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CIRM MAJOR FACILITIES GRANT APPLICATION #FA1-00609-1
Recommendation: Recommended for further consideration as a CIRM Institute
Element X Score: 96
Element Y Score: 95
Element Z Score: 91
Use & Contribution Score: 95
Public Abstract (provided by applicant)
This application will describe the depth and breadth of our Stem Cell Programs in the “CIRM Institute” category. We are requesting funds to help with the construction costs for our {REDACTED}, a free-standing new building dedicated to our Stem Cell Programs. Currently, our stem cell program and our faculty are spread across laboratories both on and off campus. Our Institute represents a unique university-wide collaboration that brings life, physical, and engineering sciences together with leaders in business, law, and education. Our stem cell programs include all three elements in the RFA: basic and discovery research (Element X), pre-clinical research (Element Y), and pre-clinical and clinical research (Element Z). The new building will house faculty who were present prior to launching our {REDACTED}, new faculty that have been recruited since 2002, and faculty who we anticipate recruiting in the next five to ten years. Our stem cell programs in Element X focus on areas including embryonic stem cell biology, reprogramming of adult somatic cells, tissue and organ adult stem and progenitor cells, and cancer stem cells. Our Stem Cell Programs in Element Y focus on ten area/organ systems for pre-clinical research. The stem cell efforts in pre-clinical development and pre-clinical research, Element Z, are currently robust in hematopoietic cell transplantation and cancer stem cells. We anticipate that as our programs in human embryonic stem cell research and reprogramming develop over the next decade, there will be a parallel progression from Elements X and Y into Element Z. The new building will house relevant faculty supported by state-of-the-art core facilities including an animal vivarium with in molecular imaging, human embryonic teaching laboratory, and cell and tissue bank. In addition to the scientific cores, the new structure will house space for our Program in Regenerative Medicine and clinical trial support. Finally, we have a strategic plan to recruit new faculty in all areas of our stem cell program over the next five to seven years. Clearly, not all of our stem cell faculty and programs will be housed in the new facility, but it will act as the “hub” of our efforts and link our affiliated stem cell faculty and programs across the campus via the Program in Regenerative Medicine. This facility will not simply “reshuffle” our existing faculty in the Stem Cell Program. In contrast, it will provide a critical mass of faculty, the opportunity to recruit additional faculty, and core facilities in the X, Y and Z Elements all in a single location. This new facility will synergize collaboration across all seven schools on our campus to promote innovation, new diagnostic tool, and novel therapies, with biomedical ethical oversight in stem cell biology and regenerative medicine.
Statement of Benefit to California (provided by applicant)
This proposal will provide real benefits to the State of California and its citizens. The proposed new facility for which we are requesting CIRM funds will be a free standing {REDACTED}. Our stem cell programs include efforts in basic and discovery research (Element X), pre-clinical research (Element Y), and pre-clinical development and clinical research (Element Z). The Institute will bring together faculty in our stem cell programs that are currently housed in many locations both on and off campus. Furthermore, our {REDACTED} collaboration that brings together over 100 faculty in life, physical, and engineering sciences, together with leaders in business, law, and education. The new Institute will benefit California and its citizens in the following ways: First, by bringing together faculty in exploring basic, translation, and clinical research (the X, Y, and Z Elements) in one building, unique interdisciplinary collaborations will be greatly expanded. Second, new state-of-the-art core facilities will support the faculty in their pursuits of novel stem cell therapies. Third, the Institute will be the “hub” of our stem cell programs, but connect with stem cell and related faculty across the campus in all seven schools. Fourth, allow us to recruit additional world class faculty into embryonic adult and CSC biology into the Institute over the next decade. Finally, by bringing together the stem cell faculty in one building and connecting and coordinating (via our program in regenerative medicine), our effort across the campus will maximize our capability to develop innovative new diagnostics, tools, and novel therapies in stem cell biology and regenerative medicine. These innovations will improve the lives of Californians and beyond and bring additional research talent and business into the State. It is important to emphasize that our new facility will not simply “reshuffle” our existing faculty in stem cell programs. In contrast, the new facility will provide a critical mass of faculty, existing and to-be-recruited, and core facilities in the X, Y, and Z Elements in a single location. This will synergize collaboration across all seven schools on campus to promote fundamental discovery through to clinical trials, with biomedical ethical oversight, in stem cell biology and regenerative medicine. {REDACTED} has an outstanding track record for innovation in medicine in all of the X, Y, and Z Elements. The new {REDACTED} facility will promote discoveries and their translation into novel clinical therapies by bringing together a critical mass of stem cell faculty with basic and clinical scientists to unravel the genes, developmental programs, and in vivo biology of stem cells from all four stem cell research areas.
