Buenos Aires to New Haven: A dream trip
Authors: Roberto J. Groszmann
Journal: Hepatology (2010)

"Dream no small dreams for they have no power to move the hearts of men." Goethe I would like to thank Dr. Lindor and other members of the editorial board of HEPATOLOGY for honoring me by asking me to contribute to the "Masters of Hepatology" series. My background is very different from that of other renowned hepatologists who have already contributed to this series. For this reason, I will go back to the beginning of my medical career to explain why I left Argentina to continue my medical career in this country and why, once in the United States, I decided to pursue an academic career. I hope that this brief memoir will inspire potential researchers in this generation with the excitement of scientific discovery that has sustained me through my career. FHVP, free hepatic venous pressure; HVPG, hepatic venous pressure gradient; NSBB, nonselective beta blocker; VA, Veterans Administration; WHVP, wedged hepatic venous pressure. I was born in Buenos Aires, Argentina, where my father was a Jewish Hungarian immigrant and my mother was Argentinian of Jewish Hungarian descent. My father arrived in Argentina in the 1920s fleeing an already convulsed Europe. I attended public school and then studied medicine at the University of Buenos Aires School of Medicine, which was also public and free. At the time, the best schools were public and funded by the government so tuition was free. In order to limit class sizes, to matriculate at the School of Medicine, it was necessary to pass a rigorous academic exam that excluded many candidates. Nevertheless, the medical students' classes were very large (approximately 4000 students the first year) and impersonal and did not allow for any close contact between students and professors. The intensely interesting study of medicine in Buenos Aires in the early 1960s took place against a dramatic backdrop of inescapable political unrest and violence in a country that was alternately governed by short-lived democratic government and military dictators. Dr. Bernardo Houssay, one of three Nobel Prize winners from the University of Buenos Aires, had brought the Department of Physiology at Buenos Aires School of Medicine to its highest prestige. Dr. Houssay and his collaborators had written a seminal textbook of physiology from which we studied at that time and which was also widely used in translation at U.S. medical schools. The tradition in Physiology was to teach through practical demonstrations in classical experimental models. Most experimental demonstrations were performed in a toad (Bufo arenarum Hensel, a species commonly found in Argentina). I found this part of my medical education especially riveting. From these experiences, I developed a great respect for the power of well-designed experimental models to translate science from the realm of ideas to the laboratory bench and from there to the clinical bedside.1 After completing my medical studies in 1964, I won a competitive scholarship to work on liver research in the Argentine National Institute of Gastroenterology. That was one of the few opportunities open to young physicians to enter the medical research world. At that time, the institute was headed by Marcelo Royer, who was an established investigator of the National Research Council headed by Bernardo Houssay. Under the direction of Dr. Royer and Dr. Beatriz Noir, Ph.D., I began working on the metabolism of bilirubin while learning basic laboratory techniques, progressing from the simple use of a pipette to reading a then-sophisticated spectrophotometer. My very first publication2 came from this early work. During the period from 1964-1966, the Argentine political situation again deteriorated to the point where several first-rate scientists from the National Research Council emigrated to the United States and Europe. Many local problems precipitated this exodus, including extremely low salaries, instability of the research positions in the National Research Council and in the Universities, and for some, political persecution. At the time, there was a democratic government but a military coup was not far away. I too began to consider emigrating; after my future wife, Aida Zugman, completed her studies in pharmacy, we married and moved to Chicago. In Chicago, I began a residency program in internal medicine which was at the time directed by the well-known hepatologist Dr. Hyman Zimmerman. I followed Dr. Zimmerman to Washington, DC, and completed my 3-year residency program at the Veterans Administration Medical Center. My long and productive relationship with the Veterans Administration began at that time. The VA was especially receptive to foreign medical graduates. This was not the case for first-rate university hospitals, and because many VA hospitals had close associations with top medical schools, this was my best chance to be closely affiliated with a prestigious medical school. I quickly discovered that the VA Medical Center in Washington, DC, had an excellent department of medicine. During an elective rotation in the medical residency program, I met Dr. Jay N. Cohn, a young cardiologist interested in cardiogenic and septic shock. Dr. Cohn was also very interested in the vascular abnormalities observed in patients with cirrhosis. He headed a section of "Clinical Hemodynamics" within the Department of Medicine (eventually Dr. Cohn