The road not taken or how I learned to love the liver: A personal perspective on hepatitis history
Authors: Harvey J. Alter
Journal: Hepatology (2013)

I was born rather abruptly in a year so distant it pains me to reflect on the number. My birth arrived without fanfare in Beth Israel Hospital in Manhattan. Fifty years later, I was invited back to Beth Israel to give Grand Rounds. I had visual memories of my birthplace, but nothing looked familiar on my return. Had it changed or had I changed? It was Beth Israel where I first saw a hospital room, and perhaps that was imprinted on my mind because I have always been comfortable in hospital settings. Being the only son of Jewish parents in New York City, it was preordained that I would become a doctor. One of my friends, of similar background, chose not to be a doctor and has never been heard from again. In truth, my father, the brightest of nine children born to immigrant parents, desperately wanted to be a doctor, but financial concerns dictated otherwise. Nonetheless, he was chosen by the family to be the first to attend college, where he excelled. He ultimately became a successful businessman, but never lost interest in medicine, and I remember him reading Science Digest and other medical compendia in lieu of reading the sports pages. I, on the other hand, prefer the latter. In any event, my father had a strong influence on my road to medicine, though I think I would have chosen this path even without his inspiration; the biologic sciences always seemed more interesting to me than any other discipline…. except, of course, baseball. I would have dropped medicine in a millisecond to play for the Brooklyn Dodgers. There were, however, certain impediments to my becoming a professional baseball player—I couldn't hit and I couldn't field. Thus, I sublimated my "field of dreams" to become a doctor. Nonetheless, going to ball games at Ebbett's Field with my father is one of my fondest memories, and the exodus of the Brooklyn Dodgers to Los Angeles, in the midst of my youthful fervor for that team, is one of the great tragedies of my life—a day of infamy surpassed only by Pearl Harbor. My mother was not as well educated, but she had street smarts and was a conservative counterweight to my father's excesses. Over the years, they agreed on little, but both had high levels of integrity and genuine generosity. Their intrinsic values far exceeded their ability to negotiate with one another, but they survived 57 years of marriage until their deaths at about age 81. My mother had enough anxiety to fill my epigenes with neurotic tendencies just short of Woody Allen. Through the years, I have managed to divest myself of some of these tendencies and to somehow use the others to my advantage. My mother was a superb cook, and it was the bane of her existence that my sister and I were rail thin. In elementary school, I was separated from the "normal" kids and put into a health class. This class was a consortium of the frail, the fat, the mildly retarded, and other assorted types the school, in their infinite wisdom, felt would benefit from one-room teaching, an extra glass of milk, and an afternoon rest period. It was probably here that I learned to doze through afternoon lectures. It was only later that I developed the skill to also doze through morning lectures. Being separated from my normal classmates was a devastating blow to my fragile ego and was the second great tragedy of my life after the loss of my beloved Dodgers. Nonetheless, as has been my strength in life and perhaps the theme of this essay, I made the most of the hand I was dealt. Because I was the smartest of this low-achieving group, I skipped ahead one year and broke out of PS 77 at age 13. Those of you who now think me old have to factor in that I had this very early start. The disadvantage of skipping ahead was that I was socially inept and my high school days bore no similarity to those I watched in the movies, where everybody was dancing, singing, and making out. I did not learn the subtle art of making out until my freshman year in college (details available upon request). Socially, I was a high school survivor, but, academically, I was, in the words of Garrison Keillor, "above average"—not brilliant, but a good student, the same ranking I would give myself today. College to me was everything that high school was not. After visiting several small, coed northeastern schools, I settled on the University of Rochester because it had a medical school and my course was already set in that direction. I did not apply to Harvard or Yale, figuring that if they really wanted me, they would call. Somehow, they did not, but I had a great moment many years later when I was invited by Jim Boyer to give the Klatskin Lecture at Yale. After, I went to the administration building and shouted out, "You should have called!" In college, I struggled academically during my first semester in college and saw my hopes of medical school evaporating. Particularly painful was a "D" on my first English paper, the one subject I thought was my strong suit. The teacher said I was too wordy, a trait, as