Connecting the Lab and Clinic: Challenges and Innovations

reprinted from Issue 16, Spring 2013 of Frontiers of Medicine (PDF)

Bill Seaman, MD

At the start of my career, it was thought possible to be excellent in clinical care, teaching and research," says William Seaman, MD, associate chair for research for the Department of Medicine. "These fields are so challenging now that no one can truly master all. Yet it’s still important to have a group of people who have significant training in clinical care and research."

Physician-scientists face a double challenge: as clinicians, they need to keep up with the latest treatments of disease, as well as newer fields such as improving the quality, safety and value of care. As researchers they face an unprecedented explosion of scientific knowledge and tools.

"The declining numbers of physician- scientists working at the bench is a national trend – it’s not something specific to UCSF," says Arthur Weiss, MD, PhD, the Ephraim P. Engleman Distinguished Professor of Rheumatology and an HHMI investigator. "There are huge impediments for young people becoming bench scientists. It’s ironic, because today we have more oppor- tunities than ever before to address human disease-related problems. Technological advances allow us to ask questions that were impossible in the past. But such sophisticated and advanced technologies are not readily accessible to people who have not had scientific training.

Arthur Weiss, MD, PhD

"Physician- scientists have experience with disease that you can’t get from experimental models," says Weiss. For example, lab scientists work with genetically identical mice, a situation that only occurs in humans with identical twins. But real life is much more complicated, as physician-scientists know from seeing many different presentations of disease in clinic. "Patients are very, very heterogeneous," says Weiss. "Relating animal studies to patients is sometimes very artificial and inappropriate. We need to begin to understand more about how the patient got to the current state of disease."

For instance, a physician-scientist treating patients with asthma may wonder why some respond well to a certain medication, while others do not. "We now realize that asthma is not one disease," says Seaman. "It probably comes from many factors that lead to a disease that looks roughly similar between patients – but when you really dig down, you find that the patients differ." Much of this "digging down" now happens at the molecular level, using relatively new tools to diagnose and treat disease by understanding the way genes, proteins and molecules interact.

Turning Theory into Practice

Joseph (Mike) McCune, MD, PhD

Physician-scientists are also uniquely positioned to strategize which research avenues are most likely to lead to effective treatments. For example, Joseph (Mike) McCune, MD, PhD, chief of the Division of Experimental Medicine, has cared for patients with HIV/AIDS at San Francisco General Hospital since 1982. He observed that many patients have difficulty adhering to a complicated medication schedule.

"Of all the different hypotheses about how one might make patients who are infected with HIV better, the contact with the patient teaches me that whatever I develop has to be easy to take, affordable and efficacious," he says. "If that is the goal, one has to move one’s science in that direction."

"While PhD basic scientists have very much expanded their knowledge about disease applications of their research, there are perspectives that you can only understand if you have taken care of patients," says Seaman. "I don’t think we can succeed by just having basic scientists and clinicians, and then trying to have a bridge between them. It is important to have people who speak both languages."

Robert Nussbaum, MD, chief of the Division of Genomic Medicine and the Holly Smith Distinguished Professor of Science and Medicine, agrees. "There is a role for physician-scientists in basic research that is distinct from, and complementary to, that which is done by non-physician-scientists," he says. "Fundamentally, the difference lies in the utilitarian nature of the questions that physician-scientists are driven to ask, versus the pure curiosity-driven questions that non-physician-scientists usually ask. Both are valuable – I think we need them both."

Cultivating Future Physician-Scientists

Robert Nussbaum, MD

The UCSF Department of Medicine is building on its core strengths – outstanding basic science, excellent clinical care, renowned training programs and a culture of collaboration – to meet the challenges of developing the next generation of physician-scientists. "In the Department of Medicine, there is a growing recognition that we need to pay more attention to the physician- scientist pipeline, and that a laissez-faire approach just won’t suffice in this day and age," says Nussbaum. Some of these initiatives include:

