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CIRM MAJOR FACILITIES GRANT APPLICATION #FA1-00613-1
Recommendation: Recommended for further consideration as a CIRM Institute
Element X Score: 90
Element Y Score: 81
Element Z Score: 89
Use & Contribution Score: 90
Public Abstract (provided by applicant)
OVERVIEW: The CIRM Facility will support ~19K+ ASF of laboratory and vivarium not subject to federal human embryonic stem cell (hESC) restrictions including: 1) Research labs, 2) Core facilities, and 3) Career Development space. The Facility is adjacent to biology, chemistry, engineering, medicine, and clinical/translational programs, including our Stem Cell Center (SCC), FDA compliant GMP facility & CIRM Shared Research Laboratory (SRL), our Hospital, Cancer Center, Professional Schools, AIDS Institute, and the College of Letters and Science and formal inter-institutional scientific collaborations.
MAJOR PROGRAMS across Elements X, Y, and Z, include: 1) role of stem cells in hematopoiesis, vascular biology, immunotherapy for cancer and related diseases, and immune deficiencies, 2) analyses of hESC, epigenetic regulation and pluripotency, and 3) understanding epithelial stem cells including neural, cardiovascular, and skin types in normal and abnormal development. Programs include our engineered immunity consortium that will express T cell receptor genes in hematopoietic stem cells to produce cellular immunity to combat cancer and related diseases. Our neural stem cell group uses hESC derived cells to model genetic and injury-induced neurological diseases. Such projects will interact with our clinical research programs to conduct cell based human trials. Major scientific collaborations to develop new ultrasensitive diagnostic and therapeutic technologies for stem cells include the Nanosystems Biology Cancer Center Program.
CORES: The Facility includes core laboratories to provide technical and developmental support for the programs including, computational & bioinformatics analysis of stem cells; advanced cell separation technologies; bioengineering for stem cell growth including organ scaffolds; advanced & vital microscopy; advanced mouse genetics; and vector production. The cores complement existing cores directly adjacent to the Facility for small molecule screening, hESC derivation and banking, GMP and the CIRM funded SRL.
FACULTY:The Facility will house up to 15 stem cell investigators including 8 CIRM grantees. The location will facilitate interactions with other stem cell researchers. The Facility will also provide much needed space for the career development of young clinical faculty and the recruitment of 3 new stem cell scientists with important expertise. Our institution, with its college and {REDACTED} professional schools, receives {REDACTED} in extramural research support which has a major economic effect throughout the region. The Facility will build upon a strong foundation of basic and clinical research and further solidify on-going institutional collaborations including research and joint training programs. The Facility will further link the activities of {REDACTED} premier research universities in the {REDACTED}area, and drives the important goal of bringing hESC science and technology from the laboratory to the bedside.
Statement of Benefit to California (provided by applicant)
The proposed interdisciplinary, high technology, CIRM Facility will support laboratories, and innovative core services in the conduct of human embryonic stem cell (hESC) research unimpeded by federal restrictions. {REDACTED} scientists will join forces in such work. The availability of such resources will in turn lead to new insights that will further increase the prominence of California as a leader in hESC research. The research programs, core services, and young faculty development offered in the Facility will provide essential resources and mentoring of researchers trained to work with hESC, thus ensuring the increased availability of a skilled academic and industry workforce to fill jobs in academia as well as the private biotechnology and pharmaceutical industry. These individuals will be a valuable resource for California institutions and serve as an important incentive for others to relocate here. The Facility is designed to integrate basic and translational research with the goal of translating laboratory discoveries to patient care. The Facility based stem cell programs promote collaboration of intra- and extra-mural researchers and embrace physician scientists with the intent of bringing regenerative medicine and hESC based diagnostics to the clinic. As described in the application, laboratories with critical core services will provide unique support for hESC research and develop new technologies intended to decrease the time and costs of bringing scientific discoveries to patients. This “bench to bedside” philosophy is consistent with our established track record of applying basic research to treat diseases. Thus, in addition to the direct benefit to patients and their families, the use of hESC to treat chronic diseases could reduce health care costs.
