Printer Friendly

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

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 by repeatedly challenging him with smallpox material and demonstrating that he remained well. This proof paved the way for the development of the standard immunizations given today. Sir Francis Darwin summed up the situation nicely, "In science credit goes to the man who convinces the world, not the man to whom the idea first occurs." It is said that Jenner, though this experiment, probably saved the lives of more people than any other person in world history. (Riedel, 2005).

In the eighteenth century, academic physicians determined to develop a comprehensive philosophy of medicine and to base their hitherto empiric practice upon that theory. Although this seems laudable in the abstract the theory was often completely incorrect. One influential theory, proposed by an Edinburgh physician named John Brown, became known as the Brunonian System of Medicine and held that all disease was caused by either an excess or deficiency of nervous excitation. (Brown, 1780). It therefore followed that the patient should be treated with either stimulants to increase excitation or sedatives to suppress it. It is an axiom of logic that a false premise admits any conclusion, and in this case the false premise led to the conclusion that patients should be exhausted by the use of copious bloodletting, purges and emesis. This period has been referred to as the heroic age of medicine, although it is easy to see that the weight of heroism was borne by the patient. The consequences of linking practice to defective theory were not long in coming.

In 1793 a yellow fever epidemic raged in Philadelphia, the first capital of the United States. The president, George Washington, and his cabinet left the city; but Benjamin Rush, signer of the Declaration of Independence, early abolitionist, foremost physician of his age, and an early advocate of Brunonian medicine, remained in Philadelphia to care for the sick, sometimes treating more than 120 patients a day. Unfortunately, his treatment consisted of massive bloodletting and calomel (mercuric chloride) purges. He was accused, quite rightly, by his contemporaries of killing more patients than he saved; but, lest we are tempted to be sententious, it must be remembered that Dr. Rush lived before the advent of clinical trials and, at that time, the opinion about whether a treatment worked or did not work was purely anecdotal. (Powell, 1965).

A more salubrious example of acting upon theory occurred in 1854 during the cholera epidemic in London, which began after the city dumped the overflowing Soho cesspools into the Thames. John Snow, a London anesthesiologist and skeptic of the prevailing miasma theory of disease, constructed a map showing cases clustered around the Broad Street pump. Although the cholera vibrio had not yet been discovered, he became convinced that cholera was water borne, and with the aid of his maps and solid statistics, convinced his local council to remove the pump handle thereby ending the epidemic. (Frerichs, 2009).

The routine use of clinical trials to test novel therapies did not emerge until the middle of the twentieth century. There are anecdotal reports of much earlier trials, the first of which is described in the Book of Daniel. Daniel, a hostage in the court of Nebuchadnezzar II, convinced the steward of the chief eunuch to allow him and his companions to continue their diet of pulses and water instead of the meat and wine served to the Babylonian youths. At the end of the trial Daniel and his companions paraded before the steward and were judged to be fatter and fairer then their contemporaries. (Book of Daniel 1:5-16).

The first clinical trial in the modern era was carried out in 1747 by James Lind, a naval surgeon aboard HMS Salisbury. This study is particularly interesting because it shows the power of the well conducted therapeutic trial; Lind was able to find a novel and efficacious therapy even though his theory was completely wrong. During the Age of Fighting Sail scurvy was a serious problem, and allegedly caused more deaths in the British fleets than French and Spanish arms. Lind believed, like his contemporaries, that scurvy was caused by the putrefaction of partially digested food in the intestinal tract. He then reasoned that providing acid as a dietary supplement might prevent the disease. William Harvey had suggested that lemons might be effective as a preventative measure because of their acidity, and Lind put this to the test in his therapeutic trial on 12 sailors with scurvy. Two sailors were given daily cider, two dilute sulfuric acid, two vinegar, two sea water, two paste and barley water, and two oranges and lemons. In six days the group receiving citrus fruits was largely cured. The British fleet eventually adopted the use of limes, which were cheaper than lemons, as a preventive dietary supplement. Interestingly, the medical establishment was slow to give up their theory of putrefaction and tended to dismiss Lind's findings, which they could not account for, as anecdotal. The reluctance to accept new observations which conflict with old theories still plagues medicine, and is well described by Lind himself in his 1753 Treatise on the Scurvy, "... it is no easy matter to root out old prejudices, or to overturn opinions established by time, custom and great authorities ..." (Dunn, 1997).

