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CL1-00503-1: International Stem Cell Research Institute Shared Laboratory Facilities

Laboratory Recommendation: Not recommended for funding

Public Abstract (provided by applicant)

We have established the International Stem Cell Institue at Cedars-Sinai to facilitate stem cell research, including reesearch on human embryonic stem cells. The International Stem Cell Institute will advance both basic research and clinical applications of stem cell research. To aid in these goals, we have already established a central laboratory to isolate new human embryonic stem cell lines. Some of these cell lines will be normal cells, others will be genetically defective cells. In addition, we will develop “good manufacturing practice” (GMP) cell lines. All of these will be important for the stem cell research to succeed at Cedars-Sinai.

The California Institute for Regenerative Medicine has issued a Request for Proposals that seeks applications that propose to develop shared research laboratory facilities. Here we request funding for major equipment items, personnel, and renovation costs to create a shared tissue culture core facility that will be available both to investigators at Cedars-Sinai and also to investigators from other institutions in our area. Three specific institutions that have expressed desire to utilize our proposed core facility are California State University Northridge, Mount St. Mary’s College, and Occidental College. The proposed shared research lab will have four subsections: a cell derivation laboratory, an imaging laboratory, a cell sorting facility, and a laboratory that will produce cells free of animal products that could be utilized in human clinical studies. Our shared facility will enhance stem cell research at Cedars-Sinai, and will encourage partnerships with investigators at nearby institutions. Ultimately, our research efforts will develop and and test potential beneficial applications of stem cells in the treatment of human diseases.

Statement of Benefit to California (provided by applicant)

The proposed CSMC Shared Stem Cell Research Laboratory will benefit the State of California and its citizens by facilitating development of translational stem cell research applications. Cedars-Sinai already has prominent stem cell investigators, and as a result, our facility will assure that CIRM funds are utilized in high quality stem cell research applications. Our outreach efforts to less well-developed stem cell research programs at neighboring institutions will help increase the number of investigators and institutions that can conduct quality stem cell research, and will thus expand the stem cell research community in California.

Scientific Review Summary of Part One Application

SHARED LABORATORY

SYNOPSIS OF PROPOSAL: This is a proposal by a well known neurosurgeon for a Shared Research Laboratory (SRL)that is to be part of an international institute established at the applicant institution. The international institute will be led by a well-known pioneer in the human embryonic stem cell (hESC) field. This investigator will co-direct the SRL and serve on the oversight board. The main scientific focus of the facility will be on translation of hESC research in various disease areas and will include the establishment of PGD hESC lines and the derivation of GMP quality lines. The proposed facility will be 2,950 sqf in size. No techniques course is proposed.

QUALITY AND IMPACT OF THE SCIENCE: The proposal is very dependent on the expertise of one investiagtor who will serve as a co-director of the SRL and serve on the oversight board. This individual has been one of the first in the field to show directed differentiation of hESCs, perform genetic modification and conduct studies on the immunological state of hESCs. The main focus of the facility is to be in the area of translational research, the establishment of hESC based disease models and the derivation of GMP quality lines. The institution has investigators with considerable expertise in the area of vector biology though the proposed studies do not make sufficient use of these investigators. The specific areas of research proposed are in field of cardiac disorders, neurodegeneration and brain tumors, spinal disease (mesenchymal cell approaches), diabetes and angiogenesis. The scientific projects and questions listed are of interest but the proposed execution/approaches are not very novel, poorly developed and in some instances without clear rationale for hESC use. The most interesting aspects of the proposal are in the area of hESC genetics and PGD line derivation. While there is some mention that at least one normal hESC line has been derived within the institution, no details are provided and no disease targets are mentioned to be addressed using PGD lines. The translational projects are described in broad terms without demonstrated hESC leadership in these areas. Overall, the studies proposed do not make a compelling argument for a new stem cell facility. The program director (PD) has no experience in hESCs and will be dependent on the expertise of the co-director. Other investigators seem to also lack hESC expertise. Unfortunately, only 4 CVs and 3 letters of support for 30 investigators are provided making this aspect difficult to review. The participation of the co-director is the greatest asset to the application and while there is commitment from the co-director, he/she will remain out of the country for most of the time and therefore is unable to manage the facility on day-to-day basis.

