Translational Pharmacology: Harnessing Increased Specialization of Research Within the Basic Biological Sciences

Clinical Pharmacology & Therapeutics (2008) 83, 6, 797–801 doi:10.1038/clpt.2008.83 “In confronting the enormous complexity of human behavior, the investigator has two choices. He can severely simplify the phenomena under study and base all of his conclusions on this simplified model. Or he can attempt to grapple with all the complexities simultaneously, hoping for an inspired solution. Each approach has its limitations, the first one suffering from sterility and the second from hopelessness.” —Philip Kotler1 On the basis of promising results obtained in cell culture and animal models, thousands of patients have participated in gene therapy clinical trials since their initiation in the early 1990s. However, the application of gene therapy to human therapeutics has been largely disappointing. For instance, despite the incredible potential of gene therapy, it is now clear that the performance of the viral vectors used in preclinical work is significantly dissimilar to that in humans. This example highlights the importance of translational pharmacology, an overarching term used to describe the steps required for successful integration of scientific discoveries in the treatment of human disease. To this end, translational pharmacology exists within the context of a reciprocal relationship between researchers in the basic and clinical sciences. Ideally, this continuum consists of the transfer of basic scientific findings into improved diagnosis, treatment, or prevention of human disease and the subsequent channeling of clinical findings into generating testable hypotheses that can ultimately steer basic research (Figure 1). The relationships involved in translational research. PK/PD, pharmacokinetics/pharmacodynamics; RCTs, randomized controlled trials. Pharmacology is by its very nature translational. The discipline spans from molecular studies in single-cell preparations to investigations in animal models and human clinical trials. Indeed, the significant contributions of clinical pharmacologists in both the basic and clinical sciences attest to this. However, recent years have borne witness to increased specialization in all branches of the biological and clinical sciences and therefore an increased need to integrate or bridge the sciences through creation and enhancement of translational pharmacology research. Advanced technologies, such as genomics, proteomics, bioinformatics, and humanized animal models, are powerful new tools that can assist in advancing efficacy and efficiency of translational research. Nevertheless, it is well acknowledged that the success of translational research depends not only on overcoming scientific difficulties such as interspecies differences but also on surpassing financial, ethical, regulatory, legislative, and operational obstacles.2 This issue of Clinical Pharmacology & Therapeutics presents several articles in the increasingly specialized domains of in silico, in vitro, and in vivo research that both address obstacles and offer solutions to the field of translational pharmacology via use of novel approaches and improvements to predictive models. Along the alliterative “bench-to-bedside” continuum, the domains of in silico and in vitro research are arguably the farthest from the bench. In the context of translational research, in silico methods typically involve developing and validating complex mathematical models capable of representing human disease and response to therapeutic interventions. Bies et al.3 discuss three major approaches to the application of mathematical modeling to exemplify disease progression and therapeutic responses. The authors describe the trade-off observed when focus oscillates between understanding the mechanistic underpinnings of a pharmacologic effect and understanding the entire system in which the pharmacologic effect occurs; in short, the modeling approach at one level is not interchangeable with one at the other level. Mager and Jusko4 expand on translational pharmacokinetic/pharmacodynamic (PK/PD) modeling and highlight interest in coupling in silico, in vitro, and in vivo preclinical data with relevant models to streamline the drug discovery process. Integration of findings derived from this preclinical work ultimately facilitates their transfer to clinical trials. Results obtained in clinical settings could then be re-factored into integrated mathematical models to enhance their translational potential. The authors also emphasize the need for new theoretical and experimental approaches for scaling PK/PD models derived from animal work to more accurately predict complex human responses. In addition to mathematical models, in silico research may take the form of computational screening (virtual screening) in which iterative assessments are made of the likelihood that a chemical's molecular size, shape, and charge will allow it to interact with the active site of potential targets. Recent advances in both proteomics and genomics have led to the identification of an estimated 5,000 potential drug targets.5 Computational screening allows researchers to assess the potential for up to 1047 quadrillion chemicals to theoretically interact with these targets,5 narrowing the need for further in vitro screening. The ability of computational screening to identify potential drug candidates, however, is dependent on the availability and quality of three-dimensional structural information for targets. Although this obstacle is usually circumvented by using methods such as X-ray crystallography and nuclear magnetic resonance spectroscopy, a synthesis of the aforementioned advances in proteomics and genomics, as well as advances in protein modeling, are enabling in silico researchers to determine active site–containing domains and subdomains