The clinical trial as we now know it did not materialize until well into the 20th century. Torald Sollmann, the dean of American pharmacology, first suggested the use of placebo controlled trials and blinded observers in 1930 in his paper, "The evaluation of therapeutic remedies in the hospital." (Sollmann, 1930). Harry A. Gold, virtually unaided, developed the double-blind method beginning in 1937. (Shapiro & Shapiro, 1997). Equally important was the development of techniques for statistical analysis. WS Gosset, a chemist working in the Guinness brewery in Dublin, developed the Student's T-test in 1908 to monitor the quality of stout. (Raju 2005). The first application of analysis of variance was published by Sir Ronald Fisher in 1921. (Fisher, 1921). Harold Hotelling introduced multivariate statistics with the T2 test in 1931 and canonical correlation in 1936. (Hotelling, 1931 ; Hotelling, 1936). Logistic regression, an analytic technique commonly used today, was not introduced in the 1970s. Regulations protecting the rights of human subjects were not codified until 1974. (OHRP, 1993).

From Theory to Practice in the AIDS Era

As devastating as the AIDS era has been, it is almost certain that the period will be assessed by future historians as one of the shining moments in the history of medicine. Therefore it will be worthwhile to consider the achievements, as well as the failures, of that period. The rapidity in which the molecular details of the HIV life cycle were uncovered, new medications designed to exploit viral weaknesses, and those drugs tested in clinical trials, licensed and put to use is breathtaking. The HIV virus was first described by Luc Montagnier in 1983 and by Robert Gallo in 1984. (Gallo & Montagnier, 2003). The first antiretroviral drug, Zidovudine (AZT), was licensed by the FDA in March 1987. There are now 35 antiretroviral drugs, including multi-class combination products, all approved in less than one year by the FDA. The result of this remarkable success in translational research is that HIV infection, once considered a death sentence, is now a manageable disease. (FDA, 2012). Each year more Americans die of end stage liver disease from Hepatitis C than from AIDS.

The development of the new antiretroviral drugs began with a careful study of the viral life cycle, which will be summarized here. (NIH, 2005). HIV is an RNA virus, meaning that its genome is encoded in RNA, rather than DNA as is the case in humans. The virus envelope is covered with a surface protein, gp120, that binds to receptors and one of two co-receptors on the host CD4 cell. Binding allows the viral envelope to fuse with the plasma membrane of the host cell, permitting the virus to empty its RNA into the host cytoplasm. The virus converts its RNA genome into DNA by means of a unique enzyme called reverse transcriptase. The viral DNA enters the nucleus and fuses with the host's genome with the help of another viral enzyme called integrase. (Craigie, 2001). The host cell cannot distinguish the integrated viral DNA from its own and transcribes it to make proteins for viral assembly. The viral proteins are produced in one long chain, and must be cut at appropriate places by proteases to become functional. New viral particles are then assembled in the cytoplasm and exit to infect new cells.

Antimicrobial therapy is designed to exploit differences between host cells and pathogens. Therefore, any unique features of the HIV life cycle are potential vulnerabilities and may be targets for carefully designed drugs. The HIV life cycle offers several such targets: 1) binding of virus to host cell, 2) transcription of RNA to DNA, 3) integration of viral DNA into host genome, and 4) protease segmentation of viral polyprotein. (NIH, 2005). Antiretroviral medications have now been licensed to attack each of these viral targets.