Review Report
Executive Summary
This is an outstanding application, encompassing elements, X, Y and Z, for a stem cell facility (CIRM Institute) located on a vibrant campus, housing in one building many stem cell researchers spanning basic to clinical research. The facility will build upon a strong foundation of basic and clinical research, support the interactive nature of the current researchers, and promote on-going research collaborations and joint training programs with a prominent nearby institution.
The proposed CIRM Facility will support lab and vivarium space in a new building currently under construction, housing research labs and core facilities for non-NIH human embryonic stem cell (hESC) work, and a much needed space for the career development of young clinical faculty. Core facilities will include computational and bioinformatics analysis of stem cells, cell separation, bioengineering for stem cell growth, microscopy, mouse genetics, and vector production. These new cores will complement existing cores adjacent to the proposed facility including small molecule screening, hESC derivation and banking, Good Manufacturing Practice (GMP) and the CIRM-funded Shared Research Lab Good Tissue Practice (GTP) suites. The proposed facility will house up to15 stem cell investigators, including preeminent scientists, and including space for the recruitment of 3 new stem cell scientists. The facility’s location will help promote interactions with additional CIRM-funded and other stem cell researchers.
Major programs across Elements X, Y, and Z, include: 1) the role of stem cells in hematopoiesis, cardiovascular biology, immunotherapy for cancer, and immune deficiencies, 2) analyses of hESC, epigenetic regulation and pluripotency, and 3) understanding epithelial stem cells including neural, cardiovascular, and skin cells in normal and abnormal development including cancer. Element X focuses on important aspects of stem cell biology and takes advantage of a faculty with outstanding credentials. Over 80 primary faculty with 7 CIRM grants are listed, with 7 investigators (2 CIRM-funded) relocating to the proposed facility. Element Y is mainly limited to current basic science faculty, but will benefit from the experience of an existing clinical facility. The program lists 20 primary faculty with 5 CIRM grants, with 5 investigators (3 CIRM-funded) relocating. Element Z is outstanding. While several of the proposed studies appear industry-derived, the platform of cellular therapies in both cardiovascular and oncologic diseases provides for a robust development of infrastructure which will be utilizable for a variety of other stem cell clinical studies. The program lists over 10 primary faculty, with 2 investigators relocating. There is a stated commitment to add six new faculty for Elements X, Y, and Z combined, with three to be located in the new facility.
Reviewers identified the strengths of the application to be in the basic research (X) and clinical (Z) component, but found the translational component (Y) to be disappointing. There were many strengths of the proposal, including the high quality of the basic research in hESCs and hematopoietic stem cells (HSC), a strong pre-existing collaboration with a prominent institution to develop ultrasensitive diagnostic and therapeutic technologies, imaginative and enabling cores spanning bioengineering to microscopy, clinical trials with HSCs, and allotted space for new faculty in the new facility. Weaknesses were that the preclinical research programs are not highly collaborative (and thus less likely to benefit from a shared facility), a lack of engineers in the space except as core service providers, a lackluster educational program, and few details on how to ensure that researchers not housed in the center would benefit from the facility, except through the cores. Notwithstanding these criticisms, the reviewers were extremely enthusiastic about the caliber of the Element X investigators and the strong Element Z program, expressing confidence that the applicant institution may be one of the first to bring hESC to clinical trials.
Detailed Summary
Element X
Score: 90
SCIENTIFIC PROGRAM: The basic research program at the applicant institution will focus on four areas of stem cell research: ESCs, Neural Stem Cells (NSC), Epithelial stem cells, and Hematopoietic Stem Cells (HSC). These four areas represent priorities in the stem cell field, and the objectives are sound and do-able based on the scientific tradition of the applicant institution. This program is based widely enough so as not to be parochial, but is not so encyclopedically inclusive as to be excessively diffuse. The faculty involved is of very high caliber, and their basic stem cell research will inevitably contribute to our current knowledge. Reviewers were enthusiastic that faculty to be housed in the proposed new facility comprise well-known scientists, including the director and co-director of the program, and represent each of the scientific areas cited above. Furthermore, the overall program incorporates relevant distinguished experts from a prominent nearby institution and selected faculty from the applicant institution based outside the proposed facility. The combination of talent, tools, choice of project areas, and coordination of approaches is outstanding overall and highly likely to result in advances of value to the research community and other end-users. The application describes the interactive nature of the current researchers citing multiple examples.
