Right Column

CIRM MAJOR FACILITIES GRANT APPLICATION #FA1-00618-1

Recommendation: Recommended for further consideration as a CIRM Institute
Element X Score: 96
Element Y Score: 91
Element Z Score: 78
Use & Contribution Score: 92

Public Abstract (provided by applicant)

Stem cell research at {REDACTED} began over a quarter century ago and has produced important breakthroughs in our understanding of how tissues and organs develop. Recent advances have opened the potential for revolutionary progress in understanding, treating, and curing devastating human diseases. To accelerate the pace of research, we created a formal stem cell research program—{REDACTED}. The proposed {REDACTED} building will be the hub of the innovative program and will provide laboratories and technological resources to allow growth and integration of the program. To succeed, we must find ways to foster research in many different areas simultaneously, while sustaining a clear focus on our goals. We achieve this by organizing research along seven “pipelines,” each integrating a scope of research from basic science to clinical trials and each directed toward an area of clinical importance where we excel: cardiovascular, neural, pancreas and liver, hematopoiesis, musculoskeletal, epithelial and reproduction biology. These pipelines in turn interact with five research programs — human embryonic stem cells, cancer, immunology, genetics, and bioengineering — and are served by an array of advanced technology facilities. The result is a powerful, broad-based, interactive team of 123 principal investigators (PIs) dedicated to the missions of the pipelines. {REDACTED} building will house 25 key stem cell investigators and their labs, including representation from each pipeline. All stem cell program PIs will have full access to human embryonic stem cell lines, including newly created ones. {REDACTED} building is stunning and innovative, featuring split-level connections that encourage collaboration, and open, flexible-use floor plans that support non-federally funded research, intermix basic and clinical researchers, and incorporate space for visiting scientists. Core technology facilities are clustered to encourage interactions among users. The organization of the research program and the design of the building address two related realities. First, success in stem cell research demands a broad range of approaches coupled with a dedicated focus on missions—the development of therapies requires teams of scientists across the research spectrum from basic to preclinical research to clinical trials. Second, stem cell research may provide cures for grave illnesses and injuries for which no treatments currently exist, underscoring the urgency in bringing discoveries to the bedside. Maintaining a rapid research pace demands that scientists and physicians build on each other’s discoveries, whether they occur across the hall or across the world. Our research program and building respond to these challenges. Our plans are ambitious because they must be. They are backed by an enduring institutional commitment to accelerate the pace of stem cell research and to realize its potential to transform the practice of medicine.

Statement of Benefit to California (provided by applicant)

When California’s citizens voted in favor of Proposition 71, they sent a clear message that they want scientists in our state to play a role in stem cell research that may revolutionize medical treatment and produce significant economic benefits. Toward realizing those goals, we propose to create a dedicated stem cell research facility that is designed to foster the collaborative cross-cutting culture essential for stem cell research, serve as the hub of our growing stem cell program, and accelerate progress toward new cell-based therapies for the treatment of a wide range of disorders. Diabetes mellitus affects over 1.5 million people in California. Over 500,000 Californians have chronic liver disease. Over 100,000 Californians have heart attacks each year, and nearly 250,000 suffer epilepsy. Over 100,000 new cases of cancer are diagnosed in California each year. Over 100,000 Californians have Parkinson’s disease, and every year 250,000 suffer brain or spinal cord injuries causing permanent functional disability. These are just some of the disorders that stem cell scientists at our institution are working to treat or cure. The costs of caring for those affected by diseases and the strain on families and care-givers are substantial. Conventional therapies have not provided desperately needed cures. Our stem cell program combines the talents of 123 faculty researchers ranging from developmental biologists, neurobiologists, and cardiologists to bioengineers, immunologists, surgeons, and cancer researchers. Their efforts are organized around seven research areas that we have designated “pipelines” and are directed toward developing cell-based therapies. The creation of a dedicated stem cell research facility at our institution will provide space and resources needed to investigate the enormous potential of stem cells and develop new cell-based treatments for our patients. The facility will be home to the human embryonic stem cell program—an incubator for discovery providing non-federal space where ethically sound research can advance unimpeded with the best-quality human stem cell lines. The new laboratories will draw world-class researchers to our city and California, and their neighborhoods will be a testing ground for new technologies. Discoveries will generate valuable intellectual property to be shared with California. Experience suggests that new stem cell technologies will attract biotechnology interest and promote local business growth and development. Early clinical success should attract industry investment to help convert promising discoveries into safe, effective therapeutic products. The proposed new facility will be a catalyst accelerating progress in stem cell research spanning from basic discovery to clinical application and ultimately to the treatment or cure of currently devastating illnesses for the benefit of the people of California.

