reprinted from Issue 16, Spring 2013 of Frontiers of Medicine (PDF)
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Physician-scientists – individuals who devote most of their effort to seeking new knowledge about health and disease through research – play a unique and critical role in translating discoveries into new treatments that benefit patients. Drawing upon his or her mastery of both clinical practice and basic science research in parallel, the physician-scientist is positioned to make advances in the diagnosis, treatment, and prevention of human disease. A generation or two ago, a substantial number of faculty at institutions like UCSF were physician-scientists (MDs or MD-PhDs). Today, physician-scientists are almost an endangered species (currently less than 5% of the physician workforce). Helping the next generation of physician-scientists to be successful will have a major impact on how fully the latest scientific breakthroughs can be applied towards improving human health.
Dr. Trever Bivona
"As a physician-scientist, everything I do in the laboratory is fueled by the clinical experience," says Trever Bivona, MD, PhD. Bivona is a medical oncologist who also earned a PhD in cell and molecular biology, and completed postdoctoral training with UCSF alum Charles Sawyers, MD (see profile on p. 10). He is one of a number of physician-scientists in the Department of Medicine who have chosen this challenging career path. Bivona, who joined the faculty in 2011, spends Friday mornings caring for patients with lung cancer, and the rest of his time developing improved lung cancer treatments in his laboratory.
Lung cancer is the leading cause of cancer mortality worldwide. In the U.S., less than one in six people diagnosed with the disease will still be alive in five years. "Obviously, we have not been doing a very good job of effectively treating patients," says Bivona. "But over the last 10 years, there has been a sea change in the way we understand the molecular roots of cancers." Rather than lumping all lung cancers together, scientists are identifying a number of subtypes, each caused by a different combination of genetic mutations.
Instead of treating lung cancers with standard chemotherapy, which is usually ineffective and often produces terrible side effects, Bivona’s lab sequences the lung cancer genome of each clinic patient. His group then identifies mutations that are driving that patient’s cancer, and crafts a treatment plan targeting its genetic vulnerabilities – an example of an emerging field sometimes referred to as "precision medicine."
Crossing the ‘Valley of Death’
While many patients respond favorably to targeted therapy, almost all of them eventually develop resistance. Bivona is now helping to develop rational combination therapies – the "cocktail therapy" approach used so successfully in treating HIV – which target multiple lung cancer vulnerabilities.
Some drugs may already be available; sometimes the drug doesn’t yet exist. Bivona sees his role as navigating through the "valley of death" – the wide gap between exciting discovery and practical application. For example, his lab has uncovered molecular pathways that drive resistance to Tarceva, a lung cancer drug. He is working with academic and industry partners to develop new drugs that block these resistance pathways. "Completing the physician-scientist mandate of bringing new therapies to patients requires a collaborative effort," says Bivona.
Bivona was drawn to UCSF because of its collegial culture. "The amount of scientific exchange and collaboration that happens at UCSF is unlike anything I’ve seen before," Bivona says. "There is an innovative spirit here that drives science forward into new, unexpected directions." So far, he has teamed up with Kevan Shokat, PhD, chair of the Department of Cellular and Molecular Pharmacology and an expert in signaling molecules called kinases, and Jonathan Weissman, PhD, a systems biologist; both are also Howard Hughes Medical Institute (HHMI) investigators. "You just mention collaborations to these guys, and we are off and running," says Bivona.
His work does come with certain costs. "Your personal life definitely takes a backseat," he says. "It is not a career – it is almost like a vocation." He receives his greatest inspiration from patients. "We’ve had some of our patients come to the laboratory to meet the team and look at cells under the microscope," says Bivona. "That is incredibly rewarding – to see a patient who is depending on us, and is the reason why we’re doing what we’re doing. There is nothing more motivating than that."
He is optimistic about the future. "In 10 to 15 years, I think we, as a com- munity of scientists and oncologists, will be curing most patients with lung cancer," says Bivona. "There won’t be one therapy that will work for all patients, but I think there will be multiple cures."