The first of these designer drugs was AZT, a reverse transcriptase inhibitor. The exact mechanism of AZT's action is unknown but one action is to bind to the growing DNA strand and terminate it. (Lee & Chu, 2001). Interestingly AZT was first synthesized in 1964, before HIV was discovered, as a potential agent against other retroviruses but shelved when it proved inert in mice. Soon after HIV was accepted as the etiologic agent of AIDS, the NIH began testing a series of drugs in a culture of human CD4 cells. This allowed them to make preliminary assessments of safety (does it damage the cells?) and efficacy (does it kill the virus?) before tests on humans or experimental animals. Burroughs-Wellcome donated 11 compounds for testing, including AZT. NIH scientist quickly demonstrated its safety and efficacy in tissue culture and animal models, and several months later began clinical trials at the National Cancer Institute. This phase one trial showed AZT could be safely administered to patients with AIDS, raised their CD4 counts and improved their clinical status. Burroughs-Welcome then conducted a well designed, placebo controlled, double blind study proving that treatment with AZT prolonged the life of AIDS patients. (Fischl et al, 1987). On the basis of this trial the company applied for expedited licensure and the drug was approved by the FDA on March 20, 1987. Only 25 months had passed between the time AZT's efficacy had been demonstrated in the laboratory until it was licensed for clinical use. Nucleoside (or Nucleotide) reverse transcriptase inhibitors (NRTI) are now the backbone of all antiretroviral therapy regimens.

New classes of drugs were quickly developed. These included nevirapine, a non-nucleoside reverse transcriptase inhibitor (NNRTI) licensed in 1996. The NNRTIs are believed to bind to a critical region of the reverse transcriptase itself, thereby inhibiting the enzyme from changing conformations. The first protease inhibitor (saquinavir) was approved in 1995 and the first fusion inhibitor (enfuvirtide) in 2003. In 2007 two new classes of drugs were introduced, integrase strand transfer inhibitors (raltegravir) and CCR4 co-receptor antagonists (maraviroc). The latter class of drugs, also known as entry inhibitors, is a good example of the how molecular understanding can be translated to drug design. As the authors of one review state, "Thanks to the advances in the knowledge of the molecular basis of the mechanisms involved in the entry process, it has been possible to split it into several steps and design molecules to block each one of them." (Briz, Proveda & Soriano, 2009)

Unfortunately, a new complication soon arose. Although antiretroviral therapy was effective in suppressing the HIV virus, the virus quickly developed resistance to the new drugs, leading to treatment failure. The origin of this problem lies in the virus itself. The reverse transcriptase enzyme is error prone without a mechanism to correct its errors. It is estimated that the enzyme makes one error per genome per round of replication. In addition, HIV reproduces extremely rapidly within an infected cell, producing several billion viral particles each day in the untreated patient. Because of this, it is estimated that the HIV virus within an infected person produces every possible mutation every day. Most of these mutations have reduced reproductive fitness compared to the wild strain, but if the environment is changed by the addition of antiretroviral therapy, these mutants may be favored and proliferate. (Zdanowicz, 2006). Because of these factors almost all patients on antiretroviral monotherapy eventually develop drug resistance.

This problem was solved, or at least mitigated, by treating HIV patients with multiple drugs from several different classes. In one large scale study of patients on ART 72-80% were resistant to drugs from one or more classes, 48% to drugs from two classes and 13% to drugs from three classes. (Richman, 2004). For this reason monotherapy is no longer used. New HIV patients begin triple therapy, with drugs from two classes. A typical regimen will be composed of two nucleotide reverse transcriptase inhibitors (NRTI) and one non-nucleoside reverse transcriptase inhibitor (NNRTI). Alternatives include two NRTIs and one protease inhibitor, or two NRTIs and an integrase inhibitor. (Sax, Cohen & Kuritzkes, 2011). Thus there are dozens of combinations of ART drugs from which to choose in treating a new HIV patient. But this presented a further problem--which combinations were best? This was a question to which basic research had only limited answers. Certain combinations were thought inadvisable because of similar resistance patterns or additive toxicity, but in many cases theory could not predict why one combination worked whereas another did not. The answer had to be worked out empirically, in multicenter clinical trials. Fortunately, US HIV researchers agreed to collaborate and share information in large, multicenter study groups, thereby accelerating the pace of research.