Review Report

Executive Summary

The application requests funding in all three elements for a CIRM Institute, a free-standing structure intended to serve as a nexus for the regenerative medicine community at the institution. The applicants will foster groundbreaking research in stem cell biology, cell differentiation, and tissue regeneration with the goal of developing cell-based therapies and cures for human diseases. The institution has an established and highly respected reputation as a leader in relevant fields including developmental and cell biology, biochemistry, molecular biology, immunology, and cancer research. With a rich history in stem cell research, this institution is credited with substantial breakthroughs in our understanding of the molecular and cellular mechanisms of cell differentiation, tissue and organ development, and the cellular basis of many diseases. The applicants will build upon their long-standing excellence in discovery research and a robust infrastructure for designing, managing, and conducting clinical trials to develop new therapies.

This unique program is organized in three interactive dimensions: 1) seven pipelines targeted toward disorders of organs and tissues likely to benefit from cell-based replacement and regeneration therapies; 2) each pipeline is enhanced by sets of cross-cutting programs, and 3) pipelines and programs are served by a variety of basic, translational, and clinical approaches such that each pipeline incorporates strengths in Elements X, Y, and Z. Co-directors representing basic and clinical perspectives will lead the integrated efforts of each group of scientists in each pipeline. Areas of potential impact were chosen to coincide with existing areas of strength at the institution. The pipelines include: Cardiovascular, Neural, Pancreas and Liver, Hematopoiesis, Musculoskeletal, Epithelial, and Reproduction. The highly relevant cross-cutting programs are broad based, ranging from a human embryonic stem cell (hESC) program, to Cancer, Immunology, Genetics, and Bioengineering, and to a series of facilities that provide core research technologies. The building will provide the infrastructure for the derivation and characterization of non-registry human embryonic stem cell lines separate from NIH-supported laboratories in other parts of the institution. Further, the applicants have developed affiliations with local and international institutes for collaborative research and training minority candidates.

The applicants will construct a transformative new building to create a collaborative environment for 123 Principal Investigators (PIs). A world-renown architect has designed a home that integrates the pipelines and cross-cutting programs. The design establishes strategic “neighborhoods” that flow into one another vertically and horizontally to invite interactions among the 25 PIs and their research groups planned to be housed in the facility. Investigators are spread across all three elements basic, translational and clinical research (Elements X, Y, and Z, respectively), and the open space is flexible enough to adapt to changes in research programs. The 25 research groups in the building will be led by eight extant faculty, 10 more have joined within the past three years, and seven new faculty will be recruited. The program also is intended to grow outside of the building with over 20 new investigators recruited in the next 4-6 years. The building will be a vector for research for all scholars on campus plus distinguished visiting scholars from elsewhere in California, the U.S. and abroad.

Overall, reviewers are extremely enthusiastic about this proposal. The quality of investigators both within and outside the institution is outstanding, and the productivity of the group is extraordinary. Element X is built on pure, solid basic science that motivates the translational components of Element Y, which is a truly expansive program that fits together extremely well. While the translation of many basic and preclinical activities into clinical trials is as yet not far advanced, based on the excellence of Elements X and Y, Element Z should move forward with excellence and appropriate safety.

