UCSF is a health-sciences research powerhouse – a premier academic medical center that values not only the physician who designs clinical trial protocols for promising experimental drugs, but also the talented lab scientist who unearths nature’s secrets on the molecular and cellular levels.
The Year-in-Review at UCSF
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It's a place where basic scientists, population scientists and clinical researchers work together to translate basic biological discoveries into new solutions for preventing and treating human diseases.
The University also advances discovery through partnerships with business, industry and other research organizations. In the most recent tally, UCSF topped all other public universities in research funds awarded from the National Institutes of Health, the federal agency that – based on competitive review of research proposals – awards the bulk of federal health sciences research dollars.
Here are just a few of the highlights to emerge from UCSF faculty research in 2012:
Everything from inheritance, to how we eat, to whom we live with now appears to affect aging. Carla Perissinotto, MD, MHS, led an analysis of data on more than 1,600 older Americans, and concluded that loneliness is independently associated with an increased rate of death and functional decline. Even those who live with partners may report that they often feel lonely, she found.
Neil Risch, PhD
Cognitive decline and dementia are among the most feared risks of aging, but Adam Gazzaley, MD, PhD, has concluded that short-term memory loss may be due to distraction and that short-term memory and multitasking can be improved through training in both the young and old.
Neil Risch, PhD, leads a project to analyze genes and bits of DNA called telomeres from Kaiser Permanente patients whose health data has been incorporated into one of the world’s largest genetic and environmental information resources for health research. He found that people with the shortest telomeres were 20 percent more likely to die over a three-year period. In other telomere news, Elissa Epel, PhD, led a study in which researchers found that having cells with shorter telomeres is associated with having a wandering mind.
Elissa Epel, PhD. Photo by Susan Merrell
On the molecular level, Gladstone Institutes researcher Eric Verdin, MD, found that in mouse tissues and human cells in the lab, a naturally occurring molecule called βOHB – the body’s major source of energy during exercise or fasting – blocks a class of enzymes that would otherwise promote oxidative stress, thereby protecting cells from aging. This might explain the life-prolonging effects of low-calorie, “ketogenic” diets observed in some animal studies, according to Verdin.
Alcohol and Tobacco Addiction
UCSF is a world leader in efforts to understand and combat alcohol and tobacco addiction, with groundbreaking work being done at the Ernest Gallo Clinic and Research Center in the neurobiology of alcohol addiction.
The Gallo Center was chosen to manage a new $15 million Army-funded program to develop new treatments to combat abuse of alcohol and other substances. This year, Gallo researchers Jennifer Mitchell, PhD, and Howard L. Fields, MD, PhD, reported that drinking alcohol leads to the release of endorphins in areas of the human brain that produce feelings of pleasure and reward. They also found that the smoking cessation drug varenicline significantly reduced alcohol consumption in a group of heavy-drinking smokers. Impulsivity is a risk factor for addiction, and another Gallo investigator, Andrew Kayser, PhD, found that boosting levels of dopamine in the brain’s frontal cortex can lessen impulsivity in healthy adults.
Howard L. Fields and Jennifer Mitchell. Photo by Susan Merrell
Secondhand smoke causes 42,000 deaths annually to nonsmokers in the United States, according to a study led by Wendy Max, PhD, yet we remain bombarded by images of smoking in the movies. Top box office films last year showed more onscreen smoking than the prior year, according to tobacco researcher Stanton A. Glantz, PhD, reversing five years of steady progress in reducing tobacco imagery in movies. Studies indicate that youth subjected to more images of smoking in movies are more likely to become smokers. Citing Glantz’s study, officials from the Centers for Disease Control and Prevention has committed to begin tracking and reporting annually on images of smoking in youth-oriented movies.
In this chart, top-grossing films of 2011 are ranked by the number of incidents depicting tobacco use. An analysis led by Stanton A. Glantz, PhD, found that last year's films showed more onscreen smoking than the prior year, reversing five years of steady progress in reducing tobacco imagery in movies.
