Physician-scientists have always brought a unique perspective to biomedical research that is inspired by their personal experience in caring for patients. Indeed, throughout history, physicians have played a central role in advancing the science of medicine as the "translators" of medical research. Yet there has been growing concern over the past 3 decades that the workforce of physician-scientists, at least in the form we have come to know them in previous generations, may be vanishing.

We have a problem

Andrew I. Schafer, M.D.

There is ample evidence to support this worrisome trend. Although the numbers of National Institutes of Health (NIH) grant applications and applicants over the past 15 years has more than doubled, those numbers have been essentially flat for M.D.-only physician-scientist applicants. During the 5-year period from 1998 to 2003, during which the NIH budget doubled, there was a 43% increase in first-time R01 applicants with Ph.D.s as principal investigators (PIs) and a 104% increase in applications with M.D.-Ph.D. PIs -- a very small percentage of the total pool of applicants. In contrast, applications from those with M.D. degrees declined by 4%.

Perhaps even more disconcerting are data about the recent attrition of NIH-funded physician-scientists. As reported by Theodore Kotchen et al. and Howard Dickler et al. in The Journal of the American Medical Association in 2004 and 2007, respectively, about 40% of M.D.s with K08 (mentored clinical scientist development) awards do not even apply for a subsequent first independent (R01) grant. Furthermore, unsuccessful first-time M.D. applicants for an R01 grant are consistently less persistent than their Ph.D. counterparts in reapplying after an initial failed attempt. And M.D. applicants who do have an R01 grant are less likely than Ph.D. applicants to apply for a subsequent R01 grant. So in recent years, at every point in the early life cycle of NIH funding, physician-scientists have been more likely than Ph.D. scientists to leave the NIH grant-applicant pool.

These numbers suggest that, however serious the problem of insufficient numbers entering the physician-scientist workforce, there's an even more important factor: The pipeline is broken, or at least leaking badly.

How did this problem happen?

What are some of the fundamental causes for the decline in the physician-scientist workforce? At the core of it, I think, is the reality that the arenas of basic biomedical research (on one side) and the clinical practice of medicine (on the other) have progressively and dramatically separated. This widening chasm has created a rapidly increasing language barrier between basic biomedical scientists and practicing clinicians. It is a two-way barrier: Midcareer clinicians today are unable to understand even the basic vocabulary of molecular biology and genetics, and biomedical investigators (even those with M.D. degrees) are increasingly losing track of rapid advances in clinical medicine, which is always increasing in technologic complexity.

In addition to its linguistic aspects, the chasm between basic science and clinical practice is also both scientific and cultural. The scientific chasm was created largely by the reductionism in medical research in the early years of the molecular biology and genetics revolution throughout much of the second half of the 20th century. This reductionist approach to medical science dictated that complex systems can be understood only by first reducing them into the study of their smallest, individual, analyzable parts. Reductionism moved medical research further and further away from the whole patient. More recently, reductionism has been counterbalanced by the emergence of "systems biology," which I expect to reanimate the crucial link between basic science, clinical research, and medical practice.

The cultural chasm between science and clinical practice involves the very distinct mentalities required to practice clinical medicine and to do basic biomedical research. Barry Coller insightfully described this chasm in The Vanishing Physician-Scientist?:

- Clinicians are motivated by the need for immediate action (sometimes to even save a life), whereas scientists are conditioned to avoid rushing to judgment;

- Clinicians are taught to adhere to standards and guidelines of practice, whereas scientists are encouraged to challenge existing paradigms;

- Clinicians traditionally respect hierarchy and expert authority, whereas scientists tend to critique and challenge accepted wisdom;

- For clinicians, errors are potentially mortal threats, whereas for scientists, errors are inevitable manifestations of the creative process;

- Clinicians focus on the unique, whereas scientists look for generalizable principles.

In addition to the scientific and cultural chasms, contemporary forces are now contributing to the weakened physician-scientist career pipeline. The number of women graduating from medical school today equals the number of men. The dramatic change in medical student gender demographics has not been accompanied, however, by a proportionate increase of women in senior faculty ranks and leadership positions, even after the expected time lag. It has been noted that women tend to find physician-scientist careers less attractive than men do for a number of reasons: They (1) are concerned that it will be impossible to combine a successful medical research career with childbearing and family life; (2) feel that they have to be better than their male counterparts to be considered equal; (3) receive little encouragement to become physician-scientists; and (4) lack compelling role models.

