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CIRM MAJOR FACILITIES GRANT APPLICATION #FA1-00610-1
Recommendation: Recommended for further consideration as a CIRM Center of Excellence
Element X Score: 80
Element Y Score: 75
Element Z Score: N/A
Use & Contribution Score: 80
Public Abstract (provided by applicant)
The Stem Cell Center is a cornerstone program of campus biomedical research that capitalizes on our strengths in basic and preclinical research, as well as collaborations with neighboring research institutions, to support high impact investigations with several major emphases: (1) stem cell self-renewal, (2) hematopoietic differentiation, (3) neural differentiation and neurodegeneration, (4) cardiovascular and skeletal muscle differentiation, and (5) cancer and cancer stem cells. The proposed CIRM Center of Excellence (CoE) will be the focal point for these efforts and will be critical to our ability to expand this program of world class basic and preclinical stem cell research.
The CoE will assemble a critical mass of investigators who will promote interdisciplinary collaborations among campus biologists, engineers, and physical scientists to make important discoveries that lay the foundation for developing new therapies for human disease. Basic investigations of genes that control stem cell self-renewal and pluripotency will aid the engineering of synthetic microenvironments for the large scale, safe expansion of human embryonic and other stem cells for cell replacement therapies and diagnostic applications. Likewise, elucidation of fundamental mechanisms of neurodegenerative disease will lead to new regenerative medicine therapies for Alzheimer’s, Lou Gehrig’s, and other diseases, as well as retinal diseases that cause blindness. Furthermore, insights into the mechanisms of muscle stem cell differentiation will aid our preclinical research in novel cardiovascular therapies. Importantly, the CIRM CoE will be located in a new building adjacent to several other disease-focused research programs, including neuroscience, cancer, and computational biology. Close interactions among these programs, as well as with leading bioethicists, will greatly benefit our basic and translational stem cell research.
The CIRM CoE will also enable an ambitious program to recruit five additional stem cell researchers, two in basic discovery and three in translational research, to complement seven established investigators in the CoE. Important areas of research that build and extend upon the strengths of the Stem Cell Center include the use of stem cells to study human disease mechanisms, the creation of new animal disease models, and the development of novel cell replacement therapies.
In addition to state-of-the-art laboratory space, the CIRM CoE and surrounding building will house important core facilities, including a vivarium, animal imaging, molecular and cellular imaging, flow cytomery, and cell culture core, each crucial for campus-wide efforts to translate stem cell research into new therapies. The result will be the focal point of the Stem Cell Center, driving the integration of biology, the physical sciences, and engineering to create a world class environment to translate basic and preclinical stem cell research towards new therapies for human disease.
Statement of Benefit to California (provided by applicant)
The major objectives of our Stem Cell Center are to carry out the highest quality basic and translational stem cell research essential for the development of novel therapies to treat human disease; to assemble and recruit the best scientists and engineers in the rapidly advancing field of stem cell biology and regenerative medicine in order to establish a highly interactive and synergistic research community; and to foster interactions between faculty and students of the Center and world class biologists, chemists, biophysicists, computational biologists, and bioengineers. The resulting research program will greatly enhance the scientific, technological, and economic development of the State of California. The most important results, however, will be the basic and preclinical research that will lead to new therapies that directly benefit human health.
The proposed CIRM Center of Excellence (CoE) for basic and preclinical research will greatly enhance our ability to achieve these objectives. State-of-the-art laboratory space and facilities will be crucial for creating a critical mass of established and new stem cell investigators and thereby further developing our interdisciplinary research culture. Our basic and discovery research program provides crucial knowledge for the development of new therapies, including processes that regulate stem cell self-renewal and differentiation, as well as mechanisms that underlie human disease, that lay the foundation for developing novel therapeutics. Furthermore, interdisciplinary research that melds biology, physical sciences, and bioengineering is necessary for translating these results towards regenerative medicine approaches and technologies to create new therapies for treating human disease.
Our successful tradition of translating basic and preclinical research into the private sector will ensure that our discoveries will lead to the creation of new therapies. Furthermore, our strong record of translating intellectual property into industry, particularly in California, will benefit the technological strength and economic development of our state. Finally, the CIRM CoE will greatly aid our public mission to educate undergraduate, graduate, and postdoctoral students and researchers in high impact interdisciplinary science, technology, and ethics, thereby creating valuable human resources for the State of California.
Review Report
Executive Summary
This proposal is composed of Elements X and Y, and seeks to establish a CIRM Center of Excellence (CoE) that will serve as the headquarters for and expand on the existing stem cell program at the applicant institution. The proposed center will occupy two floors of a 200,000 sq ft center for biomedical sciences (scheduled for construction beginning in 2008 and finishing in 2010), housing basic and discovery research programs to be integrated with preclinical programs. This proposal will complement the roughly $100 million of private matching funds to build the biomedical science building.
