring role in the Prop. 71 campaign. He helped shape the proposition and attracted crucial funding for it, meeting privately with politicians, influential Hollywood producers and other deep-pocketed supporters including Bill Gates. Weissman also became a go-to expert for the news media and even starred in a TV ad for the "Yes on 71" campaign. He has taken up the cause before the U.S. Congress, President Bush's Council on Bioethics and the late Pope John Paul II, warning at every turn that limiting or blocking stem cell research would hamper development of potential treatments and cures—a moral dilemma of its own.


Weissman stumbled into the issue in 2001 when he chaired a National Academies panel on cloning, a scientific technology that overlaps with stem cell biology. While Weissman abhors the idea of cloning humans—and the panel he chaired called for a legally enforceable ban of the procedure—he saw that using cloning technology to derive embryonic stem cells opened a new world of medical possibilities. That's when he decided to champion the idea. "I didn't choose this position, I promise you," he says. And though Weissman pioneered the discovery of stem cells in adults, his academic labs and the three biotechnology companies he co-founded, SyStemix, Inc., StemCells, Inc. and Cellerant Therapeutics, Inc., do not yet work on human embryonic stem cells. As he likes to half joke: "My advocacy of human embryonic stem cell research is in fact probably felt by my companies to be competitive to their interests."

Before leaving Epel at the Hopkins Marine Station, Weissman confides that he is attempting to lure a prominent human embryonic stem cell researcher from Massachusetts to Stanford—part of Weissman's continued efforts to bolster California's prominence in the field. The researcher is scheduled to lecture at the Hopkins Marine Station. "I thought I would drive him down and try to convince him how nice the West Coast is," says Weissman. Then he gazes at Monterey Bay and grins. "Let's hope it's really sunny that day," he says.





To date, scientists worldwide have made more than 100 different human embryonic cell lines. Still, the existing lines have serious limitations. Most have been grown on a lattice of mouse embryonic skin cells for support. Consequently, the human embryonic cells are contaminated by mouse cells, and though they're still useful for research, Weissman says, they are "absolutely useless" to develop therapies. Even if they weren't contaminated, the existing lines probably could help only a patient who had a close genetic match to the embryonic stem cells, as the patient's immune system likely would destroy any cells that got transplanted. And cells kept in culture can change, acquiring mutations that could lead them to cause cancer or other diseases.


Scientists also say that cloned embryonic stem cell lines could be a boon to the study of genetic diseases. Researchers could make embryonic stem cell lines from people with genetic diseases, then study exactly how a disease process works, including possibly pinpointing flawed genes that cause the disease. Such cells would allow scientists to assess whether experimental drugs were likely to harm or help people. "You're on a road that we can't even approach in modern medicine," says Weissman. "Every human genetic disease theoretically could be studied in this way. And there's no other way to do that."

Embryonic stem cell research is entangled with the issue of abortion in myriad ways, and indeed the Bush administration's position has roots in the 1973 Roe v. Wade decision that made abortion legal in the United States. Worried that scientists might use aborted embryos or fetuses for research, Congress in 1974 passed a "temporary moratorium"on the federal funding of any such work. Subsequent legislation extended this ban to the creation of embryos. With the breakthroughs in stem cell research in the late 1990s, Weissman and many other scientists urged Congressto reconsider this sweeping ban. Then, on August 9, 2001, President Bush gave a speech on national televisionfrom his Texas ranch that focused on stem cell research, describing a new policy that attempted to please people on both sides of the issue.

Bush declared that researchers who used federal funds could work on human embryonic stem cell lines that scientists had already created but could not make any new ones. Bush, who characterized the issue as "one of the most profound of our time," said that he was worried "about a culture that devalues life" and said that he had arrived at this compromise after "prayer and considerable reflection." About two dozen stem cell lines meet his criteria for federal funding.













