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CL1-00521-1: Laboratory for Stem Cell Biology and Engineering

Laboratory Recommendation: Recommended for funding
Laboratory Score: 81

Course Recommendation: N/A

Public Abstract (provided by applicant)

Regenerative medicine is an emerging area that will only realize its great potential through novel collaborative research approaches, and the University of California at Santa Barbara (UCSB) is well positioned to make significant contributions by leveraging fundamental biomedical research efforts with enabling technologies in materials, microfluidics and bioengineering. This proposal details plans for the development and renovation of shared-use laboratory facilities for the culture of human embryonic stem cells (hESC). The Laboratory for Stem Cell Biology and Engineering will be designed to promote stem cell research by investigators at UCSB, as well as those at neighboring universities and research institutions on the California central coast. Availability of a core stem cell laboratory will facilitate expansion of current stem cell studies at UCSB and stimulate new investigations into the biology and engineering of stem cells. The Laboratory will be embedded within a new UCSB Center for Stem Cell Biology and Engineering that is planned for the 3rd and 4th floors of Biological Sciences 2 building. Our clientele will include researchers in 13 different Departments and Institutes at UCSB, as well as nearby institutions. Research supported by the facility will include: investigations of the molecular mechanisms of hESC proliferation and differentiation; translational bioengineering to study novel methods of hESC culture, sorting, and delivery; and studies in regenerative medicine that test hESC derivatives in animal models of disease.

Statement of Benefit to California (provided by applicant)

California, like much of the United States, is facing a staggering challenge to its health care system. Increasingly physicians are treating chronic, debilitating, and therefore expensive diseases with organ specific impairments. Examples include diabetes, cardiovascular disease, and Parkinson’s disease. The demographic wave of the Baby Boomers will accelerate many of these issues. By 2020 they will average 64 years of age. As a result, the percentage of the elderly in California is expected to grow from what was 14 percent in 1990 to 22 percent in 2030.

Treatment of chronic degenerative diseases of an aging population, which is proportionally a high percentage along the Central Coast, is an imperative. Degenerative diseases are those diseases caused by the loss or dysfunction of cells. Examples include cardiovascular disease, osteoarthritis, Parkinson’s disease, osteoporosis, and macular degeneration. Among these, stem cell work at UCSB would leverage a strong existing program in macular degeneration, a condition that is not being addressed in the stem cell field nationally or in California. Stem cell work for eye disease holds the promise of being a poster child for the entire field. There is no doubt that an early clinical success will benefit the state.

In terms of advanced biomedical research our geographic region is not well represented, but its engineering sector is primed with enabling technology. The area is ripe for growth in biotechnology that would serve as a pipeline to large pharmaceutical corporations as stem cell technologies move toward the clinic. The proposed Laboratory for Stem Cell Biology and Engineering will promote this movement and enhance the research stature of The University and attract leading researchers to California.

Scientific Review Summary of Part One Application

SHARED LABORATORY

SYNOPSIS OF PROPOSAL: Stem cell researchers from this applicant institution propose the formation of a shared laboratory to expand existing stem cell studies and to stimulate new investigations of the biology and engineering of stem cells at the home and neighboring institutions. Currently nine of the twenty-five assembled research groups use human embryonic stem cells (hESC), nine others have plans to, and five eventually intend to use non-registry lines. Funding from CIRM has supported several research groups to begin their hESC work. Space within a new center for stem cell biology will be renovated to create one common lab with four well-equipped workstations for ES cell manipulation and culture plus a support lab for maintenance, quality control and storage of master ES cell stocks and to derive non-registry lines. The Program Director (PD) and members of the oversight committee who have hESC-research experience and have been the driving force behind the creation of the Center and the recent recruitment of an hESC pioneer. A PhD scientist trained in hES-cell technology has been supervising a small hESC facility. For the new shared lab, this lab manager and two full-time associates will guide researchers through compliance requirements and provide regular expert assistance to produce, maintain and analyze hESCs, one-on-one training for common cell and analytical techniques, and specialized training on demand. The institution has committed meaningful space, funds and other support to help ensure the start and continuation of a viable hESC-research community.

QUALITY AND IMPACT OF THE SCIENCE: hESC research at this institution is new and growing. As yet, there is only one publication by the endogenous Principal Investigators (PIs) listed that uses hESC. Nonetheless, a strong basic science base with direct relevance to hESC biology and applications does exist, and it has been assembled by the PD who is a departmental chair and is involved with stem cell programs at the home institution. The PD is a senior PI who is quite productive, yet currently has no publications in the hESC field. Moreover, while at least nine of the twenty-five listed investigators seem to be involved in early stages in hESC research there does not appear to be any published hESC work from these investigators. Recently, however, a notable PI in the hESC field was recruited to establish a lab at the home institution.