Review Report
Executive Summary
This applicant institution is committed to translational medicine, as evidenced by the five interdisciplinary institutes for translational medicine created as part of a strategic plan developed in 2001. These five institutes each have a unique focus: stem cell biology and regenerative medicine; neuroscience; cardiovascular; infection, transplantation and immunity; and cancer. This application requests funds to support a new building dedicated to stem cell research, which will house the institute for translational medicine in stem cell biology and regenerative medicine (“the Institute”). Formed in 2002, the Institute is a multidisciplinary effort in stem cell research with to date more than 100 affiliated faculty dispersed in laboratories both on and off campus. All three elements are requested (Elements X, Y, Z). The applicant institution has an outstanding world-class faculty in stem cell research with remarkable breadth and depth in multiple areas. Many of the key concepts in stem cell research such as cancer stem cells, prospective isolation of stem cells, and identification of key signaling pathways came from investigators at the institution. The applicant institution is particularly strong in basic stem cell research but there is clear evidence of successful translation.
At the heart of the proposal is a new building that will be occupied by key members of the original faculty hired prior to inception in 2002, faculty hired since 2002, and new faculty to be recruited. Reviewers noted that the application included an innovative organizational plan. The program will be organized around four areas of stem cell biology, integrated within the new institute. Four areas of research focus are proposed: 1) human embryonic stem cells (hESCs), 2) nuclear reprogramming to produce pluripotent stem cells (NRPSCs), 3) mature tissue or organ stem cells (TSCs), and 4) cancer stem cells (CSCs). Within each Element (X, Y, and Z) a clear plan for current and future leadership is presented. Key leadership positions are filled, with the exception of one area in which the chair still needs to be identified, and all will be located in the new facility. Investigators are organized around organ / disease areas within the basic, preclinical and clinical study domains. Reviewers uniformly commented that research in all the basic stem cell areas proposed is exceedingly strong.
Initially, twelve investigators will be housed in the new facility, in the Element X, Y, and Z areas, along with bench space for up to 60 collaborating investigators (described in “collaborative benches” below). A ten-year strategic plan commits to an additional twelve investigators to be recruited and located in the new facility, in both the Element X and Y areas. Because the proposed space cannot accommodate all the proposed efforts, the applicant institution has included a creative space utilization plan, also uniformly noted by reviewers. A significant percentage of the total space is dedicated to a “collaborative benches” concept, committed to support collaborating scientists in fundamental, translational and clinical stem cell biology research. Teams (“collaborative units”) supervised by an institute faculty member and a faculty member whose main laboratory / clinic is outside the building will be approved upon successful application to a Steering Committee, and may occupy the space for several years, based on an annual review. This idea is already put to work at the current hESC facility located off campus. Therefore, an additional key role of the new building is to serve as a hub for the many outstanding investigators that are currently dispersed all over the campus.
