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CIRM MAJOR FACILITIES GRANT APPLICATION #FA1-00614-1
Recommendation: Recommended for further consideration as a CIRM Special Program
Element X Score: 72
Element Y Score: N/A
Element Z Score: N/A
Use & Contribution Score: 71
Public Abstract (provided by applicant)
The promise of stem cell-based therapies is critically dependent upon being able to direct stem cell decisions (i.e., pancreatic cells for diabetes, cardiac cells for cardiac diseases, neural cells for neurodegenerative disease, etc.). A fundamental understanding of the cues in the microenvironment that guide stem cell fate decisions is essential to develop strategies for disease-directed regenerative medicine. Development of robust, reproducible protocols for stem cell differentiation therapy is dependent upon a fundamental scientific understanding of the variables that influence stem cell fate decisions. The unique theme of our stem cell research program is quantitative analysis of single cells at the micro/nano-scale level using innovative molecular, cellular and bioengineering approaches to interrogate and manipulate individual cells in precisely controlled microenvironments. The proposed Stem Cell Instrumentation Foundry (SCIF) will provide stem cell researchers throughout California access to advanced instruments, techniques and collaborators for single cell analysis. The SCIF will be housed in a 5,420 asf facility which includes Class 1000 and 100 clean rooms for micro/nano fabrication, facilities for human and mouse stem cell culture, quantitative cell imaging, and workstations. The SCIF is particularly unique because it will provide a range of microfluidic-based systems enabling researchers, with no prior knowledge of micro/nano techniques, to custom design devices online to their specific needs, rapidly adopting cutting edge research technologies. The SCIF will be equipped with advanced collaboratory technology to connect researchers to online support, workshops and collaborators. Ancillary core services include materials characterization, vivarium, and computational biology. The SCIF will allow easier adoption of cutting edge technologies by stem cell researchers throughout California, and will provide service and training to participants so that they can fully understand and use these devices in their research. By disseminating research and technology outcomes to the community through on-line training, introductory courses and interactive laboratories, the SCIF will bring a new dimension of quantitative biology to stem cell researchers in California and enhance existing stem cell programs at our institution. In addition, establishing a cutting edge stem cell facility at our institution will allow a rapidly growing and underserved region of California to participate in and benefit from the opportunities generated by stem cell research, thereby ensuring that Prop71-mandated resources are distributed across California.
Statement of Benefit to California (provided by applicant)
A fundamental understanding of the cues in the microenvironment that guide stem cell fate decisions is essential to develop strategies for stem cell-based regenerative medicine. The unique theme of our stem cell research program is quantitative analysis of single cells at the micro/nanoscale level using innovative molecular, cellular and bioengineering approaches to interrogate and manipulate individual cells in precisely controlled microenvironments. Development of robust, reproducible protocols for stem cell differentiation therapy is dependent upon a fundamental scientific understanding of the variables that influence stem cell fate decisions. The proposed Stem Cell Instrumentation Foundry (SCIF) will provide Californias stem cell researchers with advanced instruments, techniques and collaborators to enable or enhance cell fate decision investigations at the micro/nanoscale. This unique resource will enable researchers, with no prior experience or knowledge of micro/nano techniques, to design custom devices online to their specifications and needs. For example, an investigator wishing to understand the role that calcium plays in the commitment to cardiac cells may design a device that enables precise manipulation of calcium levels in the environment and quantitative measurements of cell response to those manipulations. An investigator wishing to examine stem cells developing into neural cells may build a different device. The SCIF will reduce the activation energy for stem cell researchers throughout California to adopt new cutting edge technologies. In addition, the SCIF will provide training to participants so they can fully understand and use these devices in their research. By disseminating research and technology outcomes to the community at large through on-line training and introductory courses, the SCIF will bring a new dimension of quantitative biology to stem cell researchers in California. Our institution is located in a region of California with limited access to higher education and one of the fastest growing populations in the State. Establishing a cutting edge stem cell facility at our institution will ensure that this region participates in and benefits from the opportunities generated by stem cell research. Importantly, it will distribute the Prop71-mandated resources across California, rather than just at large established research centers. The proposed SCIF will attract quality stem cell researchers to the campus and the State, leveraging resources of multiple partners and collaborators. With close to 50% of our undergraduates enrolled in science and engineering majors, and close to 50% of the students from under-represented backgrounds, the SCIF will provide unprecedented opportunities to train the next generation of stem cell researchers, extending the benefits of state-of-the-art facilities to all segments of California.