APPROPRIATENESS OF SPACE AND EQUIPMENT TO SCOPE OF PLAN: The proposed SRL of almost 3000 sq ft space will be created in a renovated space, with plans to allow 10-15 scientists and technicians to work at once. The space is quite generous and should suffice for the effort. This space has been committed if funded, but it is unclear what will happen if not. The lab will be integrated in the larger stem cell efforts of the institution that are currently being planned. Renovations of up to $11 million suggest commitment by the institution in the stem cell field. Currently, there is no hESC facility available despite the establishment of the international institute for stem cells and despite the fact that apparently a hESC line was already derived in-house. A quite extensive list of equipment purchases is proposed. However, many items are not detailed (e.g. items described as “electro-gene transfer”) and some of the elements have not been clearly justified such as a purchase of HPLC system, ELISA readers, FACS machines and analyzers. Basic equipment from hoods and incubators to 15 computers are requested; so it looks like there is little institutional support for equipping this facility. The efforts listed for manager and associated staff may not suffice for the size of facility proposed. The lab manager seems to have to work largely alone without dedicated technical staff.

QUALITY OF MANAGEMENT PLAN: The management plan is not well developed and the application lacks essential information. The oversight committee consisting of the program director, co-director, the vice president of research at the applicant institution, the chair of the Biomedical Sciences department and the administrative services manager for facilities has little balance to objectively manage the science. The day to day details are left to the lab manager, who is described both as a post-doctoral fellow at the applicant institution and as the lab manager (100%) for this facility. While the program director has no experience in hESCs, the lab manager has been trained by the co-director. However, it is unclear from the information provided whether the lab manager has actually yet completed a PhD degree and may be somewhat junior for running such a facility without the help of the co-director. The lab manager’s staff consists of the Manager of the Confocal Microscopy Facility (20%); a lab manager from a PI lab (50%) who will “assist where needed with regulatory compliance documentation and testing, quality control and general maintenance and operational tasks”; and the manager of the Flow Cytometry and Cell sorting Facility (30%). Not only is there little justification for such a large percentage of the salaries for this staff, it is unclear how day to day priority will be dealt with. No dedicated technicians are proposed to support the lab manager, which seems problematic for a facility of such size and scope.

The proposal has not been planned carefully. No details are provided on the line that was derived in-house. There is a lack of information on how and where the GMP lines will be generated. It is not clear whether a GMP facility is already available and whether staff is trained in GMP procedures. There is some evidence that the institution has successfully run a number of core facilities. An oversight committee is listed that will meet on a monthly basis. However, the exact task of the committee is not described. There is not information on project selection and prioritization. The PD mentions that the institution has a SCRO committee in place. The potential outside investigators beyond the applicant institution mentioned in the application may not have the research strength required to fully benefit from the facility. However, these neighboring colleges may get an educational benefit from the facility.

DISCUSSION: The limited number of biosketches for key personal, including the program director, was problematic for all reviewers, as it was therefore difficult to assess scientific merit and expertise of this application. A biosketch was included for the co-director, who is considered by the one reviewer to be a leader in the field of hESCs. There are several major problems with this proposal. According to one reviewer, the main problem with this proposal is that it was developed in haste. The scientific plan is poorly developed and key personnel have little expertise. The co-director is apparently the only one to provide expertise in hESCs. No clear rationale for the use of hESCs was provided in the studies described although some scientific strengths in the area of vector development were noted.

Key leadership is not on-site and the facility is to be run by a junior person with no dedicated technical support. Additionally, 3000 sq ft seems rather large for the planned facility which will not be GMP compliant. The equipment listed, e.g. the flow cytometer, was not not justified clearly and items such as an HPLC do not fit with the context and purpose of the laboratory. The intended shared users outside of the applicant institution include schools known for their teaching not their research, so it is unclear how neighboring institutions will contribute to the research. The primary reviewer is not excited by the potential to develop a strong hESC scientific program given this plan, and acknowledges the main strength is the contribution of the co-director. Other reviewers agree and had the impression the entire proposal was assembled hastily and poorly by very busy people.

The following Grants 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:

• None