Overview
The Laboratory
The Cooperative Agreement between the University and the Department of Energy that funds the Laboratory is entering its final year of the current agreement period. This fifth year will continue the process of refocus and transformation of the Laboratory started four years ago. Renamed the UCLA-DOE Laboratory of Structural Biology and Molecular Medicine (LSBMM), the Laboratory has as its revised mission: (1) The partnering of structural and computation biology in the determination of folds for proteins in genomes, and the analysis of function and interactions from genome sequences. (2) The development of molecular nuclear medicine, including new diagnostic biological imaging procedures and their relationship to drug therapies to improve the quality of life.
LSBMM is one of several Organized Research Units (ORU's) on campus. The director reports to the provost of the School of Medicine, who in turn reports to the chancellor. The provost and chancellor play important strategic roles with respect to LSBMM programs.
The Nuclear Medicine (NM) Division of the Lab is headed by Associate Director Michael E. Phelps, who has been a leader in the development of biological imaging and in merging molecular biology and genetics with biomedical imaging. The NM Division is pioneering many aspects of molecular nuclear medicine by continuing to incorporate an increasing number of goals and principles of molecular and medical pharmacology into molecular medicine.
The Structural Biology and Genetics Division (SBG) is headed by Associate Director David Eisenberg. He has recruited Principal Investigators for the new division and set up divisional core facilities. The Division is working at the interface of structural biology and genomics, as detailed in this report.
The general goals set by Drs. Eisenberg and Phelps for the Laboratory are to offer opportunities to DOE for advancing its research mission and to enhance the overall productivity and focus of the Laboratory. Specific goals set by the Director and Associate Directors for the present 5-year period of the Cooperative Agreement include the following:
- Establishment of the new Division of Structural Biology and Genetics, to advance the structural and function implications of DOE's human genome initiative. This new division is attacking the problem of sequence-structure-function relationships of proteins.
- To develop and advance molecular nuclear medicine, with special emphasis on the marriage of molecular biology with advanced imaging methods. These include miniaturization of PET technology for imaging genetically engineered rodents and the merger of PET and MRI into a single imaging technology. These latter activities are carried out in a partnership with the UCLA Crump Institute for Biological Imaging.
- To develop the means to image gene expression processes of transcription and translation in vivo, initially in mice and then in man.develop the means to image gene expression processes of transcription and translation in vivo, initially in mice and then in man.
- To relocate programs previously carried out at Warren Hall to the UCLA Core Campus, to give the UCLA-DOE Lab stronger interactions with the UCLA scientific and medical communities, and enhanced visibility.
- To establish interactions between the UCLA-DOE Lab and the National Laboratories, involving exchange of principal investigators and students, the sharing of facilities, the organization of workshops, and the development of computer networks. Towards this goal a joint workshop was held in April 1994 with LANL, and Dr. Terwilliger of LANL presented a series of lectures on the Bayesian Approach to Crystallography at UCLA. In another joint program, researchers at the UCLA-DOE Lab, LANL, and BNL are discussing the formation of a PRT to renovate beamline X-8C at NSLS.
- To establish outreach to the commercial community. The NM Division has been at the forefront of a campus initiative to engage industry by developing a fast, efficient contracting system, and several partnerships have resulted, including ones with both instrumentation companies (i.e. CTI, SIEMENS, ADAC, CONCORD, NEOPROBE) and pharmaceutical companies (i.e. AMGEN, DARWIN, MERCK, SYMATICS). The SBG Division has joint projects with several industries, including AMGEN, XOMA, and SCRIPTGEN. Joint seminars and workshops are held with structural biologists at AMGEN.
- To establish outreach to the educational community. The Lab has sponsored an internship program with the Los Angeles Science and Discovery Learning Center.
- To enhance human subject protection continues as a priority of the Division of Nuclear Medicine and the Lab. It is our objective that our laboratory's new procedures will become a model for other human research at UCLA.