you can see, that has not diminished to this day. Nonetheless, I buckled down and learned to study and my grades rose to the point, where, in my fourth year, my college advisor gave me the left-hand compliment that I had done much better than they ever expected. I was elected to the junior and senior honor societies and was managing editor of the school newspaper, where I wrote humorous, and sometimes even serious, editorials. This had an unexpected benefit because when I interviewed at Rochester Medical School, the dean, Len Fenninger, had read my editorials and we discussed these and other diverse matters for over an hour. I learned afterward that Dr. Fenninger was known to be an intimidating interviewer who chewed up aspiring medical students. Fortunately, we hit it off and I was accepted into the Rochester class of only 70 students. Of note, my second interview that day was with a very kindly old gentleman named George Hoyt Whipple, who, I later learned, had received the Nobel Prize for his seminal discoveries linking vitamin B12 to pernicious anemia. I never see a patient with megaloblastic anemia without thinking of him and that interview. I loved medical school, even anatomy, which we took for a whole year. I became close friends with Herman, our cadaver, and smelled of formaldehyde until my senior year. My favorite course of the first two years was pathology because the faculty, headed by Lowell Orbison, was superb and the subject matter was beginning to bear on clinical issues. I signed up to take a year out to do research in pathology, but, at the last minute, reneged because I lost my enthusiasm for cadavers. I also knew, at that time, that I was not interested in a research career, even though I was drawn to the academic life. It would take almost a decade more before my internal struggle between clinical practice and research would come to resolution. There was not a course or rotation in medical school that I did not like, and, sequentially, I was drawn from pathology to ophthalmology to pediatrics and finally to internal medicine and, particularly, to hematology. Though not drawn to hepatology at that time, I now see that hematology and hepatology are kindred disciplines and draw the same kind of physician mind sets to their study. As a fourth-year medical student, I was the first to make the diagnosis on a perplexing case of acute renal failure in a truck driver. Based on his occupation and a chance article in the esteemed journal, Reader's Digest, I deduced that he had carbon tetrachloride poisoning; I found that CCl4 is nephrotoxic when inhaled, rather than hepatotoxic. A field trip to his truck revealed a CCl4 fire extinguisher clamped above the truck bed where he slept on long-distance travel; it was empty, even though never used. I became a short-term hero for elucidating this case and, as a fourth-year student, gave my first Grand Rounds not just as the case presenter, but also as the discussant. I relate this story because, this year, I am recipient of the University of Rochester Distinguished Alumnus Award, and I will be giving the Whipple Lecture in the very same auditorium where I gave Grand Rounds as a student. My life keeps coming full circle. I enjoyed Strong Memorial Hospital so much that I stayed on to do an internship and residency in internal medicine. In applying for internships, once again, Harvard and Yale did not call. Internship, despite its hardships, was the most satisfying year I ever spent in medicine. At Rochester, interns were given almost complete control of patient care and were forced into a very steep learning curve. Suddenly, glucose and acid-base metabolism began to make sense, and, gratefully, there was no need to memorize the Krebs cycle or the intricacies of steroid synthesis. I was unmarried during my internship, lived in the staff house, and ate most of my meals in the hospital, a carbo-loading experience like none other. This sparse lifestyle was important because we earned only $600 per year in those days. Fifty dollars a month doesn't go far, but if room and board is free and one doesn't smoke, it sufficed. There wasn't much time for "nights out on the town," and my greatest entertainment pleasure was watching weekly episodes of the original Untouchables. Because I lived in the staff house, I was not overly concerned when an early October Rochester blizzard buried my car in snow. I became more concerned when, 5 months later, it was still buried, and, in truth, my car was not thawed and extricated until mid-May. Such was life in Rochester, but I would do it all over again exactly the same way. It was in my first-year residency at Strong Memorial that I received a letter that would change the course of my life. It was from the U.S. government and began with the terrorizing word, "Greetings." This was in 1961 and was the long-dreaded letter from my draft board. In late summer 1961, there was a crisis in Berlin and a shortage of doctors in the military. Residents all over the country were being called to duty. I still have that draft letter today. Notable was the fact that I was to report to Fort Dix, New Jersey, on