Review Report
Executive Summary
Investigators from the applicant institution propose to develop a Stem Cell Instrumentation Foundry (SCIF) to provide stem cell researchers at the institution and throughout California access to advanced instruments, techniques and collaborators for single cell analysis. The vast majority of studies elsewhere examine whole stem cell populations; the single cell analyses emphasized, while technically challenging, could provide more definitive data regarding the extracellular signals that affect stem cell self-renewal and fate specification down multiple lineages. Specifically, the SCIF would provide “quantitative analysis of single cells at the nanoscale and microscale level using innovative approaches to analyze and manipulate [stem cells] in a precisely controlled environment.” The proposal lists 8 investigators from 2 departments (Biology and Engineering) with a broad range of expertise including cell biology, bioengineering, and computational analysis.
The proposed SCIF would occupy 5420 square feet in a building that is 7 miles from the main campus, but is the projected site of a future Medical School. Also at the site are a core for material characterization, and the Genome Center of Excellence, as well as NMR and mass spectrometry facilities.
The worthy aspiration for the SCIF is that it will provide a unique core to stem cell researchers throughout California by providing expertise in nano and microfabrication, single cell manipulation and analysis, as well as a tightly controlled microenvironment in which to conduct such research. It is proposed that the SCIF will reach out to stem cell investigators around the state not only by providing collaborations, expertise and temporary lab space, but also by providing online support and workshops.
The program seems to be well integrated into the already existing infrastructure on campus and thus appears extremely innovative, focused and will likely have an impact on stem cell biology.
Detailed Summary
Element X
Score: 72
SCIENTIFIC PROGRAM: The faculty of the SCIF comprise the insitution’s stem cell consortium. All 8 faculty have been recruited to the applicant insitution since 2005. The general theme of the stem cell consortium is “quantitative analysis of single cells at the micro/nano-scale level, using innovative approaches to interrogate and manipulate individual cells in precisely controlled microenvironments”, which is precisely what is proposed in this application.
Although the 8 faculty are from different departments, their research programs are highly collaborative and they are located in close proximity to one another in the same building. Of the 8 total faculty members, 6 are promising young assistant professors who finished their Post-doctoral studies within the last few years.
The primary goal of this program is to develop new ways to study stem cells at the single-cell level using micro/nano tools. The small scale engineering expertise primarily resides with one assistant professor (an awardee of a CIRM SEED grant). The micro lab-on-a-chip (LOC) device developed by this individual for the project within the SCIF is considered the prototype for the systems that other stem cell investigators across California can emulate. The other engineering faculty are primarily trained in tissue engineering and materials, while the other faculty are scientists trained in immunology and drosophila stem cells. This means that all microscale engineering will have to go through one person, at least in the beginning, which is a drawback. It would be stronger to have 2-3 microscale engineers, given that the facility is dedicated to this purpose. A second weakness is that there are only two senior researchers: a professor with expertise in hematopoiesis and a professor who is a world leader in mathematical and computer models of biological systems. Only one of them works in the stem cell field. On a positive note, the researchers have already started working together, seem eager for more collaborations, and have a diverse set of scientific backgrounds.
One of the major concerns is that they have the capacity to engineer highly complex chips, but they don’t have specific scientific applications. They are proposing to build a factory, but they don’t yet know precisely what products they will be producing. The feasibility of the proposed core facility would be more assured if any of the microfluidics LOC had been published or data presented proving that they function as promised.
FORMAL INSTITUTIONAL COLLABORATIONS: There are no formal institutional collaborations indicated. Unfortunately, the applicants misunderstood the RFA and thought formal collaborations were restricted to only one institution. The proposed facility wishes to formally interact with many institutions, and thus opted for no collaborations rather than be constrained to one. A reviewer indicated that it would have been helpful, however, to detail a plan on how those collaborations would be put in place and maintained in the event of an award.