left the VA in Washington, DC, and became the chief of Cardiology at the University of Minnesota). My relationship with Dr. Cohn altered the course of my medical career (Fig. 1). While working with him, I observed that patients with advanced liver diseases basically had the same systemic hemodynamics as some patients in septic shock (high cardiac output and low arterial pressure). That was when I understood the important role that hemodynamics plays in the pathophysiology of liver diseases and its complications3 (Fig. 2). Furthermore, Dr. Cohn approached the circulatory abnormalities observed in liver diseases as he approached all other circulatory syndromes that he was studying in those times (septic and cardiogenic shock), which made the experience even more attractive to me. Dr. Jay N. Cohn (first on the left) Roberto J. Groszmann (middle right) and other members of the "Clinical Hemodynamic Section" Veterans Administration Hospital, Washington, DC (circa 1967–1968). Vasodilatation: The Source of All Evils. Reproduced from HEPATOLOGY, Vol. 43(2), Suppl. 1, 2006. After moving to Boston for 1 year to complete my work with Dr. Zimmerman, I returned to Washington to work with Dr. Cohn on hepatic hemodynamics. At the time, it was clear to me that the circulation of a particular organ could not be isolated from the study of the systemic circulation. Therefore, from June of 1968 to September of 1971, I became a "cardio-hepatologist" under Dr. Cohn's tutelage.4 I worked in the arterial hypertension outpatient clinic and consulted on patients for the clinical hemodynamic section of the Department of Medicine. The patients were for the most part in cardiogenic or septic shock, but there were also many patients with cirrhosis who had advanced hemodynamic derangements, including refractory ascites and the hepatorenal syndrome. The prognosis for patients with end-stage liver disease was extremely poor in the era preceding liver transplantation, but my clinical role afforded me an important opportunity to learn to perform hemodynamic studies in patients with cirrhosis. These were very productive years because together with Dr. Cohn and collaborators, we described new techniques to measure both hepatic blood flow5 and portal systemic shunting in patients with cirrhosis,6, 7 and documented the existence of a hyperdynamic splanchnic circulation in this group of patients.8 My collaboration with Dr. Cohn produced a series of publications, but more importantly, this experience focused my research interest on the circulatory abnormalities of patients with liver disease and portal hypertension. By 1970, I found myself at a crossroads. I had developed a unique area of specialization and scientific interest in a field that was only practiced at a few academic medical centers. My clinical expertise did not conform to the recognized and typical clinical subspecialities, and the next steps were unclear to me. Meanwhile, my family had grown with the births of my two children. Since marrying, I had asked my wife to move four times in order to pursue my academic calling, but now the political situation in Argentina had improved somewhat because the military government promised to hold free democratic elections. My former medical chief and mentor, Dr. M. Royer offered me a solid academic position as a scientific investigator in the Argentine National Research Council. Aida and I acquiesced to the expressed wishes of our families and our own desire to be closer to family and old friends and we moved back to Buenos Aires in 1971. Back in Argentina, I rejoined the group that I had worked with previously at the National Institute of Gastroenterology, now renamed Policlinico A Posadas, an indication that there would be a new emphasis on clinical medicine. I was very warmly welcomed and I enjoyed the personal support of my colleagues. However, despite everyone's best efforts, the lack of institutional funding, equipment, and scientific support from the hospital authorities made scientific research very difficult. I remained committed to a career as a physician-scientist and found ways to acquire new skills at the Posadas Hospital in clinical and experimental liver research as well as in the clinical management of liver disease. I improved my skills in generating and working with small and large experimental models and also in performing splanchnic angiography.9-12 These techniques provided an invaluable foundation for my future academic career. Despite my disappointment in the public commitment to scientific research, I do not regret many collaborations that began for me in those days. During those 4 years in Argentina, I met Professor Jean Pierre Benhamou, a leading French hepatologist who was also interested in liver hemodynamics. Dr. Benhamou invited me to spend 3 months in his liver research unit at the Hospital Beaujon, in Paris. This trip, which was financed by the French government, allowed me to observe closely the workings of a first-rate clinical hepatology unit. Perhaps my most important professional and personal experience in Argentina was encountering a group of young physicians who were as enthusiastic as I was about experimental and clinical research. We shared the same curiosity and interests in liver diseases. Unfortunately, at the time, there was little chance of pursuing this line of research because of a lack of resources. Among this promising group of young scientists were Mario