May 2011

Culturing controversy

Strict regulations on stem cell research in the U.S. resulted in many scientists moving their labs abroad.

The development and propagation of human stem cell lines was hailed as the Scientific Breakthrough of the Year by Science magazine in 1999.

Madison, Wis., 1998: After months of waiting, watching and testing, James A. Thomson was finally ready to announce to the world that his laboratory had performed the first successful isolation and culture of human embryonic stem cells (1).

The cells were a veritable cellular fountain of youth: They were immortal and able to divide nearly without limit, but they also had the valuable property of being able to differentiate, under the proper conditions, into more specialized cell types. The possibilities seemed endless: a deeper understanding of developmental biology, lab-grown tissues for transplantation, even a cure for cancer.

Fanfare and furor

The development and propagation of human stem cell lines was hailed as the Scientific Breakthrough of the Year by Science magazine in 1999 (2). “We salute this work, which raises hopes of dazzling medical applications,” read the write-up. The alluring sparkle of human stem cells drew scientists in, and the number of publications on stem cells increased markedly. But along with the enthusiasm came a measure of doubt. The cells were derived from germ cells, from embryos, from potential living, breathing human beings. Was it ethical for scientists to do experiments on embryonic stem cells, or were they getting a little too close to playing God?

No one was more aware of these questions than Thomson. Several years earlier, he had consulted with bioethicists at the University of Wisconsin about the implications of his research. In a 2007 interview with The New York Times (3), Thomson spoke about his uneasiness regarding the use of human embryos in his work. “If human embryonic stem cell research does not make you at least a little bit uncomfortable, you have not thought about it enough,” he commented. “I thought long and hard about whether I would do it.”

Thomson’s discomfort was shared by scientists, the public and politicians alike. An appropriations bill passed by Congress in Oct. 1998 declared that federal funds could not be used for “research in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury or death,” allowing the funding of research utilizing a human embryonic stem cell line but not the creation of new stem cell lines (4). Restrictions tightened even further in 2001, when President George W. Bush announced that federal funds would be made available only for research on existing embryonic stem cell cultures, limiting National Institutes of Health-funded labs to the use of eighteen lines.

Follow the money

Thomson himself had been very careful to perform work related to the establishment of the embryonic stem cell line in a separate lab that was privately funded by Geron Corporation rather than relying on the NIH for financial support (4). But the hassle of finding alternate sources of funding and the mess of keeping separate laboratories and accounts was too much for some stem cell researchers. At the same time, other countries were investing in biotechnology and using financial incentives and less stringent research regulations to entice American stem cell scientists to move overseas.

Singapore was one of these countries – it had developed an ambitious National Biomedical Science Strategy in 2000 (5) and built Biopolis, a gleaming new complex of buildings that served as Singapore’s biomedical research hub. Singapore also had established regulations regarding human embryonic stem cell research, permitting cloning for therapeutic – but not reproductive – purposes (6). The city-state’s appetite for science and the availability of research funding convinced Neal Copeland and Nancy Jenkins to leave the National Cancer Institute for Biopolis in 2006. “We will be on the ground floor of something new and exciting,” Copeland said in an article in Nature (7). Molecular cardiologist Judith Swain and her husband Edward Holmes, a translational scientist, made the move from the University of California, San Diego, to Singapore in 2006 as well, citing “federal hostility towards embryonic stem-cell research” as a factor in their decision (8).

Singapore’s appetite for science and the availability of research funding convinced Neal Copeland and Nancy Jenkins to leave the National Cancer Institute for Biopolis in 2006.

The United Kingdom scored a prominent scientist of its own: Roger Pedersen, a leading researcher in the area of the differentiation and specialization of stem cells. Pedersen resigned from his position at the University of California, San Francisco, and went to England, where he started the Cambridge Center for Stem Cell Biology and Medicine in 2003. The regulations governing the use of human embryonic stem cells in the UK are similar to those in Singapore, which made it easier for Pedersen to carry out his research. “Here, there is government funding,” Pedersen said of the UK, “and the funding goes where the science goes” (9).

Brain drain?