Prop. 71, among other things, provides funds for a new state agency, the California Institute for Regenerative Medicine. Its governing board will award grants to scientists based on the quality of their research proposals, which will be evaluated by other scientists. In September, the institute, headquartered in San Francisco, announced that its first grants will train scientists and clinicians in stem cell biology and attendant ethical and legal issues. The institute plans to fund stem cell research that is done within the state's borders, "has the greatest potential for therapies and cures" and is "unlikely" to receive federal support. For now, however, lawsuits filed by opponents of Prop. 71 are holding up the distribution of money.


Klein says California is putting its chips on "intellectual infrastructure," the equivalent of the bridges, harbors and roads that forward-thinking states built in the last century. "You're investing in knowledge that can have a 50 year or longer life of value," says Klein, who sounds like a politician on the stump but insists he has no ambition to run for public office.

Klein mixes the personal with the political. A U.S. Senate bill that repeatedly has died in committee and then resurfaced would make using cloning techniques on human cells—regardless of whether the goal is a baby or a line of stem cells for therapy—a crime punishable by up to ten years in prison. If the bill became law, says Klein, he could face a prison term and a $1 million fine for taking his diabetic son to another country for treatment with therapeutic cloning. "They're going to deny families access to this therapy outside this country," says Klein, sounding incredulous. He warns that despite the passage of Prop. 71, the proposed Senate bill to criminalize cloning, and other opposition, could undermine California's stem cell revolution. "Realize that we have won a major battle, but we have not won the war," he says. "Unless we stand up now, we will not have the opportunity to change the future of medicine."

As fervently as Klein believes that Prop. 71 is good for California, the bottom line for him does not involve the state budget. It's about what this legislation means to his son, who faces a daily struggle to maintain blood sugar levels as well as the disease's potential long-term complications. "One of the fundamental benefits to my son is hope," he says. "And that hope doesn't have to be that it will cure the disease. Its hope that he won't have blindness. Hope that he won't have kidney loss. It's a major hope that you don't lead your life with multiple amputations. That would be a huge blessing."

A short walk from Irv Weissman's spacious office and sprawling lab on the Stanford campusis the cramped workplace of one of his principal adversaries in the stem cell debates, William Hurlbut, 59, a physician. Hurlbut earned his undergraduate and medical degrees at Stanford and has known Weissman for 30 years. As a member of the President's Council on Bioethics, he has President Bush's ear. But many of his academic counterparts all but groan when he speaks: not only does Hurlbut mix religion and science, he proposes what they see as dubious scientific solutions to sidestep the ethical minefields. "I'm basically persona non grata, as you can imagine, with my colleagues," says Hurlbut.

Hurlbut also has a child whose condition helps shape his thinking. Three decades ago, a week after he graduated from medical school, Hurlbut's wife went into labor with a breech baby, which required an emergency Caesarean section. Just then, he says, another woman giving birth at the hospital had a sudden, life-threatening problem. "Everybody ran to take care of her and left my wife and baby unattended, and by the time they got back, there was no heartbeat," says Hurlbut. His baby daughter survived, but was severely brain damaged. "From that point, life became so difficult I simply couldn't return to clinical medicine," says Hurlbut, who went on to do postdoctoral studies in Christian theology and medical ethics. Today, he teaches biomedical ethics at Stanford University. His daughter Sarah is 30 and has serious cognitive and emotional disabilities, but Hurlbut says "by some good blessing she is much better off than anyone expected," and can walk and talk, remember things, and "see deeply into the hearts of others. . . . She's a perfectly worthy-to-be-alive human being," he says.

When Hurlbut joined the President's Council in 2002, he decided to rethink his beliefs, what he calls his "seamless garment of a pro-life perspective from conception to natural death." Ethicists and theologians had made many intriguing moral arguments he wanted to weigh, such as the possibility that life begins at 14 days, the point that defines individuality because the embryo no longer can split into identical twins. "I both support and am excited by the speculative but interesting possibilities of embryonic stem cell research," says Hurlbut. "I just don't support getting the embryonic stem cells from the disaggregation of living human embryos. I feel worse about it when they are intentionally created, but I also have concerns about the use of IVF spares." And he opposes the prospect of creating embryos to serve, in his words, as body shops to "harvest parts."