For each element (X,Y, and Z), reviewers’ comments are summarized below. Reviewers uniformly felt that Element X is a well written, strong part of the proposal, with excellent content. Reviewers concurred that investigators are thought-leaders that have pioneered many of the key efforts that have led to where the SC field is today. Many strengths were highlighted, including: a great vision for stem cell biology, focused programs built to clear strengths of the applicant institution, and a tradition of multidisciplinary and collaborative work within the institution. Based on these strengths, one reviewer stated that there is no doubt that the applicant institution will make key contributions to the field of basic stem cell research. Only minor issues were raised: suggesting one area of basic stem cell biology could be augmented, and that the proposal seemed heavy in one disease area, when there are many good scientists in numerous fields at the applicant institution. Despite these minor critiques, the panel expressed strong enthusiasm for this Element of the proposal.
Element Y of the proposal expands on the proposed basic research effort, and covers nine disease areas. The institution has an established leadership position in the translation of stem cell biology and preclinical testing. The institution has the breadth to focus on all nine proposed organ systems / disease areas, and is very strong in all areas with a key strength in cancer. Proof of principle has already been demonstrated in specific diseases, and clear translational potential exists for many projects built on cutting edge ideas. The proposal also has a strong program outside the facility. A few minor weaknesses were identified in the proposal. Programs could benefit from utilization of more diverse preclinical models. Other reviewers noted that collaboration outside the institution is somewhat limited. But, this was not perceived by reviewers as a negative. Because it is such a huge institute and has good quality faculty across all disease areas, reviewers felt the applicant institution does not need to go outside for expertise. The collaborative benches concept will allow for formal interactions within the university to occur. Overall, this element was reviewed with strong enthusiasm by the panel.
Reviewers concurred that the strength of Element Z in this application is that this institution has pioneered efforts to translate stem cell therapies to the clinic, and has a track record in at least two different disease areas in moving stem cell resaerch towards the clinic. Reviewers noted that this part of the proposal was less focused on performing clinical trials or Good Manufacturing Practice (GMP) production of cells, but rather serving an administrative function in assisting investigators with promising projects to fing the right preclinical partner(s) for development, IND filing, and subsequent clinical trials. Ground-breaking work by this applicant institution was seen as a prototype for this type of collaboration. This concept gained somewhat mixed reviews by the panel. One panelist commented that the optimal location to conduct the translational work will depend on the disease, and perhaps it should be done closer to the clinic, but not in a building dedicated to research. Another reviewer noted that since the Z-element is more administrative in nature with the main thrust of outsourcing the actual translation to the many strong existing facilities on the campus or to commercial entities, the plan seemed appropriate to the goals. Reviewers commented that the GMP strategy was not clear in the proposal. One reviewer commented that locating the GMP facility and expertise outside of the new building was a missed opportunity to co-locate production experts next to more basic researchers, which would allow early consideration of factors essential to ultimate translation. In summary, concepts proposed in this element were reviewed as innovative along with the history and track record that demonstrates feasibility of the model.
The institute for stem cell biology and regenerative medicine will house relevant faculty and many state-of-the-art core facilities, including an animal vivarium with molecular imaging, human embryonic teaching laboratory, and cell and tissue bank. These facilities are particularly strong for use in basic science (Element X): in addition to the scientific cores, the new structure will house space for the program in regenerative medicine and for clinical trial support. A strategic plan is proposed to hire additional faculty into the institute in all four focus areas discussed.
Detailed Summary
Element X
Score: 96
SCIENTIFIC PROGRAM: The applicant institution has a remarkable strength and track record in basic stem cell research particularly in the areas of cancer stem cells, hematopoietic stem cells (HSCs), signaling pathways acting in stem cells and early development. The applicant institution has been awarded significant numbers of NIH and CIRM stem-cell-related grants, and has made a number of key recruitments recently to further enhance their strength in stem cell research. This is an outstanding proposal with great overall vision for basic stem cell biology. It clearly spells out key strengths within the institution and points towards strong areas of focus and potential for future growth.
The proposed Element X component is organized around the four fundamental areas of stem cell biology: human embryonic stem cells (hESCs), nuclear reprogramming to produce pluripotent stem cells (NRPSCs), mature tissue or organ stem cells (TSCs), and cancer stem cells (CSCs).
