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Features May 2004: Volume 1, Number 2
   

Stem-Cell Revolution
By Sylvia Tiersten

Basic scientific research, cures for intractable human diseases, regional economic prosperity and training resources for young scientists. These are some of the promising aspects of California’s new stem-cell research initiative. Not so fast, say those who voted against Proposition 71, last November. Among their looming worries is an initiative that was oversold to the public, conflicts of interest in awarding research grants, insufficient government oversight, and right-to-life issues that won’t disappear anytime soon.

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It’s November 3, 2004, election results are in, and UCSD scientist Lawrence Goldstein Ph.D. has reason to celebrate. Californians passed Proposition 71 by almost 60 percent of the vote. Goldstein was responsible for some of the language, and much of the advocacy, for the California Stem Cell Research and Cures Initiative, which authorizes $3 billion worth of tax-free state bonds to fund human stem-cell research over the next 10 years. The measure bars the use of Prop-71 funding for human reproductive cloning research.

For Goldstein the victory is bittersweet. “This is a terrible way to do science policy, but we have no choice,” he says of Prop 71’s passage. “Ordinarily, the federal government should take the lead in funding basic science. By doing it on a national level rather than a state or local level, you make sure you fund the best ideas in a big country. A national approach encourages diversity as well as uniform standards.”

As a UCSD professor of cellular and molecular medicine and
an investigator for the Howard Hughes Medical Institute, Goldstein uses human stem cells in his studies of neuro-degenerative disorders such as Alzheimer’s disease, Lou Gehrig’s disease and Huntington’s disease. “I try to understand how certain processes work inside cells and inside organisms,” he says. “That work has led to some new ideas about different diseases and I’m hoping to translate them into therapy someday.”

As a tireless champion of publicly funded scientific and medical research, Goldstein has racked up tens of thousands of frequent flyer miles over the past decade—traveling to Capitol Hill to testify before congressional committees. “America has a long tradition of national-government support for basic science,” he says. “It has led to the Internet, modern defense technology and medical-research revolutions. Typically there is federal funding at the early stages, and then the private sector steps in.”

But not this time. Stem cells often come from embryos that are discarded after in-vitro fertilization. Some people are morally opposed to the use of these cells for medical research. It’s tantamount to destroying a life, they say.

The 1996 Dickey amendment—tacked on to an appropriations bill by Representative Jay Dickey, Republican-Arkansas—banned federal funds for experiments that destroy human embryos. The amendment was renewed in 1998 and 2000.

“It’s unprecedented to interfere with an area of science
based on a narrow ideological view,” says Goldstein. “There isn’t a social consensus that we shouldn’t do embryonic stem-cell research. If anything, there’s a majority opinion that supports it. And yet our government has decided that we shouldn’t do it—and I think that’s wrong and narrow-minded.”

A recent survey conducted by the Opinion Research Corp. for the Civil Society Institute in Newton Centre, Mass. found that three out of five Americans back embryonic stem-cell research and 70 percent support federal legislation to promote such research.

Even the No-On-71 group, which urged California voters to reject the state bond initiative, voiced support for stem-cell research in principle. For many of these opponents the devil was in the Prop-71 details.

Writing in the official voter information guide, State Senator Tom McClintock, Orange County Treasurer John Moorlach, and oncologist H. Rex Greene, medical director of the Dorothy E. Schneider Cancer Center in Burlingame, Calif., argued: “It’s wrong to launch a costly new state bureaucracy when vital programs for health, education and police and fire services are being cut. We all strongly support stem-cell research, but oppose this blatant taxpayer
rip-off that lines the pockets of a few large corporations.”

The No-On-71 people also criticized the lack of state-government oversight and the potential for backroom deal-making by pharmaceutical company executives and venture capitalists.

The initiative passed by roughly 59 to 41 percent. “At the end of the day they couldn’t persuade more than about 40 percent of people that they were right,” says Goldstein of the measure’s opponents.

***

In August 2001, President George W. Bush enabled federal funding of research for 23 existing human embryonic stem-cell lines. At the same time, he barred government subsidies from being used in the creation or destruction of additional embryos.

While America dithered, other countries rushed into the breach. Singapore opened Biopolis last year, a 2 million-square-foot complex dedicated to life sciences and embryonic stem-cell research. In Korea, Seoul National University developed 36 stem-cell lines. China lured scientists away from top U.S. universities to operate research centers on its mainland. When Roger Pedersen, a senior stem-cell investigator at UC San Francisco Medical Center, decamped to Cambridge, England, to take advantage of a kinder, gentler regulatory environment, murmurings of “brain drain” reverberated throughout America’s research communities.

