Human embryonic stem cell (hESC) research promises to be of fundamental importance in the study and treatment of various human diseases, including cancer, neurodegenerative disorders and organ failure. In recent years we have made great strides in advancing hESC research as documented by the large number of successful, high-impact laboratories and breadth of research projects here. In addition, we are situated among several other first-rate institutions, all of which have joined in an unparalleled research environment for hESC research.
Since the creation of the California Institute for Regenerative Medicine, we have devoted both space and financial resources to promote hESC research. Our institutional commitment has as a cornerstone the creation of a core facility for hESC research to foster and promote hESC research at this and surrounding institutions. To date the facility has served to (1) train scientists in the basic methodologies to conduct hESC research (2) facilitate hESC research for many investigators, both established and beginning scientists, and (3) provide a “safe haven” that is sheltered from any federal funding sources thus allowing unimpeded hESC research. However, due to the high demand on space, equipment and technologies, the present facilities are insufficient to sustain the ongoing and proposed research projects.
We therefore request funding from CIRM to expand this facility and enhance its scientific output and creativity. In addition to providing expanded adequate facilities for our many scientists and clinicians embarking on hESC research, our major scientific goals for the shared research laboratory are (1) the development of protocols for the generation of genetically marked HESC lines, (2) the improvement of protocols for derivation of mature cell types, with an emphasis on neural differentiation, and (3) the development of novel surfaces and materials for the large scale growth and production of hESCs. These goals synergize the expertise of several departments, including the departments of Bioengineering, Materials Science, Biological Sciences, Pharmaceutical Sciences and the School of Medicine.
The support provided by this shared research grant will allow our institution to enhance our interdisciplinary stem cell program so that we may accelerate our goals of improving health and conquering diseases through regenerative medicine.
Human embryonic stem cells (hESC) provide the “raw material” that can potentially provide mature cell types for developing new disease therapies. Understanding how to control the growth and differentiation of hESCs, however, requires extensive research. Unfortunately, federal restrictions limit progress.
In 2005, our institution established a shared research laboratory which has provided essential training and has made space and technologies available to conduct hESC research without federal restrictions. However, the needs of researchers are beginning to exceed our limited resources. CIRM funding will allow expansion of the existing facility and the development of key technologies essential to ongoing and proposed projects at this and other institutions throughout California.
The proposed expansion includes creation of a satellite with emphasis on bioengineering technologies needed to develop therapeutic delivery vehicles and grow tissue engineered implants from hESC-derived cells. This satellite will leverage our international leadership in cell and tissue engineering and significant experience in translational research and technology transfer. The unique strength of interdisciplinary partnerships will accelerate translation of new scientific discoveries to clinical practice and new therapeutic agents that will benefit California’s healthcare system and global competitiveness.
CIRM funding will be enhanced by the investment already made by our institution in hESC research. The proposal integrates scientific need with the proposed expansion in cell biology and engineering abilities. Our request comes in direct response to needs of productive, experienced researchers in a context where professors, doctors, ethicists, social and political scientists can contribute to advancements in service of human health. Our context provides the teaching environment that will help engage California’s best young minds, and impart the latest discoveries to our students.
SYNOPSIS OF PROPOSAL: This application proposes to build on an existing core facility at UCSD, established in 2005 with private funding. Demand for this facility has outgrown the current space and funding, hence this proposal. This includes the development of a satellite facility at UCSD’s engineering school to design and test new approaches and technologies for manipulating human embryonic stem cells (hESCs). There are four scientific objectives for this proposed facility. The first is the development of methods for efficient gene modification of hESCs. The second is the improvement of differentiation methods. The third objective is the establishment of culture systems for large-scale expansion of hESCs. The fourth is to design and synthesize novel materials for the growth, differentiation, and characterization and delivery of hESCs.