In the area of hESCs, the applicant institution plans to focus on early human development, its relationship to hESCs, and hESC-derived germ cells, through the pioneering studies of an investigator who was recently recruited to the institution. There is also strong research towards a molecular understanding of hESC self-renewal, chromatin state and the identification of novel growth factors. There is some strength regarding directed differentiation of hESCs particularly through the work of one investigator. However, other hESC work in this area is more at the nascent stage and mostly based on the concept of prospective isolation of hESC-derived intermediates. However, no significant publications are yet available on this interesting topic by the applicant institution’s groups.
In the area of Nuclear Reprogramming this applicant institution has recruited a key individual as a postdoc into a prominent investigator’s lab. The recruit is the lead author in a recent landmark publication in this field. While a director for the nuclear reprogramming effort still needs to be identified, they have a number of strong investigators that can contribute in specific areas.
Goals are clearly articulated in the area of mature tissue and organ-specific stem cells (TSCs). A very important idea along these lines is the derivation of TSCs from hESCs using prospective isolation. Such stem cell intermediates could serve as landmarks during hESC differentiation. The overall effort of TSCs is led by a true pioneer in the field, and supported by a distinguished faculty for each of the Elements X, Y, and Z. This focus area is particularly strong in the area of HSC and NSCs.
In the area of Cancer stem cells (CSCs) the program is being led by an investigator who pioneered aspects of the CSC concept. Key goals are articulated in this focus area, which includes the development of new therapies based on targets identified by the multiple strategies outlined in the proposal. A strong interaction with clinical groups is presented to get access to primary tumor tissue and to establish CSC banks and data resources. In addition to the program leader, there is an outstanding team of PIs supporting the CSC effort including two additional prominent investigators among others. Many of the key faculty moving into the new building have a particular interest in CSCs.
The availability of a new facility will not only enhance the already strong interaction among these outstanding investigators, but also will serve as a hub for interactions with the other stem cell-related faculty within the campus. The quality of the outside faculty is again outstanding and complements the effort. Particular strengths of the outside faculty were noted by reviewers in genomics and screening platforms (one investigator was named) and imaging (3 investigators were named). An enormous strength in two more disease areas at the applicant institution can intersect with the basic stem cell biology efforts proposed. There is no doubt that based on the track record, research potential of the outstanding faculty, and the overall vision presented, the applicant institution will make key contributions to the field of basic stem cell research. There is also a great tradition of interaction in a multidisciplinary fashion, such as the integration of bioengineering and other disciplines, exemplified by a specific initiative.
Minor questions about the proposal were raised. In the hESC focus area, there is mention of derivation of ESC lines under GMP to produce clinically qualified master banks, a strong indication that preclinical validation and ultimate clinical usage is being considered at this early stage. Given this, several reviewers noted that it was unclear why no GMP capability to support Element X research was planned within the new facility. An extramural GMP laboratory is identified for Element Z. If the intent were to use this extramural GMP facility, that should have been better detailed in the plan for Element X. One reviewer noted a significant, almost over reliance on a single mouse model for basic science and preclinical evaluation; analysis in other models (and testing of the matching species ESC or reprogrammed adults stem cells) could strengthen the basic science program, and would clearly facilitate the preclinical and translational programs. Finally, the application implies a requirement for complete molecular understanding of fundamental stem cell biology before advancement to clinical testing is warranted. While this is a laudable goal for the true basic scientist, there are many examples of successful clinical studies proceeding without complete mechanistic comprehension. The systematic approach may result in fewer “mistakes”, but will considerably extend the time frame for clinical development and ultimate patient benefit.