Prop 71 recast the die. “In early November, the world changed in terms of stem-cell research. Any migration to Australia or Europe or Singapore or South Korea stopped, because suddenly there was a new game in town. Today the best research minds in the world are thinking about California,” says Duane Roth, executive director of UCSD CONNECT. The regional program links high-tech and life science entrepreneurs with technology, money, markets, management, partners and support services. Roth believes that for San Diego, economic benefits of Prop 71 could be substantial—even early on. “Every researcher who relocates here, or is funded here, probably supports 30 to 50 people directly,” he says.

“Prop 71 will jumpstart California as the center of the universe in terms of stem-cell research, and leverage other money,” says Judith L. Swain, M.D. ’74, director of UCSD’s new College of Integrated Life Sciences (CORES).

As for the long-term impact of Prop 71, a May 2000 U.S. Congressional Joint Economic Committee (JEC) report on “The Benefits of Medical Research and the Role of NIH” offers fiscal and humanitarian food for thought. JEC estimated the economy-wide rate of return on publicly funded research at 25 to 40 percent a year.

***

It’s February, it’s snowing in Boston, and Massachusetts Governor Mitt Romney is airing his opposition to therapeutic cloning or somatic cell nuclear transfer (SCNT). Instead of using a frozen embryo from a discarded fetus, SCNT technology requires removing a cell from a living person, extracting the nucleus, implanting it in an unfertilized egg from which the nucleus was removed, and creating a kind of tailored stem-cell line.

Meanwhile, Larry Goldstein has just returned to his lab-after a brisk run around La Jolla. “California is a wonderful place to do science—and Prop 71 just raises the bar,” he says. “Have you been out there? It’s 80 degrees and gorgeous.”
Goldstein maintains his offices and labs on the top floor of the Leichtag Family Foundation Biomedical Research Building, on the UCSD School of Medicine campus. The floor is leased to the Howard Hughes Medical Institute, a private philanthropy.

As one of 300 Howard Hughes investigators nationwide (there are seven at UCSD), he has the luxury of pursuing stem-cell research in a state-of-the-art space that is insulated from federal legal constraints. But it’s lonely at the top, not to mention inefficient and frustrating.

“If I’m the only one who can do this experimental work in this large community,” says Goldstein, “it means I have to solve every single technical problem myself. Science works well if there is a diversity of approaches—people discovering tricks and sharing them. Proposition 71 will bring in several other investigators and accelerate what I can do.”

Meanwhile, he has shared his lab space on an occasional basis with a handful of UCSD cardiac researchers and a faculty member who wants to experiment with growing stem cells on various types of surfaces. “I can let a few colleagues work in my lab, but I am a small operation compared to the size of this medical school—and this is only one medical school,” says Goldstein.

Because of federal constraints on stem-cell research, federal money brings strict accounting rules. Prop 71 doesn’t eliminate this welter of record keeping that Goldstein wryly refers to as “separation of church and state.” In a scientific climate fraught with ethical and political landmines, he anticipates “a high level of scrutiny” as far as cost allocations and resource sharing. “Some of the gray areas could be dealt with more harshly than usual,” he reckons.

That’s why Goldstein and his staff have a color-coded ordering system in place. Normally, he explains, if you had five projects representing five different funding sources, you’d buy one bottle of reagent and use it for all the projects. “You try to get your allocations about right without buying five bottles of sodium chloride and duplicating everything, which is wasteful,” says Goldstein. These days, he reckons, it’s better to be safe than thrifty, and five bottles are better than one.

In the aftermath of California’s November elections, there are other troubling allocation questions. “Suppose you have people working for you whose salaries are 100 percent paid by federal sources,” ponders Goldstein. “Can they
analyze research data from non-approved cells?”

***

Prop 71 established the California Institute for Regenerative Medicine (CIRM), a kind of state-based, mini National Institutes of Health (NIH), to disperse about $300 million
a year in loans and grants to scientific institutions and
universities. A 29-member Independent Citizens Oversight Committee (ICOC) serves as the governing board.

Funding for the initial round of proposals could come as early as summer 2005. A program to train young scientists with an interest in stem-cell research is reportedly in the works. CIRR would support the effort with contracts to major California universities and scientific institutions.

“We need a pipeline of people as well as a pipeline of cells,” says Edward W. Holmes, M.D., UCSD vice chancellor for health sciences, dean of the School of Medicine and an ICOC board member. “With 10 years of sustained funding available for stem-cell work, I am confident that young
people will now feel they can have a career in this field.”