The ESC and HSC programs are the most well-developed. They feature the strongest scientific programs, including interactions between faculty inside and outside of the proposed facility. This may be due to the fact that the director and co-director of this program, two very well-known investigators, specialize in these areas. The hESC research program also notably features the most interactions among life scientists and engineers. The quality of science in the NSC and Epithelial stem cell programs is excellent, althought they are more limited and have fewer interactions among members.
FORMAL INSTITUTIONAL COLLABORATIONS: Both intra- and inter-university collaborations have been well described and developed. There are several pre-existing formal collaborative agreements with one prominent nearby institution, a most favorable relationship. The collaborations occur in areas of 1) nanotechnology for cancer applications, which has led to several high impact articles, but the relationship to hESC technology is not stated nor completely obvious; 2) utilization of stem cells for the development of immune responses to cancer and infectious diseases; and 3) educational endeavors, i.e. a common medical scientist training program between the institutions. Other collaborations between the institutions focus on NSC and HSC. The two institutions, and more importantly the many investigators in this proposal, have prior experience working together. For the purposes of this facility application, the applicants propose to make the core facilities available to researchers from the collaborating institution, with a formal committee to oversee access.
CORE SERVICES: A major strength of the proposal is the depth of core laboratories to be established or enhanced. The cores to be located in the facility will provide key enabling technologies including a Microscopy Core with capability for live physiological measurement; an Advanced Mouse Genetics Core designed to speed up the generation of transgenic and knockout mice; and an innovative Bioengineering Core that has the potential to provide game-changing technologies for stem cell biology, but is only briefly and vaguely described. The capability of the proposed Computational/Bioinformatics Core, whose details are not fleshed out, will depend on whether the applicants create a far-thinking computational core or simply a data analysis center. The proposed Microarray/CGH core comprises interesting systems for genome-wide array-based genetic and epigenetic analyses.
There are a number of relevant cores existing in other locations that are described. However, there is little discussion of the overlap of these existing cores with proposed cores. Vivarium space seems inadequate for the work proposed, and does not indicate where necessary clinically relevant model work would be done. Some complex technologies that are not yet routine operations, like small-molecule screening, would have benefited from more detail. This is a minor distraction, though, in the scheme of an overall outstanding proposal.
The cores will be run on a daily basis by non-academic staff hired in each core with oversight from a faculty member assigned to each core. There is no discussion of how the cores will be supported financially, other than that some existing cores operate without deficit. The lack of a business plan for the cores reduces enthusiasm, but overall the planned cores appear to be necessary and will have high usage. There is an operational intellectual property and technology transfer office in existence.
PLANS FOR GROWTH: The plan for growth is to hire six new faculty in Element X, Y, and Z combined, three of whom will be housed in the new facility. In addition, the applicants plan to assign space in the facility for starting physician researchers, a welcome move. Unfortunately, there is no emphasis in the future plan for faculty in engineering or technology development. The plans for increase of educational efforts are thin; the applicants describe expanding their stem cell training programs, but no concrete plan exists at this time. One reviewer described the plans for growth as adequate but unremarkable.
DISCUSSION: The reviewers considered Element X to be strong judged by the caliber of the participating faculty, a highly productive group of investigators based on numbers of grants and publications, and by the proposed facility, but less so on the programs that were laid out in the proposal. Reviewers commented that integration of participating faculty relied on physical proximity and no specific recruitment plans or management plan of operations was presented. One reviewer, while appreciating the quality of on-going engineering projects, pointed out that no engineers will be housed in the new facility. These criticisms were considered minor, though, in an overall fantastic proposal.