QUALITY AND IMPACT OF THE SCIENCE: This is an outstanding proposal. It addresses critical components of propagating hESCs and developing optimal implementation procedures. According to one reviewer, there is no doubt that genetic engineering will become a key aspect of acquiring the best cell types. Also, large scale culture systems are of pivotal importance for therapeutic implementation. This reviewer is particularly impressed with the proposed inter-disciplinary scientific approach of working with experts in nanotechnology and biomaterials to test novel encapsulation procedures as well as matrix/growth substrate development. This comprises true “cell engineering” and this is what the scientific community needs.
The program director, Dr. Willert, is an assistant professor who was hired as an assistant adjunct professor in 2005. The facility will participate in the San Diego Consortium for Regenerative Medicine. According to one reviewer, there is no question that this facility will serve some of the best scientists in the world. The San Diego Consortium alone can boast of being approved for nearly 20 CIRM SEED awards. However, it was not clear to this reviewer how many of the investigators will rely on this particular facility for hESC culture and the extent to which this facility will be crucial for their work.
APPROPRIATENESS OF SPACE AND EQUIPMENT TO SCOPE OF PLAN: The institution’s current stem cell core facility located in the School of Medicine consists of 2,211 square feet of lab space. An additional 12,000 square feet has been allocated for active and future faculty recruitments in hESC research. Researchers at UCSD were recently approved for 6 CIRM SEED awards, placing a greater demand on the core facility. The School of Engineering has allocated an additional 3,950 square feet for a satellite facility. This proposal requests funds for the renovation of these two spaces and additional equipment to meet increased demand due to funded and pilot projects. Toward the goal of developing methods for genetic manipulation, particularly homologous recombination of hESCs, funds are requested for the following equipment: a FACS Aria machine, confocal microscope, electrophysiology unit, centrifuges, biosafety cabinets, Amaxa Nucleofector electroporator, and a computer network and server. Additional equipment for the satellite lab and the engineering school includes a live cell imaging and purification system, a Fourier Transform Infrared spectrometer, GPC light scattering detector, microarray spotter, and polymer encapsulator.
In general, the reviewers agree that the space and equipment are appropriate to the scope of the plan, although sufficient details were not provided in the application for some of the equipment (e.g. the "polymer encapsulator”).
QUALITY OF MANAGEMENT PLAN: Reviewers agree that the management plan is excellent. The proposed scientific direction and staff for this facility are excellent and will draw primarily on the current staff of the core facility, including Dr. Karl Willert as Program Director, who has been in charge of the UCSD core facility since its inception in 2005. One reviewer points out that Dr. Willert is not highly experienced in hESC research or in management of a major facility, being just a few years out of his postdoctoral fellowship, although with industry experience. Oversight for the core facility will be conducted by an inter-departmental steering committee, overseeing the strategy, budget and management of the shared laboratory. UCSD has demonstrated its commitment to hESC research since its establishment of a non-federal core facility in 2005, and has since maintained and characterized several stem cell lines successfully.
DISCUSSION: This is an outstanding proposal from a program director who is promising, energetic, and fairly junior. This proposal differs from others in the proposed interdisciplinary studies with engineers who are expert in nanotechnology and biomaterials; this could be key for developing encapsulation technologies which may be important for successful cell transplantation. The proposal for large scale culture systems is also regarded by a reviewer as a very useful component of the shared facility. This Shared Research Laboratory clearly will be useful as core facility and the institution has already put a great deal of effort into developing hESC research. There is no overlap with other institutions in the San Diego consortium. The likelihood of success is good because the management has been running a hESC core since 2005. A reviewer points out that the program director is only 4-5 yrs out of his PhD training and therefore this director does not have the ‘gravitas’ that other facility center heads do; this reviewer would have preferred more a more senior investigator to direct the facility. While another reviewer agrees, s/he points out that this program director is likely to be dedicated to the success of the Shared Research Laboratory whereas more senior scientists are less accessible, so the program director’s career stage also could be considered an advantage.