Chojkier, M.D., Andres Blei, M.D., and David Kravetz, M.D. By 1974, the economical and political situation in Argentina had deteriorated rather than improved. We began to discuss the possibility of returning to the United States, knowing that this time it would be a permanent move. Economically, the Argentinian currency was quickly devaluating and salaries could not keep up with the inflation. There was political unrest with kidnappings, killings, and a looming threat of yet another military coup which did occur just months after our departure. This military dictatorship was the worst one ever suffered by the Argentinian population, and was one of the darkest periods in Argentina's history (1976-1983) which left 30,000 people dead or missing. During this time, some people had to emigrate to literally save their lives. This second departure from Argentina was extremely difficult. We left family and friends but most painfully we left aging parents, who understood that we were leaving for good, taking with us the grandchildren that they had enjoyed so much. Dr. Harold Conn recruited me as an Assistant Professor of Medicine to Yale University and the West Haven Veterans Administration Hospital in August 1975. Complicating the decision to return to the States was the legal necessity to fulfill all the requirements needed to practice medicine in this country (including a 2-day exam). Soon after I arrived at Yale, I received a Career Development Award from the VA that allowed me to dedicate most of my time to the laboratory. I cannot overstate the value and importance of the support I have received from the VA system in my development as a physician-scientist. I believe that Dr. Montgomery Bissell expressed this clearly in his Master's Perspective article,13 when he said that at the beginning of a career as a physician-scientist, the young physician needs "80% of protected time for keeping a steady focus in research". Thankfully, the VA Research Associate position permitted me 3-4 days a week in which I could focus on research. Because I was at the VA Medical Center, I was also free of certain university committee obligations that can consume much of a young researcher's precious time. In 1979, I was promoted to Associate Professor of Medicine, but by then my laboratory was well-established and I could afford the time that departmental duties took up. My opportunity for collaboration with physicians and scientists throughout the world began in earnest when I returned to Yale. I am proud to say that my good friends, Mario Chojkier, Andres Blei, and David Kravetz all collaborated with me in my laboratory at the West Haven Veterans Administration Hospital.14-17 We have remained close friends through all these years, meeting at every American Association for the Study of Liver Diseases (AASLD) and Digestive Disease Week meeting. Each now occupies a distinguished position in different medical schools in this country; sadly, Andy Blei is no longer with us, and we miss him dearly By the late 1970s and for next three decades, the polyglot nature of my laboratory was established with a steady arrival of bright physicians coming from the United States, Argentina, Spain, Italy, Switzerland, Israel, India, Japan, Taiwan, South Korea, Brazil, Mexico, Turkey, and Germany. At times, the laboratory sounded like a "Tower of Babel", where English was the common language spoken with many different accents (Fig. 3). It was a magnificent time not only as a scientific but also as a personal experience. (A) From left to right: Andres Blei, Roberto J. Groszmann and Mario Chojkier. New Haven, CT USA (circa 1975–1976). (B) In the office (circa 1984–1985): Standing in the back from left to right: Shiv Sarin (India), Paul Genecin (USA), and Carlo Sabba (Italy); in the middle from left to right: Giovanna Ferraiuoli (Italy), Maryann Vergato (secretary) and Martha Shea (laboratory technician); sitting in the front from left to right: Roberto J. Groszmann and Luis Colombato (Argentina). Because of my past experience treating patients with arterial hypertension, it was clear to me that to make significant advances in the treatment of portal hypertension we needed to improve on the methods available to measure portal pressure. The only acceptable method available in the mid-1970s was the hepatic venous pressure gradient (HVPG) performed with a straight catheter that had to be advanced to the wedged position and withdrawn to obtain the free pressure in the hepatic vein. HVPG, the difference between the wedged hepatic venous pressure (WHVP) and the free hepatic venous pressure (FHVP) represents the gradient between portal vein and intra-abdominal vena cava pressure. The advantages of using HVPG are (1) both WHVP and FHVP are equally affected by intra-abdominal pressure, but their gradient, HVPG, is not; (2) unlike portal vein pressure or WHVP, which can be elevated falsely by elevated intra-abdominal pressure or ascites, the measurement of HVPG incorporates its own zero reference point so it is not affected by increases in intra-abdominal pressure; and (3) the external zero reference point, another important source of error, is also eliminated by the use of HVPG.6 I learned to measure the HVPG with Dr. Cohn during my fellowship and used it extensively during my stay in Buenos Aires. However, to study the effects of drugs on the HVPG, it was necessary to have a catheter that could be left in place for 1 or 2 hours