November 30; attached to the letter was a subway token that somehow was supposed to get me there. I still haven't figured out that subway route. I did not expect to be drafted because I had already applied to the National Institutes of Health (NIH) and had been accepted. However, I had not yet been assigned a position or commissioned in the U.S. Public Health Service (USPHS). I had applied to the NIH not because I planned a career in research, but because that was the best, and most sought after, venue for anyone who even remotely considered entering academic medicine. The draft letter initiated a series of frantic conversations with the chiefs of medicine and hematology at Strong Memorial and a call to the USPHS. The latter informed me that if I could find a position at the NIH, receive my PHS commission, and report to the NIH before I was supposed to report to Fort Dix, the PHS would have supremacy over the army when it came to possessing my body. Fortunately, Scott Swisher, the chief of hematology and a favorite teacher and mentor, had close ties with the Division of Biologic Standards (DBS), which later was incorporated into the U.S. Food and Drug Administration (FDA). Scott pulled strings, and I attached myself to those strings and arrived at DBS three days before I was to report to Fort Dix. I thus became a member of the "Yellow Berets," a cadre of draft-dodging physicians whose primary military function was to protect the NIH campus from invasion by Johns Hopkins. The two pathways I faced were highly divergent. An assignment to the army would almost invariably have been followed by a career in private practice, which fit well with my plans since late childhood. In contrast, my tenure at the NIH somewhat reluctantly led me down the academic-research path that I chronicle in this memoir. I think I would have had a satisfying life in private practice, but it would have been a totally different life, and I clearly would not ever have been asked to write a Master's Perspective. I often think of the dramatic turns my life has taken based on single, unpredictable events, but this one was, by far, the most life changing. The NIH Blood Bank in the early 1960s was part of DBS, and while there, I got my first taste of research and learned some techniques of blood fractionation that would later serve me well. Subsequently, the blood bank was transferred to the Clinical Center Department of Clinical Pathology and I moved to the Clinical Center where I would spend most of the next 50 years. I was in desperate search for a research project and decided to study the cause of febrile transfusion reactions that were unrelated to the cellular elements of blood. It was my hypothesis that persons who were transfused might be exposed to serum proteins different from their own and develop antibodies (Abs) that could initiate febrile or other deleterious reactions. To test this, I prepared agar gel plates in the fashion described by Ouchterlony and had metal templates fabricated by the NIH workshop that consisted of a seven-well punch, creating one center well surrounded by six equally spaced peripheral wells. Serum from a transfused patient was placed in the center well and normal donor serum in the peripheral wells. When the diffusing samples met, a white precipitin arc would form in the presence of an immune reaction. I became immersed in agar, but not in success. One fateful day in 1962, Richard Aster, then a young investigator in the blood bank and now a world-renowned investigator in platelet immunology, told me that he heard an interesting lecture and that the speaker was performing experiments very similar to my own. He advised that I talk to him. As it turns out, that speaker was the Nobel Prize winner in waiting, the late Baruch (Barry) Blumberg. I went to see Barry the next day and we immediately established what would be my first, and, in retrospect, most important, research collaboration. Blumberg, I would learn, was a complex, gregarious, and very interesting man. He was a philosopher as much as a research scientist and he could pontificate at length on almost any given subject. He liked nothing better than to "smooze" over morning coffee or afternoon tea. Blumberg was a geneticist and his interest was in protein polymorphisms. He and Tony Allison had already established that polymorphisms exist among the serum lipoproteins, and I informally joined his lab to help study this further. I subsequently went through more Ouchterlony plates than Ouchterlony himself, each day testing multiply transfused patient sera against an array of samples that Blumberg had collected on his many treks around the globe. Characteristic of the lipoprotein reactions was that the precipitin arcs they transcribed turned blue when Sudan stain was applied. One day, I observed a precipitin line that did not take up the lipid stain, but stained intensely red when a protein counterstain was applied. Searching the template for that experiment, I found that this novel immune reaction was between the serum of a patient with hemophilia and that of an Australian aborigine, the latter serving as the population du jour