Detailed Summary

Element X

Score: 96

SCIENTIFIC PROGRAMS: One reviewer feels that if someone were to write the perfect grant, this would be it. The scientific program consisting of seven pipelines is designed to maximize the effectiveness of teams of investigators who are pushing the frontiers of scientific knowledge in stem cell biology. The research extends as broadly as can be envisioned and is the collective and synergistic work of a large number of research groups. The objective is to embrace the mission of discovery research that deciphers basic mechanisms of biology, motivates translational research that mimics and deciphers complex physiological processes and searches for answers to the realities of human disease. Each pipeline focuses, but not to exclusivity, on an area of organ/tissue repair that has profound impact on human life. The pipelines represent a promising and prodigious panacea of logical choices that span the spectrum of human disease. Cardiovascular emphasizes muscle repair, while neural seeks answers to differentiation, migration, and characterization of cell lines, for example, in generating specific phenotypic cell types to test in animal models of epilepsy, Parkinson’s disease and many others. Pancreas and Liver will probe the mechanisms of endodermal progenitor differentiation into insulin-producing cells and hepatocytes with a goal of applying discoveries to determine why pancreatic cancer is refractory to chemotherapy. Immune tolerance and rejection are of high importance to insulin replacement strategies. Hematopoesis will focus on regulatory signaling to understand the forces that drive malignancies. Small molecule drug interventions are a translational goal. Musculoskeletal is designed to understand differentiation into chondrocytes, osteoblasts and myocytes, the latter to restore skeletal muscle integrity in disease such as muscular dystrophy. Bone, cartilage and tooth repair are ultimate objectives. Epithelial will focus on basic mechanisms of epidermal and gastrointestinal cell growth that can lead to therapeutic approaches for a wide variety of disease and conditions such as burn, cancer and many others. The seventh pipeline, Reproduction, will study basic elements of how cells develop and differentiate from germ cell selection to trophoblast lineages and reprogramming during somatic cell nuclear transfer.

Fourteen of the 25 research groups to be housed in the facility will utilize basic and discovery approaches in their research. The quality of these investigators is outstanding, and given the breadth of expertise and the limits on the length of the application, it is perhaps not surprising that the description for this and other elements is more global than specific. The PIs are thought leaders in their fields and their publication lists read like a primer on how to establish world-class programs that are at the cutting edges of scientific discovery. The numbers of papers publishes in leading journals, including Nature, Science, PNAS, and disciplinary journals such as Neuron, Nature Genetics, Cell and many others is not just exemplary, but frankly rather staggering. It represents a peer review testimony to the exceptional quality of the investigators and the relevance of their work. The PIs productivity is represented by over 2,800 publications in stem cell or relevant fields since 2000; as well as 150 patents granted or applied for, 10 FDA-approved Investigational New Drug (IND) applications and 145 clinical trials where the PI is a lead or contributing investigator. Together, they have been awarded 22 CIRM grants, 268 relevant NIH grants since 2000 and 371 from other sources.

It is also fair to say that many of the PIs focus more on issues of cellular differentiation and tissue development rather than the challenges specific to regenerative medicine (even at the basic and discovery level). While this emphasis and overall strategy is to date on par with the evolution of the field, it is somewhat disappointing that the strategies for moving beyond this more limited perspective are outlined in fairly vague terms.

FORMAL INSTITUTIONAL COLLABORATIONS: The web of interactions established by members of the regenerative medicine community with a basic or discovery emphasis is dense and long-established. The quality of the collaborating investigators external to the program likewise is outstanding and their selection is based on specific synergies that benefit the pipelines and cross-cutting programs. For example, the scientific accomplishments of one PI, who was recruited from a nearby institution to act as Co-director of the Cardiovascular pipeline, are impressive and fit the mission perfectly. In addition, collaborations with nearby institutions will provide important opportunities for underrepresented minority students to matriculate through programs that are supported by other grants. Additional scientific collaborations have been established with several other institutions, and collaboration is further represented by agreements with over 40 companies in the private sector.

