Translational research in liver disease† (2008)

The goal of the American Association for the Study of Liver Diseases is to prevent and cure liver disease, and thus the association represents a group of individuals who are, by definition, dedicated to the support of research that is translational, rather than pure discovery. A major problem is exactly what constitutes translational research, and the definition often depends on who is doing the counting and why. Unfortunately, to borrow a phrase from United States Supreme Court justice Potter Stewart, this is not a case of “I know it when I see it.” In its broadest definition, translational research encompasses any research activity that is related to the diagnosis, treatment, or prevention of disease or the maintenance of human health; however, the relationship of a given research activity to a specific disease state may lie in the eye—or the need for justification—of the writer. HALT-C, Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis trial; HCV, hepatitis C virus; NIH, National Institutes of Health. A stricter definition of translational research is that it is dependent on the use of human tissues or samples. For liver disease, in particular, there are many areas in which there is literally almost no substitute for human samples. For example, for my own research on the immunology of hepatitis C virus (HCV), the only widely accepted animal model is the chimpanzee, which is extremely expensive and restricted to a few groups of investigators. Due to the ability to manipulate immune responses, the existence of this animal model was a key factor in understanding the role of adaptive immune responses in acute HCV infection,1, 2 yet other questions can only be answered in fibrosis progression in humans. For example, the role of cellular immunity is best studied in humans, because chimpanzees do not appear to develop significant fibrosis with chronic infection. Other examples abound, and even those with long-standing research programs using animal models might concede that the ease of manipulation of the model often inversely correlates with the relationship to the disease state under study. Many factors have been implicated in the increase in pure discovery, as opposed to disease-oriented research, including a decline in the proportion of those with National Institutes of Health (NIH) Research Project (R01) grants who are M.D.s, the explosion of molecular biology, and even the dramatic increase in the NIH budget.3 There are additional factors that are appropriate to ponder, such as whether the well-recognized pressure in academic settings to publish large numbers of articles in high-quality journals plays some role in the process. When deciding whether or not to submit a manuscript to a journal, a common mechanism is to examine whether or not similar types of articles have been published in that particular journal. In order to determine how well top journals, including HEPATOLOGY, support translational research, I examined the track records of journals in terms of publication. To conduct this study, I focused on selected top biomedical journals, geared toward both the general biomedical research community, and those within the field of gastroenterology. I excluded journals that focus on clinical research, as well as journals that publish other scientific disciplines, such as astronomy or physics, in addition to medicine. I then compared the total number of original published articles with the percentage identified as translational by my own highly arbitrary definition of the same. For the purposes of this analysis, these articles were defined as original studies that utilized any human material, required bench laboratory resources, were linked to some disease state, and were published within 2006 (in order to allow review of the article). Thus, clinical trials or studies of human cell lines characterizing basic signaling pathways unrelated to any disease state were not counted, but studies that described expression of aberrant genes in human disease samples and tested this hypothesis using transgenic mice were included. At this point, I shall take the obvious step of pointing out that this definition might not pass review by my fellow editors, let alone rigorous peer review. Moreover, the identities of these journals are deliberately not being disclosed to protect the (innocent) editors of these journals. For the top general journals in medical research, which do not have a particular disease focus, the percentage of articles meeting this definition was only 20% of all original articles. For the top journals within the general field of gastroenterology and hepatology, the percentage was higher overall, but still was around 40% of all original articles. Of note, approximately half of the articles that were designated as “human” by the National Library of Medicine PubMed database met this definition. I did not examine trends over time, but certainly the sense among many, including the leadership of the NIH, is that clinical or translational research has declined in prominence compared to pure discovery. Certainly it is easier as an author to clearly state a hypothesis and test it in a cell line or animal model. Human studies are fraught with confounding variables, and it can be difficult for both authors of a study and reviewers to sort out what is relevant and what is not. For example, in a study of immune responses in HCV, concomitant alcohol use might or might not influence the results of the study, yet it can be difficult to accumulate a cohort when the resources to perform validated alcohol surveys are not available to the individual investigator. The role of Associate Editor often requires one to balance the demands of the reviewers for additional data with the need to publish the major findings of a study: will the need to acquire additional patient material, and the time required to do so, substantially improve the article? An additional challenge in the field of liver disease is the lack of a research infrastructure to support translational research. Translational research is more difficult, and may even be impossible, for an individual researcher to accomplish, than are experiments using isolated cell lines or transgenic animals. Several disciplines have benefited from the existence of large networks in which the emphasis may be on clinical trials but where a strong tradition exists of parallel laboratory-based research to complement the clinical research in a broad area; examples include the AIDS Clinical Trials Group and the National Cancer Institute Cancer Centers. Although individual institutions have maintained centers in liver disease, there has been no long-standing multicenter research groups focused on liver diseases. Networks have been created to address specific questions—for example, the HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) network was formed to address the question of whether long-term maintenance with interferon was beneficial in patients with chronic HCV infection—but after the specific question was addressed these networks have been disbanded. Given the investment involved in developing and maintaining the infrastructure of a network, it is unrealistic to expect that NIH, in these days of constrained resources, will develop new networks. One solution is to invite those who organize clinical trials to think creatively about ways to engage those with basic research interests in ancillary studies that can be conducted in the framework of a given clinical trial. This can be challenging, because the requirements for timely and adequate sample collection for a laboratory-based study may conflict with the main study; my clinical colleagues on the ancillary studies of the HALT-C network will surely attest to some of the difficulties we encountered over the years in putting these studies together.4 Again, based on personal experience, I would submit that the best way to do this is to engage both the clinical trial team and the basic research team at the outset of the study, rather than performing retrospective analysis of samples collected without a specific research question in mind. For their part, basic researchers need to examine the relevance of their models and examine whether observations made in vitro or in animal models can be confirmed in the setting of human disease. I think we can all do better at translating the findings at the bench to the clinic, and back again, but it requires the clinical and basic research teams to work together.