FORMAL INSTITUTIONAL COLLABORATIONS: There is evidence of very strong interactions within the applicant institution. Particularly interesting in this context is the proposed flexible space allocation in the new facility, and the collaborative benches that will benefit primarily collaborations within campus but may also benefit those with outside institutions. The proposed translational benches concept is highly innovative and exciting and likely to lead to unanticipated but highly productive learning and new collaborations. The application also details numerous intramural collaborations encompassing the medical center, graduate schools, law school, engineering, etc., with access to a remarkable team of scientists, educators, lawyers, and ethicists, to name a few, who bring an enormous depth and breath to the projects proposed. Several reviewers felt this collective expertise in the area of stem cell biology is unique to this university.
Reviewers expressed concern that very little extramural collaboration was presented in the application, but acknowledged the great breadth and depth of experience within the institution. A number of collaborations proposed with nearby institutions are all properly documented in letters of collaboration, and focus on: bioinformatics and computational biology, Parkinson’s disease, and a nearby clinical research facility.
CORE SERVICES: A strong set of core facilities is proposed to enhance research within the new building. Those inside the proposed facility include: human embryo, oocyte, hESC and somatic cell banks; human embryology, hESC and nuclear reprogramming education core; microfluidics core; FACS; and a cancer stem cell tissue core. The cell bank, the microfluidics core facility, and the cancer tissue bank were noted by reviewers as exciting, and having potential to develop into resources not only for the applicant institution, but also as “powerful operations” with impact beyond the applicant institution. The application also includes cores services outside the proposed facility including over forty academic service centers, seventeen of which are located in the School of Medicine.
PLANS FOR GROWTH: The application detailed the specifics of a 10 year plan for recruiting more faculty in both Elements X and Y that will be housed in the new building. Some searches already underway for up to two new recruits in designated areas. Significant growth is also planned outside the facility that will benefit from the hub function of the new building. The relevant outside institutes include among others the Comprehensive Cancer Center, Neurosciences Institute, and relevant departments such as Developmental Biology, Obstetrics and Gynecology, Medicine and Bioengineering.
DISCUSSION: Reviewers uniformly felt that this is a well written, strong proposal, with excellent content. Reviewers concurred that investigators are thought-leaders that have pioneered many of the key efforts that have led to where the SC field is today. Many strengths were highlighted, as discussed above. Only minor issues were raised. One reviewer felt that the proposal could be augmented in the area of differentiation of stem cells. Another felt that the proposal is heavy on cancer, when there are many good scientists in numerous fields at the applicant institution. Reliance on a specific mouse model system seemed evident in the application, to the extent that the application ignores other more clinically relevant models. Despite these minor critiques, the panel expressed strong enthusiasm for this proposal.
Element Y
Score: 95
SCIENTIFIC PROGRAM: The applicant institution has had a leadership role in the translation of stem cell biology and testing preclinical potential in multiple research areas. There is very strong integration with research elements in X and many investigators will contribute very strongly to both the X and Y elements. There is also a strong track record of innovation, achievement and collaboration. Several cell-based approaches have been moved forward from basic research all the way to clinical trials.
The programs to be housed inside the facility are: Cancer Stem Cells; Hematology and Immunology; Nuclear Reprogramming, Reproductive Medicine and Fetal Health; Neurosciences; and Endocrinology/Diabetes. Reviewers commented that all programs have clear areas of focus and are innovative, often with exceptional leadership that includes many who have pioneered work in the specific area. Four programs were described as cutting edge, in addition to the qualities mentioned above. One of the five programs was noted by reviewers to be an excellent program, but without much novelty within this area. This was clearly the exception.
Scientific program elements outside of the facility are also detailed in the application, and provide routes of expansion across many clinical disciplines. Nine programs are described in the application including: cancer, hematology/immunology, reproductive medicine and fetal health, neurosciences, cardiovascular biology, musculoskeletal biology, endocrine/diabetes, gastroenterology, and otolaryngology. Most areas were considered by reviewers to have world-class leadership. Beyond disease-specific expertise, a world-leading team of technical innovators in cancer imaging and diagnostics is available at the applicant institution, and they already have produced evidence of moving research forward and developing Y or even Z element compatible imaging platforms. On balance, the individual disease research teams were felt to be highly skilled and capable of performing the proposed work.
