Investigators from three major regional research and clinical institutions have instituted a stem cell research center. Numerous collaborations among our community of investigators have successfully utilized both Federal registry and non-registry human embryonic stem cell (hESC) lines in the center; however, the available resources for the culture and maintenance of these lines place inherent limitations on the research. We therefore propose to establish a Human Embryonic Stem Cell (hESC) Shared Research Laboratory for cell culture and investigation, which will serve as a central resource to greatly enhance stem cell science and technology in the region.
This resource will greatly benefit numerous ongoing research project areas. First, the ability of human embryonic stem cells to self-renew, that is grow and maintain their ability to differentiate into presumably every cell type in the adult body, is a hallmark property this is incompletely understood. Investigations of self-renewal mechanisms will lead to improved approaches to mass produce these cells for numerous therapeutic and diagnostic applications. In addition, understanding how hESCs differentiate into blood cells will enhance the treatment of numerous disorders including cancer, diabetes, and infectious disease. Moreover, studying how hESCs differentiate into numerous types of neurons will have implications for neurodegenerative disorders, including Parkinson’s Disease and Lou Gehrig’s Disease. Furthermore, regenerative medicine efforts to engineer new cardiomyocytes and blood vessels will improve the treatment of heart disease and congestive heart failure, still the leading loss of life in the United States. Importantly, the ability to control and harness hESCs as a limitless source of differentiated blood cells, neurons, cardiomyocytes, and other cell types will also greatly enhance high throughput drug screening, toxicology screens, and diagnostics efforts. Finally, novel bioengineering approaches to create robust and scaleable technology platforms for expanding, differentiating, and grafting hESCs will benefit all such therapeutic and diagnostic applications.
The Shared Research Laboratory will be located in two nearby sites on the host institution, within a new building and a modern biological sciences building, to provide convenient access to all researchers on campus and in the surrounding community. The Laboratory will provide a central repository and resource for culture and maintenance of numerous lines, and imaging and cytometry analysis. The Laboratory will also build upon our strong tradition of and success with shared core facilities to synergistically enhance our stem cell research capabilities. The resulting culture and analytical facility will thus provide a strong, shared resource to benefit stem cell research in the regional community.
Our Human Embryonic Stem Cell (hESC) Shared Research Laboratory will strongly enhance the scientific, technological, and economic development of California. The most important net benefit will be to human health.
The Laboratory will meld three outstanding research institutions: a university with a history of major contributions to the scientific knowledge and technological capabilities of the State, a research institution that bridges basic science with clinical translation, and a national laboratory with leading research in genomics and cancer biology. This collective expertise is poised to make major advances in stem cell biology and engineering, which will be greatly stimulated by the establishment of a collaborative laboratory for hESC research.
Our proposed Laboratory includes leaders in cell biology, developmental biology, immunology, neuroscience, and bioengineering. This expertise is being applied to understand mechanisms that control hESC self-renewal and differentiation, and the resulting advances will help establish California as a leader in stem cell biology. Furthermore, our team has leaders in regenerative medicine and bioengineering who apply basic biological information to create technology platforms for expanding, differentiating, and grafting hESCs for therapeutic and diagnostic applications. Collectively, this work will impact the treatment of cancer, autoimmune disease, infectious disease, heart disease, and neurodegenerative disorders.
Furthermore, we have a long and successful tradition of translating science into practice through interactions with industry and the clinic. Continuing this history in the area of stem cells will enhance the technological strength and economic development of the State. Finally, this Laboratory will provide a collaborative training environment that will expose many students and fellows to leading, interdisciplinary science and technology, thereby creating valuable future employees of California.
SYNOPSIS OF PROPOSAL: The applicants request support to establish a shared research laboratory for stem cell culture and analysis at Berkeley. Other neighboring users of the facility are anticipated to include the Children's Hospital Oakland Research Institute (CHORI) and the Lawrence Berkeley National Lab (LBNL). No Stem Cell Techniques Course is proposed.