The HIV experience has taught us that the fundamental insights obtained in focused basic research can result in clinical trials and practical applications in months. It also shows that unforeseen problems arise in clinical application that cannot be explained by existing theory. However, these clinical conundrums present new problems for basic researchers to ponder. The lessons learned from the AIDS epidemic are already being applied to other diseases. A detailed study of the Hepatitis C virus life cycle has yielded two protease inhibitors that have been studied in numerous clinical trials and shown to improve cure rates in certain hard to treat groups by 30%. (Pearlman, 2012). Other drug classes, including RNA polymerase inhibitors, are currently undergoing clinical trials.

The New Frontier

What is the new frontier for translational research? Some predictions can be made with confidence. It is almost certain that the translational techniques pioneered during the AIDS epidemic will be applied to viral diseases which are either newly discovered or have no specific therapy. Molecular biologists will study the life cycle of these pathogens and design drugs that exploit these insights. But what opportunities await that are less obvious?

The first area that comes to mind is the use of complementary and alternative medicine (CAM). At first glance research in CAM seems to be oriented in the opposite direction from the translational research that has been described so far. It is not so much a matter of bringing proposed therapies to practical application as it is to validating the efficacy of existing therapies and discovering the basis for their putative effects. In other words, CAM research seems like it is moving from bedside to bench, rather than the reverse. However, preliminary research into some CAM modalities raises basic questions that may find their application in novel and exciting therapies. Take the example of acupuncture. There is now general acceptance throughout western medicine that acupuncture has legitimate therapeutic applications. NIH has even released a consensus statement that acupuncture is clearly effective as treatment for postoperative, chemotherapy and pregnancy induced nausea and vomiting and for postoperative dental pain. The NIH panel also admitted that acupuncture might be useful as adjunctive therapy for such diverse problems as addiction, tennis elbow and fibromyalgia. (NIH, 1997). But although there is a consensus that acupuncture is effective for some ailments, there is little understanding of its mechanism of action. Recently, researchers have used new neuroimaging techniques, such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) to study acupuncture. (Hammerschlag, 2009; Rosen, 2009). These studies suggest a new paradigm for understanding the central nervous system with connections between the autonomic nervous system, the neuro-immune system and hormonal regulation. (Cho et al. 2006). It is quite conceivable that this new understanding, fueled in part by CAM research, will lead to novel therapies in the future.

A second area that has great research potential concerns understanding the genetic differences among patients that explain their differential responses to medications. If one examines the results of any clinical trial of a new drug it will be found that some of the experimental subjects respond favorably whereas others do not. If we could better understand these differences in response we could individualize therapy. Although in most cases we cannot say why a patient did or did not respond to therapy, in some cases we can. It had been observed that Afro American patients have much lower cure rates (sustained virological response) for Hepatitis C than do Caucasians, when treated with pegylated interferon and ribavirin. It turns out that a single polymorphism near the IL28B gene on chromosome 19 is associated with a two-fold reduction in response to interferon, and that this allele is much more frequent in Afro American patients than it is in those with a European ancestry. (Ge et al, 2009). A second example of genetic differences comes from HIV therapy. Abacavir (ABC), an NRTI, is an especially valuable antiretroviral drug because viral strains that are resistant to AZT and lamivudine (3TC) are usually sensitive to Abacavir. However, some patients have a severe and sometimes fatal hypersensitivity to the drug. It was found that this sensitivity was associated with the presence of HLA-B*5701. This HLA-B allele occurs in about 5% of European populations but in up to 10% of some Indian subpopulations. Screening for this polymorphism has virtually eliminated the hypersensitivity reactions and preserved the drug as a useful therapeutic agent. (Mallal, et al. 2008).

