May 14, 2003, Summary

Supporting Technologies/Tools in Basic Research Working Group

Members Present

James Battey (NIDCD, Chair), Melissa Carpenter (Robarts Research Institute), Greg Downing (NCI), Victor Dzau (Harvard University), Allen Eaves (British Columbia Cancer Research Centre and Stem Cell Technologies), Lawrence Goldstein (University of California at San Diego), Pamela Robey (NIDCR), Ralph Snodgrass (VistaGen Therapeutics), Allen Spiegel (NIDDK).

Other Attendees

Amy Blackburn (NIDCD), Arlene Chiu (NINDS), Laura Cole (NIDCD), Sherry Dupere (CSR), Charles Goldthwaite (science writer), Della Hann (OER), Marie Nierras (Juvenile Diabetes Research Foundation International), Baldwin Wong (NIDCD).

Summary of Participants' Consensus Suggestions

• Consider a mechanism to provide supplemental funds for researchers who wish to purchase stem cells.
• Work with stem cell (SC) suppliers to help them provide quality controls (e.g., purity, sterility, karyotype analysis, surface antigen analysis, verification of a lack of contamination) to accompany each lot of human embryonic stem cells (hESCs) that is shipped.
• Inquire whether current SC suppliers evince any interest in a central SC repository.
• Lower legal barriers to commercialization and access (e.g., intellectual property issues, material transfer agreements (MTAs)). It was proposed that a standard MTA be created that features terms reasonable to both the academic investigators and small biotechnology companies.
• Create and standardize a "starter kit" to insure that recipients of SCs will be able to grow the cells, provided that protocol is followed.
• Provide standardized, quality-controlled media (or perhaps a "universal medium") and reagents for cell growth and expansion. Mechanisms proposed to accomplish this and the previous suggestion included Small Business Innovation Research (SBIR) and contract mechanisms.

Welcome and Charge to the Group

Dr. James Battey welcomed participants to the meeting of the Stem Cell Working Group on Supporting Technologies/Tools in Basic Research and thanked them for their expertise and willingness to share their thoughts on such a timely issue. He noted that many tools are needed to advance the field of SC research, and meeting participants would be helping to chart the course of future SC research by providing suggestions and ideas. He noted also that acceleration of the SC research enterprise is a goal of the NIH, which currently provides a host of initiatives for training, collaborative opportunities, and funding of investigator-initiated research.

However, basic research that uses hESCs presents many challenges to the investigator. For example, currently viable cell lines require a variety of conditions for culture, and the various components of the stem cell culture process are not standardized. In addition to difficulties with growing the cells, availability and pricing of hESCs discourages young investigators from entering the field. Dr. Battey noted that the goal of the NIH Stem Cell Task Force is to lower barriers that hamper research, thereby moving the field forward. To that end, he encouraged participants to discuss issues frankly and openly, challenging commonly-held notions when necessary. He noted that the meeting would be structured as follows:

1. Brief introductions by participants in which each participant states several key issues of concern regarding supporting technologies for stem cell research.
2. An open discussion resulting from participants' suggestions.
3. A summary of consensus suggestions to be drawn from all of the ideas forwarded. (A list of consensus suggestions appears at the beginning of this summary.)

Discussion related to the consensus suggestions follows.

Increase Access to Stem Cells for Use in Research

Participants agreed that a distribution system is mandated, preferably within the commercial sector. It was also suggested that a central supplier of cell lines be selected that has the capacity for good manufacturing practices. Assessment of standards could be verified independently, and a scientific advisory group could oversee the process.

Some participants voiced their opinions that the 11 cell lines currently available for distribution are not sufficient.

Cost was also seen as a barrier. For academic clients in the United States, hESC cells cost $5000/vial; this increases to $8000/vial for Canadian customers ($1000 of which is for shipping cost). Respondents felt that, even if these costs remained fixed, an assurance of quality control must accompany shipment. Currently, cells may be contaminated or difficult to grow once thawed. Respondents discussed the possibility of the NIH subsidizing the suppliers on a per-vial basis for each vial shipped.

One respondent suggested that the NIH could subsidize the cost of cells for all NIH-funded investigators. Currently, investigators funded by R01 mechanisms can list the cost of cells as a direct cost, although this often leads to bureaucratic difficulties. Moreover, the opportunities for non-R01 investigators to be reimbursed for cells (e.g., via R21 and pilot grant mechanisms) are less clear. It was also suggested that NIH-funded investigators could apply for supplemental funding, which could be quickly reviewed by program staff.

The NIH Stem Cell Characterization Unit, which is currently being developed, will provide side-by-side comparisons of the eleven hESC lines currently available. These quality controls will be in addition to the lot-by-lot quality assurances that suppliers would be asked to provide. However, this facility will not serve as a repository, because the NIH does not own the cell lines, and it is unlikely that suppliers will be persuaded to relinquish their ownership. It was noted that issues regarding distribution will be vetted at an upcoming NIH-sponsored meeting of the Infrastructure grantees in June.

Create New Tools and Technologies

Participants stressed the need to create a technology platform to support hESC research. There is a real need for improved ways to manipulate the SCs genetically, from the development of vectors to an increased understanding of immune factors and various pathways that govern differentiation.

However, it was noted that the development of a defined and reproducible protocol for culturing stem cells continues to be the rate-limiting step. The development of several media that do not require feeder cells was suggested as an avenue for enhancing the transferability of technologies. One participant suggested that the media could be adapted to the cells through a rigorous methodology that selects the most favorable media conditions. An example proposed was the recent observation by researchers at Harvard that the addition of ascorbic acid to the cell medium promotes the differentiation of murine SCs into cardiac myocytes (Takahashi T, et. al. Circulation 2003; 107:1912–1916).