Currently the stem cell effort at this institution includes 28 principal investigators (PIs) scattered over the campus. The Major Facilities money would be used to move 7 of them to the new building and recruit 5 new stem cell researchers to the CIRM site, two in basic discovery and three in translational research.
The scientific goals are the same between Elements X and Y, integrating basic and discovery research as well as preclinical research in each of five topics. The major programmatic efforts of the stem cell center are diverse: (1) stem cell self-renewal; (2) hematopoietic differentiation; (3) neural differentiation and degeneration; (4) cardiovascular and skeletal muscle differentiation; (5) cancer and cancer stem cells. This seems over-ambitious for an institution that does not have a strong track record in stem cell biology when compared to other California institutions. However, the caliber of the investigators and people involved is very high. In addition to new laboratory space, the Major Facilities grant would support a large vivarium, cell culture core, and imaging facility (from cell to live animal imaging) that are crucial for campus-wide efforts to translate stem cell research into therapies.
The strength of this proposal are the institution’s outstanding faculty, its long history of ‘translating’ bench science into industry and start-up companies, the integration of engineering disciplines into stem cell biology, and the strength of administration of intellectual property (IP) on campus. The collection of investigators listed for both elements is impressive (Element X being stronger than Element Y, and Element Y containing many engineers), and their individual accomplishments including NIH funding and patents are stellar. The stem cell center Director is a world-class scientist and renowned expert in transcriptional regulation. The institution has a good record of recruiting engineers that can work with stem cell biologists, and the appointment of an engineer as Associate Director strenthens these interactions. Finally the new lab space will be a big boost to the stem cell program.
The major weakness of the proposal is an insufficient articulation of how the goals will be accomplished and the lack of a leadership plan. Although the individual accomplishments of the faculty are truly impressive, how they will achieve integration into a cohesive and synergistic programmatic effort is left to the imagination. The director of the stem cell facility is a world class scientist but beyond the many in-house collaborations his/her group is initiating, the duties of the director in synergizing the CIRM investment are not clarified. Finally the allotment of space is unclear from the application.
Reviewers commented that this is a top institution which has made major contributions to basic science. It boasts a world-class faculty addressing some of the more fundamental aspects of research, and panelists were enthusiastic about the prospect of supporting these faculty’s stem cell research. Reviewers were also intrigued by the engineering aspects of the program, although they were concerned that the engineers were driving the biology in their sections rather than establishing true collaborations. Reviewers were not convinced that this institution is fully engaged in the prospect of stem cell research, as the institutional committment did not appear to be very strong. They were also concerned about the lack of a leadership plan. Overall, however, panelists commented that the combination of a new building, new cores, new faculty, and the act of bringing good scientists together around the topic would be a great boost to stem cell research.
Detailed Summary
Element X
Score: 80
SCIENTIFIC PROGRAM: The primary objectives of the stem cell center are 1) to carry out important basic and translational stem cell research, 2) to bring together top scientists and engineers in stem cell research, and 3) to foster interactions between faculty and students from multiple disciplines. Researchers at the stem cell center work on 1) hESC self-renewal and transcriptional regulation; 2) hematopoiesis, with a focus on differentiation of hES and cord blood stem cells; 3) neurogenesis and neurodegenerative disease; 4) cardiovascular and muscle differentiation; and 5) cancer and cancer stem cells, with a focus on micro RNAs. Of the Element X investigators to be housed in the CIRM facility, some representation of the five focus areas exists or is proposed. Reviewers commented that the scientific scope of the program seemed overly-ambitious, but that even successfully addressing one of the research areas identified would be of tremendous value to the field of stem cell research.
Twenty of the 28 PIs listed in stem cell science are in Element X. Four of these will move into the new facility, a fifth will direct a core in the facility, and two more stem cell researchers will be recruited to this Element. Each of the five investigators at the heart of the scientific program are first-rate scientists that have made stunning contributions to developmental biology, and their focus particularly on stem cell biology will certainly enrich the field. The stem cell center director is a world-class scientist and renowned expert in transcriptional regulation. The application states that the director has a long-term active program devoted to stem cell self-renewal, although his/her direct research on stem cells is relatively recent. In spite of his/her recent entry into the field, however, the director is still an absolutely superb choice for leadership of the stem cell unit.
Reviewers commented that this institution has enormous potential to lead in stem cell biology, but the proposal leaves out important details and lacks a clear vision for organization beyond assembling the investigators together. No formal plan for collaborative work is outlined – some description of successful collaborations initiated by the existing pilot program might have highlighted the vision for the the stem cell center. In addition, no leadership or organizational plan is offered in the proposal. For example, the director is also the chair of a department at the institution, but there is no mention of a plan for integrating those faculty into the activities of the stem cell center. Even something as basic as meetings to bring people together is not discussed (a stem cell seminar series already exists—how will this be enhanced by the major facility?) No ideal candidate research area is identified for recruiting purposes, either to link with existing researchers or to fill in a gap in the focus areas.
