$3 329 223
Statement of Benefit to California:
SHARED LABORATORY SYNOPSIS OF PROPOSAL: This application to establish a Shared Research Laboratory (SRL) at UCLA proposes a 4700 square foot facility that will be shared by at least 30 investigators. The laboratory will be located within short walking distance of laboratories at the School of Medicine and will consist of 4 basic cell culture labs plus a good tissue practices (GTP) lab to be located directly adjacent to their existing good manufacturing practices (GMP) human embryonic stem cell (hESC) production lab. In addition, core facilities for FACS analysis, qPCR, nucleofection, karyotyping, and a Robosep cell separator are proposed. An appropriate oversight committee is in place. QUALITY AND IMPACT OF THE SCIENCE: The expertise of the included investigators is very high, and, in general, the impact of their science is high as evidenced by the outstanding publications and strong grant support many of these investigators exhibit. Thus, the overall quality and impact of the science is excellent. The research to be conducted on hESCs is prsented in very general terms, so it is difficult to assess the specific impact of these projects. However, the fact that 7 of these investigators are approved for CIRM SEED funds is a positive indication of good quality hESC science. Furthermore, many of these investigators have a strong track-record of work on non-hESCs, and thus familiarity with the stem cell field. Two investigators have extensive experience with hESCs, including derivation and maintenance of hESCs. It is predicted that the SRL will provide services for 30 investigators including 26 from UCLA, 3 from California Institute of Technology, and 1 from California State Northridge. It is no surprise that a broad range of scientific questions are being addressed by the 30 investigators. Investigations requiring hESCs include those on identification of the genetic control of stem cell maintenance/differentiation including studies on epigenetics, mitochondria, and directed differentiation down specific lineages in blood and germ cells. Other UCLA faculty are focused on engineering microenvironments for hESCs that enhance self renewal and/or differentiation down specific lineages. Hematopoietic and immune cell development and nervous system research are particular areas of potential clinical translation that have current activity at UCLA. The proposed topics are highly relevant to the field. Dr. Amander Clark is a junior faculty member who is a recent recruit to UCLA from UCSF, where she worked with Dr. Reijo Pera on germ cell development from hESCs. She will help to oversee the laboratory and her research will involve the development of new hESC lines using the GMP labs. There is an emphasis on developing space and facilitating programs that will lead to rapid translation of the findings of this group into the clinical setting, including proposed GMP space for cell expansion and manipulation. This is a relatively unique aspect of this proposal. The investigators that are a part of this program have excellent track records and have significant NIH and HHMI funding. Based on these parameters, the impact of the research supported by this core facility is predicted to be outstanding. APPROPRIATENESS OF SPACE AND EQUIPMENT TO SCOPE OF PLAN: One reviewer described the facility that has been designed as being excellent. The facility includes three integrated compontents: four multi-investigator laboratories (includes 4 separate labs that would allow 8 investigators to work simultaneously) and hESC analytical laboratory, a hESC GTP laboratory for development of translational/clinical protocols, and a GMP laboratory space for derivation and manipulation of hESCs for clinical usage. There are plans for additional faculty recruitment and adjoining space on the same floor is dedicated for these additional faculty. The total space encompasses ~4700 asf of laboratory space. The space is well designed. The overall location of the space on the UCLA campus appears appropriate, in that it is easily accessibly by many investigators. The size and scale of the SRL appear appropriate. The space has already been designated “NIH-free”. Equipment includes standard tissue culture hoods, incubators, microscopes and centrifuges. Specialized equipment includes a BD multicolor flow analysis machine, qPCR, and Amaxa Nucleofector. This instrumentation should thus allow state-of-the-art investigation of hESCs. There will be controlled access to the GTP and GMP facilities. The space allows research on both NIH supported and non-supported hESCs. One reviewer commented that although the rationale for establishing hESC labs that comply with GTP specifications is clear, it is not clear who will use the GTP laboratories, nor is it clear how the GTP labs will be equipped. Clearly the SRL will be providing services to many laboratories that are now focusing their work on hESCs. Although the multi-user laboratories will likely provide adequate space for