Career Opportunities in Physiology Symposium Report
The Drug Discovery Process—Opportunities for Physiologists

    The overall goals of this Symposium were: 1) to expose young physiologists to new career opportunities; 2) to educate others about the important work of the physiologist in drug discovery; and 3) to demonstrate how academic collaboration with industry leads to new drug discoveries. The presenters were J.H. “Wick” Johnson, Pfizer Global Research and Development; David M. Pollock, Medical College of Georgia; Terry J. Opgenorth, Abbott Laboratories; and Albert DeFelice, Food and Drug Administration. James M. Norton, University of New England College of Osteopathic Medicine, moderated an interactive discussion with the speakers following the talks.
    Johnson’s opening remarks highlighted two important intended outcomes of the Careers Symposium at EB 2003. The first was to provide attendees with an overview of the drug development process (a process that many even in the industry do not fully comprehend) and the second was to make the audience aware of opportunities for physiologists that they may not have been aware existed, since training in the broad-based field of Physiology regularly crosses multiple disciplinary lines.
    For instance, the long road of drug development starts with an idea that can come from industry, academia or an academia/industry collaboration. Once the idea has been realized and put into practice, patents must protect any resulting intellectual property. One little known career opportunity for aspiring physiologists is with the Patent and Trademark Office as a patent examiner. A critical function of the patent examiner is to evaluate data in the patent package supporting the claims made in the patent. The Patent and Trademark Office uses scientific expertise drawn from many areas, including physiology, to perform these evaluations. Once the idea is developed and intellectual property is protected by patents, the work of establishing proof of concept begins with pre-clinical research, an obvious area of opportunity for physiologists.
    Opgenorth emphasized that physiologists have many good opportunities for employment in the pharmaceutical and biotechnology industries. However, it will be rare to see an advertisement for a “physiologist.” Rather, the advertisements or job postings to which physiologists should consider responding are, ironically, those for “pharmacologists.” There is no escaping the fact that, in general, the educational training of a pharmacologist differs in important ways from that of a physiologist. Pharmacologists receive formal training in such things as receptor binding kinetics, pharmacokinetic and dynamic aspects of drugs, mechanisms of xenobiotic metabolism, etc. Nevertheless, a primary function of many industry pharmacologists is to determine experimentally the therapeutic potential of a potential drug candidate. This involves both the characterization of the effectiveness of a drug entity in relevant animal models (“efficacy”) and any potential unwanted activities (“adverse events”).            
    Physiologists with systems and integrative training are ideally suited for this type of work. Evaluation of novel drug candidates often requires the development of new cell and animal models of disease, something which physiologists are again well suited to do.
    In addition, there are large scale efforts in industry to identify the functionality of genes by a variety of methods, including siRNA, antisense RNA, transgenic overexpression and gene deletion, to name a few. Since the effects of manipulating a gene often include unexpected systemic results, comprehensive physiologic evaluation, i.e. phenotyping, is critical to a proper understanding of the gene’s function. In industry, this activity is often called “target validation.”
    It is often the case that industry scientists are the first to have access to an inhibitor, antagonist, or agonist to a molecular target that has never been investigated before. This offers a real opportunity for a physiologist to be the first to demonstrate the importance of regulating a particular pathway, i.e., defining the physiological relevance of that protein or the pathway of which it is a part. In addition, access to these reagents provides excellent opportunities for industry physiologists to collaborate with other university scientists who are often eager to have reagents that will aid their own research. Opgenorth used the example of Abbott’s endothelin antagonist program to highlight the parallel importance of novel industry-based research and the influence of academic collaborations in the development of Abbott’s lead endothelin antagonist, atrasentan, for its novel therapeutic application in patients with prostate cancer.
    For career development, Opgenorth suggested that physiologists interested in industry employment could improve their opportunities by seeking to forge collaborations with industry scientists during their graduate and/or postdoctoral research. Most likely this would be in the form of requesting drug samples from industry scientists to apply in their own research. Having published their research incorporating the characterization of novel compounds, applicants for positions in pharmaceutical and biotechnology companies will most likely have their applications taken more seriously, and will be in a much better position, than those who have not done this kind of research.
