As modern science continues to spawn ever more dramatic discoveries about human health, there is increased interest in translational medicine, the practice of translating laboratory discoveries into patient medications devices and therapies. At UCSF, this process is alive and growing.
UCSF, one of the nation’s leading centers of translational medicine, draws from a wide range of disciplines to apply its discoveries regarding the molecular, genetic and cellular underpinnings of cancer, cardiovascular disease, neurological and neurodegenerative diseases, immunological diseases, infectious diseases and myriad other conditions.
James Alex Heller, a research assistant in the Roy Lab, Paul Brakeman, MD, PhD, (seated at microscope) collaborator and Assistant Professor of Pediatrics, and Shuvo Roy, PhD, (far right) developer of the first implantable artificial kidney.
When the National Institutes of Health (NIH) awarded a five-year, $108 million grant to UCSF in 2006 – the second-largest NIH grant for translational work – the University established the Clinical and Translational Science Institute (CTSI), which works across all schools to facilitate and encourage translational work.
“We’re trying to bring more vigor, resources, infrastructure and teaching to people who want to do translational research,” says S. Claiborne Johnston, MD, PhD, associate vice chancellor of research and CTSI director.
This includes industry, and several innovative partnerships are already formed (see academic-industry partnerships). Among them is Pfizer Inc., which is collaborating with UCSF in a new project to accelerate the translation of biomedical research into effective, new medications and therapies for patients. For UCSF, this expansive agreement represents up to $85 million in research support and milestone payments over the next five years if the partnership leads to the development of significant, new therapies for diseases with a high, but so far unmet, medical need. The partnership was announced in November 2010.
The collaboration is designed to substantially reduce the time required to translate promising biomedical research into new medications and therapies – a process now estimated to take more than 15 years and $1 billion per drug.
Basic Science in Action
Among the many UCSF faculty conducting basic science research under the translational medicine umbrella are:
- Elizabeth Blackburn, PhD: A molecular biologist, Blackburn received the 2009 Nobel Prize in Physiology or Medicine for her co-discovery of an enzyme that plays a key role in normal cell function, as well as in cell aging and most cancers. The enzyme, called telomerase, produces tiny units of DNA that seal off the ends of chromosomes, which contain the body’s genes. The finding sparked a whole new field of inquiry into treatment of age-related diseases and cancer.
- Shuvo Roy, PhD, and Tejal Desai, PhD: Roy and Desai are investigators in development of a prototype model of the first implantable, artificial kidney, which one day could eliminate the need for dialysis. Device components include thousands of microscopic filters and a bioreactor to mimic the metabolic and water-balancing roles of a real kidney.
A nationwide team of engineers, biologists and physicians is collaborating on the project, with plans for the device to be ready for clinical trials by 2017. Desai's lab is applying the same technology to an implantable pancreas for type 1 diabetes patients.
Both Roy and Desai are scientists with the UCSF Department of Bioengineering and Therapeutic Sciences, a joint department in the schools of pharmacy and medicine.
- Kevan Shokat, PhD: Chair of the Department of Cellular and Molecular Pharmacology, Shokat studies critical enzymes known as kinases, which are central to the complex communication pathways in cells, but have been difficult to isolate and study. He developed a way to mutate kinases and then, out of a group of 500 kinases, shut down just one at a time. The approach generates new insight into each kinase’s role, and helps give drug developers the ability to precisely inactivate specific proteins, one of the core concepts of modern drug making. There is potential for the work to lead to new therapies for cancer, neurological disorders, autoimmune diseases and tissue rejection.
- James McKerrow, MD, PhD: A parasitic diseases expert, McKerrow puts the translational concept to work in tackling diseases of the developing world. He focuses on diseases caused by microscopic worms and other parasites that kill or disfigure millions of people in the tropics every year, but do not attract adequate investment by the pharmaceutical industry because of insufficient financial return. He is leading an unusual research and development effort within and outside UCSF to discover the parasites’ weaknesses, identify drugs to kill them and test the drugs in clinical trials. Utilizing nonprofit and philanthropic support, phase I clinical trials are underway to treat Chagas disease, the leading cause of heart disease in Latin America, and leishmaniasis, which has infected 12 million people worldwide and causes disabling lesions.
