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CIRM MAJOR FACILITIES GRANT APPLICATION #FA1-00617-1

Recommendation: Recommended for further consideration as a CIRM Special Program
Element X Score: 83
Element Y Score: N/A
Element Z Score: N/A
Use & Contribution Score: 84

Public Abstract (provided by applicant)

We propose a 13,200 square foot research facility dedicated to basic and discovery research in stem cell biology on the top floor of a planned, state-funded biomedical research building. The facility is designed to house six stem cell faculty and to support all institute affiliates through the establishment of several core facilities, including cell culture, cell sorting, microscopy, electrophysiology, a sequencing center, and dedicated space in a new animal facility in the same building. Other institute affiliates will be located on other floors of the building or in buildings nearby. The facility will house {REDACTED}, an interdisciplinary program currently involving 18 faculty from 5 departments and numerous collaborators from other institutions. {REDACTED} combines the unique strengths of a diverse group of researchers to address many of the most challenging problems in stem cell biology. Some of the projects {REDACTED} faculty are undertaking include:

• Developing computer programs and a database to analyze the wealth of data being generated in stem cell research labs throughout California, and making the data available on a public web browser
• Studying the mechanisms by which DNA packaging, gene expression, and RNA processing are regulated to orchestrate the ability of stem cells to self-renew and to differentiate into the myriad cell types of the human body
• Studying the molecular mechanisms by which neuronal stem cells generate specific types of neurons, and defining the conditions under which specific types of neurons can be reliably generated and maintained
• Exploring the biology of hematopoietic stem cells and applying that knowledge to clinical applications o Revealing how the regulation of RNA is responsible for the development of muscle cells
• Developing bone marrow stem cells that are resistant to the toxicity of certain cancer chemotherapies
• Studying the behavior of neural stem cells transplanted into post-stroke brains and optimizing post-stroke motor training in a mouse model
• Applying “adaptive optics” technology developed by astronomers for the Hubble telescope to imaging cells and structures deep within experimentally generated embryos to better understand early development
• Using “lab-on-a-chip” technology to develop a stem cell environment capable of growing billions of stem cells per square centimeter, for large scale production of therapeutic stem cells

These studies have potential clinical applications for many conditions including myotonic dystrophy, ALS, spinal cord injuries, stroke, certain heart diseases and cancers, and others. This opportunity will more than double the NIH-free stem cell space available to {REDACTED}, allowing new faculty to be hired and co-located with necessary core facilities and other biomedical research labs. The proposed facility will greatly assist our recruitment efforts and ensure the continued growth and vitality of our stem cell research.

Statement of Benefit to California (provided by applicant)

The proposed facility for {REDACTED} will enable new research that integrates the expertise of several strong research groups focusing on problems in stem cell biology, provide research space for new stem cell faculty hires, facilitate the collaborative work of many of our faculty with colleagues at other institutions, and add another node to the network of stem cell institutions in the state. At our institution, molecular, cell and developmental biologists will join forces with bioinformaticists, engineers, and even astronomers to perform basic and discovery research that will contribute to the foundation of knowledge that will serve as the underpinnings of important advances in stem cell-based medicine. The proposed facility will position {REDACTED} faculty to make significant headway in several keys areas of stem cell research, with a number of projects holding promise for eventual pre-clinical studies. Specific benefits to the state of California for providing space for {REDACTED} include:

1) More projects entering preclinical studies, 2) Recognition to the state of California for its role in advancing stem cell research, education and training at an institution with a strong track record in training minority graduate students, 3) Attracting more stem cell scientists and companies to California, 4) Development of new technologies to overcome problems associated with analyzing single cells, deep-tissue imaging, and growing large populations of stem cells for harvesting, 5) Technology transfer from academia to the private sector, 6) Quicker development of therapies, 7) Development and characterization of stem cell lines that will populate an envisioned stem cell bank in California. In addition, building {REDACTED} will enable a web-based database and browser with bioinformatics tools to analyze the wealth of data being generated in stem cell research labs throughout California, integrating the data and making it available to the public.

Review Report

Executive Summary

This application presents a request for Element X support only. It is a tightly focused proposal looking for support for a single floor of a planned state-funded research building on the campus of the applicant institution, which will begin construction in late 2008. The proposed facility is well justified as it will allow expansion of an existing stem cell program by relocating three existing stem cell faculty and by housing three of four new stem cell faculty recruits and several core facilities in the new location. The proposed facility would double the space available to non-NIH human embryonic stem cell (hESC) research. Given that the program is relatively new (3 years old), program growth is impressive, with seven new faculty hired in the past 2 years.