and could then be used to obtain several determinations of HVPG without having to advance or withdraw the catheter to obtain a new measurements. Withdrawing and advancing the catheter could lead to catheter contamination and loss of reproducibility. For these reasons, we developed a technique using a balloon catheter. We tried it first in experimental animal models, and once we were able to establish the safety and accuracy of the technique, we began to use it in patients.14 Using this technique, the balloon catheter is introduced into the jugular vein and advanced to a hepatic vein under fluoroscopic guidance (Fig. 4). FHVP is the pressure measured while the balloon is deflated and the catheter is floating freely within the hepatic vein. The balloon is then inflated until that branch of hepatic vein is completely occluded and the WHVP is obtained. The advantage of the balloon catheter is that serial measurements of free and wedged hepatic venous pressure can be obtained serially using the same catheter, inflated and deflated repeatedly. The catheter can also be left safely in place for several hours so that the effects of pharmacologic agents on portal hemodynamics can be monitored over a period of time. Furthermore, unlike conventional catheters where the WHVP is measured in a small hepatic venule, the balloon catheter allows measurement in the hepatic veins at the lobar and sublobar levels. This allows the investigator to obtain pressures in several segments of the liver and then to average them in order to more closely represent the true portal venous pressure. The procedure of measuring HVPG has been proven extremely safe and the rate of successful hepatic catheterization is greater than 95%. It took many years for this technique to come into widespread use, but it is now used by most of the centers that perform these hepatic hemodynamic measurements worldwide.18 (A) The straight catheter is wedged into a small hepatic vein. Because there is regional variability of fibrosis, the WHVP of the more fibrotic area (inset I) is higher than that of the relatively normal parenchyma (inset 2). (B) The balloon catheter eliminates this inconsistency by averaging WHVP over a wider area of the liver. (Reproduced from HEPATOLOGY Vol. 39(2), 2004.) In 1981, Dr. Jaime Bosch from the Liver Unit of the Hospital Clinic in Barcelona, Spain, came to spend a sabbatical year working in my laboratory (Fig. 5). This event marked an important chapter in my academic career not only for the professional collaborations that ensued but also the solid friendships that developed with Jaime Bosch and Juan Rodes one of the founders of the Barcelona Liver Unit. From left to right: Drs. Roberto J. Groszmann, Julio Vorobioff and Jaime Bosch. Hepatic Hemodynamic Laboratory, West Haven VAMC (circa 1981). After I completed the Veterans Hospital Research Associate Program, I applied and received a Career Development Award from the National Institute of Health. This award allowed me to take a ten month sabbatical at the Physiological Laboratory in the University of Cambridge in the United Kingdom to further my study of vascular physiology. While living in the magnificent college town of Cambridge, I learned more about the physiology of the systemic and splanchnic circulation. With the exception of my beloved family dog, who was not invited into the UK, my whole family had the opportunity to experience living in Cambridge, which my children still look back on as an enriching and useful interlude. In the late 1980s and early 1990s, many changes were occurring in the Section of Gastroenterology at Yale. Jim Boyer became chief and under his leadership, the Liver and Gastroenterology sections were united as a section of Digestive Diseases. Guadalupe Garcia-Tsao (Fig. 6) joined us and began a long and fruitful collaboration in clinical research. These developments allowed me to increase my time in the experimental laboratory. From left to right: Drs. Guadalupe Garcia-Tsao, Roberto J. Groszmann and Jaime Bosch during the EASL Monothematic Conference Portal Hypertension: Advances in Knowledge, Evaluation and Management Budapest (January 2009). It has always been my driving interest to use the experimental laboratory to answer fundamental clinical questions that cannot be answered at the bedside. The hyperdynamic state of the cirrhotic patient was a phenomenon of great interest to me it was a clinical problem that was particularly well-suited to this scientific approach. First, I attempted to develop an experimental model and a method that would make possible the study of all the circulatory abnormalities observed in portal hypertension. The radioactive microsphere method proved to be a seminal approach to the study of systemic and splanchnic hemodynamics in the portal-vein-constricted and cirrhotic rats. To quote Adrian Reuben from one of his "Landmarks in Hepatology": "in one fell swoop the investigators (Vorobioff J, Bredfelt J, and Groszmann RJ) confirmed that in rats with portal hypertension and extensive portosystemic shunting, the expected and substantial hyperkinetic increases in the splanchnic and peripheral circulation, and peripheral arterial vasodilatation do occur" (Fig. 7).19 Because the presentation20 and subsequent publication21 of this study, these data have been confirmed and extrapolated in many other experiments. By then it was becoming increasingly clear that vasodilatation was the primary