CORE SERVICES: The core services provided both within and external to the institute are excellent and ideally suited to meet the demands of the participating laboratories. These include cellular imaging and tracking, FACS, histology, high-throughput DNA sequencing, small animal surgery, an IVF tissue bank, and an hESC core. Additionally, there will be outside cores, which include over 80 technology core facilities providing services to all investigators at all applicant institution campuses. It is somewhat surprising that the application does not identify a core for fabrication of scaffolds and other structures of defined architecture for purposes of cell-type specific expansion and differentiation.

Equipment for many cores will be provided by non-federal funds (a major gift from a private foundation is cited as an example). All but one core will be new, and the proposed cores are duplicative to some extent of pre-existing ones outside of the facility, but the redundancy of facilities can be justified on the basis of efficiency and demand. One criticism is that PIs within the new building will be given priority access, but all other institute members will have access as well. A governance committee will review policies and practices twice monthly, and it is recommended that prioritization occurs in such a way that recognizes the equal value of the more than 100 laboratories in this program.

PLANS FOR GROWTH: The plans for growth are appropriately aggressive and impressive. In fact, they benefit the program substantially because when space is vacated by a move into the new building, that space will be dedicated to recruitment of additional faculty whose research is relevant to regenerative medicine. At least 10 additional faculty will be added by various departments as a consequence in relevant areas including tissue engineering, mesenchymal differentiation, genetics, cancer and many others. The planned recruitments outside of CIRM will likely strengthen Elements Y and Z.

DISCUSSION: All reviewers agreed that the quality of the investigators and the science in Element X are exceptional. Synergies among theses scientists will undoubtedly occur by bringing them together into this great space, and the formal institutional collaborations are excellent.

Element Y

Score: 91

SCIENTIFIC PROGRAM: This element of the application is extremely well-written, and as outlined is very convincing. Here, as in Element X, there will be the same organizational structures with the seven pipelines outlined under Element X, which are, in turn, supported by the same cross-cutting research programs and by an array of core technologies. Each pipeline and program in Element Y has translational research as its central goal. The new building is designed to place the right people in proximity to one another and to essential core facilities to promote this goal. Multiple examples are provided for each pipeline area and it is clear that the investigators have thought through many possible avenues for potential repair as a result of work to be completed. For example, if members of the Neural Pipeline successfully differentiate hESCs to a desired phenotype they can interact with scientists in the cross-cutting programs to identify or develop animal models in which the cells can be tested for their replacement or repair capabilities. Investigation also may proceed with members of the Cancer program to establish safety of the new line with respect to tumorigenesis. Others such as bioengineering can provide methods for tagging the novel neurons for tracking purposes after they are implanted. In another example the Immunology cross-cutting program recognizes that immune regulation and tolerance present as major obstacles to overcome when hESCs are used for therapy in the future. Consequently they stand ready to assist with the development and testing of tolerogenic drugs that selectively turn off parts of the immune system.

There is every reason to believe that the faculty of Element Y will be successful in each of the seven pipelines. Of the 25 research groups to be housed in the facility, 20 will be involved in translational research, which includes eight recently recruited “vibrant young” faculty as a further testament to the institution’s commitment to stem cell research. Much of the preclinical work is currently taking place in the labs of PIs situated outside of the institute, but several of the planned recruits will fall within this element. The Element Y programs are defined in detail and all are quite outstanding. As an example, a PI in Cardiovascular will develop methods to promote angiogenesis and vascular repair following ischemic injury and use an animal model to test homing capabilities of human stem cells to injured cardiac muscle. The work of about two dozen key investigators is highlighted in the proposal, which includes many notable scientists. The set of PIs both inside and outside of the institute that are classified as participating in Element Y overlap to a substantial extent with the ones identified in Element X. Their strengths lie in their accomplishments as developmental biologists, and their plans in the preclinical realm in many areas are still at an early stage (for example, in the neural pipeline). However, it is reasonable to assume that moving into one building would foster the potential synergies to would promote efforts in Element Y. These are highly respected, long standing investigators who have devoted their scientific lives to mechanisms of repair and will bring substantial senior leadership to these complex, interactive and complimentary programs. The support by the cross-cutting programs will be a major contributing factor.