On the research side, UCSD faculty members are writing joint proposals with investigators at the Salk Institute for Biological Studies, The Scripps Research Institute and The Burnham Institute. There is talk of consortiums in San Diego, and of funding a joint facility with Prop-71 money.

“This initiative has galvanized the community,” says Swain. “If you can bring those institutions on the mesa together for stem-cell research, maybe that will lead to coming together around a lot of other things, such as cancer or heart disease.”

In the initial flurry of proposal writing, the neurosciences and cardiovascular research have emerged as promising areas of activity. State money for neuroscience would help support stem-cell work that is already in progress and financed through private sources. This includes Goldstein’s programs at UCSD and those of Rusty Gage at Salk and Evan Snyder at the Burnham.

“We live in one of the most exciting biomedical research communities in the nation,” says Holmes. “There is a confluence of sets of expertise that goes from chemistry to biology to pharmacy and medicine. On top of that you have the second or third most robust biotechnology community in the nation.”

Ultimately, Holmes envisions San Diego’s research institutions will partner with the private sector in manufacturing drugs and cells for clinical use. “When it is time to move the concept out of the research laboratory and into the development mode, we have the commercial community here to do that,” he says. “When it’s time to bring the product back and test whether it works, we have UCSD medical school and it’s ideally positioned for that.”

***

The selling of Prop 71 was always a double-edged sword. “During the election campaign the sound bites got shorter and shorter—and promised more and more,” says Leon Thal, M.D., UCSD Department of Neurosciences chair and an ICOC board member.

Separating hype from reality is a post-election chore. “One of my greatest fears is that expectations will not be realized as quickly as people would want,” says Holmes. “Interest and confidence in the program will be lost, and human stem-cell research will be dropped as an area of concern.”

One such expectation is the belief that cures for Alzheimer’s disease are just around the corner. “I hope I’m wrong,” says Holmes, “but I think we’re looking 10 to 15 years down the line before cell-replacement therapy is going to be in the clinic.”

First up is fundamental science. “We know that embryonic stem cells can self-renew indefinitely and turn into any organism in the body,” says Holmes, “but we don’t really understand the biology of these cells and how to grow them—how to make a heart cell, for instance, rather than a brain cell.”

Federal funding guidelines prohibit somatic cell nuclear transfer (SCNT)—another promising avenue of research. This technology was the basis for the cloning experiment involving Dolly, the six-year-old sheep. “We’re not talking about cloning human beings,” says Holmes, “but about therapeutic cloning: establishing a cell line that’s very individualized.”

In the short term, embryonic stem-cell research could improve traditional therapies such as the formulating of small-molecule drugs or pills. For Alzheimer’s, Parkinson’s and other devastating diseases, for instance, “we don’t have good animal models for testing our ideas,” says Holmes.
By growing human stem cells in a petri dish, “we might be able to create models that will allow us to test hypotheses with conventional drug approaches to treating disease. This will probably happen sooner rather than later.”

***

Meanwhile, at San Diego’s Ethics Center for Science & Technology, cofounder Michael Kalichman ticks off the moral conundrums associated with California’s stem-cell initiative. “There is, of course, the status of the embryo—or abortion issues revisited,” says Kalichman, an adjunct professor in charge of UCSD’s research ethics program.

Informed consent of the embryo donor is also high on the list, as is the possibility of conflict of interest. “If there is a financial conflict of interest for an individual or group, there is the risk of unintentional bias and of doing things wrong,” he says.

Vioxx is a recent case in point. When a government advisory panel concluded that the painkiller could be safely placed on the market despite potential cardiac risks, some experts who voted to move ahead had financial ties to the drug manufacturer.

“The ethical question in some national cases is: Did this go wrong because people had their eye on potential profits for personal gain rather than on protecting the interests of the public, and the quality of the data collection?” asks Kalichman.

“The Center can broaden the ethics discussion about embryonic stem-cell research and include the wider community,” says Holmes. “Irrespective of what side of the argument you might be on, it’s an important philosophical discussion—and one that needs to be done in public, and in a rational way.”

Goldstein made a compelling moral case for supporting embryonic stem-cell research in 1999. Speaking before
a senate subcommittee and motioning toward actor Christopher Reeve, he said: “There are ethical concerns for not proceeding with this [embryonic stem-cell] research. What happens if in five years we find that adult stem cells don’t work? What do we tell people like Christopher Reeve? That we’re sorry? They may not have another chance.”

Sylvia Tiersten is a freelance writer based in San Diego.

"We live in one of the most exciting biomedical research communities in the nation."