Element Y
Score: 81
SCIENTIFIC PROGRAM: The Preclinical Research Program will focus on NSC and HSC in good alignment with Element X, and also on cancer stem cells (CSC). Various faculty working in these areas will relocate to the new facility and many overlap with Element X.
The NSC program is very strong. The advances in generating and manipulating NSCs are being applied to model developmental disorders and neuro-degenerative diseases. The HSC program is also impressive. The CSC program is least well-developed at a preclinical level, suffering from a plethora of targets, and the described programs are mostly disparate individual efforts in understanding CSCs. To facilitate migration of basic and preclinical research into the clinical setting, the programmatic structure of a collaborating cancer center includes shared leadership by a basic scientist and clinician. This is fairly standard for cancer centers, and it is not clear how this structure affects the proposed research on stem cells or the proposed facility. Furthermore, although relations with an islet research center were mentioned in the proposal, there is little engagement of the proposed facility with diabetes research. One reviewer, despite judging Element Y as over-ambitious, was still confident that the proposed program will lead to good progress.
FORMAL INSTITUTIONAL COLLABORATIONS: The cited formal institutional collaboration for Element Y is the same as the one mentioned for Element X. This group meets regularly and has a focus on translational studies as well as basic research. It is not explained how this facility grant would influence/improve that collaboration, which has a broad base of other funding. Clinical trials derived from this collaboration are discussed in Element Z. This collaboration has a strong record of success, and one reviewer assumed that its contribution to the proposed facility will be more than merely NIH-funded stem cell work.
CORE SERVICES: The Cores for Element Y are essentially the same as for X, except for the inclusion of the Vector Core, which will provide viral vectors to researchers. This Core will be of use to researchers involved in Elements X and Y. One reviewer felt that there is impressive quality, impressive depth and meticulousness of thought applied to the cores.
PLANS FOR GROWTH: In addition to the six faculty to be recruited for Elements X, Y, and Z combined, there is a poorly defined commitment of some faculty positions open in clinical departments being used for stem cell researchers. It would have been nice to see a more imaginitive growth plan for Element Y; as proposed there is no particular programmatic focus or strategy. The housing of physician researchers in the facility will be especially useful for Element Y (and Z).
DISCUSSION: Reviewers generally felt that this was the weakest among the 3 elements. One reviewer pointed out that the applicant institution has always had an outstanding translational program, but in this application, the stated focus and the formal institutional collaborations for Element Y are the same as the ones for Element X, which led some reviewers to score this element less favorably. Although the HSC group has been very productive, their proposed work is not that original, albeit a logical extension of the basic science. For an effective bridge between Elements X and Z not enough cores requisite for translation were proposed. The CSC program description was diffuse and suffered from a plethora of targets, rather than focusing on a few cell types, and not much detail in the description of the proposed islet cell work was provided. Plans for growth were not substantiated by letters of commitment from the Chairs of the clinical departments.
Element Z
Score: 89
SCIENTIFIC PROGRAM: The proposal ably articulates the applicant institution’s clinical research excellence and the formidable body of stem cell trials underway. The participating investigators are the leaders of the field, and the presence of a preeminent scientist from a collaborating institution swings the balance for the applicant institution very favorably towards being an instrumental player in this area. One reviewer stated that the clinical applications as proposed represent the best effort in the country and therefore deserve funding. In the translational area, the applicant institution stands out as the most serious about tackling the difficult problems associated with stem cell work.
The preclinical development and clinical research program will focus on HIV and cancer. One exciting program is to combine the work on anti-HIV engineering of HSCs (already in clinical trials) with work on differentiating engineered hESCs into HSCs. Critical to this is the existence of a GMP-based hESC core at the applicant institution. The Phase I anti-HIV clinical trial has led to the opening of a Phase II trial for additional patients. This and other proposed studies involving genetically-engineered HSCs are of highly generalizable importance.