Entry and retention in physician-scientist careers also appears to be impeded today by a generation gap in expectations. The current generation of medical school graduates, regardless of gender, has very different priorities. They attach much more importance to work-life balance and controllable lifestyles that they believe, perhaps erroneously, to be incompatible with serious research careers. Finally, at least partly as a function of these new forces, there has been serious erosion in the quantity and quality of effective mentoring in its traditional dyadic, "mentor mentee" format.

So, are physician-scientists marked for extinction?

And yet, as I have concluded in The Vanishing Physician-Scientist?, I believe that physician-scientists should be considered "endangered" today only in their current state, not in the sense of permanent extinction. What is vanishing -- if it ever really existed -- is a mass of physician-scientists matching an earlier generation's idealized concept of the "triple threat" who could, as a solitary clinical investigator, move effortlessly between bedside and bench, managing a busy clinical practice and a productive research laboratory while devoting significant time to teaching and mentoring.

How can I make it?

This is part of an article series for CTSciNet, the Clinical and Translational Science Network, an online community. These articles are published on both Science Careers and within CTSciNet.

So how can young physician-scientists realistically flourish under these circumstances? First, you must recognize that the current structure of medical schools and universities, with their anachronistic, rigid "up or out" promotion and tenure systems, were designed to accommodate the male physician-scientist of earlier generations whose career ambitions were supported by stay-at-home wives who assumed all household and child-rearing responsibilities. It will take some time for academic systems to catch up to the contemporary realities of being a successful physician-scientist today. During this period of transition, I would offer the following advice.

1. Be proactive in carving out your own physician-scientist career path. In the past, young physicians with a passion and aptitude for research were nourished and incubated in highly supportive environments. They could assume that their paths to independence as investigators would be carefully groomed and personally guided by readily available, experienced, dedicated, and influential mentors who would also create for them the personal connections they need for collaborations. If you are in such an environment now, consider yourself extraordinarily fortunate. The great majority of young physician-scientists today will not have the luxury of being the passive recipients of such spoon-fed career development. So, be proactive, resourceful, and aggressive in searching for and engaging the guidance you will need.

2. Along these lines, seek and cultivate mentors. Of course, above all, you must have strong scientific mentoring. But you must also have role models, confidants, champions, and experienced and influential people who can provide you with connections and show you the ropes (people whom I refer to as academic "godfathers" or "godmothers"). These characteristics are rarely found all rolled into one individual, so assemble your own personal mentoring circle. In many cases, you will find them outside your own department and even outside your institution. Work to recruit them to your mentoring team and then cultivate them by reciprocating as a "good mentee" -- someone who accepts criticism well, keeps an open mind, frequently gives credit to the mentor, and can bring real value to the mentor-mentee relationship.

3. Navigate the diverse missions of academic medicine with self-discipline. You should learn great time-management skills. These are mostly hard-earned, self-taught, acquired skills, not innate abilities, so don't just say, "I don't have good time-management skills" and leave it at that. Try very hard to organize your calendar to enable you to devote large blocks of uninterrupted time to each of your core professional activities -- at least several hours in any given day, preferably whole days or even several consecutive days. This means learning to be able to say "no" -- or "not now" -- in a gracious and disarming way. For example, when asked to give a lecture when you are engaged in writing a grant application, offer a different time when you can do it, after the grant deadline.

4. Learn that medical research today is a team sport. During this generation, the breathtaking pace and scope of progress in both the science and the practice of medicine has vastly outstripped the capacity of any individual physician-scientist to maintain even a semblance of currency in both arenas. The key to success is your ability to thoughtfully surround yourself with partners, particularly Ph.D. scientists, who offer complementary expertise. And for each project, you and your collaborators should try to agree in advance what each scientist's role will be and who will be the "driver." Insisting on being the sole principal investigator on every project, or even most projects, will prove to be counterproductive. Can you be a team player and still be a star? Yes. Remember that the greatest sports stars have been the ones who were able to elevate their teams to win championships.

Without a doubt, this is a difficult period to become a physician-scientist because academic structures and reward systems are lagging well behind the contemporary realities that constrain traditional physician-scientist careers. It is a particularly challenging period for young women physician-scientists. Rather than railing against the system, you should be a constructive, even outspoken, catalyst for change in your home institution. Do not allow systemic adversities to defeat you: The same amazing intellectual rewards that physician-scientists of previous generations enjoyed are most certainly available for the current and future generations.

References

N. C. Andrews, " The other physician-scientist problem: Where have all the young girls gone?" Nature Medicine 8, 439 (2002).