Reviewers noted a few areas in which specific disease areas could be more fully developed. Cardiovascular biology was noted as an area of future growth, and as an area in which hESC expertise could be added. Reviewers also noted that the area of musculoskeletal biology could be further enhanced by more inter-institutional collaboration. Reviewers commented that much of the work in neuroscience was done in collaboration with outside institutions and further expertise should be developed in house to fully exploit this area.
Reviewers summarized that the components in Element Y are very ambitious but well laid out. Given the amazing quality of investigators in most of these areas, it seems likely that there will be progress on nearly all fronts and that the new facility will serve to further accelerate interaction and progress.
FORMAL INSTITUTIONAL COLLABORATIONS: The same collaborations described under Element X are put forward for Element Y. Formal agreements exist with three outside organizations as described in Element X. In addition, interaction with a local Contract Research Organization is proposed to foster the development of innovative technologies. Very limited detail is provided for each of these collaborations.
However, a strong case is made that – for the applicant institution – it is not really necessary and advantageous to engage in too many inter-institutional collaborations given the number and quality of outstanding investigators in all these fields on campus. The key is clearly to foster collaboration within the campus that has been hindered in the past by the dispersed location of key faculty involved in stem cell research. For one reviewer, however, this was a weakness. This reviewer stated that the lack of external collaborations is unfortunate since additional testing in other more clinically relevant models would be able to provide additional important information in assessing preclinical and clinical utility.
CORE SERVICES: In addition to the cores presented in X there will be a number of cores specific to Element Y. These include within the new facility: 1) a vivarium and transgenics facility; 2) an advanced in vivo imaging core; 3) a behavioral and functional neuroscience laboratory; and 4) a rapid autopsy/tissue service within the cancer stem cell bank. All these cores should enhance the efforts of the new facility. The applicant institution has an excellent track record for running such facilities. However, there is very little detail to judge management and operating procedures of individual cores.
Outside the new facility there will be additional service centers and transgenic facilities. A cancer biostatistics core and an outstanding cancer imaging core are available outside the facility. One could argue that there is some potential overlap in scope of the inside and outside core facilities. However, to have these cores within the building should greatly accelerate research and increase the use and functionality of the cores and productivity of the potential users.
A core GMP clinical translational laboratory is availableoutside the facility to support projects in Elements X, Y and Z. This is an important and rare resource that is essential to comply with FDA regulations for manufacturing cells and cellular products for human therapies. The presence of this resource strengthens this application. In addition, the Office of Technology Licensing will address legal, business and Intellectual Property (IP) issues related to development of novel technologies and therapies, again strengthening the application.
PLANS FOR GROWTH: As described under X there is a detailed 10 year plan to allow significant growth for filling additional faculty positions in both the X and Y elements. Overall the facility has a rather heavy cancer stem cell focus, so it is appropriate that the applicant institution has identified other focus areas for growth.
The main growth capability will likely be outside the facility as there is a huge commitment towards establishing physical space for the various translational institutes. Three free-standing translational medicine institutes are in planning that will be particularly important to the Y element of the current application. They involve extensive preclinical modeling groups in the Neurosciences, Cardiovascular Medicine, and Infection, Transplantation and Immunity.
In summary there is significant growth potential within and outside the new facility and the new building will likely serve as a hub to connect these efforts regarding aspects that intersect with stem cell biology.