Division Of Structural Biology And Genetics
The goal of the Division of Structural Biology and Genetics (SBG) is to determine protein (and RNA and DNA) structures by experimental and computational methods. Computational methods are in a period of rapid development, and the initial emphasis is being placed on improvement of algorithms for inverted and direct protein folding. Computational and data storage facilities will be updated. The new methods will be applied to predict structures for protein sequences determined in human genome projects. As protein prediction becomes more reliable and the methods developed, the associated databases and programs are shared with the com-munity of structural biologists and molecular geneticists, in part through workshops and symposia, and in part through the World Wide Web.
Because computational studies of biological structure flourish in a lab determining structures, and vice versa, it is important to foster and enlarge X-ray and NMR structural efforts of the Lab. Plans for the Division include enhanced ability to clone and express proteins, extension of robotic and other modern methods of crystal growth, expansion of the x-ray laboratory equipment, expansion and modernization of the NMR laboratory equipment, and development of a Core staff who can main-tain and customize instruments as required. Equipment for the study of proteins and protein folding in solution will be added.
The present three principal investigators in the SBG Division (James Bowie, Robert Clubb and David Eisenberg) will now be joined by Christopher Lee, coming to the Lab from Stanford University. At the moment, the Lab is recruiting for a fifth PI, and a sixth will be added in FY98. Recruitment of new principal investigators is proceeding in accordance with the recommendations of the External Advisory Committee: the goal is to enhance the capabilities of the Lab in computational genomics and in the study of molecular recognition.
Five Core Facilities have been created within the SBG Division. These are the Computer Core Facility, the Protein Expression Laboratory (under the direction of Dr. L. Jeanne Perry), the X-ray Core Facility, the NMR Core Facility, and the Biopolymer Core Facility.
The Web site of the SBG Division has been extensively upgraded, and opened to the community of structural biologists and functional genomicists. Automatic assignment of genome sequences to folds is now available via this site. Very recently a new database has been created to document and organize the functional interactions of proteins: the Database of Interacting Proteins. It is anticipated that this database will become a major resource for scientists analyzing genome sequences and functions.
Division of Nuclear Medicine
The Division of Nuclear Medicine is in the fourth year of efforts to merge modern biology, biotechnology, and advanced imaging technologies with drug design. The goal is to identify the original molecular errors of disease within cells, and design ways to correct these errors. This is a redefining approach to disease and to medicine. The Division is strengthening synergistically in partnership with the Department of Molecular and Medical Pharmacology, the Crump Institute for Biological Imaging, the Nuclear Medicine Clinic and the Ahmanson Biological Imaging Center. Central to this process has been the close association among the faculty of all the partnering departments andthe recruitment of bright young faculty who join the division as associate investigators. This year, a program in gene therapy has been initiated in the Department of Molecular & Medical Pharmacology, and we are looking for opportunities to integrate this program with the DOE Lab particularly in the merging of biological imaging with the DOE genome project (see paragraph three below).
Human subject protection continues to be a priority in the Division. Supplemental funds were recently requested to support the development of a human subject database that we hope will be a model for the entire University. The task force I appointed last year to review our internal procedures continues to regulate the departmental mechanism for review and subsequent submission to the various IRB's of human subject, animal research and medical radiation safety applications.
In this fiscal year, we are continuing the development of our project in imaging reporter gene expression in vivo headed by Dr. Harvey Herschman. The project is a synthesis of Dr. Herschman's molecular and cellular experience and Dr. Phelps' experience in chemistry and biological imaging. The result is an attempt to marry the technolgies of cell biology/molecular biology with biological imaging by PET. Scientists will be able to repeatedly image transplanted reporter genes, in real time, in the same individual! This technique for imaging gene expression within the living body will allow us to actually watch genes transcribe messages and translate those messages into specific proteins. This is only one way that the Division hopes to redefine the standard approach to disease and to medicine.
Bridging programs with clinical and basic science colleagues continues, as do the forging of new agreements with industry. For instance, this year the Division has been at the forefront of a campus initiative to engage industry by developing a fast, efficient university contracting system. Several partnerships have resulted, including agreements with CTI and Amgen that would have been impossible to negotiate only a year ago.
In summary, biology is merging with medicine in a way that will change medicine forever. As the resulting Molecular Medicine is formed, the DOE Laboratory is poised as one of its pioneers; an imaging partner offering a new vocabulary for medicine.