Translational Research in Clinical Practice

Now consider how an individual physician might engage in translational research, moving back and forth between basic science and clinical care. One example is the practice of Dr. William Nyhan, a specialist in metabolic disease and formerly Chairman of Pediatrics at the University of California, San Diego School of Medicine. The following account is based on a lecture given by Dr. Nyhan in February 1984. His remarks are paraphrased here. "Sometimes I encounter a child whose symptoms suggest a metabolic disease but who tests negative for all known disorders. I know that many children with metabolic diseases excrete abnormal substances in their urine, so I take a specimen back to my lab and run it through a gas liquid chromatograph (GLC) to separate and analyze the compounds in the patient's urine. The GLC output is a graph that shows a series of peaks, each peak corresponding to a different substance. I compare the graph of the patient's urine with the graph from a healthy patient. If I see abnormal peaks I know that the child has something in his or her urine that shouldn't be there. Then I ponder what kind of compound would make peaks like that. I make a guess, based on my knowledge of metabolites and GLC, and then synthesize that compound. I then run it back through the GLC and compare the outputs. I keep tinkering until I can find a compound that, when passed through a GLC, produces an output that perfectly matches the abnormal peaks in the patient's urine. Now I have a candidate substance. I then design a test for this compound in urine. Then I study the charts of metabolic pathways to determine at what point a disruption would result in such a compound being excreted into the urine." The virtue of this approach to clinical care is undeniable and has resulted in the discovery of several new diseases. (Jellum, Stokke & Eldjarn, 1972). This approach has been used in many fields of medicine as practitioners transition from population-based guidelines to a more personalized approach. Although this approach is exciting it presents numerous obstacles that must be overcome during its translation from bench to bedside.

The Role of Research Administrators

In light of this discussion the interested research administrator may wonder what role he or she has to play in advancing translational research. The authors offer the following suggestions based on their years of experience in basic research, clinical research and patient care.

1) Basic science researchers, and to a lesser extent clinical researchers, have a very narrow focus, and therefore are often not aware of other research that goes on in their own institution. Bringing basic scientists together with their clinical counterparts will stimulate new ideas and collaboration. Holding institutional conferences will not suffice. Clinicians must see laboratories and molecular biologists must see clinics. Social networking may provide a technological bridge to achieve this objective.

2) Encourage participation in large multicenter trials. These are usually well designed and will allow your junior researchers to collaborate and interact with senior investigators.

3) Hire an experienced statistical consultant who understands machine learning and involve him or her in every aspect of the research program. Statistical software packages are not a substitute.

4) Encourage postdoctoral fellows in clinical specialties to participate in both a basic research project and a clinical one so that they will be exposed to a wide array of research tools and learn skills necessary for both types of investigation.

5) Insist upon excellence in research design. Use blinding, randomization and placebo controls when applicable. Poorly designed trials waste money and convince no one.

6) Bring in guest speakers who have new techniques and new approaches to research problems. Examples include catastrophe theory, chaos theory, neural networks, complexity and nanotechnology.

7) Eliminate funding stovepipes that separate support for basic and applied research.

8) Foster public-private partnerships to facilitate innovation transfer.

Reflection

The metaphor upon which this issue of the Journal is built is that of transformation, and it is difficult to imagine a more fitting example of transformation than translational research itself. Translational research seeks to transform our understanding of how the world works into something practical, something that can used to relieve human suffering. Although humankind has struggled with this problem since before the advent of human history, it is only in the past one hundred years that our efforts have become scientific, with the beginning of controlled clinical trials. The emergence of research administration as a profession has paralleled the growth in our understanding of research design and human subjects protection. Although once thought of as consisting of little more than clerical and bookkeeping duties for assisting biomedical or physical science research, research administration now embraces leadership to assist research in history, law and ethics, other academic disciplines and technical specialties. It is very likely that, in the future, it will be research administrators, rather than the scientists themselves, who will promote the innovative direction upon which research will proceed. And, like midwives, research administrators cannot determine what will be delivered, but they will play a crucial role in ensuring the quality of the product. Are research administrators ready to assume that role and that responsibility?

