Animal Models in Today’s Translational Medicine World

Abstract

Translational medicine drives progress of research along the continuum from basic biomedical research findings into clinical practice. Animal models play a central role in the above continuum. The recent explosion in molecular biology and generation of human physiological system in animals has led to an increasing use of in vivo animal models in today’s translational medicine.

Translational Medicine: Introduction

Early Definition of Translational Medicine

Discovering new treatment and prevention of disease depends on a research continuum from basic biomedical research findings into clinical practice. Various methods and strategies have developed to bridge the gap between the discoveries generated in laboratory and implementing those findings in human clinical trials. The term “translational research” appeared in early 1990s but was used in the context of bench research involving molecular genetics and immunology spanning basic and clinical research.¹

“Bench to Bedside” Definition of Translational Medicine

In basic and clinical research literature, multiple attempts have been made to define ‘Translational Science’ or ‘Translational Medicine’ or ‘Translational Research.’ The National Institutes of Health (NIH) offered the following definition:

“Translational research includes two areas of translation. One is the process of applying discoveries generated during research in the laboratory, and in preclinical studies, to the development of trials and studies in humans. The second process of translation concerns research aimed at enhancing the adoption of best practices in the community. Cost-effectiveness of prevention and treatment strategies is also an important part of translational science.”²

Translational research according to the above NIH definition is continuous process with the ultimate goal of improving patient health by moving, efficiently and expeditiously, laboratory research discoveries into clinical human trials and finally to the patient bedside. The first stage of translational research also known as T1 in literature is a bridge between laboratory research and human clinical trials in which findings generated in laboratory though the means of animal models, cell culture and molecular studies can be used and forwarded for application in human clinical trials. The next stage in the continuum is considered as T2 which moves results from clinical trials eventually to clinical practice with the ultimate goal of improving community health (see Figure 1).

Figure 1.

The first stage of translational research (T1) is often carried out using animal models, cell cultures, or other experimental systems. Clinical research in the figure encompasses human subject research studies that involve direct interaction between investigators and human participants. The second translational process (T2) takes results from studies in humans and applies them in clinical practice with the ultimate goal of improving community health.

Broad Multidirectional Definition of Translational Medicine

Recently, an argument was made that the concept of translational research demonstrated in Figure 1 defines translational research too narrowly.³ Rubio et al.⁴ added a T3 arm with a new definition for translational research such that it is defined as multidirectional integration of basic, patient oriented, and population based studies leading to ultimate goal to improve public health (see Figure 2). T1 research involves bidirectional interaction between basic and patient oriented research for better scientific understanding with T2 coordinating between patient-oriented and population research for improvement of patient outcome, and finally T3 interacting between population and basic research for understanding human health and disease. Figure 2 demonstrates a dynamic interplay between basic, patient oriented, and population research with bidirectional arrows.⁴ Basic research is often considered as the first step of the translational process and as per the American Cancer Society it provides the foundation of clinical research and involves laboratory studies, including animal models.⁵

Figure 2.

Model for translational research, as proposed by the Evaluation Committee of the Association for Clinical Research Training (Adopted from reference ⁴)

Use of Animal Models in Translational Medicine

Introduction to Animal Models

The history of animal models goes back more than a millennium, when animals were used for experimental surgery. The first textbooks on anatomy were based on dissection on pigs and apes, not on human cadavers. Use of animal models is well known for some of the greatest discoveries in history. William Harvey’s great work on circulation⁶ and Louis Pasteur’s work in microbiology⁷ are few examples of use of animal model for great discoveries. Nowadays, the main use of animal models is for translational medicine and that role is considered the central point in the multidirectional paradigm of translational research.

Examples of Animal Models in today’s Translational Medicine

Translational research is primarily developed through the use of animal models. Examples in cancer research include xenografting, in which human cancer tissue is transplanted into nude mice (immunosuppressed to avoid rejection) allowing cancer development to be studied in vivo. Subsequently, the focus has shifted to development of “human physiological systems” within the mouse model. One of the steps in the development of humanized models is the production of mice with targeted mutations in genes to knock out further immune response. Human hematopoietic stem cells are then engrafted into these mice to colonize the bone marrow and differentiate into the multiple cell lineages that constitute a human immune system. These models are used in various research fields including immune, infectious and oncology research and are considered central to recent and future advances in translational research, including pharmaceutical development and personalized medicine. In a recent study by Thomas et al utilizing cultured hepatocellular cancer cells from a humanized mouse model, an experimental combination therapy was found to be effective in reducing tumor burden.⁸ The above observation led to an investigator-initiated Phase 1B-2 dose escalation trial with combination drugs in patients with HCC.⁸

In addition, selective breeding, genetic modification, and advances in molecular imaging have provided a better understanding of disease processes and insights into possible interventions that were not possible previously. For a long period of time, neurodevelopmental disorders such as autism and fragile X syndrome were considered medically untreatable. However, selective breeding and creating mouse models for behavioral phenotypes, such as the BTBR T+tf/J mouse model, have made it possible to better understand the behavioral phenotypes and design potential pharmacological interventions with the possibility that a single targeted pharmacological intervention may alleviate multiple diagnostic behavioral symptoms of autism.⁹ The robustness of such data increasingly contributes to the translation of biomedical breakthroughs from preclinical studies to clinical applications. For instance, a protein known as Sema3A was found to facilitate bone regeneration in mice by simultaneously reducing bone destruction and increasing bone synthesis, and could lead to a new class of dual-action therapeutic agents for osteoporosis in humans.¹⁰

Use of mice is invaluable for translational research because of the ease of genetic manipulations to produce mice models for human disease. A trans-NIH initiative, the Knockout Mouse Project (KOMP), was conceived in 2003 with the aim of “knocking out” each of the genes in the mouse genome to create multiple new lines of knockout mice.¹¹ This project will make knockout mice available to researchers through live mouse models, embryonic stem cell clones, or frozen embryos and sperms with the goal of developing better models of human disease.

Although mice may be considered as a standardized translational device, various other animal models including primates are being developed and available for translational research and drug discovery.¹² Similar to the Knockout Mouse Project (KOMP), the National Primate Research Centers (NPRCs) established Working Groups (WGs) for developing resources and mechanisms to facilitate collaborations among non-human primate (NHP) researchers as well as to develop Genome Banking. The Genetics and Genomics Working Groups are developing resources to advance the exchange, analysis and comparison of non-human primate genetic and genomic data across the National Primate Research Centers.¹³

Limitations of Animal Models in Translational Medicine

Similar to human clinical studies, use of animal models for translational research with the goal of translation of bench research to clinic has few limitations. Involving young and healthy animals for research always carries a risk of selection bias.^{14, 15} Natural dissimilarities between physiological and pathological system of various animal models and humans is one of the challenges of translation of bench research to clinical practice. Various remedies and approaches are underway to circumvent these differences. This includes work at the genetic, molecular, cellular, and clinical scale to understand the link between these elements within animals and humans. The ultimate goal of translating data between species via interdisciplinary approach will require techniques and expertise from mouse genetics, stem cell science, clinical research, comparative genomics, pathology, and medicine.

Conclusion

In the present era, animal modeling is considered the backbone of understanding various disease pathophysiologies and provides enormous opportunities for novel, effective therapy for a wide spectrum of presently untreatable disease and injuries. Recent advances in molecular technology are leading to the development of superior animal models and providing unprecedented opportunities to test both gene and pharmacological therapies prior to clinical trials in humans.

Biography

Abhishek Choudhary, MD, (above) and Jamal A. Ibdah, MD, PhD, are in the Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Missouri School of Medicine.

Contact: ibdahj@health.missouri.edu