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.
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.
SYNOPSIS OF PROPOSAL: Stem-cell researchers at the University of California at Santa Barbara (UCSB) 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 UCSB and neighboring institutions. Currently 9 of the 25 assembled research groups use human embryonic stem cells (hESC), 9 others have plans to, and 5 eventually intend to use non-registry lines. Funding from CIRM supports a training program for 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 4 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 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 an hESC pioneer. A PhD scientist trained in hESC technology has been supervising a small hESC facility. For the new shared lab, she and 2 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. UCSB has committed meaningful space, funds and other institutional support to help ensure the start and continuation of a viable hESC-research community.
QUALITY AND IMPACT OF THE SCIENCE: hESC research at UCSB is new and growing. As yet, there is only one publication by the endogenous Principal Investigators (PIs) listed (Kosik) 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 Program Director Dr. Clegg who is Chair of Molecular, Cellular, and Developmental Biology (MCDB), and Director of the CIRM-funded hESC training program at UCSB. Dr. Clegg is a senior PI with an interest in the role of the extracellular matrix, including integrins, in the context of eye/retinal development. He is quite productive, yet currently has no publications in the hESC field and seems without current NIH funding. Moreover, while at least 9 of the 25 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. A notable recent addition is Dr. James Thomson of the University of Wisconsin, an adjunct professor from WiCell and first to grow human ESCs, who has been recruited to establish a satellite lab at UCSB.
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 at UCSB 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. Within this group, novel investigations center around the directed differentiation of hESC into retinal pigment cells for potential therapies of retinal diseases. Particular strengths of the current and prospective human stem cell users lie in this expertise in ocular disease and the initiation of hESC projects relevant to therapy. A special advantage at UCSB 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, Dr. Thomson brings wide ranging expertise directly relevant to research groups interested in ES cell growth and differentiation and to bioengineers. A Regenerative Medicine group with strong ties to the basic sciences may be ready to lead the nation in using hESC to treat retinal diseases. The users are highly productive, with notable contributions in their respective fields, and are well funded from major granting institutions. A core of 6 PIs has ongoing projects with hESC, but the majority have only recently committed to stem cell research projects. Dr. Thomson will join the California NanoSystems Institute as an Adjunct Professor at UCSB with a satellite lab and will provide a strong research presence of 5-8 researchers and an unparalleled resource for collaboration. Dr. Thomson has identified several areas of collaboration with demonstrated feasibility. In fact, the impact of the facility could have benefited from more direct input from Dr. Thomson and his staff who themselves will not be directly involved in the facility (e.g. training). 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 for the central coast area, the institutions listed such as Cal Poly and the Santa Barbara Cottage Hospital are primarily teaching institutions; a branch of the Burnham at Santa Barbara will also use the facility. Further, the applicants propose a number of non-approved lines including Harvard lines and a line from Prime Gen Inc. No clear argument is made for the need of non-approved lines, and it is unclear whether the Prime Gen Inc line is indeed a bona fide hESC line or a more restricted neural / eye derivative or rather a 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 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, 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 scopes. The designated area is distinct from NIH-funded research space.
QUALITY OF MANAGEMENT PLAN: The application has been quite carefully planned 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, NMR, 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 Program Director and key personnel have proven excellence in management - the director is chair of MCDB, the leader in stem cell efforts at UCSB, and brings certainty to commitments made by that department. The lab manager, while rather junior, has excellent training through a course at Stanford and work with Dr. Evan Snyder’s group, and experience managing the current stem cell lab. Here as before the proposal could have benefited from the stronger participation of Dr. Thomson’s group by involving some of his staff more directly in the facility. The oversight committee is well constituted, with the Program Director and two Co-directors (who established the current small hESC lab on campus), the Director of the neighboring Sansum Diabetes 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 Dr. Thomson 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 UCSB 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 ESCRO and the 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: Dr. L. Jananovic, adjunct Professor and Director of the Sansum Diabetes Research Institute has a collaboration with Dr. Clegg, and Dr. A. Zauner at the Santa Barbara Cottage Hospital plans collaborative work with Professor Kosik. Clear UCSB support 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 Dr. Thomson at the California NanoSystems Institute, 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, but not yet outstanding, nascent stem cell group; 4) there is a very good biotech and biomaterials core available, and there appears to be a remarkable spirit of collaboration especially with the Institute of Collaborative Biotechnology at UCSB. 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 UCSB has a CIRM training grant. 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 UCSB is the interaction between the ocular disease group and a biotechnology company (Advanced Cell Technology). 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 Dr. Thompson. The letter from Thompson describes the establishment of a satellite lab at UCSB and 4 collaborations, 3 of which have been initiated (including 1 with the PD) and 1 of which is to be initiated. Dr. Thompson offers experience in growing cells in serum-free, feeder-free conditions. How Dr. Thompson will work out the situation with a satellite lab is unclear, but he suggests that 5-8 people will be working on-site at UCSB. It was noted that Dr. Thompson will provide advice and consultation but there was no percent effort commitment nor any indication of how much time 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.