    Pollock described the variety of ways in which academic, university-based investigators can and do participate in the drug discovery process, most frequently at the level of either pre-clinical development or clinical trials. More specifically, basic scientists can contribute to pre-clinical studies through the identification of new chemical entities and the identification of new drug targets. This could include identifying new hormones, autocoids, enzymes, receptors etc., that might provide the basis of new drugs or drug targets. A second, and perhaps more common role of the academic scientist, is to conduct investigations referred to as “target validation” or “proof of concept” studies. These experiments are a critical and necessary part of establishing a drug as a candidate to be tested in human clinical trials. Often, the way an academic investigator gets involved in such studies is through the development of unique experimental models and research tools or capabilities, such as: creation of specific animal models of disease; access to transgenic and knock-out animals; creation of unique cell lines; possession of methodologies that may not be readily accessible in industry; and demonstration of skill with relevant tools such as DNA probes or antibodies.
    The academic researcher most often works in conjunction with a private drug development company through collaborations, specific grant programs or licenses. Collaborations with industry can take on many different forms, just as in collaborations among academic researchers. The successful collaboration must be designed to provide mutual benefit to both participating parties. In other words, collaborations must be structured to allow both parties to achieve something they would not be able to do alone. While financial support may be one of the benefits, this cannot be the driving force in a successful collaboration, but rather the collaboration should focus on the acquisition of new information related to both drug development and the scientific interests of the academician. In addition to collaborations, some companies have grant programs or will offer license agreements to specific investigators where they need to establish a longer-term relationship.
    In order for the collaboration to succeed, both parties must have a clear understanding of mutual goals and must have a means of communicating with one another in a timely fashion. Too often collaborations fail because one party or the other does not deliver their part of the work in a timely fashion. For example, a company may want to have a prototype drug evaluated in a unique animal model. This prototype drug may be very useful for an academic investigator who wants to have a better understanding of the pathogenesis of a certain disease. The company may supply the compound to the investigator, but all too often, the compound will sit on the investigator’s shelf because the academic investigator and the company have not clearly communicated with one another regarding the level of priority of the studies.
    Academia also plays an important role in drug development through clinical investigations. A large number of Phase II and Phase III trials are conducted at academic medical centers because these centers provide access to large numbers of patients with the target disease. There are a number of opportunities for physiologists in industry to work as clinical research associates, whose function is to help design and coordinate trials. These individuals have a variety of educational backgrounds, but all must have a good understanding of experimental design, data management, and general scientific principles. Also, research hospitals have individuals working in a similar capacity to oversee and coordinate clinical investigations.
    A more recent development that bridges the gap between academia and industry involves what are referred to as “technology transfer offices” that have been established at most academic institutions. These offices typically help academic researchers work with large and small companies to facilitate development of intellectual property developed by an academician—a patented compound, a medical device, or a service—so that it can potentially become a marketable product.
    DeFelice emphasized that the timely submission and evaluation of animal pharmacology and toxicologic pathology data—which importantly includes functional aberrations in the major body systems—is an integral part of the deliberate and coordinated process of FDA approval of new drugs. Distinguishing homeostatic responses secondary to pharmacodynamic activity from primary toxicity due to physiologic processes is an example of the important role that physiologists and pharmacologists share, one that is not generally appreciated. The personnel currently employed by the FDA to review and evaluate such pre-clinical data were hired from the ranks of scientists with doctorate degrees in pharmacology, physiology, molecular biology, experimental pathology, among other disciplines. This reflects the diversity of pre-clinical data submitted by the pharmaceutical industry prior to, and during, clinical evaluation. Through course work, reliance on FDA guidances and other policies, other professional development, and consults, each new reviewer acquires the broader training, experience, and ability to evaluate effectively and efficiently such ancillary pre-clinical data, and to project clinical relevance where appropriate. A major responsibility—and source of job satisfaction from being a member of the review team which eventually recommends regulatory action—is the integration of pharmacodynamic (both targeted and unintended) and safety data (pathophysiologic and toxicologic pathology) to supplement clinical determination of risks and benefits. The identification and evaluation of any potential risk of irreversible or hard-to-identify toxicities (reproductive; genotoxic; carcinogenic) is an important aspect of risk-benefit determination, and is also a statutory labeling requirement of new drugs. The critical evaluation of adverse findings in such assays—and the projection any corresponding risk to future patients—requires an understanding of the physiology underlying such tests, and the pathophysiological mechanism(s) responsible for the adverse findings.
    The presentations of Johnson, Opgenorth, Pollock, and DeFelice prompted many questions by attendees of the session during the interactive discussion sessions. A number of the graduate and postdoctoral students in the audience found the sessions very informative and potentially very helpful in their future choices of career paths.

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