The goal of this proposal is to establish a premiere center for human embryonic stem cell (hESC) research and education in the state of California. Our center builds on the established excellence of faculty with research organized into four thematic areas: Human embryology, derivation of hESC lines, including disease-specific lines, and SCNT, Cell fate specification and hESC reprogramming,Cancer and cancer stem cells, and Directed differentiation to cardiac and neural lineages. Here, we seek funding to renovate facilities that will house a human embryo/oocyte resource center and database, hESC line derivation, as well as other research and educational training including a central repository for growth, characterization and distribution of hESC lines to scientists in our community. The success of the faculty in this Center in garnering funding for hESC research, including CIRM funding, mandates the expansion of our research facilities. In addition, an accompanying curriculum in Stem Cell Techniques Courses is complementary to the research efforts and builds on a history of teaching excellence. This curriculum will encompass three areas: Basic hESC Biology covering core essentials of hESC biology for individuals with little or no previous experience in hESC research, Advanced or Specialized Stem Cell Techniques courses that will provide individuals with tailored instruction to enhance forward momentum in selected scientific topics, and Systems Biology that reaches across institutions to bring together scientists in hESC and computational research. We anticipate that the outcome of our training initiatives will be both an expansion of knowledge and the building of teams to tackle tough basic and clinical challenges. Finally, we note that our human embryo/oocyte resource center will provide expertise, materials and a complete, decoded database for use of precious resources in hESC research. This will enhance efforts to provide early diagnostics for reproductive and somatic disorders, cancers and onset of disease. Thus, this Center builds on a regionally unique combination of scientific and clinical excellence of Stanford University and neighboring institutions to provide critical research and educational support to scientists in California.
Statement of Benefit to California:
This proposal provides real benefits and value to the citizens of California in that our Center is established with a foundation built on: a scientific faculty that is unsurpassed in knowledge of human development and disease and dedicated to pushing forward in hESC research, a program director with numerous publications on hESCs and extensive experience in the State of California in establishing and directing an hESC Center with both research and teaching components, a Shared Tissue Resource that is supported by the largest, and most accomplished academic IVF (in vitro fertilization) Clinic in California to support research protocols, in an appropriate manner, that range from derivation of normal and affected or disease-specific lines to reprogramming of somatic cells via nuclear transfer, an established, decoded database system that will allow data from hESC research to be translated back to improvements in assessing embryo health (and thus decrease adverse outcomes that impact women’s health such as repetitive miscarriages), a core curriculum that has been successfully implemented for group and individualized instruction, and a central location in Northern California within Silicon Valley that allows us to draw additional expertise from neighboring institutions and open our doors to training diverse members of the scientific community on one contiguous campus. Thus, the combined facility and teaching resource proposed will benefit the citizens of California by consolidating and accelerating research within the northern and central California region as well as by providing advanced training opportunities for investigators and research personnel throughout the State. This will enable a broad range of stem cell applications, promote the rapid translations of new discoveries to the clinic and also provide well characterized clinical grade reagents to support these efforts.