Dr. Julie Zikherman
"Even as it’s inspiring to see patients and do research, it’s also daunting to spend enough time doing each," says Julie Zikherman, MD.
Zikherman is a physician-scientist who trained in the laboratory of Arthur Weiss, MD, PhD, the Ephraim P. Engleman Distinguished Professor of Rheumatology and an HHMI investigator. She joined the faculty in 2008, and sees patients one afternoon a week with a wide variety of rheumatic diseases, including rheumatoid arthritis and lupus.
"I see colleagues who are solely focused on clinical work, and they are able to bring a unique amount of expertise to the table," says Zikherman. "Conversely, sometimes it would be nice to focus completely on research, because you need long periods of contiguous time to get things done in the laboratory."
Yet Zikherman loves both parts of her job. "I enjoy asking questions, and designing experiments to try to answer them," she says. "It’s even more fun if you’re doing something that has clinical implications. There is a lot of freedom and scope for creativity. It’s potentially a very fulfilling career, both from an intellectual and an emotional stand- point, where you have long-term relationships with patients."
As a physician-scientist, she brings additional depth and focus to both clinic and lab. For example, her scientific training helps her discern what kind of autoimmune disorder might underlie a patient’s disease. "While we see patients who clearly have a disease like rheumatoid arthritis, we also see those who have some sort of autoimmune process that’s hard to pin down," she says. "Having a basic science focus allows you to step back and think very mechanistically about what’s going on, and how to treat it."
She is also establishing her own lab, continuing her research into how B cells – a type of white blood cell – develop and respond to foreign antigens and microbes, while maintaining tolerance to the body’s own tissues. "Dysregulation in that process might play a role in some of the autoimmune diseases I see in patients, particularly lupus," says Zikherman. "Most of the current treatments involve suppressing the immune system pretty broadly, and there is a lot of potential for more specific and targeted therapies."
"What we can discover in academia and what industry brings to the table are really complementary," she says. "Biotech companies tend to target final common pathways of disease. In academia, we can focus closely on basic mechanisms of disease pathogenesis. That can lead to new, unexpected therapeutic opportunities that industry might overlook."
Feeling the Funding Squeeze
It is increasingly challenging for physician-scientists such as Zikherman to enter the field. It usually takes four to six years for trainees to complete postdoctoral training. Clinical revenue from seeing patients is not enough to cover their salary, and K awards and other transitional grants from the National Institutes of Health (NIH) are highly competitive and relatively small.
Zikherman considers herself fortunate. She is supported by the Rosalind Russell Medical Research Center for Arthritis which, through its fundraising efforts, provides crucial support to junior faculty such as Zikherman in the Division of Rheumatology.
New faculty members usually receive a startup package to launch their labs, but after that initial funding they are responsible for covering lab expenses and salaries for themselves and their team. However, after an upswing in the 1990s, NIH funding has not kept up with inflation, and more applicants are competing for fewer dollars.
For example, the NIH’s main grant for health-related research is the R01. A decade ago, the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) – one of the main agencies that supports Zikherman’s field of research – had an R01 "payline" of 22 percent, meaning that about 22 percent of proposals submitted were funded.
Percentage of R01 Grants Funded by the National Institute of Allergy and Infectious Diseases (NIAID)
This year, NIAID’s R01 payline was 14 percent for new and early- stage investigators, and 10 percent for established investigators (see figure above).
"That is shocking, because it’s not like just anybody applies," says Zikherman. "These are people who have already been given startup packages and have started a lab. Historically, R01 paylines have been much higher. A lot of talented people can be discouraged from pursuing this career path, or can become frustrated and leave." In the coming year, NIAID paylines are projected to be even lower. Paylines for other NIH agencies have also declined in recent years.
"There are definitely significant funding challenges facing physician- scientists both during training and afterwards, but the opportunity to improve our basic understanding of how autoimmune diseases develop and how we might treat them continues to inspire me," says Zikherman.