Although the mouse study shows that Hurlbut's proposal is feasible, some of the field's foremost researchers say he downplays the technical hurdles of adapting the approach to human embryos. And, they say, there's nothing morally wrong with research that uses normal early embryos. Weissman has a slightly more charitable reaction. "When Bill Hurlbut says do that, I say, Go to it," Weissman shrugs. "Don't talk about it. Do it."

Other alternative strategies for harnessing the potential of stem cells exist, the most widely discussed of which involves adult stem cells, Weissman's area of expertise. Scientists have discovered human adult stem cells in the blood and in several organs including the heart and brain. Some research has suggested that adult stem cells may perform as nimbly as embryonic stem cells, able to turn into almost any type of cell in the body if manipulated correctly. Few assertions rile Weissman more, and he has spent countless hours debunking those studies. "I'd have been delighted if blood-forming stem cells or brain-forming stem cells could make or repair any other tissue, and so would the companies I helped found," says Weissman. "We tested the claims rigorously,"he says, "and they failed."


And Weissman, like many of his colleagues, sees an ethical dilemma created by the notion that today's research should stop, as many opponents of embryonic stem cell research demand, until scientists discover less contentious methods. "If we delay, and in that delay, for no good reason as far as I could see, people are dying who had a chance to live, that's morally unacceptable to me," he says.

Weissman points out that most people who object to destroying human embryos for research don't protest IVF itself, which routinely produces embryos that end up being destroyed. Hurlbut, for his part, calls this seeming contradiction "the single hardest question," but says the issue is ethically different because IVF clinics aim to create life.

Hurlbut urges stem cell researchers to more aggressively explore strategies that do not destroy viable embryos. "We've just put our feet onto Plymouth Rock," he says. "We have a whole continent to explore. It's too early to say which one of these approaches will lead to the most fruitful science and clinical applications."

One of the most puzzling phenomena in all of biology today is that an egg can turn an adult cell into an embryonic one, that is, the cloning phenomenon. "We have to learn how the egg does it," Rudolf Jaenisch tells Goldstein, Weissman and a few hundred other colleagues gathered to hear his keynote lecture at the Stem Cell Biology and Human Disease conference at the Salk Institute in March. "It's not a miracle. It's a biochemical reaction."


The Salk Institute gathering attracted a who's who of stem cell researchers from around the globe, who together, have made progress using the cells to cure diabetes, Parkinson's, immune deficiencies, heart disease and brain injuries—in mice. When it comes to human disease, no group has moved further than the one led by another speaker at the meeting, South Korea's Woo Suk Hwang, whose team created, in 2004, the first human embryonic stem cell lines using cloning techniques. (It was also Hwang and his colleagues who cloned the first dog, an Afghan hound named Snuppy, reported this past August.) His lab has now made embryonic cell lines from people who have spinal cord injury or immune disorders, a first step toward using personalized cultured cells to study these afflictions.


A Harvard University researcher opens his talk by thanking Weissman and Goldstein for their work on Prop. 71."You guys have done a tremendous amount for the field and our nation," he says.

Weissman opens his own talk with a call to arms. "I consider everything we do in this field to have a chance of advancing medical therapy." If embryonic stem cell research is delayed, he says, "some lives will be lost because of it. That's very important to know. I know it sounds slightly emotional, but I think that's the reality. While you wait, while you hold it back, while you have philosophical discussions, there are people who could have been saved."

Jon Cohen, a correspondent for Science magazine, is the author of Coming to Term: Uncovering the Truth about Miscarriage.
Photographer Mark Richards is based near San Francisco.