The exodus of top scientists was worrying. “American scientists have been pioneers in all major branches of medical research,” observed Senator Orrin Hatch in 2007. “If we don’t act quickly, the United States may lose the opportunity to lead the world with stem cells” (10). A 2006 study examined this so-called brain drain by analyzing the results of two surveys, one administered to stem cell scientists and the other to scientists who didn’t work on stem cells (11). The surveys asked scientists to document the number and source of job offers received in the past year, hypothesizing that if the brain drain was real, stem cell scientists would have entertained more job offers than other scientists – especially offers to move overseas. And indeed, this was the case: Researchers working on stem cells were 1.6 times more likely to receive a job offer, and 5.3 times more likely to receive an international offer, than researchers working in other fields (11).

In the meantime, states were taking matters into their own hands. In 2004, New Jersey became the first state to appropriate funds for adult and embryonic stem cell research. Later that year, voters in California approved Proposition 71, which provided $3 billion to fund stem cell research while prohibiting research on reproductive cloning. Money from the bond proceeds was distributed by the California Institute of Regenerative Medicine to scientists like Cynthia Kosinski, who received a grant when she was a graduate student at the University of California, San Francisco. While the federal restrictions didn’t apply to Kosinski because she worked with adult stem cells, she noted that for researchers who worked on embryonic stem cells, the CIRM funds filled holes when federal grant money couldn’t be used. “CIRM funding actually attracted some scientists to California,” says Kosinski, “which has helped to make California a hotbed of stem cell research.”

The 2006 report supports Kosinski’s observation: Of the domestic job offers received by stem cell researchers, a third originated in California, compared to 11 percent for non-stem cell scientists (11). In effect, California – as well as states such as Massachusetts and New Jersey in which legislation supporting stem cell research had been enacted – was playing the role of a local Singapore. The budgets may have been smaller, and there wasn’t a Biopolis, but scientists didn’t have to move their stem cell cultures across oceans either.

Change and change again

“Living in a state that doesn’t have state-approved [embryonic] stem cell funding can be frustrating and risky, because the policy on stem cell research can change from administration to administration,” says Kosinski. Stem cell scientists have found themselves riding a roller coaster of federal regulations with dizzying highs and sickening lows. One of the highs came in March 2009, when President Barack Obama issued an executive order revoking President Bush’s 2001 restrictions on the federal funding of embryonic stem cell research and increasing the number of cell lines acceptable for use in NIH-funded labs. The celebratory mood among stem cell scientists was short-lived, however: In August 2010, federal Judge Royce Lamberth banned federal funding for work involving embryonic stem cells based on the Dickey-Wicker Amendment, which was intended to stop the destruction of human embryos. Judge Lamberth’s ruling brought funding of research involving embryonic stem cell lines to an immediate halt. To allow the research to resume, the Department of Justice quickly filed a stay, so for now, work on embryonic cell lines continues, cautiously – with U.S. scientists watching and waiting to see what happens next.

References

1. Thomson, J. A., Itskovitz-Eldor, J., Shapiro, S. S., Waknitz, M. A., Swiergiel, J. J., Marshall, V. S., and Jones, J. M. (1988) Embryonic stem cell lines derived from human blastocysts. Science 282, 1145 – 1147.
2. Vogel, G. (1999) Capturing the promise of youth. Science 286, 2238 – 2239.
3. Kolata, G. Man who helped start stem cell war may end it. The New York Times. Nov. 22, 2007.
4. Marshall, E. (1998) A versatile cell line raises scientific hopes, legal questions. Science 282, 1014 – 1015.
5. Normile, D. (2007) An Asian tiger’s bold experiment. Science 316, 38 – 41.
6. Walsh, B. Asia’s stem cell city. Time Magazine, Asia Edition. Oct. 23, 2006.
7. Wright, J. (2006) Neal Copeland and Nancy Jenkins, principal investigators, Institute of Molecular and Cell Biology, Singapore. Nature 439, 1028a.
8. Wright, J. (2006) Ed Holmes, executive deputy chairman, Biomedical Research Council, Singapore; and Judith Swain, executive director, Singapore Institute for Clinical Sciences. Nature 442,106a.
9. Rohm, W. G. The Stem Cell Refugee. Wired Magazine. December 2003.
10. Senator Dianne Feinstein press release. Senators Hatch and Feinstein promote stem cell research, human cloning ban. March 8, 2007.
11. Levine, A. D. (2006) Research policy and the mobility of U.S. stem cell scientists. Nature Biotech. 24, 865 – 866.

Leslie ChinnLeslie W. Chinn (leslie.chinn@gmail.com) is an ORISE fellow at the U.S. Food and Drug Administration.


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