October 24, 2002, Summary
Stem Cell Research Career Pathways Working Group
James Battey, (co-chair), NIH; Ron McKay, (co-chair), NIH; Robert Hawley, American Red Cross; Brigid Hogan, Vanderbilt Medical School; Gordon Keller, Mt. Sinai School of Medicine; James Thomson, University of Wisconsin-Madison; Irving Weissman (conference call), Stanford University School of Medicine; Leonard Zon, Howard Hughes Medical Institute
Greg Downing, NIH; Donald Fink, FDA; Charles Goldthwaite, science writer; Michael Gottesman, NIH; Della Hann, NIH; Frank Holloman, NIH; Mark Rohrbaugh, NIH; Walter Schaffer, NIH; Lana Skirboll, NIH; Richard Tasca, NIH; John Thomas, NIH; Anne White-Olson, NIH; Baldwin Wong, NIH; Judith Vaitukaitis, NIH; Elias Zerhouni, NIH
The meeting of the Stem Cell Research Career Pathways Working Group was called to order by co-chair James Battey. After welcoming participants, he noted that the meeting would be structured as follows:
- A summary presentation of current NIH efforts and programs regarding human embryonic stem cell (SC) research.
- Brief introductions by participants; each participant should also state several key roadblocks or issues on career training of scientists to expand the field of human embryonic SC biology.
- An open discussion resulting from participants' suggestions.
- A summary of consensus recommendations to be drawn from all of the ideas forwarded.
The meeting also would feature a scheduled visit from Elias Zerhouni, M.D., Director, National Institutes of Health.
Dr. Battey prefaced his summary presentation of NIH activity by reminding participants of the meeting's goals. To enable SC research, barriers must be located, lowered, and eliminated. The assembled group was chosen so as to remain small and nimble, and the five working groups will provide the insight to impact NIH efforts in human embryonic stem (ES) cell research and SC research in general. He stressed that discussion should be informal, and participants should feel encouraged to speak candidly about all relevant issues. Although the NIH cannot control administrative guidelines about human ES cell research, Dr. Battey reiterated that the NIH is a strong supporter of such research.
Participant introductions became a forum for open discussion, which is captured in the following section.
One respondent, citing the inter-species focus on cellular reprogramming at this year's Germ Cell meeting at Cold Spring Harbor, suggested focusing SC research efforts on fundamental cell biology processes that cut across disciplines and species (e.g. reprogramming of cells, the roles of chromatin and non-coding RNAs). Large program projects focused on core issues of chromatin control or genetic readouts could encompass SC research for mice, zebrafish, primates, humans and other species. For such an approach, the participant noted that targeted funding will not work; the criterion should center on projects that investigate stem cell biology. An example was cited of a recent paper from the Jessell lab [Wichterle, et. al., Cell 2002 110(3):385–97] that investigates the differentiation of ES cells into specific classes of motor neurons.
Initial efforts should focus on creating tools with universal application for SC research (e.g. cell surface markers, monoclonal antibodies against embryonic proteins). These tools could be developed initially using mouse models, which could then be expanded to other model systems. Human ES cell research could then be based on results from known systems. It was also suggested that applications for funding should provide justification for the particular model system(s) to be studied.
Also, research is necessary on the biological differences between human and mouse SCs.
One participant noted that such fundamental research is descriptive and may be seen as boring. However, understanding the mechanics of growing SCs is absolutely necessary to the success of the larger enterprise. It was noted that human ES cell research is still in its infancy with respect to training. Thus, it was proposed to center efforts around several robust facilities that could provide researchers with basic training in how to grow the cells. However, any core centers of education and training must interact with researchers using other model systems. For example, if a core center focuses on mouse SC research, it must consider how to transfer such knowledge to other model systems.
Regarding this "Centers of Excellence" concept, panelists suggested that the centers should feature collaborative researchers, not simply act as cell growing facilities. It was suggested to invest more in animal models (e.g. primates) for in vitro tissue grafting experiments that can translate to mouse or human systems. Although currently there are only a few primate centers, new ones could be established through such mechanisms. Training at such centers could be relatively short, dependent upon need and the number of applicants requesting training. A P20 exploratory centers mechanism that matures into a P50 specialized center was proposed.
One participant noted that the P01 program projects could also be used as precursors to larger centers. These multidisciplinary projects could be designed just as described above by the first respondent. NICHD encourages just such an approach. P01s can also have a training core. P01s are typically reviewed by special study sections after preliminary screening of potential applicants by NICHD program staff. This screening helps to ensure that only applications are submitted that adhere to the NICHD guidelines for P01s and would therefore have improved chances for success.
