About the Authors
n 1998, Yoram G. Weiss, M.D., was a well-trained and reasonably accomplished anesthesiologist/intensivist at the Hadassah Hebrew University Medical Center in Jerusalem. Like many university physicians in Israel, he was told he needed to spend “time in America” to solidify his academic credentials. Therefore he sought an additional educational experience in critical care in the United States. Since he had received extensive training in critical care, both as part of the basic residency in Israel (which encompasses five years and includes a full six months of critical care) and as a fellow, clinical work was only a small part of his interest. More importantly Dr. Weiss wanted some sort of formal training in research.

At the time, Clifford S. Deutschman, M.D., was an associate professor at the University of Pennsylvania. Beyond the care of the critically ill surgical patient and the education of others in this discipline, Dr. Deutschman’s primary interest was in the molecular changes induced in the liver by sepsis. He had developed a modestly successful “boutique” research program but had never thought beyond investigating hepatic abnormalities. Dr. Weiss’ application for a fellowship dramatically changed things for both of them.

Sepsis Study
During the first year of a two-year fellowship, Dr. Weiss distinguished himself as an outstanding clinician and teacher. More importantly, however, he convinced Dr. Deutschman to rethink the animal model of sepsis that had been used to study sepsis. Dr. Weiss was interested in changes in the lung and was looking for an appropriate model. After several conversations with Irshad Chaudry, the renown Ph.D. researcher who had first proposed and standardized the “cecal ligation and puncture” (CLP) model of sepsis in mice and rats, we became convinced that this approach also would affect the lungs. Specifically, preliminary studies made it clear that CLP induced significant lung injury that was analogous to acute respiratory distress syndrome (ARDS), as it most often arose in surgical patients. Dr. Deutschman’s work with the liver had demonstrated that sepsis pathologically altered gene expression. Dr. Weiss was convinced that the same was true in the lung and set out to identify a deficiency. Once this was accomplished, they hit upon the idea that these abnormalities could be corrected using “gene therapy;” that is, restoring expression of an underexpressed gene by introducing a copy of that gene attached to an attenuated adenovirus. The lung was especially well-suited to this approach as the techniques had been standardized by others and because tracheal instillation limited viral spread to other organs. Dr. Deutschman, as a somewhat more-seasoned investigator, expressed skepticism but was won over by Dr. Weiss’ energy and enthusiasm. The results, detailed in the Journal of Clinical Investigation in 2002 were, in their opinion, remarkable.

Trans-Atlantic Collaboration
When Dr. Weiss returned to Israel, they both desired to continue their collaboration. This time, however, skepticism was bilateral. The ability to maintain a useful trans-Atlantic collaboration is difficult for basic scientists. For two busy clinicians, the idea seemed almost foolish. Nonetheless mutual interest and a relationship that had grown from a shared professional interest to a strong friendship made it important that they try. Today, seven years after the initial meeting, they have been able to create a true trans-Atlantic collaborative research endeavor, which involves mutual research projects, joint grant proposals and the opportunity for meaningful intellectual discourse. They have drawn in important collaborators on both sides of the Atlantic. In addition Dr. Weiss has been able to establish a thriving research initiative despite the difficulty inherent in doing so, and Dr. Deutschman has expanded the scope of his work to include areas he never dreamed of exploring.

It is clear that the binational research collaboration has been useful for the two authors of this article. What, however, is the value in sharing this experience with the general ASA readership?

Authors Reflect on Research
We believe there are several important lessons. The first lies in an understanding of just what anesthesiologists in countries other than the United States do and how that differs from the American experience. The second relates to the re-establishment of critical care as a primary focus of anesthesiologists in this country. Finally we believe that the future of both academic medicine and anesthesiology as a medical specialty lies in translational research. There are strengths and weaknesses, and similarities and differences, in the way anesthesiologists practice both in the United States and in Israel.

Our research collaboration has provided us with a firsthand basis for comparison. Of direct importance here, critical care is more strongly emphasized in Israel. Thus more anesthesiologists include the intensive care unit in their practice. In the United States, more educational programs are able to provide an opportunity for fellows and junior faculty to engage in research. Thus there are more investigators in the United States.

In both places, however, there is an increased emphasis on clinical service, to the detriment of “academic” endeavors and subspecialty practice. Therefore the number of individuals either interested in or able to engage in either critical care or investigative activities is declining. The economic price for those pursuing an academic/research career is limiting participation.

We feel that this current trend is unfortunate. Our experience is that research is enjoyable, stimulating and essential to understanding the diseases we treat and of key importance in providing value to our patients.

Increasing Challenges
Despite the great strides we have made in the treatment of diseases in the critically ill, mortality and morbidity remains high. In essence this is because the pathophysiology of sepsis, septic shock, ARDS, myocardial ischemia, multiple organ dysfunction and “chronic critical illness” remain poorly understood. In the near future, the problem is certain to increase as enhanced life expectancy results in an increase in the number of patients admitted to ICUs with these syndromes. In addition, dysfunction will be aggravated by chronic disease in these older individuals. This represents the true challenge to critical care physicians in the near future.

Currently our approach to the treatment of patients with sepsis, septic shock, ARDS, myocardial ischemia, multiple organ dysfunction, asthma, exacerbations of chronic obstructive pulmonary emphysema and other forms of critical illness is primarily supportive. Because most research into these syndromes has focused on their early initiating phase, we have some understanding of the pathophysiologic changes that precipitate these deadly disorders. Most arise, at least in part, from an overexuberant inflammatory response. We can manage these early phases of inflammation appropriately, and death from hyper-inflammation is rare.