One participant commented on the difficulty of transfecting SCs efficiently. Another participant pointed out the recent article in Nature Biotechnology by Zwaka and Thomson (21: 319-321), which describes a method for homologous recombination in human embryonic stem cells. Vectors are needed to make knock-ins and knock-outs, yet publication opportunities from such developmental work are low. Thus, it was suggested that the NIH invest more heavily in vector development in relation to hESCs, perhaps following the lessons learned from the field of recombinant DNA research.

Another attendee suggested that an automated, high throughput optical screening system is needed, and the development of this system could represent an ideal opportunity for collaboration with the private sector.

Develop New Mechanisms to Fuel Collaboration and Partnerships

Suggestions included:

• Attract businesses by changing the structure of SBIR and STTR grants (e.g., eliminate Phase I, shorten Phase I to allow rapid expansion to Phase II, or increase funds available to companies).
• Lower the hESC access fee for customers from the private sector, which is currently set at $100,000/vial.
• Develop mechanisms that will allow centers to bring together interdisciplinary teams.
• Provide academic/biotechnology partnership awards for differentiating cells and commercializing SC-related products.

Related Discussion

Respondents suggested the Immune Tolerance Network, sponsored by the National Institute of Allergy and Infectious Diseases, the Beta Cell Biology Consortium (sponsored by the National Institute on Diabetes and Digestive and Kidney Diseases), and Canada's Stem Cell Genomics and Therapeutics Network (STEMNet) as examples of successful networks that bring together and fund subsets of investigators. Coordinating centers within these networks can designate funding to participating members.

One respondent suggested that private-sector interests funded by the government must be afforded the same access to cells as academic users. The development of standard tools and antibodies can be handled through a contract mechanism. Currently, however, incentives are low for the private sector to invest in the field of SC research. Where possible, SBIR and contract mechanisms should be coupled with venture capital funds. It was noted that SBIR and STTR applications are often low when an initiative is not tied to a specific disease model.

One model proposed is the UC Discovery Grants, which are awarded by the Industry-University Cooperative Research Program (IUCRP) and form a three-way partnership between the University of California academic campus system, the State of California, and industry sponsors.

It was also noted that R21 and R33 mechanisms fail to engage the private sector. By contrast, NSF grants involve the private sector early in the development process. In this model, the government supplies one-third of the funds upfront. Industry commits another one-third at a later date, and the final one-third is subsequently matched by the government.

Intellectual property issues continue to elicit trepidation from venture capitalists and large pharmaceutical companies. MTAs, which are required for all cell lines that involve public funding, are currently the rate-limiting step, and it was suggested that the NIH investigate options for lowering associated barriers.

One respondent commented that contracts that focus around SC biology are well-suited to be the bases of commercial products or programs.

Provide Flexibility by Expediting the NIH Time Frame for Review of Proposals
Participants concurred that the NIH should investigate ways to expedite the grant review and approval processes. The recent expedition of the council review process for post-doctoral awards by the National Institute on Deafness and Other Communication Disorders was cited as an example.

One attendee suggested that investigators or companies that wish to apply for NIH grants for SC research need an easy way to gauge the fundability of a proposed project. It was suggested that prospective recipients could ascertain the NIH's level of interest in a timely manner by submitting a one-page "pre-proposal" that describes the proposed project. Thus, recipients could determine rapidly whether a grant submission would have a chance for funding success. This rapid turnaround, when coupled with non-exclusive licenses for commercial application, would provide incentive for companies to develop commercially viable products and tools for SC research.

Develop Disease Models

It was suggested that human models of disease (e.g., Alzheimer's disease or Huntington's disease) may serve as foci for SC research. For example, cDNA libraries of knock-out and knock-in models with lineage-specific fluorescent markers amenable to flow cytometric analysis would add value to SC lines that are currently available for use. These libraries could be based on hESC lines that feature the "most popular" modifications. The NIH is developing cDNA libraries for several of the eleven available hESC lines.

It was noted that an understanding of epigenetic factors (e.g., methylation sites) will be critical to maximize the use of these disease models.

Produce a Database to Link Gene Expression Data

Participants agreed that a centralized, on-line database will enhance research efforts. GenBank, a database established by the National Center for Biotechnology Information (NCBI), was cited as an example, and the NCBI was suggested as a resource for advice and database design. The Mammalian Gene Collection (http://mgc.nci.nih.gov/) was also mentioned. Several respondents voiced concern about maintaining a level of rigor in an open-field database to which anyone could contribute their data. One respondent suggested that a key capability of the database is a search tool that allows the data to be sorted by contributor.

The Progenitor Cell Anatomy Projects for various cancers (e.g., liver, gastrointestinal, bone/mesenchymal, and prostate cancers) will include gene profiling at various stages of disease. The database for these projects was suggested as a model for databases of hESC disease models.

Participants agreed that the database effort must be a trans-NIH initiative, and that it must be mandatory for data to be formatted uniformly and for contributors to communicate with each other.

It was also suggested that such a database should provide information on the amenability of the various cell lines to siRNA treatment.

Develop Specific Contract Mechanisms that Target Small Companies

It was agreed that contracts and RFAs are needed to develop certain lineage-specific tools, and these contracts should be of sufficient scale to attract the interests of smaller biotechnology companies. One respondent suggested that specific Cooperative Research and Development Agreements (CRADAs) could be tailored toward companies with expertise in high throughput sequencing and proteomics.

Explore the Status of Current SC Patents

Respondents concerned about the cost to companies for vials of stem cells requested that the NIH review the legal specifications of the patent currently held by the University of Wisconsin.

Conclusion

Dr. Battey thanked participants again for their time and enthusiasm. The meeting was then adjourned.

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
Fax: (301) 402-2265
E-mail: stemcell@mail.nih.gov