The existing stem cell program is a high caliber, interdisciplinary program involving 18 faculty, 6 of whom are stem cell scientists, and numerous collaborators from other institutions. There are five areas of strong expertise in the existing stem cell program: (1) a bioinformatics group whose work focuses on the use of existing genome browser systems to streamline stem cell biology-related bioinformatics; (2) a chromatin and epigenetics group planning to apply their experience to stem cells; (3) an RNA regulation group with expertise in studying noncoding RNA and splicing, again a topic they wish to extend to stem cells; (4) a developmental biology group, which naturally overlaps significantly with stem cell biology; and (5) a technology group including faculty bioengineering synthetic stem cell niches, optical scientists developing new microscopes for deep imaging, and researchers working on novel sequencing technologies.

Overall, the projects encompass very diverse areas of expertise with the idea that they will be applied in a coordinated manner to the field of stem cell biology. The particular emphasis reflects a current strength at the applicant institution in genomic biology, chromatin structure, and bioinformatics, and it is proposed that they will focus their work into the overall theme of studying the mechanisms of differentiation of neural stem cells (NSC) and hematopoietic stem cells (HSC) during development, using hESC as well as adult cells. The reviewers felt that the different projects are not well integrated: developmental biologists will be housed in the new facility but not principal investigators (PIs) representing the genome browser and the new technologies, two areas of particularly strong merit and potentially far-reaching impact on the stem cell field. Overall, the reviewers were very supportive of this young, vibrant group of investigators.

Detailed Summary

Element X

Score: 83

SCIENTIFIC PROGRAM: The proposed CIRM-funded facility is well justified, as it will provide space for existing researchers working with stem cells, and also space for 3 of 4 new faculty hires in the near future. The planned program has the virtue of a tight focus on the genomic regulation of stem cell behavior, especially in the areas of neural and hematopoietic stem cells. That focus builds on the acknowledged strength of the applicant institution in bioinformatics and genomics. However, one reviewer pointed out that there is no track record in hESC research, and that there is no clear plan to expand expertise in this field. The head of the existing stem cell program is a well-known, HHMI-funded investigator of genomic structure, who is focusing some of his/her research program on bioinformatics approaches to stem cell biology.

The investigators of the existing stem cell program are high caliber. Their convergence toward the study of stem cells is a clear sign that the applicant institution intends to seriously tackle fundamental issues in the basic studies of stem cells. The group as a whole is reasonably well-funded by NIH and non-NIH sources, and two faculty members have received CIRM SEED grants. The applicant institution has already developed outstanding research and training programs in stem cell biology, including a new training program funded by CIRM. There is also an External Advisory Board comprised of preeminent California and out-of-state investigators.

The scientific program is divided into five elements:

1. The bioinformatics group at the applicant institution created the widely used Genome Browser, and they propose to create a CIRM-wide genomics resource to store and analyze high-throughput genome-oriented data on stem cells. Since the 3 PIs involved in this project will not be housed in the new facility, it remains unclear exactly how the obviously strong bioinformatics resource will integrate into efforts to study stem cells.

2, 3. Two groups of accomplished PIs, who study epigenetics / chromatin dynamics and microRNA and other RNA molecules, are associated with the existing stem cell program but will not move to the proposed facility. They have outstanding publication records. These investigators have studied mostly model organisms and are now beginning or planning to apply their important findings to hESCs.

4. Three established and three recently-hired developmental biologsts are listed in the stem cell program, and some are clearly quite accomplished stem cell researchers with good publication records. One reviewer emphasized that one of these investigators is pursuing a very timely and interesting idea related to cell fate decisions, whereas the fate mapping studies proposed by another PI were considered less well justified. Overall this is the strongest group as far as stem cell biology is concerned, with an emphasis on NSC and HSC. Several investigators are proposing to move into hESC work. Three of the developmental biologists will be housed in the new building.

5. A set of new technologies that will strengthen the endeavors throughout the stem cell field world-wide are proposed. One of the goals is to develop adaptive optics, a very intriguing idea, integrating faculty from the Astronomy department. The second goal is niche fabrication, based on the understanding that biological niches are critical to stem cell biology. The final aspect of technology is single cell analysis and sequencing. Overall these are outstanding technology platforms very well suited to stem cell research, and feasibility is supported by the excellent track record of the involved PIs. There is, however, a paucity of information as to how these groups will work together, and how the work will be integrated into the bioinformatics and biology approaches. None of these investigators will be housed in the proposed facility.