We are, however, fundamentally ignorant with respect to the abnormalities that perpetuate and extend these deadly syndromes. We lack understanding of the subacute and subchronic pathophysiological changes that follow the initial inflammatory response. This has led to a situation where patients transition from an acute, inflammatory illness (which may arise from a number of initial disorders) into a state of “chronic critical illness.” In this paradigm, patients settle into a remarkably stable state that also is remarkably abnormal. They can be kept alive almost indefinitely but require exogenous support of virtually all organ systems.

We have yet to decipher the abnormalities that lead to chronic critical illness or how the initial inflammatory response precipitates this situation. This remains a basic flaw in critical care practice.

Research Process
A gap in the understanding of a medical condition requires research. While it is important to study the fundamental behavior of molecules and cells, we believe that physicians are best suited to investigate conditions directly related to the diseases and syndromes that they treat. The hope of physician-scientists is that their findings can be applied directly to patient care. Given our lack of knowledge regarding the effects of inflammation and the transition from inflammatory state to chronic critical illness, we chose to investigate aspects of this particular enigma.

Translational research is a multifaceted process. Our joint approach has been to start with a basic assumption regarding a process that often requires the use of an animal model to simulate one of the diseases that kill our patients. On occasion we need to examine processes and effects that, using current techniques, cannot be investigated in animals. In those cases, we resort to cell culture experiments. This “hypothesis-testing” approach represents the first phase of translational research. It is hoped that this type of laboratory research will culminate in a proven hypothesis that can be extended to patient care at other institutions in Israel, the United States and in Switzerland.

Thus the object is to provide the basis for a clinical trial, an approach often referred to as “bench-to-bedside.” The ability to study complex biochemical and cellular processes, in animals or cell preparations, requires the participation of people of diverse talents. While physicians can best identify the problems to be studied, they most often lack expertise in the techniques required to optimally study these issues. Their participation is priceless. Thus a multifaceted team is required. Since the breadth of expertise required may be vast, participation of more than one academic institution may be optimal.

Identification of abnormalities that contribute to the pathogenesis of a clinical syndrome is another key aspect of translational research. Some translational research is therefore based on the study of large populations of patients. Such studies require the involvement of many clinical centers to achieve significance. This approach is designed to define specific groups of patients who may present with a specific biochemical/physiologic abnormality or genetic trait. In the case of the disorders that constitute critical illness, such abnormalities often predispose to or identify an overexuberant or deficient inflammatory response.

This approach requires teams of dedicated investigators collecting data at many different sites. Examples include the current sepsis “Glue Grant” sponsored by the U.S. National Institute of General Medical Sciences (in which Dr. Deutschman participates) and the “Gen-O-Sept” study into the genetics of septic shock sponsored by the European Society of Intensive Care Medicine and the European community (where Dr. Weiss is a participant). The basic approach uses screening processes that identify gene polymorphism or variations in the expressions of genes, either on the mRNA or protein level. When a marker is identified in a large cohort of patients with a specific disease, it can be investigated more fully. Often it will suggest a hypothesis to be tested in animal models or cells. Such an approach is “hypothesis generating” and leads from bench to bedside.

It is hoped that these efforts ultimately will culminate in a number of medications tailored to sustain or extinguish specific parts or phases of the inflammatory response. In other words, we will come from the bench back to the bedside.

Branching Out
Both of the above approaches to research are well-served by multinational collaboration. The “bench-to-bedside” approach, which we have used extensively, allows us to collaborate not only with each other but to involve a talented group of investigators and the vast resources of both our institutions. We are beginning to “branch out”: This approach has led to strong collaborations with well-known basic science researchers at our home institutions, at other institutions in Israel, the United States and in Switzerland. Modern telecommunications and overnight delivery systems make it relatively simple to conduct research that spans individual countries or even an ocean. We maintain daily contact via e-mail, and we frequently hold telephone conversations or even teleconferences. Despite the understandable increase in scrutiny required for the transfer of biologic material between countries, we exchange material on a regular basis.

The need for and value of trans-Atlantic cooperation in “bench-to-bedside” research is even more obvious. Large-scale clinical investigations require the participation of multiple institutions. Since inflammation is a universal condition, ethnic and national diversity in the patients to be studied is an added benefit.

The examples presented here highlight that translational research has a much wider meaning than in the past. It requires the interaction of investigators with different specialties and fields of expertise. We are anesthesiologist/intensivists, but our colleagues and collaborators are surgeons, pulmonologists, critical care internists, infectious disease specialists, biochemists, cell and molecular biologists and a host of others. Research is complex. The more experts involved, the better.

Critical illness is not limited by country or continent. Worldwide cooperation may well be the key to providing our patients with the care they deserve.

Yoram G. Weiss, M.D., F.C.C.M., is Senior Lecturer in Anesthesia and Critical Care Medicine, Hadassah Hebrew University School of Medicine, Jerusalem, Israel, and Adjunct Assistant Professor in Anesthesia and Critical Care, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.

Clifford S. Deutschman, M.D., M.S., F.C.C.M., is Professor of Anesthesiology and Critical Care and Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.