"Physician-scientists are uniquely positioned and motivated to address clinically relevant questions, and I hope that we as a community can support this career path."
Dr. Mark Anderson
The immune system is an exquisitely tuned instrument, vigilantly defending the body against bacteria and other invaders. But when something goes awry and the body attacks itself, autoimmune diseases such as type 1 diabetes can develop.
Autoimmunity is complex and not yet fully understood. Mark Anderson, MD, PhD, the Robert B. Friend and Michelle M. Friend Endowed Chair in Diabetes Research, is discovering more about how it develops to create better therapies for patients. Anderson joined the faculty in 2003, and is both an endocrinologist – a specialist in hormone-producing organs – and an immunologist. "Many of the endocrine disorders we see in clinic are autoimmune problems, and I’m trying to unravel the interface of endocrinology with immunology," he says.
T cells play an important role in curing the body of infections from bacteria, viruses and other living organisms that are "foreign" to the individual. To do this, they have to detect and respond to foreign substances called antigens, but not to self. Each T cell expresses receptors on its surface that identify only one antigen, but there are millions of T cells and together they can detect and respond to almost all foreign antigens.
A central question in immunity is how T cells keep from attacking the body’s own antigens. This does happen sometimes, causing autoimmune diseases such as system lupus erythematosus or type 1 diabetes. In most people, however, T cells ignore host antigens. In part, this occurs during development, when T cells mature in a specialized gland called the thymus. If T cells encounter host antigens during that time, they are eliminated. In essence, the thymus is a "school" where T cells learn to recognize antigens. If a T cell in the thymus recognizes a self antigen, it is expelled from school.
As a postdoctoral researcher, Anderson studied a gene called Aire, which is active in the thymus and helps to expand the group of self antigens that T cells can recognize. Anderson’s lab found that Aire was able to promote the manufacture of small quantities of thousands of such antigens in the thymus – at low levels, but enough to train T cells. If Aire was inactive, T cells were not properly schooled, and they attacked the host.
Building on these discoveries, his lab found other genetic mutations linked with poor "schooling" of T cells and subsequent development of autoimmune disorders. These include type 1 diabetes, in which the body destroys insulin-producing cells in the pancreas, and some forms of interstitial lung disease, a group of conditions involving scarring or inflammation of the lung.
Anderson hopes his discoveries will eventually lead to better treatments. "Having a foot in both the clinical and basic science world, I would very much like to see some evidence of a clinical application of our lab work," he says.
Training the Next Generation
Anderson wears a third hat, directing the UCSF Medical Scientist Training Program (MSTP). It is one of 43 centers nationally receiving NIH funding to train students earning a combined MD/PhD degree. In its latest grant renewal process, UCSF’s MSTP program was recognized as one of the best in the country. It accepts 12 outstanding trainees annually.
"These are really bright students," says Anderson. "But the world has gotten more complicated. Both clinical and science training are getting longer. People are in their late 30s or early 40s, starting families, and are just now getting their first job and applying for their first independent grant."
Anderson worries that some trainees opt out of physician-scientist careers for financial reasons, choosing instead to become full-time clinicians or industry researchers. "We need to be much more supportive of people, particularly when they are finishing their training but aren’t quite ready to start their own lab," says Anderson. "Right now, it’s sink or swim: if you get funding, we’ll let you stay around.
"These are tough things to navigate," he says. "When I was a postdoc, I looked at a private practice job for these very reasons. Ultimately, I found that finding the answer to an important scientific question and the thrill of new discovery was too enticing. If you get through all the obstacles, it can be a really rewarding and fantastic job.
"I don’t think that any department is going to be on the cutting edge if we only have clinicians that spend a little bit of their time doing investigation, or basic scientists who occasionally try to find clinical relevance for what they’re doing," says Anderson. "This is what UCSF as an institution is about – translating discoveries to help human health."