QUALITY AND IMPACT OF THE SCIENCE: Although some weaknesses are noted, this is a strong application from UC Berkeley. The quality of the proposed science is outstanding and the potential for clinical and translational impact is excellent. The research base spans a broad range of scientific questions pertinent to hESC biology and technology. Four areas of research of exceptional quality by focus groups in the Center are deemed exceedingly relevant. They are: 1) mechanisms of hESC self renewal, 2) hematopoietic development and differentiation, 3) neural development and differentiation and 4) cardiovascular and muscle tissue engineering. The bulk of the work proposed will involve hESCs although some experiments with neural stem cells are proposed. A major strength of the application is the roster of accomplished potential users from the faculty of UC Berkeley. Additional potential users from the Children's Hospital Oakland Research Institute (CHORI) and the Lawrence Berkeley National Lab (LBNL) bring added value to the proposed shared laboratory on the Berkeley campus. These strengths are undercut to a certain degree by the appearance that some of the proposed work from well regarded, “blue chip” investigators at Berkeley would not seem to require access to unregistered hESC lines. Indeed some of the proposed work might proceed more expeditiously with well characterized registered lines or with genetically accessible murine models. There are some additional 1) concerns over the space and equipment plan (see below) and 2) the depth of commitment from LBNL to hESC research (see below).
The research contingent comprises 30 investigators, 9 of whom are currently working with hESCs. The UC Berkeley investigators are outstanding and highly productive, with strong and longstanding contributions to their fields; many have begun projects with hESCs. CHORI members also are productive, with major expertise in human cord blood stem cells, although only 3 of the 7 list major grants and none have published in the field of hESCs. Dr. Kuypers conducts an NIH-funded multi-center clinical trial to investigate cord cells as a source of therapeutic cells for hematopoietic disorders. Two are prominent experts in genomics (de Jong) and epigenetics (Martin). Major roles appear collaborative or with hESC projects in the planning stage. The two members from LBNL are very productive in areas relevant to stem cell self-renewal and gene control: chromatin function and cell growth control. Neither has published on stem cells and their roles are likely collaborative or advisory. The research and experimental goals are highly relevant to progress in the hESC field.
APPROPRIATENESS OF SPACE AND EQUIPMENT TO SCOPE OF PLAN: There is some space already available for non-registered stem cell lines in the Life Science Addition (LSA) Building at Berkeley but the applicant states that it is quite small with only a single 4' culture hood. Anticipated expansion of stem cell research at Berkeley and surrounding institutions demands an expansion of existing capabilities. Towards this end, a second small room in the LSA building will be equipped with a 6' hood and two incubators. Moreover, a second area for stem cell research consisting of ~700 square feet will be created in the new Stanley Bioscience Bldg that will open in April of 2007. The plans to split the shared laboratory into two separate buildings seems suboptimal. Although the two buildings are stated to be only a 10 minute walk from each other, there will be significant economies of scale lost in this arrangement with respect to salaries, equipment and ongoing supply purchases.
The user group maintains 16 hESC lines; 12 are not in the NIH registry and more are anticipated. Thus, there is a sincere need for well-equipped, NIH-free lab space. Particularly intense need for cells and lab use is expected by the neuroscience group and the bioengineers. The hematopoiesis group particularly requires intensive flow cytometry, cell sorting and imaging. The size of the 2 laboratories is appropriate for the likely number of users and services. Three cell culture hoods are expected to fill the anticipated needs of the initial community, and space for 2 more is present. In lieu of estimates for the number of researchers using each lab and the number of service-events such as providing cell cultures, it is hard to assess personnel needs. However, it seems improbable that one worker will be able manage both labs effectively. The needs of the host institution will be well served by improved access to hESCs, to NIH-free space, and to necessary imaging equipment and flow cytometry services and equipment. Ensuring access with two separate labs for hESC work is particularly appealing. Because the needs of neighbor institutions for hESC work is not clear, it is difficult to judge whether those needs will be met. Most hESC work by CHORI is in the planning stage. But access to the Shared Lab will help ensure those plans progress to funded studies, since the major hurdle to beginning can be an effective facility. Current NIH-free space is extremely limited.
QUALITY OF MANAGEMENT PLAN: Dr. David Schaffer is a strong researcher in biomedical engineering and an excellent choice for director with a vested interested in hESC bioengineering that should help ensure success. He is an Associate Professor of Chemical Engineering who will devote 11% effort to the affairs of the shared laboratory and seems well qualified for the task. There is a thorough plan to manage the Shared Lab, including verification of protocol approvals, sharing culture and imaging time, access to flow cytometry and yearly renewal of access privileges. The Lab will be maintained by two high level staff research associates to be hired at the commencement of funding. One will manage all aspects of both lab sites. The number and the intensive nature of some responsibilities will tax the ability of one person divided between two locations, and a more realistic plan should be considered. The second will be responsible for the new FACS and the user-operated flow cytometer. Incorporating this into the existing Flow Cytometry Facility and oversight by Dr. Winoto is a strength. Dr. Susan Fisher, current Director of the hESC Program at UCSF, will help with the derivation of novel hESC lines and make their training curriculum accessible to UCB researchers should CIRM fund their Stem Cell Technique Course. An Oversight Committee with appropriate representative membership has been established that will codify procedures for access permission, protocol approval, including those for investigators from CHORI and LBNL.