In spite of this lack of an integrated plan, one reviewer commented that there is synergy at this institution. Investigators who study the regulation of self-renewal and pluripotency are aiding engineers in creating artificial microenvironments for expansion of different stem cell types including hESC. New discoveries in neurodegenerative disease are proposed to guide bioengineers to translate discoveries. Also, studies of muscle stem cell differentiation are aiding preclinical research in novel vascular and cardiovascular therapies, as well as regenerative medicine efforts for aged tissue and organs.
FORMAL INSTITUTIONAL COLLABORATIONS: This proposal does not contain a serious collaborative component outside of the institution, although numerous individual collaborations exist with two nearby medical/biomedical institutions. The applicant institution and one of these institutions have major strengths in basic and preclinical stem cell research, which are complemented by the final institution’s strengths in preclinical and clinical stem cell research. However, these two collaborations were fostered by the stem cell center and are currently augmented in part by a CIRM Training Grant. It is unclear that there are any new collaborations, rather this proposal appears to recycle old collaborations.
The 12 investigators to be housed in the proposed CIRM facility are part of a larger stem cell researcher group from multiple departments across campus. It is not made clear how the new facility will facilitate interactions amongst stem cell researchers outside of the proposed facility. The application also mentions an institute for quantitative biosciences on campus, although no specific nascent collaborations related to stem cells is discussed.
CORE SERVICES: The proposed center will encompass two new core services, discussed under Element Y: 1) a flow cytometry core, and 2) a cell culture core. It is not clear how this new flow cytometry core will differ from the existing flow cytometry facility serving the entire campus. Each of these cores is well-justified and will be used to capacity
The core facilities will be integrated with other proposed services to be built in the new biomedical sciences building but outside of the umbrella of CIRM funding, including an animal facility, an animal imaging core, and a molecular imaging core. A vivarium will be housed in the new biomedical science building to be finished in 2010. The imaging core leverages a $4.5 million gift. A temporary brain imaging center will be moved to the new biomedical sciences building, and will provide infrastructure for physical and neuroscientists to study dynamic functioning of the human brain. Additionally, investigators in the new center will be able to use the institution’s intellectual property and industry outreach office to disclose patentable new inventions and develop private startup companies licensing this technology.
These core services are excellent and perfectly suited to the scientific aims of this proposal. The track record of the institution in the management, operation, maintenance, and productive use of core services is without parallel. The institution also has excellent resources and experience in handling intellectual property, tech transfer, and facilitating collaboration with other institutions.
PLANS FOR GROWTH: The proposed space will allow for the consolidation and growth of the stem cell center. The plan for growth seems well thought-out and builds on the institution’s excellent track record of attracting world-class talent. Two new stem cell researchers will be recruited to the institution for the X Element of this application. The proposal identifies areas for future expansion: blastocyst differentiation, mammalian development, derivation of new hESC, and the bioethics/legal aspects of stem cell research policy and practice. In addition, the institution will be strengthening its legal and bioethics program, which will be housed in the facility, and intends for this program will further link engineers and biologists. The bioengineering department is actively recruiting and hiring young scientists with interest in stem cell biology.
DISCUSSION: Reviewers concluded that the excellent quality of science at the institution will provide a very special edge to stem cell research. The PIs, including those to be housed outside of the facility, of are the highest caliber and maintain an environment of outstanding research.
The major weakness cited was the lack of an organizational plan. No organization is proposed, no programmatic effort is described, and the role of the director is not well-described. One reviewer was particularly concerned about the cell culture core, which was poorly conceived and described. In the area of collaborations, it was not clear which ones were past, present, or planned.
Some reviewers felt uncomfortable about being asked to take the large leap of faith that good scientists put together would come up with a good stem cell program. However, another reviewer commented that a director was not always needed, as a bottoms-up approach can work quite well in science.
Element Y
Score: 75
SCIENTIFIC PROGRAM: The scientific goals are the same as those listed in Element X. The science programs in Element Y represent high priority in the field but still suffer from the same surplus of ambition delineated above in Element X. Investigators propose to 1) engineer stem cell culture systems to support self renewal or directed differentiation for cardiovascular and neuronal regeneration; 2) perform genome-wide screens for genes that promote neural stem cell and ESC self-renewal; 3) develop live cell imaging in animals; 4) develop gene delivery/targeting approaches; and 5) develop artificial extracellular matrix that can be administered in vivo to promote cell engraftment and tissue repair. One reviewer would have prefered a narrower focus with a greater chance for success, rather than tackling a wider breadth of problems.