An additional effort involves the use of cardiac progenitors, with several clinical trials planned or underway, including a Phase II/III, double-blinded and randomized multicenter study to treat myocardial infarction. The cardiovascular applications are less innovative and are dependent on just one, albeit excellent, mid-career investigator. However, the path forward has been very well defined and includes two exciting clinical trials of adipose-derived cells underway in Europe (different routes of delivery, and different clinical indications), based on this researcher’s preclinical studies. One reviewer observed that there seems to be an oddly missed opportunity to strengthen an auspicious pipeline: little or nothing was said about adipose-derived cells for cardiac repair in Elements X and Y.
While several of the proposed studies appear industry-derived, the platform of cellular therapies in both cardiovascular and oncologic diseases provides for a robust development of infrastructure which will be utilizable for a variety of other stem cell clinical studies.
FORMAL INSTITUTIONAL COLLABORATIONS: With established track records, the collaborations among the investigators from the applicant institution will certainly be instrumental in achieving the success of the facility’s scientific goals.The cited formal institutional collaboration for Element Z is the same as the one mentioned for Elements X and Y. An additional collaboration with an investigator at a different institution is noted for the utilization of certain vectors.
CORE SERVICES: A consistent feature of the application is the excellence of cores. The applicants describe the use of the bioengineering core described for Element X and the vector core described for Element Y, both located in the proposed facility, as central to Element Z. The importance of the vector core is apparent, although one reviewer noted that there is no discussion of how such vectors will be financed, with each vector likely costing ~$300,000 for production and certification. The use of engineered matrices from the bioengineering core is not discussed in the research plan and thus is less clear.
Cores that already exist at the applicant institution include the hESC GMP and GTP suites, which are admirably explained. The strategic value of the PET and PET/CT facility is clear. For both modalities, one reviewer felt that more should have been said about what is routine, what is incremental, and what, if anything, is a revolution.
PLANS FOR GROWTH: Plans for growth include 1) recruitment of six new faculty for Element X, Y, and Z combined, 2) faculty development, and 3) stem cell training programs, as described for Element X. One of the six faculty slots will go to someone working at the basic science/clinical interface, with a focus on hESCs, which is an intriguing idea.
DISCUSSION: The reviewers were enthusiastic about Element Z in this application. It represents a very strong clinical program, and it seems very likely that the applicant institution will be one of the first institutions in the world that will bring hESC into clinical studies. The cardiovascular project, which includes the use of adipose-derived stem cells, is supported by the fact that related approaches are in clinical trials in Europe. The original discoveries for the use of such stem cells occurred at the applicant institution, i.e. this is their product. A panelist raised the question of whether the applicant institution has enough capacity to run more clinical trials, and a reviewer replied that there was a lack of detail with regard to operations.
The reviewers commented on the appropriate choice of one collaborator for viral vectors, and although the same investigator is also cited as collaborator on other applications, this was not considered unusal since this collaborator is the right person for the job. Furthermore, the collaboration with a preeminent investigator at another institution was highlighted as a major plus.
Use & Contribution
Score: 90
This application fulfills the three criteria listed by CIRM as crucial, including well-integrated elements, well-planned use of the proposed facility, and contribution of the proposed facility to the development of the applicant institution’s stem cell program. The space utilization is logical, useful and contributory. For these reasons, this proposal ranked the highest in one reviewer’s group of applications. However, another reviewer pointed out that the facility will be used to house faculty that are already collaborating, as well as newly hired faculty and some additional existing faculty. There is no specific plan outlined for integration of activities other than physical proximity. The faculty to be relocated are apparently currently housed in a distributed fashion, and thus the facility would encourage further collaboration, though the exact nature of where people currently are housed was unclear. Collaborations between faculty housed in the facility and those not in the facility are not detailed, and there was no specific management or operations plan mentioned other than the leadership role of one the preeminent investigators.
The following Working Group members had a conflict of interest with this application and were therefore recused from participating in review of, discussion of, and voting on the application:
- Feit, Marcy
- Sheehy, Jeff