H. B. Dickler et al., " New Physician-Investigators Receiving National Institutes of Health Research Project Grants: A Historical Perspective on the 'Endangered Species.' " The Journal of the American Medical Association 297, 2496 (2007).

T. A. Kotchen et al , " NIH Peer Review of Grant Applications for Clinical Research." The Journal of the American Medical Association 291, 836 (2004).

T. J. Ley and B. H. Hamilton, "The Gender Gap in NIH Grant Applications." Science 322, 1472 (2008).

T. J. Ley and L. E. Rosenberg, " The Physician-Scientist Career Pipeline in 2005: Build It, and They Will Come." The Journal of the American Medical Association 294, 1343 (2005).

A. I. Schafer, Ed., The Vanishing Physician-Scientist? Ithaca, New York: Cornell University Press. (2009).

In the spring of 2006, Laura Gault was frustrated. A clinical faculty member in the autism clinic at Yale University, Gault was doing something she loved -- working with children -- but her inability to offer these desperate young patients and their families better interventions was beginning to gnaw at her.

A self-described "real geek" as a child, Gault had pursued a medical degree and a Ph.D. in neuroscience at Case Western Reserve University in Cleveland, Ohio, as well as a child psychiatry residency at Yale School of Medicine. "My interest my entire life has been in asking and answering a question. That's what drove me," Gault says. But at Yale, she found she wasn't drawing on her research skills when she immersed herself in clinical duties. "I'd never intended to spend all of my time in the clinic," she says. "The clinical frustration combined with my inability to do research served as a wake up call telling me that I wasn't where I should be."

It's true, Gault says, that she probably could have arranged for protected time to conduct research, but it wouldn't have happened quickly, and she would have found it difficult to stay away from the patients who needed her. So she began to explore alternatives where research would be her primary responsibility. She landed at a pharmaceutical company: Abbott Laboratories in Abbott Park, Illinois, leading their pediatric attention deficit hyperactivity disorder (ADHD) program. "Being anchored in my clinical specialty [child psychiatry] made it pretty easy to make the jump into industry," Gault says.

This is part of an article series for CTSciNet, the Clinical and Translational Science Network, an online community. These articles are published on both Science Careers and within CTSciNet.

Gault is in good company. After thoroughly analyzing their personalities and interests, many M.D.s, M.D./Ph.D.s, and Ph.D.s find their best match in industry. That's not surprising when you consider the crucial role for-profit industry has always played in the development and deployment of basic scientific discoveries.

Choosing a career in industry may seem risky at a time when the pharmaceutical industry has shed many scientific jobs as a result of the global recession and looming restructuring of the drug-development process. However, many industry insiders say these changes are opening up unique opportunities for researchers who focus on translating basic science into real-world cures and are eager to explore the molecular mechanisms of disease, test hypotheses, and do work that benefits patients.

Choosing industry

Bruce Littman

The opportunity to directly help patients is a powerful attraction to the pharmaceutical industry for some scientists, especially scientists with medical training. Bruce Littman, president of Translational Medicine Associates, LLC, in Stonington, Connecticut, moved to an industry position at Pfizer after studying the pathogenesis of rheumatoid arthritis as a professor at Virginia Commonwealth University in Richmond. The decision to move to industry was born of a desire to work someplace "where the focus was still very much on the science but there was still a likelihood that my work will have an impact on human health within my lifetime," he says.

Mario Saltarelli, who once worked with Littman at Pfizer, concurs, noting that after he had completed medical school, a neuroscience residency, and a Ph.D. in neuropharmacology, he found that studying epilepsy as an academic clinician didn't adequately exploit his skill set. He was participating in some industry clinical trials, but the route to helping patients wasn't direct enough. The move to industry has allowed him to "bring therapies to millions of people who weren't able to be helped," says Saltarelli, now divisional vice president for neuroscience development at Abbott Laboratories.

Although the work may benefit patients more quickly, economic considerations can bring projects -- and, hence, a life's main professional pursuit -- to an unceremonious end. Gault got a lesson in this roughly 9 months into her work at Abbott when the ADHD program she was working on was discontinued.

Laura Gault

Gault transferred to a new research area -- Alzheimer's disease -- where she is now responsible for several proof-of-concept trials, also known as phase II clinical trials. "I think this really drove home to me something I already knew: In industry, it is highly unlikely that you will study the same thing for your entire career," Gault says. "Things in industry change more quickly, and you have to be adaptable."