DISCUSSION: Reviewers concurred that the strength of this element is that the applicant institution has the breadth to focus on all nine organ / disease areas named in the application. Investigators are strong in all nine disease areas, with a key strength in cancer. Additional recruits will also be leaders in this effort. Programs reviewed are expected to have a high likelihood of success to be translated to the clinic, based on the cutting edge ideas with the existence of proof of principle for many, and the track record of the faculty. The program was viewed to be equally strong outside the facility. A minor weakness was identified in the proposal, and that is that the disease modeling is very heavily focused on one particular murine model. Other reviewers noted that collaboration outside the institution is somewhat limited. But, this was not perceived by reviewers as a negative. Because it is such a huge institute and has good quality across all disease areas, reviewers felt the applicant institution does not need to go outside for expertise.
Element Z
Score: 91
SCIENTIFIC PROGRAM: The applicant institution has a strong record in translating research and currently has over 900 active clinical projects involving human subjects. Several of the key faculty have been involved in clinical trials and a number of faculty have experience with INDs. Most of the investigators with such experience are primarily appointed in X or Y. Only a single investigator with an IND and actual clinical trail experience has a primary appointment in Element Z.
The applicant institution has five translational institutes, each with a different area of focus: stem cell biology and regenerative medicine; neuroscience; cardiovascular; infection, transplantation and immunity; and cancer. Strengths in individual areas were highlighted by reviewers, which included the investigators, and track records in each of the groups. In the area of stem cell research the applicant institution is strong in hematopoietic stem cells and cancer stem cells, and also in cancer signatures. There have been cutting-edge stem cell-based clinical trials that were initiated by investigators at the institution (two specific examples were cited by reviewers). Most of these trials have been outsourced to private companies rather than performed within the applicant institute. This may be an efficient approach in many instances, as it could be difficult to translate the work within the new facility given space constraints. The applicant institution has demonstrated successful collaborations and partnerships between itself and companies focused on cell-based therapies. The applicant institution has both the scientific, business, legal and ethical acumen to establish ground rules and procedures to allow the necessary partnerships between the for-profit and not-for-profit / academic worlds. This truly remarkable accomplishment will accelerate progress in bringing new therapies to the clinic.
There is a statement that hESCs are at least 10 years away from clinical usage, and therefore there are not ongoing clinical projects in hESCs. This comment could be leveled against any of the applicant institutions, since hESCs are an emerging field. Thus, the application describes previous HSC discoveries and the clinical translation of autologous transplants, along with a new neural stem cell patient study, as prototypes of anticipated hESC clinical work. Preclinical animal model assays for CSCs have led to possible new antibody and drug treatments for leukemia. The application reviews the success of several PIs in starting companies, although the direct relevance to this RFA was not exactly clear.
The key elements proposed for Z are less focused on performing clinical trials or the GMP production of cells, but rather in serving an administrative function to assist those investigators with promising projects in finding the right partner for preclinical development, IND submission and clinical trials. While this is a reasonable approach the proposal was somewhat ambivalent about pushing forward Element Z within the facility. One reviewer noted that no GMP component is proposed within the new facility, but rather is located external to the facility at least for the immediate future. This was recognized as a missed opportunity to have leaders in GMP production next to the more basic researchers which would allow early consideration of factors essential for ultimate translation. This office will also have an educational mission that could mitigate some of the concerns raised above.
However, there is clearly the potential to move forward toward a Z element with strong integration of the campus-wide program in regenerative medicine. The program in regenerative medicine will connect with the stem cell Institute for Translational Medicine and related faculty across the campus. This Institute for Translational Medicine will have its administrative headquarters in the new proposed facility, and should serve again as a hub function bringing different expertise together towards ultimate translation.
FORMAL INSTITUTIONAL COLLABORATIONS: No new collaborations are proposed for Element Z beyond those discussed in X and Y. The plan focuses on collaboration with translational institutes within campus and possibly industrial partners as was done successfully in the past. At least one reviewer viewed this as a weakness, citing that single institution clinical studies are important, but additional critical information comes from testing the ability to translate knowledge to new sites, and evaluating outcomes in a new environment.