It is anticipated that non-campus users of the facility will be mainly from CHORI and from LBNL. The CHORI has its own Stem Cell Research Oversight (SCRO) committee and plans are being implemented that will allow the UC Berkeley SCRO to accept the review and approval of the SCRO from their Oakland-based colleagues. Interestingly enough, the LBNL does not have its own SCRO and has no plans to convene one in the foreseeable future. Potential users from LBNL will be able to access the shared laboratory facility but they will have to do so via formal collaborations with Berkeley or CHORI investigators. Depending on traffic conditions, the LBNL is a 60-90 minute drive from the Berkeley campus. This torturous commute combined with (what might be perceived as) an administrative lack of commitment to stem cell research raises some doubts as to the degree of usage that the shared laboratory will receive from LBNL faculty.
An Oversight Committee with appropriate representative membership has been established that will codify procedures for access permission and protocol approval, including those for investigators from CHORI and LBNL. The Committee includes the directors of the successful campus sequencing and flow cytometry facilities, and this should help ensure proper management oversight. The plan to hire the staff research associates includes reasonable criteria for expertise in relevant areas, evaluation of candidates by the Oversight Committee, and hiring in consultation with the Director. There is strong institutional support for hESC research at UC Berkeley and cord-blood stem cell research at CHORI. UCB has made extensive and unambiguous commitments to help support a Shared Research Lab, including laboratory space at two locations to facilitate access by researchers across the UCB campus, parking permits for members from CHORI and LBNL, matching funds for equipment and renovation, and business administrative support. These guarantees come from the Director of the Berkeley Stem Cell Center, the UCB Chancellor, and the Vice Chancellor for Research. One concern is the amount of matching funds available for equipment; although the total cost is estimated at $1.2 million, only $0.2 million appears committed. There is ample precedent at UCB for acquiring next-generation funding to maintain state-of-the-art shared facilities at peak effectiveness for the long term, and so the likelihood of continuing a valuable Shared Lab after an initial round of CIRM funding is high.
DISCUSSION: This is the flagship campus of the University of California and includes a “blue chip” list of about 30 well regarded faculty. The application is of high quality as are the users. The PD has an interesting background as a chemical engineer. The science proposed is also very interesting in focusing on synthetic extracellular matrices; the faculty claim broad expertise in basic stem cell biology, neural, and muscle development and engineering. One of the reviewers expressed concern that only 9 out of 30 members are current users of hESC technology. The other users listed seem “decorative”. Another reviewer agrees that the research base is excellent, and feels that 9/30 people using hESC is a high proportion. The fact that Dr. Tjian is already involved in hESC analysis studying pluripotency issues, raised enthusiasm. His participation is seen as an important leadership contribution. A third reviewer agrees with the previous reviewers, finds the work on synthetic niches for hESCs to be very innovative and considers the bioengineering aspect of the application to be a great addition. Berkeley has strength in chemistry, therefore designing synthetic surfaces is an important contribution and increases enthusiasm.
The Shared Research Laboratory will be situated in two locations which are about 10 minutes apart. One reviewer was concerned about the consequent loss of economies-of-scale that would be imparted by a single shared resource. A second reviewer is intrigued by the establishment of 2 laboratories to distribute the shared resource to the campus research community, but felt that there was a problem with staffing in that only one technician is proposed to oversee management while a second technician is responsible for cell sorting.
CHORI and LBNL are listed as the neighboring institutions that may use the facilities. LBNL is included almost exclusively as an adviser on chromatin changes during differentiation. The CHORI group drew some concerns because this institution has a clear interest in cord blood and it is unclear if their investigators will make the transition to studying hESCs. One panel member commented that the criticism against people without hESC experience is unreasonable because CIRM wants to attract people into this field. The level of commitment of UC Berkeley to stem cell research was unfavorably compared to that of other leading institutions in California.
PROGRAMMATIC REVIEW: A motion was made to recommend this Shared Research Laboratory application for funding and the motion passed.