What about data in such a situation? The lack of preliminary data impedes committee approval, generating a Catch-22 situation: Data is necessary for funding; funding is required to generate data. Review could be structured so that a lack of preliminary data is acceptable for select P01s, such as those proposing human ES cell research. The NIGMS solved this dilemma by taking a stepped approach in their recent program announcement for exploratory centers grant proposals (P20s) for human ES cell research. One respondent suggested a combination of an R21 and an R33 exploratory/developmental grant to support novel, high-risk research.
Is it reasonable to plan for 2 or 3 such centers? All respondents replied in the affirmative.
Training issues were also discussed. Dr. Battey began by addressing the current T15 continuing education mechanisms, which provide for the development of training courses. Current T15 mechanisms reflect a joint effort from the FDA and 11 NIH Institutes. The NIH hopes to receive 5 solicitations this month to fund courses for Spring 2003. A T15 funds up to $150,000/year for one course at one location; renewable for up three years. Such mechanisms may also fund training components within the multidisciplinary centers. Respondents generally found such courses useful, although several speculated that, as the field grows, so also will the number of people requesting such training. Offering only one such training course will likely be insufficient, whereas five courses should be enough.
How much time/money is needed for training new investigators? Panelists felt that training components of R21 mechanisms, which provide for one year, were insufficient for obtaining preliminary data. One participant recommended provisions for five years of funding, perhaps through a Centers of Excellence grant. Alternately, a collaborative consortium of three labs could be established similar to the sacromyces genome consortium at the University of Washington.
One respondent noted that money will be necessary for research assistants and technicians, as Level III research assistants could probably train many people in basic stem cell culture techniques once the techniques have been standardized. A P50 grant could fund such personnel. One participant noted that growing human stem cells is not as difficult as is widely imagined; thus, the information and know-how can be transferred relatively quickly.
What resources or tools are needed now? Participants agreed that cell surface markers are a primary area for focus, as these markers have not been characterized well in model systems such as the mouse. Also, reagents are needed. One participant noted that a national stem cell repository is needed; the concept is currently being discussed by NIH.
What about intellectual property issues? It was suggested that a company may be issued a contract for growing monoclonal antibodies. Such an approach is directed and goal-oriented. However, this would require that the company give up its antibody to a resource; would providers do this willingly? It was noted that a similar problem was overcome in the NIH's mouse genome initiative by stating that the animals could not be patented. Another respondent cited experience with the Mammalian Gene Collection at the University of Wisconsin, where academic researchers unwilling to donate cells to a company felt more comfortable donating them to another academic center.
Dr. McKay commented about embryonic germ (EG) cells. It was noted that current needs for these cells include cytokines, growth factors, and markers.
How can we attract people to this new field? Participants agreed that an R21-like mechanism, a high-risk, high-impact grant with little expectation of immediate data, is attractive. It was suggested that applications for such awards could be judged by an ad-hoc committee of experts, as such high-risk proposals traditionally fare poorly in R01 study sections. It was suggested to create a three-year award offering $150,000 for direct costs; selection would be based on the investigator's track record rather than a wealth of preliminary data.
Respondents also suggested that K18 and K22 career awards were currently either conceptually flawed (K22 is pitched toward scientists in mid-career who have the luxury to take a year or two for retraining) or insufficient (K18 offers up to 2-years, $50,000 supplement which was deemed insufficient by panelists).
What about publicity and availability of information? Several participants expressed dissatisfaction over the current NIH Human Embryonic Stem Cell Registry web page, noting that it was misleading and difficult to navigate. Respondents noted that it was not entirely clear which cell lines were available and from whom. Vendors tell the NIH that they have cells ready for shipment, yet investigators find that the cells are not ready as indicated. There is no provision against the cell providers charging for their cells (the NIH sets upper limits only), and there is no guarantee of manufacturers' productivity. The cost of cells can be charged to R01 grants. For international manufacturers, the NIH has only the power to terminate the accord if dissatisfied with performance. These issues have resulted in much confusion and dissatisfaction with the Web site, and the NIH is currently working with the administration to reword it for clarity. Five human ES cell lines are currently available for shipment.
One respondent suggested that the cells could perhaps be moved to an NIH repository if created. Currently, there is no characterization between the cell lines. An NIH repository could, in theory, characterize these cells, although companies may not be tractable. Another respondent suggested that guidelines could be set for future cell lines (it is too late for current ones) through the Howard Hughes Medical Institute, the NIH, or a combination of the two. A third participant proposed adopting a British model of centralized distribution.