CORE SERVICES: No new core facilities specific to Z are proposed but the human embryo facility, oocyte, hESC, and somatic cell bank have clear potential for clinical translation. However, to this end eventually a GMP facility needs to be available (e.g. for producing appropriate hESC cells for translation), as discussed below. Clinical trial support is proposed within the building through the administrative seat of the institute for regenerative medicine. In addition, all the regulatory and oversight committees are in place for managing translation, but are all located outside the new proposed facility.
Outside the facility there is access to world-class Z-type facilities for preclinical development including multiple state-of-the-art GMP facilities. The existing facilities located on campus include some of the most sophisticated cell processing and cell separation techniques. The proposal states there is no current need for the existing GMP facility located in the School of Medicine, but the applicants are prepared to build a new GMP in 5-10 years. There is a statement in the application that flexibility of design will allow for subsequent conversion of lab space to GMP. While this may be technically correct, it is likely not the most efficient approach. These comments in the proposal suggested to one reviewer that it was unclear whether the NIH funding issues were resolved for use of these GMP facilities.
PLANS FOR GROWTH: Growth plans include a commitment for faculty searches and recruitment of Z type faculty to be housed in the new building. It is stated that several MD/PhD applicants with backgrounds in hematology, oncology, and radiation oncology are just making their way through the recruitment process. Such candidates would have the opportunity to retain patient attending duties in order to remain current in clinical aspects, as well as act as PIs on clinical trials arising from technology and discoveries at the applicant institution. A current investigator is mentioned as an example for such a position, though s/he is not really a key stem cell faculty and not located in the new building. It seemed that the plan was not strong on the clinical trial front (e.g. by planning a senior recruitment to stimulate such efforts). Most senior recruitments were into Elements X or Y.
DISCUSSION: Reviewers concurred that the strength of this application is that this institution has pioneered efforts to translate stem cell therapies to the clinic, and examples are given in two different disease areas. All agreed that these examples speak to the applicant investigators’ very strong track record. There was some discussion that at least one stem cell trial was conducted in conjunction with a commercial provider before it went to the clinic. Reviewers were divided on whether this was a strength or weakness of the application. A panelist commented that it is a strategy that worked for the applicant institution in at least one case. One minor criticism noted was that it is not clear how translational efforts are going to be integrated into the new building. One panelist commented that the optimal location to conduct the translational work will depend on the disease, and perhaps it should be done closer to the clinic, but not in a building dedicated to research. Another noted since that the mission of Element Z was more administrative in nature, the proposed location made sense in the strategy. Overall, reviewers felt that the applicant institution’s strong track record suggests that success in stem-cell based therapies would continue from this group.
Use & Contribution
Score: 95
There will be 33 basic lab modules spread over three floors. At capacity, the proposed facility will house up to 24 faculty. Translational collaborative bench units (up to 60 such benches planned for the new building) will focus on 4 stem cell areas: ESC, nuclear programming, TSC, and CSC. These are intended to cover all X, Y, Z elements; although as noted previously only a small component of Element Z will be in this facility. The use of translational collaborative bench units is a good strategy to optimize space usage and foster interaction with outside investigators. The space allocation plan is well laid out, and should allow for sufficient critical mass to have an important impact while remaining small enough to foster interaction. The building appears to be designed for interaction which is critical for the key mission of serving as a hub for catalyzing stem cell research at the applicant institution.
The applicant institution has already raised $75 million to match the funds requested which speaks to the commitment for growth in this area.
There will be a strong external advisory committee with top leaders in stem cell research from outside the applicant institution, who will meet annually to advise the Director. There is also a strong internal steering structure with a powerful oversight committee. One reviewer noted seventeen individuals named in the application, and stated that a chair will be selected on a rotating basis.
The numerous internal cores described in the various sections will also facilitate interaction and collaboration and provide for hESC training to inside and outside investigators. Outside faculty will be able to access cores and also other apsects through the novel translational collaborative bench concept. These units will be awarded in up to three year rotations, governed by the steering committee, with priority given for previous CIRM awardees.
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
- Zwacka, Thomas