First published online May 10, 2006
Stem Cells
Vol. 24 No.
6
June 2006, pp.
1412
-1413
doi:10.1634/stemcells.2006-0279; www.StemCells.com
© 2006 AlphaMed Press
OPEN ACCESS ARTICLE
Embryonic Stem Cell Research and U.S. Policy
Mahendra S. Rao, M.D, Ph.D.
In August 2001, President George W. Bush instituted a dual-track policy that permitted federal funding for human embryonic stem cell research using lines derived prior to August 9, 2001. The President directed the National Institutes of Health (NIH) to help facilitate research on lines derived before that date, and the NIH has done an incredible amount within the constraints of the policy. I would emphasize that government funding for this new field, while modest, has been critical in helping at least jump start the field. The NIH has done its best to facilitate the process by identifying derivations worldwide that were produced prior to the deadline, helping to organize agreements that permitted cells to be freely available, helping to train scientists in the culture and propagation of human embryonic stem cells (hESC), setting up a Web site to make information freely available worldwide, setting up a bank, and participating in global policy discussions.
This effort is, however, a far cry from what could have been possible, and the evidence that government policy has slowed research in the U.S. is quite compelling: many smaller countries, and even U.S. states, have provided more support for hESC research than the federal government; some researchers have moved out of the country to pursue research or have moved to private industry; the number of papers published on hESC from other countries is larger than the number from the U.S.; U.S. researchers have set up companies abroad, and there are more hESC companies situated outside the country than within it; the NIH intramural program has not been the leader it usually is, and the big U.S. pharmaceutical companies have failed to move aggressively in this field.
A particularly pernicious interpretation of the policy was that research on other lines, no matter how potentially useful, could not be conducted using federal funds or in facilities using any federally funded research infrastructure. Since the government has been a prime supporter of basic research and the development of new technologies, either through the NIH, the National Science Foundation, the Department of Defense, or branches of the Department of Health and Human Services, much of the research infrastructure in this country has some federal contribution, particularly in new instrumentation, research facilities and overhead, and maintenance support. This effectively means that work on post-August 9 lines is not simply deprived of access to the $30 million or so in direct NIH-funded support for hESC research, but would need to abandon technology, tools, and infrastructure that have taken decades to develop. This was perhaps an unanticipated effect of the current policy, but what it has done is to impose a de facto Hobson’s choice on researchers either to have access to federal funds, support for students, and critical infrastructure, or strike out on their own and find funds elsewhere.
It is also important to note that the NIH intramural program is considered a special case, as these investigators are considered full-time government employees and as such cannot possess non-federal sources of funds. Any grant obtained by an NIH intramural researcher is considered a gift to the government and as such is classified as governmental funds. The NIH itself is therefore constrained in scope—limited to examining, evaluating, and posting data on only the 25 or so lines derived prior to August 9 which are currently being shipped. This limitation has severely restricted the number of intramural scientists who work on hESC and limited the in-house expertise that is available.
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FAR-REACHING EFFECTS OF THE RESTRICTIONS
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The effects of this policy have been quite severe on a policy level, as it has effectively prevented the NIH from playing its usual leadership role. The NIH possesses no regulatory or monetary control over a significant portion of the research that is being undertaken, and because the regulatory agencies cannot themselves perform controls and tests, they cannot effectively test the claims made by private industry. The Food and Drug Administration (FDA), for example, has a vigorous research program and has published several key papers on hESC. However, they cannot test the properties of any of the new Good Manufacturing Practice grade lines that are likely to be used for therapy.
This is in stark contrast to other scientific breakthroughs. Historically, the U.S. has been the leader, but in this situation, it cannot take such a leadership role. This is despite the fact that hESC were first derived in this country; the company that holds the largest number of issued patents is based here; and, moreover, the first commercial applications of ESCs are likely to be pioneered by private industry in the U.S. Unfortunately in the case of hESC research, current policy has relegated the U.S. government’s role to a passive observer role at best.
Another pernicious effect of this policy has been the uncertainty it has created. This policy was meant to be temporary, to allow assessment of the usefulness of hESC, and to give the bioethics commission time to make a more careful and reasoned decision. However, it seems to this investigator that there has been little attempt to re-evaluate policy or to provide clarity on where exactly the dividing line is between what is permissible and what is not. For example, does the policy apply to samples that consist of derivatives of lines derived legally with non-federal funds? Can a federally funded researcher access the published data and use it as a basis of their research? Can DNA and RNA from post-August 9 lines be analyzed or compared to DNA and RNA from lines derived prior to this cutoff date? How does one keep track of cells and cell lines and avoid accidental mixing? How does the FDA deal with an application that proposes the use of non-federally funded ESC lines? Can the FDA perform internal quality-control tests, or must it rely on tests performed by facilities that are outside the normal federal purview?
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ARGUMENTS FOR CHANGING THE POLICY
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Several lines of argument suggest that revisiting the policy is important. One important and perhaps compelling argument is that the number of lines that are currently available is far fewer than the number envisaged when the policy was first enunciated. Several of the derivations have been lost, others are not available to U.S. researchers, and records for still others remain unclear. It is also reasonable to assume that as derivations have been lost in the past, available lines will also be lost over time—from contamination, change in culture, or acquisition of karyotypic abnormalities.
A second line of argument that I find compelling is that critical additional information would be available if additional lines were available. Studying allelic variability, genetic variability, immune responses, genetic abnormalities of early development, methylation changes or regulation of aging and aging-related genes all require development of new lines or lines from individuals with defined genetic abnormalities; this research cannot be performed with existing lines.
Equally important arguments have been made regarding the clinical utility of existing ESC lines. Their exposure to xeno material, which allows them to acquire antigens that would be recognized as non-human, the presence of bovine and rodent proteins and material necessitating an additional regulatory burden of testing, and the fear of transmitting zoonotic infections have all been advanced to support the proposition that newer and more improved lines should be generated.
It is my belief that the NIH and its intramural program could provide effective policy and research leadership, and it would not take much. It would be critical, however, to revisit policy, re-evaluate it, as was originally envisaged, and make the changes that science, public policy, and the new results dictate as critical to sustain the research effort. We need to build on the remarkable history of U.S. research discoveries and successes, rather than leave hESC research as an orphan that is banned from accessing the technological breakthroughs achieved by federally funded researchers.
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ACKNOWLEDGMENTS
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This work was supported by the Packard ALS center and the CNS foundation. We thank all members of our laboratories for constant stimulating discussions. MSR acknowledges the contributions of Dr. S. Rao that made undertaking this project possible.
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FOOTNOTES
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Available online without subscription through the open access option.
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C. I. Civin
Troublesome Questions
Stem Cells,
June 1, 2006;
24(6):
1411 - 1411.
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