The three scientists with pre-clinical translational research efforts to be housed in the CIRM facility are all engineering-oriented rather than biology-oriented. There are also 7 investigators and associated projects outside of the facility. Although both inside and outside investigators are all talented scientists and researchers, they do not rank as high as the scientific caliber provided in Element X for basic research. However, since translational research in this field is at its beginning, the team has all the qualifications to fulfill the goals of the RFA.
FORMAL INSTITUTIONAL COLLABORATIONS: The same lack of collaborations noted in Element X was observed. Several individual collaborations with investigators at other institutions are mentioned, but the overlap of these programs with the planned stem cell facility is never clearly outlined. Fellows from the a neighboring hospital can work in labs at the applicant institution, and there are real collaborations between the this hispital and the applicant institution mostly in the field of hematologic diseases. Some planned collaborations with new faculty are also exciting. The applicant institution, the collaborating hospital, and a neighboring institution appear to share a CIRM-funded ES cell research lab, and a memorandum of understanding is being drafted to link the hospital and the applicant institution, but the contents of the memorandum were not disclosed.
CORE SERVICES: As discussed in Element X, the Major Facilities award would be used to fund two cores: a cell culture core and a flow cytometry core.
The proposed cell culture core will have three functions: 1) triple the cell culture space outside of federally-funded space and expand research activities on “nearly” 20 non-registry hESC lines already at the institution ; 2) provide access for researchers outside of the new biomedical sciences building to cell culture space close to the vivarium in order to prepare and conduct experiments; 3) provide biosafety level 2 space in which to produce and use viral vectors. The proposal estimates that more than 15 stem cell investigators and 10 other investigators outside of the new biomedical sciences building will utilize this core facility. The description of the core is lacking in important details. This was a good opportunity to make an innovative core space, but the opportunity was not taken.
The planned imaging center sounds like it needs an enormous footprint but the square footage is not mentioned. The center will include diverse, state-of-the art equipment, although some of the details of the equipment are lacking. Later in the grant, the building design is described as fully finished, so it would have been nice to understand more about the design of this core.
These core services are excellent and perfectly suited to the scientific aims of this proposal. The track record of the institution in the management, operation, maintenance, and productive use of core services is without parallel. The institution also has excellent resources and experience in handling intellectual property, tech transfer, and facilitating collaboration with other institutions.
PLANS FOR GROWTH: The CIRM CoE will provide the space needed to recruit three investigators in preclinical stem cell research. The hope is that when the building opens and 7 stem cell people move in from other places on campus, their old spaces will be filled with new investigators also interested in stem cell biology. However, no guarantees are made that stem cell biology can be expanded this way. Outside of the proposed facility, there is recent and planned recruitment of stem cell bioengineers.
Reviewers ranged in opinion about this Element some felt that the plan is well thought-out, whereas others commented that the plan for growth in Element Y is very vague. Despite the fact that ‘several strategic areas for recruiting three investigators’ into Element Y is a summary sentence, the areas are not outlined with any clarity and reviewers questioned whether they were left vague intentionally.
DISCUSSION: Reviewer’s commented that this element does not have the same quality of scientific excellence as does Element X, probably because the institution lacks a medical school. Of the 28 stem cell projects listed, only 8 fill the Y element and this application presents no plan to fill the gap. The proposal lists a collaboration with a neighboring medical school, but reviewers were disappointed that this collaboration is not an expansion of current activities. Reviewers were also concerned that the institutions are still trying to work out their on-paper agreement. On a positive note, three new faculty would be recruited to this element.
Use & Contribution
Score: 80
The proposed facility meets the priorities of CIRM in general and of this RFA in particular. It will expand research capacity and capabilities and also facilitate collaborative interactions between hESC-related researchers. Furthermore, the building will encourage close interaction between the CIRM faculty and neighboring researchers in multiple disciplines including neuroscience, cancer, and computational biology. With the notable exception of collaborative arrangements outside of the institution, this grant fulfills the three criteria listed by CIRM as crucial, including 1) well-integrated elements; 2) well-planned and appropriate planned use of the proposed facility; 3) contribution of the proposed facility to the development of the institution’s stem cell program.
The 7 stem cell research groups from Elements X and Y who will move to the CIRM facility are now housed in 5 different buildings across campus. Localization in the new facility will promote scientific interaction and collaboration, and will allow for increased sharing of resources, thereby avoiding duplication. The new CIRM facility will provide space for expansion of the program recruit 5 new faculty, and also helps to retain current faculty.
Of the Element X investigators to be housed in the CIRM facility, there is some representation of the five focus areas (counting nascent collaborations with no publications). Two new investigators will be recruited to the basic science effort (Element X), but again in terms of a vision, no ideal candidate research area is identified, to either link these researchers above, or to fill in a gap in the focus areas.
Core directors have been named and are all suitable, experienced 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:
- Penhoet, Ed