Research Leadership 12
$7 480 036
The ‘valley of death’ in scientific parlance refers to the time period where biomedical discovery in the laboratory fails to result in a cure for a disease. While the last decade has seen extraordinary developments in regenerative biology, the translation to regenerative medicine will require successful negotiation of the ‘valley of death.’ In most cases, the scientific field has yet to prepare a model of stem cell manufacturing that will meet the Food and Drug Administration’s requirement of Good Manufacturing Practices and produce sufficient quantities of quality stem cells to meet patient need. This critical step requires the development of manufacturing technology and quality control standards for stem cell production. Using cardiac muscle cells as our model, this proposed project will develop these standards and practices to enable industry to meet regulatory requirements and produce safe and effective cures for heart disease. These lessons learned will be broadly applicable to quality production of stem cells for a broad range of pathological conditions which warrant a regenerative therapeutic option.
Statement of Benefit to California:
Protecting California’s investment in Regenerative Medicine includes prudent development of the techniques and methods required to meet regulatory requirements and the development of safe and effective cell-based therapeutics. The collapse of Geron Corp’s stem cell development program and the difficulties facing current stem cell manufacturers suggest that the lack of a defined set of Quality Control standards and methods for cardiac stem cell production are representative of a broader problem that could impede efforts to exploit bench discoveries, traverse the ‘valley of death,’ and industrialize the production of cellular therapeutics. In our proposed study, we will use stem cell-derived cardiac muscle cells as a model to develop protocols and standards for determining cell quality and their applicability for disease models in drug discovery and as cellular therapeutics in the clinical environment. The cardiac stem cell quality index we will develop benefits the State of California by facilitating safe and effective therapeutics for ailing Californians and enabling the California stem cell industry with the manufacturing practices required to meet regulatory requirements and achieve market dominance.
The candidate principle investigator (PI) is a recently promoted full professor recognized in the bioengineering field for her/his work on biomaterials and tissue mimetics. The goal of the proposed research is to develop scalable methods and quality standards for the GMP (Good Manufacturing Practices)-compliant derivation of mature and fully functional human cardiomyocytes from human pluripotent stem cells (PSC). The PI proposes to achieve this by optimizing use of biomaterials in addition to soluble factors to mimic the cellular environment in heart muscle. The resulting production process should allow consistent production of sufficient quantities of well-characterized cells to be used for regenerative medicine purposes. Research Vision and Plans - While the ability to manufacture functional cardiomyocytes at scale was felt to be a significant challenge in the field, it was felt that developing GMP quality standards for production of cardiomyocytes was not a key bottleneck for developing these therapies. - The proposed work didn’t seem particularly innovative since the general approaches to be taken are commonly used by others. Not enough information was given to assess whether the applicant would approach the problems in novel ways. - It was felt that understanding the effects of mechanical stimuli on cardiomyocytes and heart function is an important area of study that could lead to insights about heart disease as well as ability to manufacture cells at scale. It was acknowledged that the applicant is an important contributor in this area. PI Accomplishments and Potential - The applicant has multiple publications in high impact journals in both engineering and biomedical sciences, has generated substantial independent funding, and manages a large laboratory group. - The applicant is not widely recognized as a leader in stem cell research or regenerative medicine, but is known within the field of biomedical engineering for her/his experience in the development of systems to create tissue mimetic structures. - Reviewers noted that the applicant has shown that she/he is a big thinker who comes up with unique, clever and creative ideas and would have a positive impact on the applicant institution. - While some reviewers were impressed with the leadership potential of the applicant, others felt that most of her/his scientific track record is as a member of a team, rather than a leader. - Recognized leaders in the fields of cardiac regenerative medicine and tissue engineering acknowledge the impact the applicant has already had on the field, her/his capacity for innovative thinking and her/his potential to contribute to the development of transformative technologies in the field of regenerative medicine. Institutional Commitment and Environment - The institutional commitment was considered to be adequate, although not overly generous, including laboratory space with most major equipment provided and startup support with matching funds for new laboratory purchases. In addition, the applicant would have access to relevant core facilities. - The rich environment at the applicant institution was viewed as likely to be beneficial to the principal investigator and would provide opportunities to take his/her current research program in new directions. - While the potential for complementarity with other investigators working at the applicant institution was recognized, reviewers were disappointed that specific plans for collaborations were not made clear in the application or institutional support letter.
- A motion was made to move this application into Tier 1, Recommended for Funding. It was noted that the applicant rose quickly from assistant to full professor, has many publications in her/his area of expertise and has good letters of recommendation. However, there was some concern about the narrow focus of the application. The motion failed due to a tie vote.