FORMAL INSTITUTIONAL COLLABORATIONS: The formal institutional collaborations, which mirror those cited for Element X, are well defined and extensive. In addition several collaborations are in place with institutions having distinguished records in cell-based therapy. Two collaborations are focused primarily on cord blood applications. These collaborators bring valuable experience with respect to FDA regulations for cell therapies, and discovery research applied to human disease. Collaborations with the private sector include a mix of stem cell and non-stem cell therapies, with several of the non-stem cell therapies falling only loosely within the realm of regenerative medicine. More than a dozen examples are included in the proposal.

CORE SERVICES: The same core services are available as with Element X and are suited ideally for the proposed research. Of particular importance for this aspect of the institute are the planned core resources intended to track the location and fate of transplanted stem and progenitor cells, which are adequate to the purpose. They will be available to regenerative biologists outside of the institute. Genetically modified mouse cores, a human tissue bank and many other core services provide a valuable expansion of technological options for the program.

PLANS FOR GROWTH: Plans for growth are outstanding and represent a huge commitment on the part of the applicants to the benefit of the institute. The proposed facility clearly will enable this desirable expansion which otherwise would not take place due to legitimate space constraints that presently exist. Within the institute two of the planned recruitments fall within this element primarily, while others emphasizing clinical research will also have elements of preclinical investigation in their work. The applicants forecast substantial growth in this area outside of the institute, as space opens after completion of the building. This growth is a strength of the application and represents an opportunity to markedly enhance the flow of discovery research in a translational direction. Among these are recruitments targeted toward tissue engineering and toward stem cells and eye development, the latter being a cooperative plan that draws two departments into an interdisciplinary endeavor.

DISCUSSION: Reviewers concurred that the overall strength of this cadre of PIs is outstanding, and they provided several clear examples for how to move forward to clinical work. One reviewer noted a concern with this element, that despite its compelling plans, there is not much substance to the programs proposed in Element Y at this point in time. This reviewer felt that the principles are laudable, but there should be an evaluation of practical plans to achieve the research goals. A panelist also questioned why a member of the Cancer staff would be interested in receiving cells from Neuroscience. What is the impetus as a Cancer Center scientist to work in new fields? Some reviewers considered this somewhat of a leap of faith in the application, since there is no identified program director (with one exception), but others felt that clearly the building would promote these interactions because scientists are self-driven entrepreneurs who will make it happen.

Element Z

Score: 78

SCIENTIFIC PROGRAMS: With respect to the scientific program, this element is the least developed of the three within the proposed institute. This is expected, since little work is ready for clinical trial testing within the specific realm of regenerative medicine either amongst the institute faculty or those elsewhere in the applicant institution. Consequently, the scientific program for Element Z is described as in its early stages. However, this element is expected to shift in emphasis as a result of discoveries in Elements X and Y. The proposal provides many fine examples of research protocols that can and likely will be transformed into clinical trails in each of the seven pipelines. Many such as diabetes, Parkinson’s disease and cardiac ischemia are anticipated because of their high incidence in California and the nation. Other diseases are included based on the needs of comparatively small numbers of patients who likely face death as a result of a congenital or other disorders that often may be disregarded for having too little impact and potential. The applicants are to be commended for being inclusive in this regard. In general the programs are outstanding, critically important and appropriately challenging. Examples of clinical trials include the cardiovascular pipeline, although the trial is not yet up and running, where investigators might use autologous endothelial precursor cells delivered to areas of peri-infarct ischemia. Another example is from the hematopoiesis pipeline, where hematopoietic stem cells are used to correct hereditary disorders; however, this is not new and represents standard therapy at many institutions worldwide. In addition, a multicenter trial is apparently ongoing to study mobilization of local stem cells on fracture healing. It is not clear whether this trial was generated at the applicant institution. Overall, it appears that the translation of the many basic and preclinical activities into clinical trials is as yet not far advanced. Nonetheless, based on the excellence of Elements X and Y, every confidence exists that Element Z will move forward vigorously, but with careful safeguards and oversight.

