Translational research: a historical overview and contemporary reflections on the transformative nature of research.

Author:Boynton, Bruce R.
Position:Report
 
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Introduction

Recently, translational research has become a frequent topic of conversation in the health policy arena. As construed by the National Institutes of Health, the term translational research encompasses two distinct areas: 1) the process of applying discoveries generated during research in the laboratory, and in preclinical studies, to the development of trials and studies in humans, and 2) research aimed at enhancing the adoption of best practices in the community. (NIH 2005).

At first glance, the importance of such work seems so obvious that the layperson might be excused for asking why translational research has only now come to the attention of health policy leaders. The explanation lies in the increasing compartmentalization of research. Basic research, which seeks to discover the underlying principles of the natural world, is fundamentally different from applied research, which seeks to discover ways to influence or control that world. Basic researchers and applied researchers not only differ in their training and the tools they bring to research problems, but also in the way they think about the research process, and the mechanism by which their research is funded. There is seldom much interaction between molecular biologists studying the genome of a virus and clinicians conducting a clinical trial of therapy. They both may be studying the same disease, but they live, as it were, in different worlds and have different roles.

In recent years governmental agencies and pharmaceutical firms have invested considerable assets into basic science research, with the expectation that a greater understanding of the pathophysiological processes underlying disease will produce therapeutic applications and improved health outcomes. However, it is clear that funding agencies are dissatisfied with their return on investment. They point out, with some frustration, that although our understanding of disease at a molecular level has grown exponentially, the application of that understanding to disease prevention and treatment has lagged far behind. The expected breakthroughs in disease treatment have been slow to materialize. Hence the interest in translational research: How can we bring the new basic science insights from bench to bedside?

But exactly what is translational research? What does it comprise? How does one do it? Is the gap between theory and practice more a theoretical problem or a practical one? Is translational research merely a matter of rushing new drugs to market and funding novel but improbable research proposals? Unfortunately, most published and widely cited definitions of translational research are not helpful. Many descriptions are overly vague or cloaked in impenetrable prose. Consider the following explanatory excerpt from a government document: "... synergize multidisciplinary and inter-disciplinary clinical and translational research and researchers to catalyze the application of new knowledge and techniques to clinical practice at the front lines of patient care." (NIH, 2009).

If translational research consists of nothing more than an attempt to turn theorems into therapies, it is of little interest to us here. However, the thesis of this article is that translational research is a topic of fundamental importance; it is a way of thinking about and carrying out research that links insights, applications and clinical needs. We contend that the issues involved in translational research (linking our fundamental insights about how the world works with our attempts to control it) are as old as humankind. We shall trace, throughout the history of medicine, successful and unsuccessful attempts to bridge the gap between medical theory and practice using examples from the experiences of William Withering, Edward Jenner, Benjamin Rush and John Snow. Further examples will examine how basic virology research has spawned new HIV drugs, an instructive case of successful translational research. We shall give a detailed example of how one prominent physician, Dr. William Nyhan, a specialist in pediatric metabolic disease, seamlessly combines bench research and clinical practice. We shall then discuss the frontiers of translational research application, using examples from complementary and alternative medicine and the individualization of pharmacotherapy. Finally, we shall give pointers about what research administrators should know about translational research, how they can promote it and how they can manage translational research programs.

The History of Translational Research

The attempt to bridge the gap between theory and practice predates civilization itself. Our prehistoric ancestors constructed theories to explain how the world works and encoded them in myth. These myths explained such things as how the world came to be, the origin of illness and the relationship between the spiritual realm and everyday life (the sacred and the profane). Our ancestors also had practical problems. Some of these problems were straightforward, such as how to shoot an arrow or spear a fish. Other problems were more complex, such as how to ensure that there was a continuing supply of food to feed the tribe. Our ancestors dealt with the former class of problems by developing practical skills that were passed to new group members. They dealt with the latter class of problems with a primitive version of applied science, which we now call magic. (Eliade, 1957, Eliade, 2005).

An example will illustrate this. The Inuit of Alaska believed that the moon was inhabited by ferocious beings, part animal and part human, called tunghak. These tunghak controlled the passage of animal spirits between heaven and earth and, if displeased, might punish the tribe by withholding the flow of game. (Smithsonian, 2004). This was the theory. Now, how could the theory be applied to the practical problem of feeding the tribe? This job fell to a specialist, called a shaman, whose task it was to intercede with the tunghak, on the tribe's behalf. Using the principle of sympathetic magic (Frazer, 1922), in which an effect can be produced by imitating it, the shaman carried out rituals wearing carved masks that represented the tunghak. Many of these masks have wooden hands attached to their sides; hands with holes in their palms and amputated thumbs. By giving the tunghak deformed hands the shaman ensured that they were unable to grasp the animals and withhold them from the people. (Smithsonian, 2004).

Western medicine, on the other hand, has been dominated throughout its history by empiricism. The prevailing explanation of disease during the classical age was an imbalance in the four constituent humors (blood, phlegm, yellow bile and black bile). This theory was promoted by Hippocrates and Galen and passed by Islamic physicians to medieval healers. (Osborn, 2010). But whatever the beliefs of the classical world about the etiology of disease, whether caused by an offended deity or an imbalance of humors, healers observed that some treatments worked whereas others did not. Thus physicians tolerated a gap between their theories of disease etiology and their therapeutics.

It is now known that some of the ancient folk remedies were very efficacious and, on occasion, investigation into their mechanism of action led to genuine medical advances. In the eighteenth century William Withering, an English botanist, chemist and physician, learned of an old woman in Shropshire who was using a polyherbal formulation to treat congestive heart failure, then known as dropsy. After studying the concoction he determined that digitalis, a cardiac glycoside extracted from the foxglove, was the active ingredient and documented its effective use in 156 patients. (Lee, 2001).

The case of Edward Jenner and the development of vaccination is a particularly instructive example of reasoning from clinical observation. Although the story is well known there is widespread misunderstanding of the role Jenner played. The immunity of milkmaids who had prior cow pox (vaccinia) to smallpox infection had been observed by other investigators before Jenner, and at least five of these had attempted vaccination. Jenner's contribution was not only to vaccinate 8-year old James Phipps with cowpox but to prove the child's subsequent immunity...

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