On the plus side for smokers who want to quit, Neal Benowitz, MD, published a study in which he found that smokers who switched to cigarettes with tobacco that contains less nicotine did not compensate by smoking more cigarettes and inhaling more tar and toxins. It might therefore be possible to free smokers from addiction by gradually lowering the amount of nicotine in cigarettes, Benowitz says.
Katerina Akassoglou, PhD
UCSF is a leader in studies of the immune system and of how it abnormally attacks the body in autoimmune disease. In rodent studies, neurologist and Gladstone investigator Katerina Akassoglou, PhD, found evidence that a protein which leaks from blood into the brain acts as an early trigger that sets off the brain’s inflammatory response in multiple sclerosis. UCSF neurologist Hans Christian von Büdingen, MD, found that B cells of the immune system – also suspected of playing a role in MS – move in and out of the brain. Both discoveries suggest possible treatment strategies.
In another autoimmune disease, called Sjogren’s syndrome – which affects up to 4 million people in the United States, 90 percent of them women – School of Dentistry professor Caroline Shiboski, DDS, PhD, led an international team that established improved diagnostic criteria.
Basic Research on Cell’s ‘Unfolded Protein Response’
The living cell still yields basic insights when probed by researchers armed with all the tricks of molecular biology and biochemistry.
When the cell’s factories that fold and put the finishing touches on proteins cannot keep up with all the proteins they need to fold, the cell kicks into the “unfolded protein response” by throwing some switches to ramp up its folding capacity; if it still can’t keep up, it throws in the towel and activates a suicide program.
UCSF researcher Feroz Papa, MD, PhD, has learned to successfully manipulate the unfolded protein response in ways that might one day used to fight diabetes. Davide Ruggero, PhD, co-led a team that discovered cells of the blood cancers known as lymphomas often contain mutations that allow them to evade the cell-suicide program as they activate the unfolded protein response to meet their outsized protein demands.
Best Clinical Practices
Sometimes refining existing treatments can make as big a difference in preserving and restoring health as entirely new treatments.
UCSF radiologist Rebecca Smith-Bindman, MD, aims to educate physicians about radiation risks. Her research showed that radiation exposure through medical imaging exams is increasing, with some exams being unnecessary or exposing patients to higher-than-necessary radiation doses.
On the flip side, neurosurgeon Edward Chang, MD, determined that a surgical epilepsy treatment found to be effective a decade ago remains underused. And J. Claude Hemphill III, MD, MAS, chief of neurology at the UCSF-affiliated San Francisco General Hospital and Trauma Center, led clinical trials that showed paramedics using an autoinjector to inject an anticonvulsive treatment directly into the thigh were able to stop epileptic seizures more quickly and effectively than they could by giving an anticonvulsant through an IV line.
The UCSF Helen Diller Family Comprehensive Cancer Center received a major renewal grant from the NIH this year, and its researchers continue to make seminal discoveries across a wide spectrum of cancers.
Armed with a new $10 million grant to study advanced prostate cancer, UCSF will lead multi-center research that will focus on 500 patients to identify the causes of drug resistance in the disease, and to better tailor treatment to the individual.
To treat brain cancer, neurosurgeon Andrew Parsa, MD, PhD, found that a cancer vaccine shows promise in Phase II trials. Oncologists and surgeons have demonstrated ways to predict post-operative early-stage lung cancer mortality and determined that a molecular test can predict the likelihood of death from early-stage lung cancer more accurately than conventional methods.
A tean led by Eleni Linos, MD, DrPH, found that indoor tanning beds can cause non-melanoma skin cancer – and that the risk is greater the earlier one starts tanning.
Diabetes and Sugar
Robert Lustig, MD, Laura Schmidt, PhD, MSW, MPH, and Claire Brindis, DPH, issued a report in February calling for sugar to be controlled like alcohol and tobacco to protect public health. This chart compares health complications from excessive sugar intake with excessive alcohol use.