Scientific programs in the facility reflect an extant dedication to clinical research and applications. Eight of the 25 primary laboratories will have Element Z as their primary goal. Many preclinical programs also feature testing in relevant clinical models prior to human applications, which is critically important. Programs outside the facility are equally impressive and include world-class scientists and extensive use of well-funded core facilities funded by the NIH. These cores are a substantial benefit to the institute’s translational goals. Thus, all the elements are in place for clinical research once preclinical discovery and testing indicate the worthiness of a new approach.

FORMAL INSTITUTIONAL COLLABORATIONS: Formal institutional collaborations within and external to the institute are the same as those for Element Y and are ideal for this purpose. Offices for industry relations and technology management are included to advise and manage intellectual property rights and agreements. The same non-profit entities are in place for Element Z as were identified for Element Y, which bring some strength to the hematopoietic investigations. Interactions with for-profit biotechnology companies have been used to support the preclinical development of stem cell-therapies by providing access to technologies for imaging transplant fate. Other private sector collaborations that are highlighted have less to do with regenerative therapies than with issues for cancer diagnosis and therapy.

CORE SERVICES: Core services within and external to the institute are the same as those for Element Y and are ideal for this purpose. More significant for progress in this element of the program are the extensive cores for all aspects of clinical research work from planning, instrumentation and analysis perspectives, including essential examination space, which is a substantial strength.

PLANS FOR GROWTH: The institute anticipates increasing numbers of stem cell based clinical trials over the next 5-10 years and plans to recruit five new investigators when the building is completed. These new PIs will have expertise in clinical trials, and specific research interests. If successful, these recruitments would turn an area of comparative weakness into a strength. Commitment to clinical research is a core mission both for the applicant institution at large and this institute. Thus, plans are actively underway to expand representation in multiple clinical departments, in some cases jointly, which will bring a multidisciplinary flavor to the types of investigation they propose. An example given is the diabetes and liver translational research program, which will have space and funding outside of the institute.

DISCUSSION: Based on excellence of X and Y, everything will move forward with excellence and appropriate safety. However, a panelist expressed some concern over capacity issues, which seems to be unbalanced between X,Y and Z. Clearly the potential for clinical trials work is there, but it is not yet in place. A reviewer echoed this concern, saying that most of the current trials are in areas other than regenerative medicine. However, another reviewer noted that these programs are in an early stage as expected, and would be concerned if they weren’t. The goals are cautious, and this reviewer gives them credit for stating them realistically.

Use & Contribution

Score: 92

There are five primary strengths of the space utilization that serve to promote the program at the applicant institution. They include: 1) the growth of research programs by strategic recruitments; 2) a centralized facility for deriving, characterizing, manipulating, and archiving non-registry hESCs; 3) core services that facilitate groundbreaking discoveries; 4) an interactive environment that integrates research across the pipelines; and 5) a hub for groundbreaking research that spans Elements X, Y, and Z. These benefits will impact investigators with laboratories in the new building as well as the investigators located outside the building, who will interact consistently with the researchers, non-federal hESC resources, and other facilities in the building.

The institution’s administration is committed to support the operations of these facilities. Further, the institution is committed to using the facility for research in regeneration medicine beyond the lifetime of CIRM. A substantial amount of space is currently dedicated to research relevant to the institute. Once the building is up and running, this space will be released to clinical departments to be filled with new researchers whose work is relevant to regenerative medicine. This strategy assures that future development of the institute will favor Elements Y and Z. Integrating the efforts in regenerative medicine in one building will advance stem cell research and will help realize eventual application to clinical trials.

Plans for the use of the facility speak explicitly to strengthening interdisciplinary ties, by virtue of the breadth of investigators to be included, and to fostering stem cell research, by providing non-federal support for the space, facilities, and staff used to derive and characterize non-registry stem cell lines. The plan proposes a greater provision of lab space for the Basic and Discovery Element (Element X) of the Institute, but that imbalance is ameliorated, in part, by the likelihood that research will span more than one element and will shift dynamically towards more clinical applications with time.

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
• Young, Wise