To realize the potential of human embryonic stem cells (hESC) in research and medicine, it is essential to disseminate state of the art technology in this field to the scientific community at large. The Shared Research Laboratory (SRL) of the Center for Stem Cell and Regenerative Medicine (CSCRM) at the University of Southern California will aim to provide a comprehensive support service for hESC researchers at our University and at neighboring institutions. The mission of the SRL will include the following goals: 1) to supply scientists with quality controlled stem cell lines for use in their research, including cell lines that are not eligible for use in NIH-funded projects; 2) to provide space and equipment for scientists new to the field to carry out pilot projects, in order to help them to integrate the hESC platform technology into their own research programs; 3) to develop and validate new and improved methods for growing hESC in the laboratory; 4) to operate a formal practical course in hESC laboratory techniques to scientists from throughout the region.
The facility will be situated in the new Harlyne Norris Cancer Center tower on the USC medical school campus. The laboratory will have sufficient work stations to support training, collaborative projects, and research and development programs for evaluation of new stem cell culture techniques, and it will be equipped with specialized instruments required to monitor stem cells. The operation of the facility will be overseen by the Program Director and the Manager of the CSCRM Core Facility. Advice on access and management will be provided by a subgroup of the CSCRM Stem Cell Advisory Group comprising stem cell researchers from USC, Children’s Hospital of Los Angeles, and California Institute of Technology.
The SRL will support the work of CSCRM scientists and their colleagues at neighboring institutions involved in basic research on hESC, including international collaborations on standards for this research. The facility will also enable many groups involved in translational work at the USC medical school to gain experience and training in the use of hESC in their work in areas such as neurology, liver disease, cardiology, and ophthalmology. These scientists will be able to conduct preliminary studies in the facility under the guidance of experienced staff.
The SRL will offer a 5-day course on Current Protocols in Human Embryonic Stem Cell Research, to provide a comprehensive practical training for investigators wishing to use hESC lines in their research programs. Laboratory instruction will include demonstration of the most commonly used methods for cultivating hESC, methodology for assessing the purity and quality of hESC cultures, and methods for converting hESC into specific cell types such as nerve or blood cells. The training course will be available to scientists from institutions throughout the Los Angeles area and will be held 3-4 times per year.
The California Institute of Regenerative Medicine has as its goal the development of stem cell and related research for the treatment of disease. Human embryonic stem cells (hESC) could provide an indefinitely renewable source of any type of healthy human cell for use in research and therapy, and are therefore the focus of widespread scientific excitement. However, because the development of hESC technology is still at an early phase, significant technical barriers exist for new workers entering the field. The proposed Shared Research Laboratory (SRL) in the Center for Stem Cell and Regenerative Medicine (CSRCM) at the University of Southern California will act as a hub for dissemination of state-of-the-art technology in hESC research throughout the region. By training students and established investigators in the practical skills required for hESC use, and by providing shared space for pilot and collaborative projects, the SRL will vastly accelerate stem cell research in Southern California. The SRL will also carry out research and development aimed at evaluating new technologies for hESC research, and will incorporate new discoveries by participanting scientists into validated protocols for maintenance and differentiation of hESC. This role, which will include participation in international collaborative efforts for assessment of hESC methodology, will ensure that the SRL scientists benefit from the most recent advances in hESC research, and that their own discoveries are integrated into best practice for hESC research globally. California, and the greater Los Angeles area, will thus become an international focal point for hESC research. As workers involved in translational and clinical research learn to apply hESC in their studies, basic discoveries in stem cell biology by SRL trained researchers will move towards clinical application. The availability of the SRL will also provide a needed boost to the development of biotechnology in the Los Angeles area.
SYNOPSIS OF PROPOSAL: This application proposes a Shared Research Laboratory (SRL) with the goals of maintaining stocks of quality-controlled human embryonic stem cell (hESC) lines (including non-federally approved lines) for researchers, providing needed space to investigators at the host and neighboring institutions, and training researchers in the practical aspects of hESC culture. The proposed space includes six cell culture workstations and a request for major equipment to extend existing capabilities of the center's core facilities such as a flow cytometer, a spectral karyotyping workstation, fluorescence and confocal microscopes, and a Cellomics high content cell imaging system. The oversight committee will include representatives from the host institution as well as neighboring institutions. The SRL will also offer a 5-day course on Current Protocols in Human Embryonic Stem Cell Research 3-4 times per year.