factor initiating the hyperdynamic syndrome22 (Fig. 2). The next step was to find the vasodilator or vasodilators that mediate this phenomenon. While initially I applied physiological methods to the study of portal hypertension and the hyperdynamic circulation, the results of this research prompted me to transition into cellular and molecular studies.23 (A) Splenoportogram in a portal-vein-ligated rat with 97% portal systemic shunting, showing extensive collaterals that circumnavigate the liver (reprinted from Chokjier and Groszmann26). (B) Diagram of the portal-systemic collateral circulation shown in A (reprinted from Chokjier and Groszmann Am J Physiol 240 (Gastrointest Liver Physiol 3): G371–G375; 1981). (C) Combined microsphere technique in which similar sized but differently radio-labeled polymer resin precision microspheres are injected into the left ventricle and spleen, respectively, followed, after a timed interval, by counting of radioactivity trapped in organs of interest and removed in a timed reference blood sample taken from the femoral artery (reprinted from Groszmann et al). Figures reproduced with permission of the American Physiological Society. Am J Physiol 242:G156–G160; 1982. I was already looking at nitric oxide as the primary candidate24 for the vasodilatation observed in all models of portal hypertension when an unexpected and important development occurred here at Yale. This was the arrival in 1993 of the pharmacologist, William C. Sessa, Ph.D., a world expert in vascular endothelial function. Soon after Bill's arrival, we began collaborating on a number of studies that were of fundamental importance in the development of the hypothesis that nitric oxide, mainly generated by the endothelial nitric oxide synthase, is the main culprit in the vasodilatation observed in cirrhosis.24 Two research fellows from the Digestive Diseases section who bridged our two laboratories, Vijay Shah, and Yasuko Iwakiri, worked successfully with both Principal Investigators to produce a series of publications on this subject.24-26 Another important finding that arose from this work was that in cirrhosis, a vasoconstricted hepatic circulation27 coincides with a vasodilated splanchnic and systemic circulation.28 We explained this paradoxical finding also as an aspect of abnormal endothelial function in a collaborative publication with Reiner Wiest entitled "Nitric Oxide in Liver Cirrhosis: Too Much not Enough".28 In summary, the use of animal models allowed us to characterize the systemic and splanchnic hemodynamic abnormalities of portal hypertension, demonstrating that it is not only the result of an increased resistance to portal blood flow (that is, in part, functional), but also due to an increase in portal blood inflow. Our experimental models also permitted us to discover the vasoactive mediators implicated in these hemodynamic abnormalities and to explore the mechanisms leading to abnormal regulation and signaling of these mediators. The crucial step in the understanding of the pathophysiology of portal hypertension has been the translation of bedside findings in patients with cirrhosis into meaningful questions that could be answered only at the bench. In the early 1990s, clinical studies by us and others demonstrated that a sustained reduction in portal pressure, induced by the long-term administration of nonselective beta adrenergic blockers, is accompanied in patients by a significant reduction in the incidence of variceal hemorrhage (primary and secondary prevention of variceal hemorrhage). In experimental models of portal hypertension, beta-blockade was accompanied by a reduction either in the extent and/or size of portosystemic collaterals.29 Based on these encouraging studies, I led a group of distinguished investigators (Jaime Bosch in Barcelona, Norman Grace in Boston, Andy Borrows in London, and Guadalupe Garcia-Tsao in West Haven-New Haven) in an 11-year prospective randomized trial that was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), which compared a nonselective beta blocker (NSBB) versus placebo with two primary aims: 1) to investigate whether a reduction in the HVPG induced by NSBB prevents the development of gastro-esophageal varices; and 2) to assess whether baseline and sequential measurements of the HVPG are useful in predicting the development of varices and other complications of portal hypertension.30 In this group of patients we did not achieve with the NSBB a significant reduction in the HVPG and therefore we did not prevent the development of varices. However, we did clearly demonstrate that HVPG is the best predictor of the complications of portal hypertension. Normal HVPG is defined as less than or equal to 5 mmHg. From 5 to 10 mmHg, there is a silent stage in the development of the cirrhotic process. An HVPG of more than 10 mmHg is "clinically significant portal hypertension" because it is in this pressure range that patients evolve from compensated to decompensated cirrhosis.31 In addition, patients with HVPG >10mmHg have a significantly higher risk of developing hepatocellular carcinoma. During a 58 month follow-up, cirrhotic patients with an HVPG greater than 10 mmHg had a 6 fold-increase in the incidence of hepatocellular carcinoma.32 Portal hypertension and its complications are fascinating for those who work in this field and equally so for workers in other specialties or other branches of biology. We have made