on that given day. We initially called this unidentified antigen the "Red Antigen" for its staining properties, but later debated whether to call it the Bethesda antigen for the place where it was discovered or the Australia antigen for the person in whom it was found. Blumberg insisted on the latter, in keeping with evolving nomenclature for newly identified hemoglobins that were being named after the location of the patient. Later, when the Australia antigen was identified as the surface protein of the hepatitis B virus (HBV), I was frequently asked what it was like to be the first to see this antigen. In truth, it was not the "eureka moment" one would have hoped for because it was an isolated finding that had no clinical relevance at the time. It was not like reaching some long-sought-after endpoint, because neither Blumberg, a geneticist, nor I, a hematologist, were in search of a hepatitis virus. It was not even remotely on our radar, but this isolated finding set the course of my career and ultimately represented the single most important event in hepatitis discovery and prevention. A day I remember much more vividly than finding the Australia antigen was in November 1963, when I entered the Blumberg lab to find everyone morosely huddled around the radio. President Kennedy had been shot and we were all in disbelief and stunned silence. It was the end of an age of innocence that was to be further compounded by the subsequent assassinations of Martin Luther King, Jr., and Bobby Kennedy and the multiple tragedies of the Vietnam War. Scientifically, it was a time of my emergence. Politically, it was a time of despair. I spent 1963 and early 1964 trying to characterize the clinical associations and biophysical properties of the Australia antigen. I found that whereas the antigen was present in 10% of aborigines, it was present in only 0.1% of healthy U.S. blood donors. In testing Clinical Center patient populations, the striking finding was that the antigen was present in 10% of patients with leukemia. Hence, the first publication1 on this "red antigen" was titled, "The Australia Antigen: A 'New' Antigen in Leukemia Sera." Indeed, we postulated that this antigen might be part of a leukemia-inducing virus and planned to do electron microscopy (EM) to search for a particle, but somehow we delayed doing this. Had EM been performed at that time, the prolific hepatitis B surface antigen (HBsAg) particles would have been seen easily and probably shortened the road to HBV discovery by about 5 years. Instead, I studied the biophysical properties of the Australia antigen, and though this did not fully elucidate its nature, it did result in my first publication in a high-impact journal, Blood, though this preceded impact factors by decades.2 In 1964, Blumberg left the NIH to take a leadership position at the Institute for Cancer Research at Fox Chase in Philadelphia. He asked me to join him in this new venture, but, after considerable deliberation, I declined because I was still bent on completing my clinical training in medicine. Hence, this was another major decision point in my life. I am happy with my decision, but it is remotely possible that had I gone with Barry and pursued the Australia antigen to its ultimate link with HBV, I might have shared the Nobel Prize with him. Highly speculative, and I do not regret "the road not taken." Blumberg taught me a lot. The major lesson, as the antigen story played out, was perseverance. Blumberg had dogged persistence. The Australia antigen could have been dropped at any point as an interesting—but unimportant—finding, but Blumberg would not let it go. I remember a wall-size chart in his office where he would write down hypotheses, the experiments necessary to prove or disprove a given hypothesis, and the outcome of those experiments. He was never daunted by a failed hypothesis because it only generated a new one. He never ran out of ideas and never got discouraged; his tenacity and enthusiasm were great models for my later studies on non-A, non-B. The other thing that Barry taught me was the value of stored samples. I have never thrown out a sample since I met him. My "Blumberg years" were a vital part of my development and I will always be grateful to him. Barry died a few years ago at age 87 in the midst of his third or fourth unique career. He died suddenly, one hour after giving a major lecture on astrobiology to the assembled masses at NASA. In my published eulogy to him,3 I wrote the following: "Blumberg was a complex and brilliant man, a man of eclectic interests and myriad accomplishments, an imaginative and adventurous man, a tenacious and dedicated man, a deeply philosophical man, a man for all seasons—and all of these made him a Nobel man." I left the NIH in 1964 to complete a second-year residency in medicine at the University Hospitals in Seattle. It was a strong and wonderful program in a beautiful city. A coresident in that program, who has become a lifelong friend, was Blaine Hollinger. In retrospect, I would have spent a longer time in Seattle, but after being there for only one month, I had to commit to a two-year