QUALITY AND IMPACT OF THE SCIENCE: A core of 3 researchers (Pera, Ying, & Kahn) study key elements of hESC biology, including maintenance of pluripotency, growth, differentiation and signaling, that directly relate to improvements in understanding hESC technology. Dr. Pera studies renewal and differentiation and is funded by the International Stem Cell Initiative to evaluate new defined culture systems for growth and assess genetic stability. Equipment requested in this proposal will support these efforts. Description of the research base at the institution was brief, and the current and expected use by individual PIs is vague. Despite this, it is clear that the research PIs represent a broad range of stem cell interests, have excellent funding from major granting agencies, and address important questions regarding hESC biology, technology, and applications to disease therapy. Four investigators approved for CIRM SEED grants are members of the user group. Several groups with strong research efforts on adult stem cells (neural, cardiomyocyte, oral, epidermal, hematopoietic) add to the general expertise of the stem cell community, and most have plans to transition to related projects using hESCs through the Shared Lab. A particular strength is the proposed R&D by the lab to automate the evaluation and validation of new protocols and assays, marker assessments, and karyotype maintenance for QC, and justifies the acquisition of major equipment.
APPROPRIATENESS OF SPACE AND EQUIPMENT TO SCOPE OF PLAN: The SRL is needed to increase the insufficient space currently available for hESC work and to stimulate prospective hESC researchers by providing access to equipment, space and expertise for initiating pilot projects and gaining necessary training and experience for major new research projects. The current and likely future needs for USC and neighboring institutions require an increase in space of this magnitude. However, the need for NIH-free space based on the amount of work with non-NIH registry lines is not specifically justified. The program director, recently recruited from the stem cell group at Monash, is a leader in hESC methods, standards and policy. A total of 5 technical staff should ensure sufficient personnel for lab and equipment maintenance, training, routine culture and maintenance of hESCs, and hands-on direction of lab users. Ample space and equipment are earmarked for the SRL services including the training course, area for collaborative interactions with 6 workstations, and R&D by lab staff; production of cells and QC will be performed in a currently operating, small stem-cell lab. The needs of the host and neighbor institutions will be met by vastly increasing the work space and equipment for hESC work that is currently out of bounds for many researchers at USC and neighboring institutions. The NIH-free space currently available is small and not accessible to all researchers at USC or at neighboring institutions.
QUALITY OF MANAGEMENT PLAN: Overall, the plan to support, manage and maintain the SRL and equipment are adequate. One reviewer felt that the key personnel are particularly outstanding. Each has critical expertise in their major duties and responsibilities. The Director is an international leader in the field and has nearly 2 decades of experience in the derivation and analysis of human stem cell lines with a keen interest in improving hESC lines and technology. The Lab Manager has a MS in Biotechnology, 15 yrs experience with mouse ESC and 4 yrs with hESCs, and extensive experience in training, including co-instructor for two NIH hESC courses that produced one of the first hESC lab manuals. The technical staff have dazzling expertise and productivity including authorships on major hESC publications. USC has a successful track record for effective multi-user core facilities that span up to 20 yrs of service or more. Members of the oversight committee are included in the list of PIs, although most appear not to be users. Access will be enhanced by providing a single, identifiable location for the Shared Lab. Access by researchers from neighboring institutions will be encouraged by including members of neighboring institutions on the oversight committee. Guidelines and specific protocols to gain access, to acquire and certify competence and to verify SCRO, biosafety, and IRB compliance were not provided. Though not proposed, using the lab’s website for applications to use the facility would be a useful way to simplify the application process and coincidently ensure compliance by requiring specific information and uploading documentation of necessary administrative approvals. Institutional support for the SRL is part of a $10M commitment of startup funds for the Center for Stem Cell & Regenerative Medicine to establish high quality hESC research at the USC Keck School of Medicine Medical School. In addition, ample space central to stem cell investigators on the USC Medical School campus is being provided.