Research groups studying adult neural, pulmonary and retinal stem/progenitor cells and pioneering work on nematode germline stem cells contribute to the overall developmental and stem cell expertise. The research and bioengineering base resolves into three major areas – molecular mechanisms, translational bioengineering, and regenerative medicine. The Molecular Mechanisms group studies such critical issues of hESC biology as microRNA control of hESC pluripotency and differentiation, and the basic biology, growth and differentiation of hESC. This group is involved in novel investigations that center around the directed differentiation of hESC, and a particular strength of the current and prospective human stem cell users lies in the initiation of hESC projects relevant to therapy. A special advantage at the home institution is the strength of the bioengineering group that leads the field in many aspects of nano-biotechnology and biomaterials with the potential to make real advances in the manipulation, analysis and application of hESC. Five of the PIs listed are notable for interactions with the biomaterials specialists on campus, and a shared stem cell lab would greatly enhance this nascent user group. This is one of the strongest aspects of the application with clear evidence of interaction and collaboration across multiple fields. In addition, the recent notable recruitment of a well known scientific expert, mentioned previously, brings a strong research presence with wide-ranging expertise, which is directly relevant to research groups interested in ES cell growth and differentiation and bioengineering. This scientific expert is an unparalleled resource for building collaborations and s/he has identified several collaborators at the host institution, demonstrating feasibility of the plan. In fact, the impact of the facility could have benefited from more direct input from this scientific expert and his/her staff, who themselves will not be directly involved in the facility (e.g. training). Finally, the regenerative medicine group with strong ties to the basic sciences may be ready to lead the nation in using hESC to treat certain diseases. The users are highly productive with notable contributions in their respective fields, and they are well funded from major granting institutions. A core of six PIs has ongoing projects with hESC, but the majority have only recently committed to stem cell research projects. Overall, the goals of the basic science, bioengineering and regenerative medicine groups are directed to central questions of hESC biology, technology and applications.

A weakness of the application is the lack of strong projects from neighboring institutions. While important regional considerations are mentioned, the neighboring institutions listed are primarily teaching institutions. Further, the applicants propose a number of non-approved lines including Harvard lines and a line from a company. No clear argument is made for the need of non-approved lines, and it is unclear whether the line from the company is indeed a bona fide hESC line or a more restricted derivative or rather fetal stem cell line.

APPROPRIATENESS OF SPACE AND EQUIPMENT TO SCOPE OF PLAN: There is an extensive and immediate need for a shared lab, although it appears somewhat premature for the estimated fractional use of cells not in the NIH registry. Nine research groups currently use hESC, one with lines not in the NIH registry. Four of these currently share a small hESC culture lab, which would be replaced by this shared lab. Ten additional groups have plans to begin projects with hESC, including five with interest in non-registry lines. The facility will be part of the new center for stem cell biology and engineering. There is an existing facility of 500 sq ft that is inadequate in size and equipment. However, it has served as a starting point for several groups that either have begun pilot projects funded by the CIRM for stem cell studies or have begun training in the existing facility. In fact, this facility appears to be in use already by 12 labs. The new facility will be 1400 sq ft of wet laboratory space. Of these, 700 sq ft will be for facility staff and 700 sq ft for general multi-user use. This new space will provide well-equipped and staffed NIH-free space, a center for hESC collaboration, and a source of acquired expertise. The staff will provide regular expert assistance to produce, maintain and analyze hESCs, one-on-one training for common cell and analytical techniques, and specialized training on-demand. The size of the proposed lab, the equipment and the personnel are reasonable and justified, and appropriate for the predicted use. The proposal contains a good discussion on how to make the facility user friendly with nice details in the planning. Two creatively designed labs are planned. One is particularly thoughtful, with four nearly self-sufficient ‘workstations’ for simultaneous use by four projects. A separate well-equipped support lab with two technicians will maintain, quality control (QC), and store cell stocks and develop new lines (although plans and expertise are not presented); a microscope room will provide access to inverted & standard fluorescence microscopes. The designated area is distinct from NIH-funded research space.