Authors' Note

The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. Government.

References

Briz, V., Poveda, E. & Vincent Soriano, V. (2006) HIV entry inhibitors: mechanisms of action and resistance pathways. J. Antimicrob. Chemother, 57(4): 619-27

Brown, J. (1780) The elements of medicine. London. Retrieved from: http://books.google.com/books?id=ZgeyjjWsSFwC&printsec=frontcover&source=gbs_ge_summary_r&cad=0#v=onepage&q&f=false

Cho, Z.H., Hwang, SC, Wong, EK, Son, YD, Kang, CK, Park, et al. (2006) Neural substrates, experimental evidences and functional hypothesis of acupuncture mechanisms. Acta Neurol Scand, 113: 370-377.

Craigie, R. (2001) HIV integrase, a brief overview from chemistry to therapeutics. J Biol Chem 276, 23213-23216.

Dunn, P. (1997) James Lind (1716-94) of Edinburgh and the treatment of scurvy. Arch Dis Child Fetal Neonatal Ed, 76:F64-F65

Eliade, M. (2005) The myth of the eternal return. Princeton Univ Press.

Eliade, M. (1957) The sacred and the profane. Boston: Harcourt, Inc.

Fischl, M., Richman, D., Grieco, M., Gottlieb, M., Volberding, P., Laskin, O. et al. (1987) The efficacy of Azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-Related Complex. NEJM 317:185-191.

Food and Drug Administration. Antiretroviral drugs used in the treatment of HIV infection. Retrieved from: http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/hivandaidsactivities/ucm118915.htm

Frazer, J. G. (1922) The Golden Bough retrieved from: http://www.bartleby.com/196/5.html

Frerichs, R.(2009) John Snow. Retrieved from: http://www.ph.ucla.edu/epi/snow.html

Fisher, R.A. (1921) On the "probable error" of a coefficient of correlation deduced from a small sample. Metron 1: 3-32.

Gallo, R. & Montagnier, L. (2003) The discovery of HIV as the cause of AIDS. N Engl J Med, 349:2283-2285

Ge, D., Fellay, J., Thompson, A. J., Simon, J. S., Shianna, J. S., Urban, T. J., et. al. (2009) Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 461:399-401.

Mallal, S., Phillips, E., Carosi, G., Molina, J-M., Workman, C., Tomazic, J., et al. (2008) HLA-B*5701 Screening for Hypersensitivity to Abacavir. N Eng J Med 358: 568-579.

National Institutes of Health (2005) The HIV life cycle. AIDSinfo, Retrieved from: www.aidsinfo.nih.gov/contentfiles/HIVLifeCycle_FS_en.pdf

National Institutes of Health (2009) Institutional Clinical and Translational Science Award. Retrieved from: http://grants.nih.gov/grants/guide/rfa-files/RFA-Rm-06-002.html

Hammerschlag, R. (2009) Acupuncture, an evidence based assessment. National Center for Complementary and Mternative Medicine, NIH, Retrieved from: https://videolectures.nccam.nih.gov/module4/module4.php

Hotelling, H. (1931) The generalization of Student's ratio. Ann Math Stat 2: 360-378.

Hotelling, H. (1936) Relations between two sets of variants. Biometrika 28: 321-377.

Ivetac, A. & McCammon, J.A. (2009) Elucidating the inhibition mechanism of HIV-1 non-nucleoside reverse transcriptase inhibitors through multicopy molecular dynamics simulations. J Mol Biol 388(3): 644-58.

Jellum, E., Stokke, O., & Eldjarn, L. (1972) Combined use of gas chromatography, mass spectrometry, and computer in diagnosis and studies of metabolic disorders. Clinical Chemistry 18(8):800-809.