It was noted that the field of stem cell research will make substantial leaps within the next few years. Ultimately, patients and disease will drive the direction of the field. As such, development of antibodies and animal models are essential at this stage. The analogy was made between antibodies and restriction enzymes in the early days of molecular biology. One participant commented that restriction enzymes were readily embraced by the private sector, while another noted that initial impetus came from a large grant given to Richard Roberts at Cold Spring Harbor. Using this analogy, a combination of government funding and commercial enterprise may advance the field of SC research.
Participants agreed that SC research is moving quickly toward disease applications. However, study sections may be pessimistic about feasible yet futuristic SC-based proposals, such as developing midbrain dopamine neurons for the study of Parkinson's Disease. One participant suggested that the community could serve as a sort of "task force" to helping shape a trans-NIH initiative for SC research.
Dr. McKay commented that the NIH intramural program is currently underutilized in respect to stem cell research. Compared to other countries, our infrastructure is superior. A group member asked about current SC research in China, which has received much recent publicity. A participant who recently visited the SC facilities in Beijing noted that the Chinese scientists have access to tissues and are not constrained by ethical concerns. He likened the Beijing facility to a U.S. lab with the ability to work on human ES cells: The scientists are good and the cell lines seem to grow well, but the experiments are similar to those conducted elsewhere.
How should we begin to put these suggestions into action? One participant suggested that 300 quality-controlled antibodies would revolutionize the field. Another suggested that it would be more sensible to have in-depth EST sequencing of stem cells. To facilitate such strategies, it was suggested to begin with a "targeted approach" that focuses on lists of already-known candidates. These lists could be compiled and ratified quickly by surveying the community of SC researchers. Two roadblocks were mentioned: 1) few of these antibodies are currently available, and 2) primate issues are looming large for the future. One panelist stressed that with the proper allocation of resources, a good job is possible on tool development, ES cell access, and cross-disciplinary models.
A counterpoint was made to the preceding strategy. First, the parameters of the field must be defined clearly. Exactly what is the field we are hoping to create? Scientifically, the questions are not yet clearly enunciated. Who will populate this field? Only a handful of post-docs are currently engaged in human ES research, and young investigators must be recruited. Career paths must be dictated to specific people currently training in high quality labs. To facilitate this training, a participant suggested a mini-Howard Hughes Medical Institute center or a Life Sciences Institute. Through such a setup, the NIH could possibly earmark funds for human ES researchers.
It was also suggested that what is needed soon are differentiated human ES and human EG cells. Although current capabilities allow this to be done, such research is not rewarded (an exception was noted in the recent Cell paper from Jessell's lab). One participant asked why the NIH could not help to grow EG cells, and Dr. Battey noted that political issues currently shape the strategy.
What about fetal tissue research issues? A participant inquired about fetal tissue transfer for research on Parkinson's Disease. It was suggested that any program involving fetal tissue research should have a public education component, including a clear Web site that has clear definitions and is user friendly (e.g., similar to that supported by the National Institute of Environmental Health Sciences.
What is the NIH doing to educate the public about SC research? Currently, we have several online information resources, including an updated stem cell primer and the 2001 report Stem Cells: Scientific Progress and Future Research Directions. Respondents noted that stem cell research could be put into the public consciousness in a manner similar to that for the Human Genome Project. However, counterpoints were made regarding the more vocal opposition to SC research by groups basing arguments on ethical grounds.
Dr. McKay suggested that maybe we instead focus efforts on EG cell research. Would this lessen the public outreach barriers? The NIH currently funds, and can continue to fund, research on the derivation of EG cells. This research is allowed by the current administration, so promoting EG research may be a viable avenue.
Why has the field failed to embrace EG cells? It was suggested that there is a relatively small supply of fetuses from which to derive samples. This restricts research to labs in large metropolitan areas. By only having one avenue for source material, research opportunities are seen as limited. However, EG cells are perhaps easier to derive than ES cells, although panelists did not know how many people possess the requisite skills. It was noted that access is logistically difficult, and that any EG research initiatives would require a clear and easily accessible Web site and resources.
At this point, Dr. Battey called for a break. Following the break, participants were charged with developing a summary of consensus recommendations drawn from all of the ideas forwarded in the open discussion.
Comments from Dr. Elias Zerhouni
Dr. Elias Zerhouni, Director, NIH, joined the discussion briefly to thank the participants for their input and to solicit questions. His comments and discussion follow:
Dr. Zerhouni reiterated that human embryonic stem cell research is a field in its infancy. Thus, he noted, it is crucial to separate the facts from the surrounding hype. He asked participants what the NIH could do to advance the science of stem cell research. He noted that federal funding is necessary to entice researchers to enter SC research, in part due to the cloud of political uncertainty that envelops the field. Although the President's decision to provide funding was historical, all preliminary procedures must be navigated completely, thoroughly, and with careful consideration.