SHARED LABORATORY SYNOPSIS OF PROPOSAL: This is an application for a Shared Research Laboratory (SRL) and Stem Cell Techniques Course (SCTC) to be centered at Stanford University. The investigators seek funds to renovate and equip core laboratory facilities that will culture human embryonic stem cells (hESCs), derive new hESC lines, and serve as a central repository for growth, characterization, and distribution of hESC lines. They propose a “hotel” space for hESC work, where investigators could work for a few days or weeks after receiving hESC training, so as to be closer to the training facilities and to other investigators working with hESCs, prior to returning to their own lab space. The program director (PD) is an experienced hESC investigator who has participated in teaching of hESC techniques previously, and in deriving new lines. Three types of courses are offered - a basic hESC techniques course, an advanced course, and one that is integrated with systems biology. The scientific need at Stanford is high, with many investigators interested in the technology. QUALITY AND IMPACT OF THE SCIENCE: As one of California’s premier research and teaching institutions, the quality and impact of the science across the campus, and of investigators specifically interested in working with hESCs, is extremely high. Thirty Stanford faculty members are listed as prospective users of the SRL. There are stated collaborations with faculty at UCSC, the Parkinson’s Institute and UC Davis. Stanford was approved to receive 12 CIRM SEED grants in addition to 11 pending comprehensive CIRM grants at the time of the review, so the SRL would help support this work. The program director is an exceptionally well qualified, mid-career Professor of Obstetrics and Gynecology. Her co-investigators are all well-funded by peer reviewed mechanisms and publish at regular intervals in top-tier scientific journals. The investigators who will make use of the facility are loosely organized into several areas, including human embryology, cell fate specification, cancer and cancer stem cells, and directed differentiation. A strong contingent of 9 investigators including the PD will work on derivation of new human embryo stem cell lines, SCNT and human embryology (Reijo-Pera, Chiao, Baker, Behr, Hseuh, Kim, Yao, Westphal, and Tarantal). The inclusion of SCNT studies will add valuable insight into the value and reproducibility of this controversial approach. Another group will probe the molecular mechanisms that dictate the fate choice decision of stem cells to self renew or differentiate (Artandi, Chen, Fuller, Kuo, Longaker, Nusse, Scott, Wandless and Wysoka). A third group of investigators will use the shared facility to address timely questions in the field of stem cells as they relate to cancer (Clarke, Sage and Wu). Finally an outstanding cohort of neuroscientists and distinguished stem cell biologists will use the facility to address the directed differentiation of stem cells towards cardiac and neural lineages (Cooke, Kovacs, Krams, McConnell, Palmer, Quertermous, Robbins, Steinberg, Weissman and Yang). The quality of the science is outstanding as is the potential for clinical/translational impact. While there is great strength in basic science, there are also a few investigators looking at more clinical aspects, such as scaling up the production of cell types, and the behavior and function of cells after transplantation. The proposal is highly responsive to the RFA - all the work is with hESCs and most on non-NIH approved lines. The quality of the investigators, their track record and the quality of the science proposed, is among the best in the world. A non-federal, shared stem cell laboratory, providing uniform cultured cells, will add greatly to the productivity and innovation of this group of outstanding investigators. In summary, Stanford is arguably one of the leading institutions in the world in stem cell science. According to the application, approximately 90 faculty members have stem cell research planned and Stanford currently has 46 academic service centers within the various schools. This is a well written, wonderfully detailed application with excellent collaborations in place and a well-thought plan for staffing and managing both the SRL and the SCTC. APPROPRIATENESS OF SPACE AND EQUIPMENT TO SCOPE OF PLAN: A total of 3700 square feet of laboratory space comprising two laboratory suites are included in the requested renovations and/or equipment acquisition. About 2500 square feet is in the Stanford Institute for Stem Cell Biology and Regenerative Medicine, a 40,000 square foot non-federal research new facility. This is a remote site away from the main Stanford research area that will be used for teaching, deriving, and culturing hESCs, and will also contain the “hotel” space where investigators can work with hESCs for periods of time. The second laboratory suite included in the requested renovation and/or equipment request is a smaller “satellite” space of approximately 1200 square feet located on the main campus that can be used for culture of non-NIH hESC lines. This appears to be adequate at the time, but may need to be increased in the long-run. The remote location of the main space is something of a concern, as it is one reviewer’s experience that interactions decrease exponentially with distance. It is not clear at this time how much this (the location) will impede use of the main hESC facility for most of the