QUALITY OF MANAGEMENT PLAN: The application has been planned quite carefully overall. Three staff members with assigned duties should adequately manage and maintain the lab; particularly important is the plan to routinely QC reagents and stock stem cell, feeder, and user cultures. The institution has quite a strong record in running core facilities particularly in the areas of microscopy, proteomics, Nuclear Magnetic Resonance, and tissue engineering. A good plan has been developed for regulating access to the facility using a keylock and badge system, and taking into account the training, experience, and regulatory concerns for each individual user. While the appropriate requirements for user authorization, guidelines, and compliance appear to be in place, clearer and more user-friendly administrative mechanisms for users to acquire authorization and to monitor compliance are needed. The PD and key personnel have proven excellence in management – the director is chair of his/her department and the leader in stem cell efforts at the home institution, and brings certainty to commitments made by that department. The lab manager, while rather junior, has excellent training through coursework and work with a well-known stem cell biologist and experience managing the current stem cell lab. Here, as before, the proposal could have benefited from the stronger participation of the recently-recruited PI’s group by involving some of his/her staff more directly in the facility. The oversight committee is well constituted, with the PD and two Co-directors (who established the current small hESC lab on campus), the Director of a neighboring disease-focused research institute (who has extensive IRB experience), the shared lab director and a representative of the user group. There also is a good discussion on decisions, regular meetings and prioritization. Together the committee has extensive relevant experience advising and directing successful larger-scale multi-user facilities.

A weakness is that the oversight committee has little or no hands-on experience in hESC research. As noted previously, there are no hESC publications for the lab manager, PI or oversight committee members. Consequently, there is little evidence that the facility will develop novel techniques but we may assume that the close proximity of the recently-recruited PI will keep the effort state-of-the-art. Beyond this lack of hands on hESC expertise the oversight committee is well balanced regarding regulatory and administrative issues.

Embedding the shared lab on one of the two floors that will house the center for stem cell biology and engineering will ensure ready access by members of the host institution. Permission to use the facility requires documentation of training, project authorization, approval from the Embryonic Stem Cell Research Oversight (ESCRO) and the Institutional Review Board (IRB) Committees and the Environmental Safety Office. A weakness of this application is the near absence of neighboring institutions with stem cell research programs. Two starts have been made through collaborations involving an Adjunct Professor and Director of the disease-focused research institute and a nearby hospital, respectively. Clear support from the home institution is demonstrated by the establishment of a nascent center for stem cell biology and engineering with plans for ten faculty including an immediate junior faculty position and an endowed chair for stem cells, 4-years of salary support for the lab manager, the commitment of $1M to establish the newly-recruited PI, and an additional $3.5M from donors, all accompanied by support from the Deans of Science and Engineering and the Executive Vice Chancellor. A commitment to renovation of the proposed space for the shared lab is implied.

DISCUSSION: The key strengths of this application are: 1) this is a true shared research laboratory that is thoughtfully designed, user-oriented and user friendly; 2) there is excellent institutional commitment; 3) there is a good nascent stem cell group; 4) there is a very good biotechnology and biomaterials core available, and there appears to be a remarkable spirit of collaboration at the home institution. The shared lab would provide services and quality control, and would store master stocks. The current space is small and poorly equipped, and the new workstations are very well-designed with nearly self-sufficient equipment so groups can work simultaneously. One reviewer argued it would be useful to support early work in ESC technology for some of the users, to allow other users to begin using the technology, and to attract some of the biotechnology gurus on campus to hESC research. Also of note is that the home institution has current CIRM funding. The PD and a member of the oversight committee (who has hESC experience) have been the driving force in hESC research on this campus and in the recruitment of hESC scientists. While there is a lack of other strong research institutions in the area and a notable failure to bring others into the application, a highlight of the science at the home institution is the interaction between the ocular disease group and a biotechnology company. One reviewer considers this a great way to bring biotechnologists into stem cell biology.

There was continued discussion on the nature of the interactions with the newly-recruited PI. The letter from this PI describes the establishment of a satellite lab at the home institution and four collaborations, three of which have been initiated (including one with the PD), and one of which is to be initiated. This new PI offers experience in growing cells in serum-free, feeder-free conditions. How this PI will work out the situation with a satellite lab is unclear, but s/he suggests that 5-8 people will be working on-site at the applicant institution. It was noted that this PI will provide advice and consultation but there was no percent effort commitment nor any indication of how much time s/he would spend at the institution.

PROGRAMMATIC REVIEW: A motion was made to recommend this Shared Research Laboratory application for funding and the motion passed.

The following Grants 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:

• Lansing, Sherry