Translational research: bridging the widening gap between basic and clinical research

Abstract

Despite unprecedented opportunities in basic and clinical research, the gap between these disciplines has widened. Unfortunately, training of physician scientists, who have traditionally bridged this gap by translating basic science advances to improved patient care is not keeping pace. This issue mandates careful consideration by professional societies as well as public and private funding agencies. Only the most optimistic visionary could have foreseen the dramatic advances in genomics, proteomics, genetic manipulation, molecular and cellular biology, physiology, microbiology, and immunology which have enhanced understanding of alimentary, hepatobiliary, and pancreatic function and disease. Rapid detection of altered expression of countless genes by microarray to quantify and localize gene mRNA and protein expression by real time PCR, immunohistochemistry or in situ hybridization, determine transcriptional regulation by site directed promoter mutagenesis and chromatin immunoprecipitation (CHIP) analysis, and determine function by transgenic and knockout (global or tissue/cell specific), antisense, RNA and viral delivery of dominant negative or agonist molecules is now routinely applied to digestive diseases and in vitro cell stimulation. This huge data load must be analyzed by sophisticated bioinformatics specialists. Identification of susceptibility genes in complex genetic disorders by genome wide searches can intersect human murine and rat genome data bases. This technology has led to the discovery of genes involved in Crohn’s disease, hemachromatosis, celiac disease, familial pancreatitis, familial adenomatous polyposis, hereditary nonpolyposis colon cancer, and cystic fibrosis. New microbial pathogens have been identified, including Helicobacter pylori and the Whipple’s bacillus (Tropheryma Whippelii), as well as virulence factors for hepatitis B and C and H. pylori which affect infectivity, clinical outcome, and response to treatment. Molecular modeling of therapeutic targets has resulted in a plethora of potential pharmaceutical agents, which undergo automated screening for efficacy and toxicity. While the pace and productivity of the pharmaceutical industry are astounding, targets may be prioritized by anticipated commercial value rather than pathophysiologic importance. New interventions available for acid suppression, treatment of viral hepatitis, liver transplantation, inflammatory bowel diseases, and therapeutic/diagnostic endoscopy. Clinical trials have become multi-institutional, multinational enterprises. The disciplines of clinical pharmacology, clinical epidemiology, biostatistics, and outcome measurements have enhanced the quality of these studies. However, as the design, organization, analysis, and even reporting of these studies shifts from individual academic investigators to the pharmaceutical industry, the goal of FDA approval is emphasized rather than comparison to or combination with existing agents. With the increasing sophistication and specialization of both basic and clinical research, the gulf between these disciplines has widened, with fewer broadly based investigators capable of understanding and communicating with both sides. The complexity of both disciplines takes longer to master and financial incentives encourage talented clinicians to join lucrative practices and basic scientists to pursue industrial opportunities rather than continue with academic training. Unrealistic caps on fellowship and junior faculty salaries, large educational debts, and limited departmental discretionary funds provide further disincentives to continue academic career training. Furthermore, senior role models spend time consulting with drug companies rather than mentoring trainees. This flight to alternative careers is reflected by the progressive shift of NIH RO1 funding from primary M.D. to Ph.D.-dominated principal investigators (in 2001: 9765 for M.D.s; 4125 for M.D./Ph.D.s; and 25,612 for Ph.D.s). Paradoxically, translational research opportunities are rapidly expanding. As genes are associated with clinical diseases, there are increased opportunities to define genotype/phenotype associations in clinical subgroups, which selectively respond to various treatments and which predict clinical outcomes. Likewise, understanding genetic/en-vironmental interactions provides an opportunity to define triggers of onset and reactivation of disease in susceptible hosts. Pharmacogenomics provide a mechanism to predict response, toxicity, and precise dosing of a particular drug in an individual. Molecular detection of dysplasia or early stages of cancers offers tremendous potential. Finally, preclinical detection of individuals at high risk for Crohn’s disease, colon cancer, familial pancreatitis, and hemachromatosis raises the potential for prophylactic therapy and avoiding environmental risks. The pool of M.D., M.D./Ph.D. and broadly based Ph.D. investigators capable of performing this translational research to bridge the gap between basic and clinical investigators must be increased. We need to recruit, train, mentor, and retain talented trainees who are willing to devote the necessary time for multidisciplinary education. Salary caps, financial disincentives, and debt repayment must be addressed. In addition, national resources for easily accessible gene, tissue, and serum banks of compulsively phenotyped patients must be developed. Finally, investigator-initiated clinical trails with appended mechanistic basic science studies must be funded, with collection of DNA for prospective or retrospective analysis. If properly coordinated and financed, this commitment to translational research can dramatically advance our understanding and clinical management of digestive diseases, with eventual prophylaxis of at risk family members and individualized treatment for genetically defined patient subgroups.