computationally.6 Because this is coupled with increasing computing speed and capacity, future in silico research will probably play a large role in generating in vitro hypotheses involving novel chemical–protein interactions. Basic biological research encompassing a diversity of in vitro systems has contributed greatly to the development of therapeutics and our understanding of their pharmacology. Techniques ranging from high-throughput screening to drug metabolism assays are established “workhorses” in the drug development process. In recent years, a large body of promising in vitro data has been generated in systems that involve stem cells. As discussed in the Discovery article by Henderson,7 recent advances in the development of induced pluripotent stem (iPS) cells eliminate the need for human embryonic tissues and oocytes, thereby overcoming significant ethical and regulatory concerns governing current stem cell research. Because of its potential to rapidly generate an array of genetically diverse primary human cell lineages, this technology is likely to enable a wide variety of technical advances in drug-based high-throughput screening of distinct primary human cell populations using multiple platforms. As such, iPS cell–based strategies seem poised to significantly enhance the development of patient-based therapeutic strategies and aid the delineation of human disease mechanisms. In vivo research is an essential component of basic, preclinical work because in silico and in vitro techniques cannot fully model the PK/PD complexities that exist within the intact organism. It is a core desire and a common assumption in in vivo research that results obtained in animals have translational potential, at least with respect to clinical pharmacology. Indeed, the general regulatory prerequisite that drugs be tested in animals before humans suggests a belief that the physiologic handling of drugs is somewhat conserved across species. Mager and Jusko4 provide several examples of drugs for which a reasonable concordance of PK and PD properties has been shown between rats and humans. However, this assumption has faltered in the domain of drug clearance. A major impediment in animal PK studies has stemmed from prevalent interspecies differences in drug metabolism and disposition. The development and utilization of transgenic and chimeric humanized mouse models is one method by which researchers circumvent this obstacle. Muruganandan and Sinal's State of the Art article8 highlights the important application of modern transgenic technologies to develop CYP-humanized animal models to better predict the PK/PD and toxicity of drugs in humans. For instance, the CYP2D6 humanized mice not only accurately portray the metabolic and PK profiles for CYP2D6 substrates in humans but also recreate polymorphic phenotypes seen in the population. Robertson and colleagues' Translational Medicine article,9 which outlines the use of a humanized CYP3A4 transgenic mouse model to delineate tumor-mediated changes in the transcriptional regulation of CYP3A4, provides an additional example. Elevations in inflammatory mediators associated with reduced CYP3A4 metabolism and increased drug toxicity have been reported in cancer patients. Results demonstrating tumor-mediated downregulation in the hepatic transcription of the human CYP3A gene provide a much-needed mechanistic explanation of clinical observations and can further contribute to therapeutic practice. Highlighting the importance of animal models, the US Food and Drug Administration's (FDA) Animal Rule introduces the potential for drugs to be approved solely on the basis of efficacy studies in animals when clinical studies are not ethical and feasible. As discussed in this issue by Roberts and McCune,10 the FDA developed this innovative regulatory approach largely for the development of countermeasures against chemical, biological, radiological, and nuclear threats in which controlled field studies in humans are not ethical. Overall, the development of more sophisticated humanized animal models based on advances in fundamental research will enhance the capacity of preclinical research to generate results that have improved application. Furthermore, the use of these models will probably increase alongside our desire to delineate underlying environmental, pathophysiologic, and genetic factors responsible for human variability in drug response and disposition. Translational pharmacology is by no means a new concept; however, in today's research environment it faces unique obstacles stemming from increased specialization. Researchers are increasingly concerned with discrete areas of in silico, in vitro, and in vivo inquiry that are not amenable to integration. As described, these discrete areas are, in themselves, beginning to provide new solutions and technologies that can promote the potential translation of their own work. Novel initiatives have also arisen that recognize and facilitate translational pharmacology. The National Institutes of Health Roadmap initiative serves to promote and enhance translational research via the creation of a consortium of academic health centers in the clinical and translational sciences and by implementing translational research core services.11 Likewise, there has been a shift in the publishing practices of several scientific journals to acknowledge and promote translational pharmacology. For example, whereas Clinical Pharmacology & Therapeutics has historically published primary research articles focused specifically on human pharmacology, new content in the journal, such as the Discovery, Translational Medicine, Development, and State of the Art pieces, has been introduced to showcase advancements in and integration of basic and clinical research. The authors declared no conflicts of interest.

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