CORE SERVICES: The cores to be provided within the SCIF include fabrication of state of the art ‘Lab-on-a-chip’ microdevices for single cell analysis. The facility will include a P100 clean room and a P1000 clean room for microfabrication of the chips. Adjacent cores will include cell culture facilities, fluorescence microcopy, flow cytometry and lab support areas. The applicant institution also has an established Office of Technology Transfer.
PLANS FOR GROWTH: There are clear plans for growth, in aspects such as space, faculty and the development of strong collaborations with institutions and investigators that will use the facilities. This is a young campus, and tremendous growth is predicted over the next few years. They predict that they will recruit 10-12 new stem cell faculty over the next 3-4 years with membership in several departments. Some of the new faculty will likely have research laboratories in the building where the SCIF will be located.
Currently, the faculty have a few prototype LOC systems. It is predicted that the number of investigators using the SCIF will increase over time such that the SCIF could produce large quantities of the most commonly needed LOC for more widespread use. Missing from this optimistic prediction, however, is how California stem cell researchers will establish collaborations that use the SCIF, and how such requests would be prioritized in the future. Also, it is not clear whether the funding requested will cover any of the proposed research projects. The concern would be that the facility would be built but investigators without funding for this work would not be able to pursue their ideas due to lack of resources (e.g. for post-doctoral fellows, graduate students, and technicians to do the work), or due to the lack of specific stem cell applications.
DISCUSSION: Reviewers felt that this is an innovative proposal. One reviewer highlighted the application’s focus on single-cell analysis as a significant strength. In general, stem cell scientists are largely focused on cell populations and this proposal describes tools for facilitating single-cell analyses. The applicants have presented a prototype which is close to being published. A reviewer indicated that one of the best things about the proposal is that the applicants thought about the workflow of the experiments (which doesn’t exist in most labs). It is very important to have staff, development and assays in the same location as proposed.
Reviewers noted that the faculty are very junior but are highly collaborative. The team is working together and is determined to do stem cell biology; however, all the expertise is not yet there. One weakness is that all the micro-scale engineering has to go through a single investigator, who is teaching everyone else. The proposal is exciting. It might fail, but might work out well. The proposal’s weakness, according to one reviewer, is the suggestion by the applicants that this facility will be able to serve everyone who needs it. Success is highly contingent on the recruitment of a stem cell biologist to help them focus the work.
Discussion and moderate concern was presented about the location of the offices and labs of the investigators, which will be removed from the proposed facility. An example from Dartmouth was cited; when the medical campus moved away, collaboration went way down. The application states that the 10-12 stem cell biology investigators to be recruited will be located at the proposed facility, but there is no indication that all 8 existing scientists will move.
Use & Contribution
Score: 71
Reviewers indicated that the proposed facility is in line with the priorities of the CIRM in general and this RFA in particular. The proposed facility will expand research capacity and capabilities and also facilitate collaborative interactions between hESC-related researchers. The number of investigators involved is quite small at present comprising just the 8 faculty, but theoretically any California stem cell investigator can collaborate with the investigators in the SCIF.
The facility will serve as a fabrication and testing hub for the stem cell engineering efforts on campus. It is apparent that there are several two-way collaborations already occuring on campus, and it is likely that the facility will spur those further. One element missing from the plan is how to manage the facility and control access to new researchers at the applicant institution and beyond. A stated goal in the application was to make it easier for stem cell researchers in California to access new technologies, but this requires a concrete plan. Some idea of how the core will be managed would be helpful.
A reviewer noted that it is important for CIRM to consider other indirect benefits that could result from an investment in the SCIF. As mentioned, the proposed SCIF may help to attract new collaborations with stem cell faculty to the applicant institution. Also, with close to 50% of undergraduates enrolled in science and engineering majors, and close to 50% of the students from under-represented backgrounds, the SCIF will provide unprecedented opportunities to train the next generation of stem cell researchers.
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