tremendous progress in the last 50 years. The initial mechanism that leads to portal hypertension is an increase in intra-hepatic vascular resistance. Later, an increase in portal blood flow maintains and exacerbates portal hypertension despite the development of portosystemic collaterals. The critical step in the development of this concept, crucial for the understanding of the management of portal hypertension and not fully accepted until the mid 1980s, was the development of animal models of portal hypertension. In these models, the clinical picture of the hyperdynamic circulation described in the early 1950s was fully dissected in the laboratory animal. Later, the isolation and ex vivo study of the two vascular beds implicated in the syndrome, the mesenteric bed and the liver vasculature, allowed the physiologic characterization of the vasoactive mediators involved in mesenteric vasodilation and in the increased vascular tone of the cirrhotic liver. The next step was the introduction of the tools of molecular biology to identify the alterations in the signaling pathways responsible for the dysregulation of these mediators. We have gone from the patient to the molecule and are now returning to the patient in the form of various clinical treatments that are becoming available for the the treatment of the complications of the portal hypertensive syndrome. No doubt, knowledge in this area will continue to grow in basic science as well as the clinical arena, including studies in the experimental models that have given us a unique opportunity to provide a molecular basis for pathophysiological findings. Opportunities for young physician researchers are vastly different today from those available to a young Argentinian trainee in the 1960s. However, certain guiding principles for new investigators remain the same, despite the much more prescriptive and formalized medical training in today's residencies and fellowships. I strongly believe that original clinical observations remain the springboard for investigation of pathophysiology. Contrary to the opinion of many, I believe that original observations—especially clinical observations—are important and should be reported, even when the mechanisms that will explain the observations remain unknown. If the observation is important, the mechanism(s) causing the observed phenomenon will be unraveled sooner or later. Experimental models that mimic clinical syndromes or human diseases are extremely useful to the study and clarification of pathophysiological mechanisms and the exploration of therapeutic agents. In my view, translational research is a two-way highway that goes from the patient to the molecule and from the molecule back to the patient. Research can focus on any place along this highway but for the clinical investigator it should always end up at the bedside. As a final recommendation, I urge young researchers to seek out, for training, the best possible principal investigator (or laboratory) worldwide. It is important to remember that the scientific community is global. The person or laboratory is what matters most, not the university or geographical location. I have enjoyed the immeasurable benefit of visits to laboratories in many parts of the world and collaborations with scientists from every continent. I cannot end this writing without acknowledging the contributions that my postdoctoral fellows had made to the story that I just told. In my writing, I was able to name only a few of them but equal recognition goes to all. I would also like to acknowledge the Veterans Administration, Yale University, and NIDDK for their support during my entire medical career in the United States. My gratitude goes to the American Association for the Study of Liver Diseases (AASLD) and the American Liver Foundation (ALF) for the 2002 AASLD "Distinguished Achievement Award and the 2006 ALF "Distinguished Scientific Achievement Award". I would also like to thank my mentors and colleagues in Argentina, especially M. Rigoli and M. Royer for awakening my curiosity and interest for research. A word of gratitude to the University of Buenos Aires for giving me the opportunity to study medicine during difficult times and for granting me the title of honorary professor in 2000. Also my thanks go to J.N. Cohn, H. Zimmerman, and H. Conn for their support and help in my early years in the United States, and to Asghar Rastegar and Dave Coleman for their trust and support during difficult times. Thanks to C.E. Atterbury, N. Grace, and Cyrus Kapadia for their friendship and support. J. Boyer, who was up to very recently the director of the Yale Liver Research Center, deserves my recognition and gratitude for his support during the last 25 years, and special recognition goes to G. Garcia-Tsao—a friend and colleague who played a fundamental role in several major areas of clinical research. Many thanks to Paul Genecin, at one time a research post-doctoral fellow in my laboratory and now the Director of the Yale University Health Services, who was kind enough to edit this manuscript. I know that I left in the inkpot the names of many friends and colleagues that deserve my recognition and gratitude for all they have done for me but it will have been impossible to name all of them. Finally, I want to thank my wife Aida and my two children Yvette and Daniel because we were together in this odyssey and their understanding and support was always immense.