  • Molecular Medicine Pathway to Discovery: UCSF offers trainees the option to pursue a career path combining clinical practice and disease-oriented laboratory research: the Molecular Medicine Pathway to Discovery. This Pathway provides people "...with a strongly mentored, in-depth, full immersion into laboratory- based research," says Nussbaum, the program’s director.
  • Fast-tracking outstanding new faculty: One of the most challenging periods for young physician-scientists is the transition from training to junior faculty position. They usually complete one, two or even three postdoctoral fellowships before becoming competitive for such positions. One proposed solution is modeled on the UCSF Fellows Program, which fast-tracks the advancement of recently minted PhDs or MDs with outstanding promise as basic researchers. The program provides lab space and financial support for up to five years, allowing fellows to begin independent research.
  • Fostering community: The Depart- ment of Medicine is spearheading plans for a "College of Physician- Scientists" that would bring together UCSF physician-scientists from many disciplines and levels of career development, from medical students to senior faculty.

Collaborating for Success

In recent decades, basic science has shifted away from single scientists to team-based research. "The techniques that we now can bring to bear on research are so broad that no one can encompass them in their own laboratory," says Seaman. "Physician- scientists, like basic scientists, are increasingly interactive."

One particularly vivid example has been the treatment of HIV, which evolved rapidly thanks to close collaborations among scientists, industry and the community. "Patients taught us that the only way you could address this problem was in collaborative teams," says McCune. "We had to be really attentive of our teammates, in a way that most scientists are not."

One of UCSF’s stellar strengths is its collegial culture, which makes it especially well positioned to conduct team-based science. "UCSF has traditionally been very collaborative in both the basic and clinical sciences, and it’s a big advantage we have as a research institution," says Seaman. Some innovative examples include:

  • Organized research units: UCSF has a number of these disease-focused, interdisciplinary research units, such as the Cardiovascular Research Institute, the Diabetes Center, the Institute for Human Genetics and the Helen Diller Family Comprehensive Cancer Center.
  • UCSF’s Clinical and Translational Science Institute (CTSI): McCune was also the founding director of CTSI, among the first of 60 such centers launched nationally since 2006 with NIH funding. "CTSI was designed to ask the question, how can we take all this wonderful science and apply it to bring better health to more people more quickly?" says McCune. Now directed by Clay Johnston, MD, PhD, CTSI has established infrastructure, services and training to support clinical and translational research.
  • Patient cohorts: Over the last several years, the Department of Medicine has provided seed money to develop five patient cohorts – large groups of patients who give permission for scientists to collect and study their anonymized clinical data and blood samples. Cohorts function like a library, making huge amounts of information available to researchers, rather than requiring each investigator to gather data alone.
  • Leadership Initiative: Started in 2011, this effort enhances the Department’s current leadership capacity by providing professional training, including a 360-degree review and Myers-Briggs Type Indicator test, workshops on leadership skills, and private executive coaching. Says McCune, "I think this initiative is spot on: if people at UCSF want to be leaders, helping trainees and others to succeed in their careers, it’s important that they learn how to be good coaches."
  • Supporting teamwork: Collaboration may be the path of the future, but it also raises new challenges. "To be promoted at UCSF, one must show evidence of independent creative scholarship," says McCune. This is demonstrated by publications not co-authored by a mentor, and serving as principal investigator on an R01 grant. Those rules make it difficult for team-based physician-scientists to succeed, since they may be the 20th author on a 30-author paper, or a collaborator on another investigator’s R01. The Department’s Research Council has proposed changes to Departmental promotion guidelines recognizing such contributions.

Accelerating Discovery

As a premier academic medical center, UCSF plays a special role in bringingforth new treatments to help patients, and physician-scientists are uniquely positioned to accelerate these discoveries. "We have a wealth of diseases to take care of," says McCune. "I canguarantee you that in the profit- oriented, biotech-pharma environment, interventions that don’t make money will not have a team assigned to fix them. So that’s our province."

"The opportunities are really there," says Weiss. "In rheumatology, therapy of arthritis has been revolutionized over the past 10 years. You could say the same thing about HIV and cancer. Physician-scientists play an important role at the interface of disease pathogenesis and developing new therapeutics. There are many examples of successful physician-scientists at UCSF, but for an institution this great, we need more, and we need to invest in the next generation."




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