Despite the opportunities industry affords, it's not for everyone. Scientists exploring industry careers "have to have the right motivation, the right type of inquisitiveness, and have to enjoy working in a team. It's a different culture," Saltarelli says. "Part of the thing you give up when you come to industry is that you are not your own individual; you are part of a larger team, and it is because you are part of that team that you are able to do all the things you do in industry."

Gault agrees that the culture of corporate science takes some getting used to. "You live and die by Lotus Notes," she says, laughing. "Everything is highly scheduled. The work is more goal-oriented and results-oriented because it has to be."

Every step in the process, from preclinical studies to proof-of-concept clinical trials, has to take place on a timeline to prepare the product for pivotal testing, Gault says. Delays can have cascading and devastating effects on the development of a therapeutic. "You have to think about timelines in a way that you don't in other environments," Gault says. "I like it, but not everyone will."

A changing industry

Garret FitzGerald

Although pharma-industry positions have long been considered stable, the global recession and fundamental concerns about the way drugs are developed have resulted in massive industry layoffs over the past 2 years.

Those layoffs were driven in part by the skyrocketing cost of developing drugs. Many believe the drug-development enterprise is unsustainable in its current form, where a company maintains all aspects of research and development in-house. "What we are likely seeing is that the model of a vertically integrated pharmaceutical company capable of taking a molecule from discovery to market is in the process of disintegrating," says Garret FitzGerald, chair of the Department of Pharmacology and director of the Institute for Translational Medicine and Therapeutics at the University of Pennsylvania.

The traditional notion of an "industry career" is changing right along with changes in the industry. In an effort to more efficiently develop drugs, the pharmaceutical industry is focusing on highly targeted, smaller clinical studies. As a result, the emphasis in early development is on understanding the molecular underpinnings of disease and developing markers for therapeutic effects.

"I see it as an opportunity," says James Chung, medical sciences director for early development at Amgen Inc. in Thousand Oaks, California. "The blockbuster model has had its day. It worked because there were very large markets where getting 20 to 50% of the market share with a single drug was profitable. It was low-hanging fruit. The challenge and question now is, how do you develop a sustainable business model for developing drugs for smaller patient populations?"

James Chung

Scientists whose expertise is in the molecular basis of disease can now apply "the tools of small molecules to cast about hypotheses. It is an extraordinary opportunity," Littman says, noting that most people who choose this path have a clinical background of some sort as well as a strong interest in understanding disease whether they have an M.D. or a Ph.D.

The focus on early development also means opportunities for research on biomarkers to help define the patient populations most likely to benefit from a particular therapeutic intervention. Saltarelli notes that the concept of using biomarkers to conduct smaller trials to test drugs wasn't widely embraced by industry 10 years ago. "There has been a change over the last decade, and companies are putting value on early clinical trials," he says.

Working at an early stage of drug development means dropping drugs that look like they aren't going to be safe and effective, as early in the process as possible. "I see my job as figuring out what kind of legs a drug has, and sometimes the answer is that it isn't going to be efficacious or safe enough," Gault says. Littman adds, "A company that follows the evidence will be happy if you kill their drug quickly and cheaply."

This kind of research generates an enormous amount of data. Mining that data is critical to developing therapies that target key points in relevant biological pathways -- and represents opportunities for bioinformatics experts, Chung says. "There is a huge amount of data coming through, and there is a bottleneck in making sense of that data. In my mind this is the frontier, and it requires people who have both the computational and the biological background."

New opportunities

Despite all the changes, pharmaceutical companies are maintaining a strong internal development program in areas with large markets such as oncology, neuroscience, and diabetes/obesity; and they are hiring people whose skills fit with their drug-development programs. Furthermore, the shifts in the industry may herald a new, more fluid division of labor where nontraditional partnerships take on the earliest stages of drug development. "I think it may be up to smaller biotech companies and academia to come up with new drugs," Littman says. "And smaller biotech companies are very interested in generating biomarkers, working on proof of concept, and testing in smaller patient populations."

It's a modular approach to drug discovery and translational research that both FitzGerald and others believe will become prevalent. They also think this will necessitate changes in the way industry and academia handle things such as intellectual property. People choosing industry careers should be prepared and adaptable.

"I think there is a lot of uncertainty out there in the world right now," says Will West, chief executive at CellCentric, a biotechnology company in Cambridge, United Kingdom. "If you are a young graduate, I can see how basing a career in industry may seem like a difficult choice to make. I see the opposite. I think in a changing model, there is opportunity for bright people to take advantage of that change and be drivers for the solutions."

Photo (top): D. Sharon Pruitt