Putting molecular disease research into physiological context.

In a 2002 lecture to the American Physiological Society (APS) Respiration Section, former APS president Norman Staub, Sr. presents, as his first slide, two images. The first image is labeled ‘Molecular Biology’ and features a gleaming silver bullet train speeding into the distance. The second is labeled ‘Clinical Medicine’, and depicts a rickety wooden caboose standing alone. Staub uses this simplified metaphor and visual aid to comment on the state of the union – or, perhaps more accurately, disunion – between clinical medicine and molecular biology (Staub, 2002). Given the exponential increase in molecular biology advances, Staub posits the question, “Why has the potential for applications of molecular biology in clinical medicine not been realized?” He points to whole animal physiology as the discipline that connects clinical medicine with molecular biology. He suggests that basic science’s inefficient translation to the clinic, results from its limited ability to shift its findings from a restricted and controlled experimental environment to the complexity of a complete organism. The decline of whole animal physiology from its heyday in the mid 20th century is a trend that has been noted by many researchers. The neglect of systems biology and whole animal physiology has been linked to a wide variety of dead ends in scientific research. These include missing clinically important phenotypes in transgenic or knockout mouse models, which may be subtle or difficult to detect for the average biomedical researcher untrained in animal physiology, as well as wasted effort and expense incurred during novel drug development. Of the millions of dollars spent developing potentially effective drug therapies, a large expense comes from the waste incurred when novel compounds that pass tests in laboratory animal models fail in clinical trials, perhaps due to a limited understanding of the physiological relationship between model organisms and human patients. Several initiatives are addressing this gap in the research process. David Wasserman, Professor of Molecular Physiology and Biophysics at Vanderbilt University, is involved with bringing an understanding of whole animal physiology back to the forefront of research. Wasserman serves as director of the Mouse Metabolic Phenotyping Center (MMPC) at Vanderbilt, one of seven MMPC facilities in the country funded by the National Institutes of Health (NIH). These MMPC centers were established by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in 2001, to provide researchers with an expanded array of information about their mouse models by using standardized testing and diagnostic methods to expedite characterization of mouse metabolic phenotypes. The rat has been the traditional model organism for studies of physiology; however, the genetic tractability of the mouse and subsequent availability of reagents make mice tremendously popular for research (Fig. 1). As genetic and molecular manipulation techniques in the mouse continue to expand, the limitations in the physiologic tests that are necessary to identify mouse phenotypes have become more evident. “The focus of physiology departments over the last few decades has not been on physiology; it has been on cell biology, gene transcription and such similar topics,” Wasserman commented. Thus, Wasserman and colleagues are shifting the Putting molecular disease research into physiological context