He stressed that the NIH must be proactive and show leadership in this field. Obstacles should be identified, objectified, and addressed. He noted that the participants were assembled to suggest the avenues for achieving the preliminary steps; the NIH would see that the plans are implemented. He noted that he had no agenda beyond advancing science.
One participant noted that the genome project was aided by the National Human Genome Research Institute and Consortium and wondered whether a similar strategy could be used for stem cell research. Dr. Zerhouni stated that the genome project differed from stem cell research in that the final target was foreseeable and known. By contrast, stem cell research is not a classification- and characterization-based endeavor. SC research requires molecular understandings that have not been elucidated. Respondents suggested that a cohort of leaders could function in lieu of an institute; a community could be established through a small group of centers.
Another respondent commented that the genome center recognized the field and promoted professional development. Dr. Zerhouni responded that function must come first, followed by structure. Thus, what is required first is a common agreement on standardization, appropriate proofs-of-concept, and codification (e.g. monoclonal antibodies, basic sets of surface markers). He noted that his effort must happen now to produce useful future research. He charged participants with thinking about deliverables. What should be implemented now to move the field forward?
Dr. Zerhouni again thanked participants for their input and expertise.
Summary and Consensus Recommendations
Following the break, Dr. Battey reconvened participants with a summary of recommendations culled from the open discussion. His list of recommendations, amended by participants, is summarized below along with related discussion.
The four major areas of focus were:
- Multidisciplinary Centers
- Training Issues
- Enabling Resources
- Availability of Resources
The working group agreed that multidisciplinary centers could serve as important places for training and learning. Such centers could serve as a major training and career development hubs.
Dr. Battey defined multidisciplinary centers as those that exist across species, across tissues, or across specific topical interests, such as chromatin structure or germ cells. Any such center would need to meet two criteria: 1) a history of ES cell culture, and 2) the ability to train personnel. One respondent noted that for such centers there should be a strong emphasis on differentiation of cells as a transitional step to cell-based therapy.
Should such centers be funded by P20 mechanisms, exploratory grants that provide limited funds but allow the collection of preliminary data and the assemblage of investigative research teams, or by P50 mechanisms? It was noted that only 3-5 such centers currently exist that are capable of meeting such criteria. One respondent noted that P20 mechanisms would be inappropriate for such centers; a P50 would be more practical. Regarding the concerns about the P50 mechanism excluding those researchers without preliminary data, it was noted that a R21 mechanism could also be effected. The R21, a high-risk, high-impact grant that does not require preliminary data, could be used that mandates research involving human ES cells. It was also noted that any such center should have a human ES cell component or sub-project.
What about using administrative supplements in such a proposal? Do administrative supplements help to generate preliminary data? It was agreed that administrative supplements should optimally be for two years; preferably at values higher than the current $50,000 to $75,000/year stipulated for direct costs. Such supplements would complement the R21 mechanism, thus allowing new investigators into the fold. Such supplements would need to be reviewed administratively by the sponsoring institute or a group of institutes, but would not be subject to traditional peer review. Thus, the supplements would be competitive, but only in a goal sense.
Finally, it was noted that a great deal of "grunt work" is necessary initially to establish characterization methods and develop quality controls for cell lines. Should these centers do such work? One respondent suggested contracts and cooperative agreements with industry partners as possible avenues.
Dr. Battey began by addressing the current T15 continuing education mechanisms, which provide for the development of training courses. Current T15 mechanisms reflect a joint effort from the FDA and 11 NIH Institutes. The NIH hopes to receive 5 solicitations this month to fund courses for Spring 2003. A T15 funds up to $150,000/year for one course at one location; renewable for up three years. Such mechanisms may also fund training components within the multidisciplinary centers.
For K18 mechanisms, Career Enhancement Awards for Stem Cell Research geared toward mid-career investigators, it was agreed that current award stipulations of one to two years may be insufficient, although the current remuneration of salary plus $50,000 for direct costs was deemed sufficient. One participant proposed the K18 as a mechanism to train scientists to conduct somatic cell nuclear transfer research in animal models. However, several panelists noted that such awards were conceptually flawed, as few investigators in mid-career have the luxury of taking two years off to pursue new research avenues.