Stanford scientists, whose interest in hESC may be actually quite peripheral to their research interest. Otherwise, the space considerations appear adequate. There is already NIH-free space available that has been renovated, but funds are needed for equipping it. The “hotel” concept is innovative and may reduce the concerns associated with the remote facility. Space descriptions and equipment needs are carefully detailed and totally appropriate to accommodate both hESC derivation, and SCNT studies. The budget is very carefully detailed, including all items of equipment and personnel costs, all of which are appropriate and within the constraints of the RFA. In summary, the shared resource will be in a centralized facility dedicated to training and research that is unable to be supported by the federal government. The core laboratory will be housed in a ~40,000 square foot facility where space is coded as appropriate for non-federal research. Within this context, the space and equipment plan proposed is appropriate. An additional research-oriented SRL is located on the main campus. Qualified investigators from the nearby Parkinson's Institute and from the UCSC are likely to benefit from the shared laboratory as it comes on line. QUALITY OF MANAGEMENT PLAN: Overall the quality of the management plan is excellent. The PD, Dr. Reijo-Pera will direct both the SRL and the SCTC, citing 10% of her effort for each. She has re-assembled the laboratory team involved with her previous stem cell banking efforts, including lab director Eric Chiao, a well-trained, doctorate level geneticist and research associate at Stanford who will devote 50% of his efforts to SRL and 50% to SCTC. A dedicated research associate will devote 100% effort to the stem cell efforts, and there is a plan to recruit a 15% effort nurse/embryologist. The teaching team includes a technician, 50% effort, to help specifically with the teaching needs. Given the overall budget constraints of the RFA, the distribution seems excellent. This management combination seems adequate and realistic. The PD has had extensive experience with operating shared resources, particularly with her previous role as PI of an R24 national resource for registered hESC lines. Many elements already instituted by Dr. Reijo-Pera are further developed here, giving this proposal a particularly high likelihood of success. The oversight committee consists of distinguished scientists from Stanford and 3 other institutions who may have investigators utilizing the SRL. The investigators anticipate that the facility and the proposed stem cell training course (see below) will be initially oversubscribed. Accordingly, they have put forth a carefully considered plan for prioritizing the applications of lab users and course trainees. The facility use will be reviewed and is clearly prioritized for CIRM-funded investigators. It is not clear how investigators from other institutions will be prioritized relative to Stanford’s investigators, although a commitment to serve these groups is stated. The “hoteling” plan could prove problematic, but the PD has drafted guidelines for use of this space which seem reasonable. There is a clear institutional commitment to this program. Stanford has already expended substantial funds to hire Dr Pera and associates and set aside and renovated space on both the main campus and the Stanford stem cell institute, thus, the institutions commitment is very high. DISCUSSION: This is a very unique proposal, well-crafted and thorough, addressing all aspects of hESC biology. It was impeccably prepared with no stone left unturned in this proposal to renovate/equip core facilities for both a large and small satellite facility. The science is excellent. Of note were the impeccable, top quality people and blue-chip co-investigators - all well-funded and publishing in top-tier journals. Another strength is the carefully thought-out use and choice of personnel. The PD is an excellent scientist and there are excellent users. A dedicated senior investigator will spend 50% time on the facility and 50% time on teaching. SCNT has been incorporated into the core and the course, and the PD is singularly well-qualified to do this. The unique concept of a “hoteling space” where people can come in for a few weeks to months at a time to conduct research generated a fair amount of enthusiasm among the reviewers. The oversight plan was good and there is clear institutional commitment. Although the shared labs are intended to support scientists from Stanford and other local institutions such as the Parkinson’s Institute, one of the reviewers suspects that the Stanford people will monopolize the use of the facilities. One question is how will use by neighboring institutions be prioritized. Two physical SRL components are proposed including 3,700 square feet total: 1) the core SRL in a large new building and 2) a satellite facility for cell derivation. The new building, the Stanford Institute for Stem Cell Biology and Regenerative Medicine is located 5 minutes from campus and includes 40,000 sq.ft. of space is devoted to non-federally funded work. It would house the core SRL (~ 2800 square feet of laboratories) most of which is built out now with operational research offices in place. A small satellite lab (approximately 1200 square feet) will allow a safe haven in the medical school for convenience; this space does not require renovation but requires some equipment. One panelist