- Charles Craik, PhD: A professor in the schools of pharmacy and medicine, Craik and his lab colleagues are studying the chemical biology of proteolytic enzymes and their natural inhibitors. These enzymes, known as proteases, cut other proteins, an activity essential to nearly all life processes. A particular emphasis of his work is identifying the roles and regulating the activity of proteases associated with infectious diseases, cancer and development.
These studies are providing a better understanding of both the chemical make-up and the biological importance of these critical proteins, which constitute about 2 percent of the human genome. This in turn is leading to the development of strategies for regulating proteolytic activity in medical treatment.
Johnston notes that NIH is pushing for more translational work, due in part to rising public concern over the pace of new drug development.
After years of steady decline, NIH funding for research increased to $30 billion between 1995-2005 as a result of advocacy efforts by national scientific leaders, including UCSF Chancellor Emeritus J. Michael Bishop, MD.
Basic research discoveries, however, can take years, even decades, to develop into clinical services, so an increase in new drug approvals did not accompany the funding increase. The drug approval rate has remained flat since the mid 1990's, still reflecting lower funding levels from before the increased NIH budget, during which fewer discoveries were prepared to move through the pipeline. The long delay between basic discovery and therapies in public use often was not explained by the news media.
Through CTSI and industry partnerships, UCSF is working to reduce the time period from basic science discovery to clinical care by helping scientists quickly access which projects have best the potential for clinical use and avoid the many dead ends on the road of discovery.
Innovation Converging at Mission Bay
The need to provide more research aimed squarely at bridging this gap was a major driver in UCSF’s development of its Mission Bay campus, where so many of these novel approaches are converging. At UCSF Mission Bay, a once-neglected, 57-acre site south of AT&T Park, UCSF investigators are partnering with private industry, and many biotech companies are moving to the greater Mission Bay neighborhood to take advantage of UCSF’s brainpower.
Herbert W. Boyer, PhD, a former UCSF molecular biologist and the founder of Genentech, and Stanford University researcher Stanley Cohen, MD, invented gene-cloning methods they used to successfully insert genetically engineered DNA into foreign cells to make proteins. Their work is the foundation for the biotechnology industry.
Also at UCSF Mission Bay is QB3, the California Institute for Quantitative Biosciences, where more than 170 researchers explore how biological systems work, use advanced computational tools, and discover groundbreaking applications for health, energy and the environment. QB3 also provides mechanisms for scientists to interact with their counterparts in industry, often to help speed the research and bring a new therapy or tool to market faster. Since the early 1970s, an estimated 90 life sciences companies have been spawned from UCSF research, including more than 42 startups at Mission Bay.
Among those is Calithera Biosciences, which launched in 2010 out of the UCSF School of Pharmacy lab of Jim Wells, PhD, who runs the Small Molecule Discovery Center at QB3. Calithera, which received a $40 million Series A round of investment this year, brings a novel approach to killing cancer cells that several major biotech investors see as having the potential to help speed recovery from the disease.
Calithera stands as an example of the growing impetus for academic researchers to work with industry, a trend that has accelerated under the leadership of UCSF Chancellor Susan Desmond-Hellmann, MD, MPH, former president of product development at Genentech, who took the helm in August 2009.
“There are times when our discoveries need to be commercialized to get these ideas to humanity,” Desmond-Hellmann says. “It’s the difference between someone saying, ‘Eureka!’ and that translating to millions of people worldwide.”
Moving Discoveries into the World
In many respects, UCSF is the perfect place for a translational medicine push, as the University has a long track record of bringing its discoveries out into the world. The entire biotech industry was spawned from the groundbreaking work in DNA technology by UCSF’s Herbert Boyer, PhD, and Stanford’s Stanley Cohen, PhD, in 1973. Boyer later teamed with venture capitalist Robert Swanson and founded Genentech, showing the world a way to use laboratory discoveries to save millions of lives.
The first major triumph of DNA technology - production of synthetic insulin for treating diabetes - also resulted from basic science work at UCSF.
Two UCSF-patented inventions – hepatitis B vaccine and artificial growth hormone – accounted for 45 percent of the top five income-earning patents of the entire University of California system in 2009. From 1977 to 2009, 1,757 UCSF biomedical patents were issued.
UCSF continues as a center of innovation, and its vast research enterprise is one of the largest and most productive in the country, with outcomes that have significantly improved human health.