Pharmaceutical giant Sanofi is collaborating with the UCSF Diabetes Center on a $3.1 million project to develop new drugs for type 1 and type 2 diabetes. Meanwhile, UCSF and San Francisco Veterans Affairs Medical Center researcher Kristine Yaffe, MD, found a strong association between type 2 diabetes and risk for Alzheimer’s disease.
Pediatric endocrinologist Robert Lustig, MD, public health policy sociologist Laura Schmidt, PhD, MSW, MPH, and pediatrics and health policy specialist Claire Brindis, DrPH, MPH, proposed that sugar plays a central role in a global health crisis and should be regulated, as alcohol is regulated.
Viruses and parasites that get little attention from most Americans continue to plague the world, but UCSF scientists aim to turn the tide against these persistent pathogens.
In April, UCSF hosted the Bay Area World Malaria Day Symposium, which drew malaria experts who aim to eradicate the disease. They included UCSF’s Bryan Greenhouse, MD, who described strategies for tracking genetic changes in the malaria parasite in human populations to make better public health decisions about how to focus malaria control efforts, and UCSF Global Health group researchers Gavin Yamey, MD, MPH, and Chris Cotter, MPH, who described research showing that lapses in control efforts have historically played a larger role than other factors in driving malaria resurgences.
Hookworm infection is second only to malaria as a cause of disability worldwide. Conor Caffrey, PhD, directed a study in hamsters in which he used an experimental drug to target a key “protease” enzyme in the parasite’s gut that helps it digest a blood meal. The results showed that the drug cures hookworm in hamsters and suggested that similar drugs might be effective in humans. In another parasite study, James McKerrow, MD, PhD, and his UCSF and UCSD collaborators found that an inexpensive arthritis drug kills parasites that cause dysentery. McKerrow and colleagues have planned clinical trials to use the drug to target these dysentery-causing amoebas, as well as the parasite that causes giardia.
In HIV research, UCSF-affiliated Gladstone investigator Robert Grant, MD, MPH, earlier led a major study in Africa that partly served as the basis for the FDA’s decision in 2012 to approve Truvada, a combination of two antiretroviral therapies, as the first drug treatment for the prevention of HIV infection in high-risk populations. This year, Grant co-led a study in which he found that HIV prevention can be largely effective even when patients sometimes miss Truvada doses.
UCSF epidemiologist Kimberly Page is developing guidelines for other cities to adopt the San Francisco model of outreach, education, counseling and care developed at the Tenderloin Clinical Research Center. The model is tailored to young injection drug users, who are at highest risk for hepatitis C. Photo by Susan Merrell
In the U.S., hepatitis C now kills more people than HIV. Kimberly Page, PhD, MPS, and colleagues from Johns Hopkins University are leading the first multi-center, double-blinded, randomized, placebo-controlled trial of a vaccine to prevent hepatitis C infection, which chronically afflicts about half of injection drug users, as well as many baby boomers who don’t suspect that they have the disease.
New Ways to Evaluate Drugs and Medical Devices
UCSF researchers from the schools of pharmacy and medicine are working with the Food and Drug Administration (FDA) to develop and pilot more effective methods for evaluating new drugs and devices.
Laura Esserman, MD, MBA
The agency issued a “draft guidance” on clinical trials aimed toward faster evaluation of promising breast cancer drugs, based on a trial design being tested in a clinical study known as I-SPY 2. Led by oncologist Laura Esserman, MD, MBA, researchers launched the study in conjunction with a private-public partnership that includes the FDA, the NIH, pharmaceutical companies and academic medical centers.
In the realm of medical devices, the FDA selected a project to develop an artificial kidney, headed by Shuvo Roy, PhD, as a pilot for a new regulatory-approval program called Innovation Pathway 2.0. The program is intended to bring breakthrough medical device technologies to patients faster and more efficiently.
Kathleen Giacomini, PhD, also worked with the FDA, leading the development of the UCSF-FDA TransPortal. This online tool offers guidance about how to select and conduct pre-clinical studies to identify potential interactions of experimental drugs, both with proteins involved in drug metabolism as well as with other drugs that can affect drug metabolism.