DISCUSSION: One reviewer lacked enthusiasm for this proposal which in his/her view is vaguely written and it is not clear what studies investigators will perform in the shared lab space. The plan to expand from 250 sq. ft to 1000 sq. ft. is not well-described. The program director is well-known and very experienced with hESCs. A "laundry list" of potential users is presented that the director proposes to recruit but there was no discussion regarding administrative oversight or organization. Despite these criticisms, the reviewer felt that a true spirit of sharing and collaboration came through in this proposal. Another reviewer felt that the core management team (director, lab manager, and technicians) have experience that is good or better than most other applications. The program director aims to be a world-leader by creating this strong core facility. There is a large list of people, but 7 are currently using hESCs making this a pretty strong group. USC has a training grant from CIRM and has been approved to receive 4 SEED grants. They propose to maintain hESC stocks and get other people to make use of the facility. Clearly this will be a true “shared” facility making hESCs available with quality control and routine analysis and maintenance. The management plan was lacking, but the application hits the spirit of the RFA quite well. A third reviewer felt that although the science presented is not particularly exciting, it is solid. It is broad-based and what a core lab should be. Overall, it is very appropriate.
PROGRAMMATIC REVIEW: A motion was made to recommend this Shared Research Laboratory application for funding. It was noted that the institution is committed to building new space and to recruitment of new scientists. The application itself was not well written, but the reviewers felt the proposal had the necessary strengths and merited funding. A question was raised as to whether conditions for funding should be indicated, but the reviewers found no real deficiencies in the proposal. The core lab proposal is good, it will be a true shared lab, and the key personnel are outstanding. There is a need at USC with 4 approved SEED grantees and a CIRM training program. The motion to recommend this Shared Research Laboratory application for funding passed.
QUALITY OF THE PROPOSED TECHNIQUES COURSE: The Shared Research Lab will offer a course on Current Protocols in Human Embryonic Stem Cell Research to provide comprehensive practical training for hESC investigations. The course will be run by the program director and the lab manager, with assistance from 5 scientists with hESC experience from neighboring institutions, and several technical staff from the lab personnel. The quality of the lecture topics and the nature of the practical information appear to be excellent. The short 5-day duration of the course with only afternoons available for laboratory work may allow a brief introduction and mostly observation, but is unlikely to impart much technical skill. That would require more hands-on experience with one-on-one tutoring. The qualifications of the instructors are remarkable; the combined experience and awareness of up-to-date protocols may be unmatched. Technical assistance will be provided by research associates with extensive experience in major hESC-labs with major contributions to stem cell technology. Instructors are recruited from neighboring institutions. A particular enhancement is the participation of Dr. Carolyn Lutzko from Children’s Hospital of LA, who together with the Lab Manager has run a practical course in hESC culture methods for 2 years and Dr. Loring from the Burnham Institute who has instructed in a training course for the past 3 years. An insightful plan to involve course personnel in an annual one-day meeting for the general public on the science, ethics and politics of stem cell research can be expected to be an important benefit to the community. The plan for advertising will appropriately use the proposed SRL website run by the lab manager as well as the website of the International Society of Stem Cell Research, and circulating prospectuses to the major research institutions in the LA area, which are expected to be the predominant users.
QUALIFICATIONS OF THE INSTITUTION: No information is presented directly regarding the qualifications of the institution. However, the teaching excellence of USC and the Medical School, coupled with the recruitment of instructors with extensive experience in conducting just this kind of laboratory-based instruction for stem cells indicate that the course should be effective, rigorous and well-received.
DISCUSSION: The applicants propose a well-rounded, current protocols course. The applicants will recruit instructors from neighboring institutions and the lab manager has previously helped teach a course at CHLA. They have a large amount of material for this 5-day course but the course offers nothing particularly novel. The course is mostly didactic with only the afternoons available for hands on training and therefore will not impart much technical expertise to trainees. The technical experience will need to come from one-on-one tutoring. CHLA has produced a handbook that the course co-director will make available here. 1000 sq.ft is proposed for the course, which seems small but perhaps they have other space available.
PROGRAMMATIC REVIEW: A motion was made to recommend this Techniques Course application for funding. A weakness was noted that the courses proposed are short, although the qualifications of the investigators are good, and include translational research. The motion to recommend this Techniques Course application for funding passed.