Lee, K. & Chu, C.K. (2001) Molecular modeling approach to understanding the mode of action of 1-nucleosides as antiviral agents. Antimicrob Agents Chemother. 2001 January; 45(1): 138-144.

Lee, M. (2001) William Withering (1741-1799): A Birmingham lunatic. Proc R Coll Physicians Edinb 31: 77-83.

National Institutes of Health (2005) Institutional clinical and translational science award. retrieved from: http://grants.nih.gov/grants/guide/rfa-files/RFA-RM-06-002.html

National Institutes of Health (1997) NIH Panel Issues Consensus Statement on Acupuncture. Retrieved from: http://www.nih.gov/news/pr/nov97/od-05.htm

Office of Human Research Protections (1993) IRB handbook. Retrieved from: http://www.hhs.gov/ohrp/archive/irb/irb_guidebook.htm

Osborn, D. (2010) Greek medicine. Retrieved from: http://www.greekmedicine.net/b_p/Four_Humors.html

Pearlman, B. (2012) Protease inhibitors for the treatment of chronic hepatitis c genotype -1 infection: the new standard of care. Lancet Inf Dis. Retrieved from: http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(12)70060-9/abstract

Powell, J.H. (1965) Bring out your dead: The great plague of Yellow Fever in Philadelphia in 1793. Time Incorporated.

Raju, T. (2005) William Sealy Gosset and William A. Silverman: two "students" of science. Pediatrics 116(3): 732-5.

Richman, D.D., Morton, S.C., Wrin T, Hellmann N, Berry S, Shapiro ME Bozzette SA. (2004) The prevalence of antiretroviral drug resistance in the United States. AIDS. 2004 18(10):1393-401.

Riedel, S. (2005) Edward Jenner and the history of smallpox and vaccination. Proc (Bayl Univ ivied Cent). January; 18(1): 21-25.

Rosen, B. (2009) Neurobiological correlates of accupuncture. National Center for Complementary and Alternative Medicine, NIH, Retrieved from: https://videolectures.nccam.nih.gov/module10/module10.php

Sax, P., Cohen, C. & Kuritzkes, D. (2011) HIVessentials. (4th ed Sudbury, MA: Physicians Press.

Shapiro, A. & Shapiro, E. (1997) The powerful placebo: From ancient priest to modern physician. Baltimore: Johns Hopkins.

Smithsonian Institution (2004). Arctic Studies Center: Transformation mask. Retrieved from: http://www.mnh.si.edu/arctic/features/croads/amaskl.html

Sollmann, T. (1930) The evaluation of therapeutic remedies in the hospital. JAMA 94(17): 1279-81.

Twyman, R. (2004) A brief history of clinical trials. Retrieved from: http://genome.wellcome.ac.uk/doc_WTDO20948.html

Zdanowicz, M. (2006) The pharmacology of HIV drug resistance. Am J Pharm Educ 70(5), 100.

Bruce R. Boynton, MD, MPH, FAAP

Fast Track Medical Director

Corizon Healthcare

105 Westpark Drive

Brentwood, TN 37027

Tel: (615) 707-0683

Email: Bruce.Boynton@corizonhealth.com

Eric Elster, MD, FACS

Chairman, Department of Surgery

Uniformed Services University of the Health Sciences

4301 Jones Bridge Road

Bethesda, MD 20814

Tel: (301) 319-8632

Email: eric.elster@med.naw.mil
COPYRIGHT 2012 Society of Research Administrators, Inc.
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2012 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Author:Boynton, Bruce R.; Elster, Eric
Publication:Journal of Research Administration
Article Type:Report
Geographic Code:1USA
Date:Sep 22, 2012
Words:6127
Previous Article:From the editor's desk.
Next Article:Nursing research: understanding nursing innovations for the transformation of communities of care.
Topics:

Terms of use | Privacy policy | Copyright © 2019 Farlex, Inc. | Feedback | For webmasters