The Working Group identified monoclonal antibodies to characterize cells that differentiate from ES cells as a top priority. Contract support in academic centers should be given for development of monoclonal antibodies as well as pre-differentiated and differentiated stem cell derivatives. To maximize the usefulness of the monoclonal antibody research, it was proposed to present the scientific community a list of possibilities, from which the most useful can be chosen for development. It was noted that the antibody research could not be completed by one lab, making it an ideal target for NIH funding. One respondent suggested a successful precedent; antibody research promoted expansion of the hematopoietic stem cell field.
One goal is the direct comparison of ES cell lines with embryonic germ (EG) cells. This goal requires several complementary components. First, EG cell lines are variable, and human homologs are needed. Second, characterization techniques are required for distributed cell lines: cDNA, full length EST, differentiation potential, karyotyping.
Another respondent highlighted the importance of funding training programs for centers researching somatic cell nuclear transfer technology in animal models. Nuclear transfer technology refers to the processes required to transform immature oocytes into mature stages, thus eliminating the need for mature cells. Currently, we do not have the oocytes from model systems.
How should such initiatives be funded? Respondents suggested either through academic centers supported by NIH research and development funds or through industry responses to NIH Requests for Proposals. What is novel about such a plan? Could such a plan be executed using other mechanisms? In response to this question, group members noted that a human ES cell center with a non-human primate component could be created. Alternately, the center could have a thematic focus (e.g. chromatin remodeling, germ cell specification) with a requirement that human ES research constitute a large portion (e.g. 40% or 50%) of the funded projects. This human component would also set the proposal apart from existing P01 and P50 mechanisms. The descriptor "multidisciplinary" was used to characterize such centers, and it was noted that multidisciplinary is not synonymous with bioengineering. Rather, it simply means that research conducted in the center cuts across fields, both in content and application.
Currently, only a finite number of places could qualify as locations for such centers, and it was agreed that the stem cell research field needs population. How should a center's mission be phrased? One participant suggested that the focus should be on moving human stem cell research forward. To do so, an infrastructure must first be established; such a plan would involve more than just "smart science." It was suggested that we know how to make human stem cells differentiate, but we must first establish a set of quality control criteria so that the research results will be useful and meaningful.
Another respondent suggested that non-invasive imaging of mice should also be available at one center. Histology and non-invasive imaging will facilitate high throughput characterization, a capability that will become essential as human ES cell research matures.
Availability of Necessary Materials
Internet Resources: Several participants expressed dissatisfaction over the current NIH Human Embryonic Stem Cell Registry web page, noting that it was misleading and difficult to navigate. Although the site lists the cell lines available for research under the current administration's guidelines, it does not mean that these cell lines are currently available to researchers. Five lines are available currently; the number may increase to ten by November 2002. Moreover, the cost of cells (up to $6,000 per vial) is prohibitive for researchers wishing to test numerous cell lines to determine which is most suitable for their research. Other researchers expressed concern about the high passage number of some cell lines available for purchase. All agreed that the Web site must be overhauled for clarity and correctness.
Characterization of Cell Lines: To facilitate choosing the most suitable cell line for an avenue of research, everyone agreed that standards for preliminary characterization (e.g. gene expression, surface markers, differentiation under a set of controls in vitro) should be employed universally to all cell lines available on the Web site. Currently, human ES cell lines are characterized through their ability to produce teratomas following a certain number of passages. Although abnormal karyotypes have been noted in cells grown in "feeder-free" conditions, distinct cell line differences are not yet fully understood. It was suggested that a battery of techniques, including SAGE and multiple parallel sequencing, could provide accurate quantitation on a cellular level. Such work would need to be centralized within one lab, although it would become necessary only after specific cell lines have been selected for further focus. It was also suggested that preliminary results should be made available online to reduce the duplication of experiments.
Embryonic Germ (EG) Cells: It was agreed that the NIH should actively try to increase the number of available EG cell lines.
Before closing the meeting, Dr. Battey solicited input regarding any concerns not covered in the summary discussion. Several concerns were mentioned, and discussion is highlighted below:
Support for a Web site that could translate information about stem cell research to the community. It was noted that the funding for such a resource would be low, and work could begin immediately.
Chimeras. Where in the human developmental timeline can ES cells be introduced into another organism? One respondent expressed concern about the potential future use of organotypic cultures of human embryos for implantation of ES cell derivatives. It was noted that since science is moving rapidly, policy guidelines need to be developed to address many current and foreseeable questions regarding stem cell research.
Dr. Battey closed the meeting by thanking participants for their time and expertise.
If you have questions about the Task Force, please contact:
Science Policy and Planning Branch
National Institute on Deafness
and Other Communication Disorders, NIH
Bethesda, MD 20892
Phone: (301) 402-2313
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