questioned the utility of such a satellite space. A reviewer responded that Stanford wants some space close to the medical school with equipment resources for non-federally funded research. Another reviewer points out the minor issue that the satellite facility is isolated and could be bigger. A minor concern brought up in the discussion is that the separation of the facilities, even if only a 5 minute drive away, will dampen collaboration. All three reviewers said that this is the best application among those they reviewed. One reviewer considered this a “flawless” proposal and offers elements not offered elsewhere. TECHNIQUES COURSE QUALITY OF THE PROPOSED TECHNIQUES COURSE: This is a well-described, excellent teaching resource. Dr. Reijo-Pera, the PD, has several years of experience as Director of the National Center for Research Resources program to culture, characterize, and distribute NIH registry lines and provide training courses to more than 60 laboratories world-wide. The techniques course has been well designed to incorporate multiple course modules to meet the needs of different investigators. There is a 5-day course for basic hESC techniques offered 3 times a year, including making feeders, passaging cells, freezing, quality control assays, etc. The advanced training comes in two flavors. They will offer one curriculum for individuals or small groups to learn techniques related to SCNT, hESC derivation, and other specialized techniques related to human embryology and culture. The second will be for techniques related to neuroscience, including concepts in neural development, methods of transplantation and differentiation. Finally, there will be a course offering related to systems biology. This includes joint instruction with Biomolecular Engineering and will provide stem cell scientists with a background in high throughput molecular biology experiments. The need for this third module to be taught specifically in relation to the hESC funding is not clear (this could be given on the main campus and not associated with the CIRM). The quality of the proposed course is outstanding. Several world-renowned figures in stem cell biology are on the Stanford faculty and have agreed to contribute their efforts to these core courses. The nearby UCSC features strong programs in the areas of systems biology, computational biology and chromatin structure/function. Several UCSC faculty from these programs will also contribute to the stem cell curriculum and will provide considerable added value to the package. It is not clear how busy investigators such as Dr. Weissman will find time to teach a module on “directed differentiation” of hESC, and the concern about these advanced modules is how often they will be taught; they seem very time-intensive and not as well developed as the basic course. Still, the information is of real value. In particular, the module on advanced techniques related to hESCs is unique, and could be extremely important for continuing to develop hESC-related technologies. Overall, the quality of these instructors and the course plan is superb. QUALIFICATIONS OF THE INSTITUTION: The university has limited experience in offering courses of this type, but Dr. Reijo-Pera, the PD has a great deal of experience from her previous position at UCSF. It is anticipated that this experience will translate very well to the Stanford campus, and that she should have no difficulty setting up and running the course(s) more or less as designed. The course will be promted widely and throughout the state of California and students from multiple disciplines will be encouraged to participate in the course. Students will be contacted 6 months after the completion of the course to provide feedback regarding utility of the course material. They will also have access to the instructors through email and phone contact. The qualifications of the institution are very high for running the techniques course. DISCUSSION: The fundamental hESC course, which will entail 5 days for basic training, is well designed and will be offered three times a year. Another 2 advanced curricula are proposed, which will focus on SCNT (and considered very valuable), a second on neurobiological approaches. A third course would focus on systems biology with hESCs – the rationale for and significance of this course offering was less clear. There is a great staff that is dedicated to this effort. They can also gear up to do one-off offerings and the ability to do this with dedicated staff that is not doing their own research is very valuable. There is also a good description of follow up. Although in general it was noted that the instructors are great, one reviewer noted with some surprise that Dr. Weissman was listed as teaching a module in the advanced course. Another reviewer noted that the more advanced courses will be taught less often than the basic course, but since the director has a dedicated team to staff the course and shared facilities, she can be responsive to needs as they arise. The 3rd reviewer questioned the systems biology component. “Systems biology” can mean anything; it was unclear what systems biology ESC work would be covered under CIRM funding. This reviewer also points out that the association with UCSC will be an asset in the course given their expertise in genome-wide chromatin changes. PROGRAMMATIC REVIEW: A motion was made to recommend this Techniques Course application for funding and the motion passed.