the number of investigators who propose to use it initially, one reviewer felt that when and if 30+ laboratories are all using hESCs, this space many not be adequate. While there is considerable space, it is difficult to assess how the space will be shared among the large number of investigators who may wish to use it, except through a prioritization plan. QUALITY OF MANAGEMENT PLAN: UCLA has an excellent track record in establishing and running shared core laboratories led by the cancer center and by a newly formed UCLA Nanosystems Institute. Dr. Witte has presented an excellent plan, with appropriate oversight and quality control. An oversight committee will oversee quality, policies, budget and management and will have bi-monthly meetings. Access to the laboratory will be regulated via an application process that includes a description of the proposed research, verification of prior training in hESC culture and needed SCRO and IRB approvals. There is already an established procedure for regulatory and ethics oversight. A subgroup of the oversight committee (called the Laboratory Management Committee) will review these applications. All users are expected to have specific training and a specific prioritization schema was included. Once approved, investigators will receive a key card for entry. Overall the management is well thought out, functional and does not appear to be overly burdensome, according to one reviewer. Given the expertise of the individuals involved, there is a high likelihood of success. The PD is founder and director of the Institute of Stem Cell Research at UCLA. He is a member of the NAS and a HHMI investigator. Although he will have ultimate responsibility for the SRL, he will not have direct duties related to the SRL. Dr. Zack, who currently directs the GMP hESC lab, will be the chair of the lab management committee and director of the laboratory thereby taking care of day-to-day activities. Dr. Witte and his colleagues have put together an excellent and experienced team to oversee and run the laboratory. For the key personnel, 5% effort is listed for Drs. Witte, Zack, Clark and Pyle, 15% for Mr. Peckman, and 100% for 3 lab managers (Guo, Kim and Tang). The three lab managers will be responsible for quality control, equipment and ordering supplies. A total of $105,289 is requested in year 1 for personnel with 4% increases in year 2 and 3. Thus, the funding requested does not parallel the percent effort which will presumably be subsidized by UCLA. At least 1 of the 3 lab managers, Kim, Guo and Tang, will be present when work is being conducted in the SRL. Regular hours will be 7-7 weekdays, Saturday AM and Sunday afternoon, but measures are in place for investigators to gain access outside of these hours. The proposal describes 2 75% technicians, one of whom will work on validation of newly produced hESC lines and the other who will work on targeted differentiation of hESCs down specific lineages. One reviewer noted that while the applicants stated that non-UCLA personnel may have access to the SRL, it is not clear how this will be managed or prioritized There are only 3 investigators listed from outside UCLA, and it is not clear whether they are currently using hESCs or simply “might” be interested in the future. UCLA has a track-record in the operation of internal research cores, so, in principal, the core should be smoothly run. DISCUSSION: This is a well-written application and the best among those seen by one reviewer. UCLA already has a GMP core, and here they would like to build adjacent space for cell culture. This group has the potential and expertise to truly translate their research into the clinic and this represents a strength of the application. They will build four multi-user labs with a GTP lab that will allow 8 investigators to work simultaneously. One reviewer felt that the only real weakness is that the need for GTP lab is not well justified, but another reviewer felt that it is a good strategy to build a GTP lab that can scale-up. The applicants predict that 30-40 labs will request access and 10 labs are currently working with hESCs. Although the space is adequate it might still not be enough to accommodate the expected demand according to one reviewer. Other neighboring institutions will participate but it is not clear how access to non-host institutional users will be managed. The general research theme among investigators is epigenetic control and differentiation down certain lineages. The derivation of new lines is also proposed, but what cell lines would be used and why these are needed is not well-justified. There is a good plan for the review of applications for access. In addition, 3 research associates are proposed so that there is always on-site staff available. One reviewer commented that the $50k request for equipment maintenance seemed high. Overall, this is a well-organized application with great science and the group is clearly thinking strategically down the road. This SRL facility is well-justified.