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

Comment From the Editors

Translational Research: Bridgingthe Widening Gap Between Basicand Clinical Research

Despite unprecedented opportuni-ties in basic and clinical research,

the gap between these disciplines has wid-ened. Unfortunately, training of physicianscientists, who have traditionally bridgedthis gap by translating basic science ad-vances to improved patient care is notkeeping pace. This issue mandates carefulconsideration by professional societies aswell as public and private funding agencies.

Only the most optimistic visionarycould have foreseen the dramatic ad-vances in genomics, proteomics, ge-netic manipulation, molecular and cellu-lar biology, physiology, microbiology,and immunology which have enhancedunderstanding of alimentary, hepatobili-ary, and pancreatic function and disease.Rapid detection of altered expression ofcountless genes by microarray to quan-tify and localize gene mRNA and proteinexpression by real time PCR, immuno-histochemistry or in situ hybridization,determine transcriptional regulation bysite directed promoter mutagenesis andchromatin immunoprecipitation (CHIP)analysis, and determine function bytransgenic and knockout (global or tis-sue/cell specific), antisense, RNA and vi-ral delivery of dominant negative or ag-onist molecules is now routinely appliedto digestive diseases and in vitro cellstimulation. This huge data load must beanalyzed by sophisticated bioinformaticsspecialists. Identification of susceptibilitygenes in complex genetic disorders by ge-nome wide searches can intersect hu-man murine and rat genome data bases.

This technology has led to the discov-ery of genes involved in Crohn’s disease,hemachromatosis, celiac disease, famil-ial pancreatitis, familial adenomatouspolyposis, hereditary nonpolyposis co-lon cancer, and cystic fibrosis. New mi-crobial pathogens have been identified,including Helicobacter pylori and theWhipple’s bacillus (Tropheryma Whip-pelii), as well as virulence factors forhepatitis B and C and H. pylori whichaffect infectivity, clinical outcome, and

response to treatment. Molecular mod-eling of therapeutic targets has resultedin a plethora of potential pharmaceuti-cal agents, which undergo automatedscreening for efficacy and toxicity.While the pace and productivity of thepharmaceutical industry are astounding,targets may be prioritized by anticipatedcommercial value rather than patho-physiologic importance.

New interventions available for acidsuppression, treatment of viral hepatitis,liver transplantation, inflammatory boweldiseases, and therapeutic/diagnostic en-doscopy. Clinical trials have becomemulti-institutional, multinational enter-prises. The disciplines of clinical phar-macology, clinical epidemiology, biosta-tistics, and outcome measurementshave enhanced the quality of these stud-ies. However, as the design, organiza-tion, analysis, and even reporting ofthese studies shifts from individual aca-demic investigators to the pharmaceuti-cal industry, the goal of FDA approval isemphasized rather than comparison toor combination with existing agents.

With the increasing sophisticationand specialization of both basic and clin-ical research, the gulf between these dis-ciplines has widened, with fewerbroadly based investigators capable ofunderstanding and communicating withboth sides. The complexity of both dis-ciplines takes longer to master and finan-cial incentives encourage talented clini-cians to join lucrative practices andbasic scientists to pursue industrial op-portunities rather than continue with ac-ademic training. Unrealistic caps on fel-lowship and junior faculty salaries, largeeducational debts, and limited depart-mental discretionary funds provide fur-ther disincentives to continue academiccareer training. Furthermore, senior rolemodels spend time consulting with drugcompanies rather than mentoring train-ees. This flight to alternative careers isreflected by the progressive shift of NIHRO1 funding from primary M.D. toPh.D.–dominated principal investiga-tors (in 2001: 9765 for M.D.s; 4125 forM.D./Ph.D.s; and 25,612 for Ph.D.s).

Paradoxically, translational researchopportunities are rapidly expanding. Asgenes are associated with clinical dis-eases, there are increased opportunitiesto define genotype/phenotype associa-tions in clinical subgroups, which selec-tively respond to various treatments andwhich predict clinical outcomes.Likewise, understanding genetic/en-vironmental interactions provides an op-portunity to define triggers of onset andreactivation of disease in susceptiblehosts. Pharmacogenomics provide amechanism to predict response, toxic-ity, and precise dosing of a particulardrug in an individual. Molecular detec-tion of dysplasia or early stages of can-cers offers tremendous potential. Finally,preclinical detection of individuals at highrisk for Crohn’s disease, colon cancer, fa-milial pancreatitis, and hemachromatosisraises the potential for prophylactic ther-apy and avoiding environmental risks.

The pool of M.D., M.D./Ph.D. andbroadly based Ph.D. investigators capa-ble of performing this translational re-search to bridge the gap between basicand clinical investigators must be in-creased. We need to recruit, train, men-tor, and retain talented trainees who arewilling to devote the necessary time formultidisciplinary education. Salary caps,financial disincentives, and debt repay-ment must be addressed. In addition,national resources for easily accessiblegene, tissue, and serum banks of com-pulsively phenotyped patients must bedeveloped. Finally, investigator-initiatedclinical trails with appended mechanis-tic basic science studies must be funded,with collection of DNA for prospectiveor retrospective analysis. If properly co-ordinated and financed, this commitmentto translational research can dramaticallyadvance our understanding and clinicalmanagement of digestive diseases, witheventual prophylaxis of at risk familymembers and individualized treatment forgenetically defined patient subgroups.

R. BALFOUR SARTOR, M.D.Senior Associate Editor

doi:10.1016/S0016-5085(03)00341-X

GASTROENTEROLOGY 2003;124:1178