Post-Traumatic Stress Disorder
Many UCSF researchers at the San Francisco VA Medical Center strive to identify risks and treatments for post-traumatic stress disorder (PTSD).
In 2012, researchers reported studies that may help explain why women appear to be at higher risk for PTSD following trauma, and why they may face greater health risks from PTSD. One study, reported by Sabra Inslicht, PhD, suggested that women with PTSD have greater fear responses than men. Another study, reported by Aoife O’Donovan, PhD, concluded that women with PTSD are more likely to experience aging at the cellular level.
UCSF Chancellor Susan Desmond-Hellmann, MD, MPH, earlier co-chaired a National Academy of Sciences Committee that recommended the creation of an extensive data network to revolutionize medical discovery, diagnosis and treatment. This year, she called on patient advocates to push for regulations to make clinical and research data more usable while protecting patient privacy. UCSF leaders are exploring bioinformatics projects that might serve as pilots for using data more powerfully for scientific discovery and to more precisely diagnose and treat each patient’s ills.
William Seeley, MD, used MRI and other data collected from healthy people and patients, maps of neural connectivity and analysis tools to answer questions about different neurodegenerative diseases, including the two most common forms of dementia, Alzheimer's disease (AD) and frontal temporal dementia (FTD). Seeley found these diseases may be most likely to spread within the brain by moving directly between connected neurons. Image credit: Neuron
Neuroscience is one such area where massive databases, including imaging data and tools for their analysis, might be created to foster new discoveries. For example, neurologist William Seeley, MD, a 2011 MacArthur Fellow, already has used data from magnetic resonance imaging exams to evaluate predictions about how neurodegenerative diseases such as Alzheimer’s spread through nerve networks in the brain.
Stem Cell Science and Cell Therapy
UCSF’s leadership in stem cell research took center stage in 2012, as Gladstone investigator Shinya Yamanaka, MD, PhD, received the Nobel Prize for Physiology or Medicine for his discoveries with induced pluripotent stem cells, but many other UCSF faculty made important advances this year.
David Rowitch, MD, PhD, professor and chief of neonatology, in the Neuro-Intensive Care Nursery. Photo by Susan Merrell
In the second neural stem cell clinical trial ever conducted in the United States – and the first with published results – David H. Rowitch, MD, PhD, a professor of pediatrics and neurological surgery, treated young children with Pelizaeus-Merzbacher disease (PMD) In PMD, myelin, a fatty sheath needed to insulate nerves, is not produced.Rowitch and colleagues showed that the transplanted neural cells were successfully engrafted in the brain and produced myelin.
In lab studies, Gladstone scientists led by Yadong Huang, MD, PhD, reprogrammed skin cells to form an interconnected, functional network of brain cells, using a single genetic factor. In a mouse heart-attack model, Gladstone researchers Li Qian, PhD, and Deepak Srivastava, MD, used three factors injected into damaged hearts to convert scar-forming cells into beating heart muscle cells that improved blood pumping.
Ophir Klein, MD, PhD, who works to identify molecules and molecular interactions that govern how stem cells shape teeth and the bones of the face, shows a mutation in this image that affects stem-cell action in the development of mouse incisors that grow continuously (bottom image). Photo by Ophir Klein, Development.
Researchers also are investigating the therapeutic potential of transplanting naturally occurring cells. To explore treating neuropathic pain with cell therapy, Allan Basbaum, PhD, led a team that transplanted immature embryonic nerve cells from the brains of mice into the spinal cord to relieve pain.
Similarly, in studies led by Arturo Alvarez-Buylla, PhD, the survival of embryonic neurons transplanted into the brains of newborn mice has raised hopes for one day using such cells to treat neurodegenerative diseases.
Ophir Klein, MD, PhD, who spans the schools of dentistry and medicine and treats craniofacial abnormalities, continues to identify molecules and molecular interactions that govern how stem cells shape teeth and the bones of the face.