FORMAL INSTITUTIONAL COLLABORATIONS: The applicant institution and another prominent institution received a Shared Research Laboratory award. However, regarding the other collaborations listed between these institutions, one reviewer stated that it is not clear which would be considered ‘formal’, which are active, and which are proposed. By contrast, another reviewer felt that the proposed collaborations in this application are well organized. What is clear is that bioinformatics and computational experts at the applicant institution are engaged with several prominent labs at the collaborating institution, including a world leader in stem cell biology who stated that the unique expertise of the applicant institution’s faculty in bioinformatics, genome analysis, and modeling will facilitate data clarity and optimization.

CORE SERVICES: The major core service cited in this proposal is the genome browser, however, it is not clear how additional funding or a new facility will help build this core and enhance stem cell research. New core services to be housed within the proposed facility include cell culture (including hESC), cell sorting, microscopy, and electrophysiology cores, a state-of-the-art sequencing center, and a new vivarium. The applicant institution has committed funding to support the staffing of these core services. There is no direct description of how the cores will be organized. One reviewer was uncertain why a new cell culture core is needed, since an hESC core shared research laboratory at the applicant institution has already been funded by CIRM, albeit housed in a different building. In addition to the proposed new cores, the applicant institution has several existing core facilities. These cores and a vivarium are required for the accomplishment of the stated goals.

PLANS FOR GROWTH: The applicant institution has demonstrated a commitment to developing their stem cell program. Current space limitations constrain recruitment. Recruitment plans reflect the need to provide the existing set of researchers with colleagues that complement existing strengths. The cores will likely play a large role in being able to recruit talented young stem cell biologists as well as established stem cell researchers to the applicant institution.

DISCUSSION: The applicant institution has developed a unique and widely-used tool, the genome browser, and here proposes to extend this tool to integrate stem cell data. Although it was not clear to the reviewers how this will be accomplished, the reviewers agreed that the genome browser is a strength in this application, it could serve as a bioinformatics core for the rest of California, and in fact be a national and international resource, potentially synthesizing world wide data. Reviewers were also intrigued by the technology aspect of this proposal. Faculty from the astronomy department will work together with stem cell scientists to develop the next generation microscopes for stem cell research, which will be important for this field. The tissue engineering component was also praised.

Overall, the proposal describes 5 strong areas of expertise, but the different projects are not well integrated. Although developmental biologists, which are at the core of the proposal, will be located in the new facility, investigators representing the genome browser and the new technologies are not going to be housed there. Furthermore, details, such as who will oversee the stem cell group in the new facility, were missing. However, some reviewers felt that creating new contiguous space for 6 stem cell researchers, as proposed, will in itself promote interactions. Collaborations are already set up with stem cell researchers at another prominent institution, but no communication plan was presented, and no history of publications from these collaborations exists, thus it is difficult to assess how these collaborations will be implemented. Overall, the reviewers were very supportive of this young, vibrant group of investigators.

Use & Contribution

Score: 84

The allotment of space to new recruits and the housing of cores that will serve them and the larger community across campus are the primary uses for the facility. Reviewers were of different opinions when considering whether the new facility will contribute to promoting integration among the investigators. One reviewer felt that although the researchers and their science are excellent, there is a complete lack of integration of the individual science projects and it is not clear how the new facility is going to help in this area and what kind of interaction there will be between faculty in the new building and those at other campus sites. Having a balance between established investigators and new faculty in the new facility would be important. By contrast, others felt that overall, this grant fulfills the three criteria listed by CIRM as crucial, including well-integrated elements, appropriate, well-planned use of the proposed facility, and contribution of the proposed facility to the development of the applicant institution’s stem cell program. Propinquity will facilitate cross-disciplinary approaches, and that had not previously been easy. Their plan for cores is adequate and commensurate with the needs of the faculty of the stem cell program and the larger community.

The applicant institution is requesting funding for a new facility that includes space that is free of federal funding. hESC are used in some of the proposed research. A concern is that while this proposed facility is being planned in a situation in which the existing facilities are inadequate, the already CIRM-funded hESC shared research laboratory does not exist yet. But the applicant institution apparently needs more research space and the space allotted in the new building for the stem cell research program does not appear to be excessive.

It is important to CIRM to consider investments by others in this case, the applicant institution is constructing the new building and all of the researchers have external funding to support the science that will be housed in the new facility and will help to maintain the cores.

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