hematology fellowship and I wasn't ready to do that. Hence, I came back east to do a hematology fellowship at Georgetown University under Charles Rath, who became both my mentor and my father figure. Dr. Rath taught me as much about life as about hematology. He also taught me the value of humor in teaching. I have kept in touch with Charlie over the years, and, recently, when I won the Canada Gairdner Award, I invited him to a reception at the Canadian Embassy. He was there front-row center, which wouldn't be so remarkable except that he was 94 years old and still telling me jokes. After a year of hematology fellowship at Georgetown, I stayed true to my childhood dream and applied for a position in clinical practice with a prestigious group of Washington internists. I was deeply disappointed to find that they selected someone else, presumably on the grounds that they needed a cardiologist more than a hematologist. In my disappointment, Rath took me under his wing and encouraged me to stay at Georgetown with the terse statement, "You can always go into practice." As further inducement, he doubled my salary from $6,000 to $12,000 a year. Charlie was generous of spirit, but not so generous of money. At Georgetown University Hospital, I was an instructor and then assistant professor of medicine and also head of hematology research. I spent 50% of my time teaching, 50% seeing patients, and the other 50% doing research. I was spread very thin and my math wasn't very good either. Two things became apparent to me. First, I was not the triple-threat academician that I was supposed to be and, second, that I enjoyed seeing patients in a hospital setting and I gradually lost my desire to go into private practice. Nonetheless, the pace of my position and the frustration over being unable to fulfill my research responsibilities was getting to me. Then, in 1969, I received another life-changing communication. It was a call from Paul Holland and Paul Schmidt at the NIH Blood Bank informing me that the Australia antigen I had studied was now known to be associated with HBV and that they would like me to return to the NIH to pursue studies of transfusion-associated hepatitis (TAH). I jumped at the opportunity and have never looked back. I was married in 1965 during my hematology fellowship to Barbara Bailey, a woman I had met during my fellowship at the NIH. It was a good marriage, but, sadly, ended after 12 years. However, two joyous events emerged from that marriage: the birth of my son, Mark, now an M.D./Ph.D. embarking on his own research career and the subsequent birth of my daughter, Stacey, currently a teacher in Colorado. My children have been wonderful from day one and are a source of great pride. They have given me four grandchildren, one of whom was born prematurely at the Hep-DART meeting on Kauai, weighing only 1 pound, 15 ounces. Miraculously, he is now age 10 and will soon be attending his third Hep-DART meeting. In 1984, I met a collaborator who has never entered the lab or participated in a study, but who has collaborated intensely in my life. I speak of my current wife, Diane, who has put up with the long hours and anxiety-ridden deadlines incumbent on a research career and who has done so with grace and elegance. She has been my staunchest advocate and has had more faith in me than I have had in myself. Diane has blessed me with two stepdaughters, Lydia and Erinn, whom I consider very much my own and who, in turn, have given me five more grandchildren. My immediate family is now a small village, and a recurrent dilemma is how to give each member enough time, especially while continuing to work. Time has been my constant enemy. I have never had enough and never given enough to my family. I think I have been a reasonably good father and husband, but all of my relationships have suffered, to varying degrees, by the conflicting pull of time devoted to work. I have stolen time from my family not just to achieve professional goals, but also merely to keep up with all that was required. I have already written my graveside epitaph to encompass my recurrent temporal dilemma, namely, "As in life, he ran out of time." It was wonderful to return to the NIH in late 1969. I was coming home, a home that has nurtured me ever since. As the Australia antigen/HBV story was breaking in the late 1960s, the NIH Blood Bank, under the direction of Paul Schmidt and the vigor and enthusiasm of Paul Holland, had initiated a prospective study of TAH. Integral to that study was a collaboration with Robert Purcell (Fig. 1). Bob would become my decades-long collaborator and mentor and would teach me most of what I know about research design and implementation. I owe him an enormous debt, and it is, by now, clear that I will never pay it off. Holland, Schmidt, Purcell, and John Walsh had already completed a prospective study showing that the incidence of TAH in multiply transfused patients was near 30% and that the prime determinant of that inordinately high rate was the use of blood from paid donor sources.4 Thus, in 1970, we decided that the use of commercial blood sources could no longer be tolerated, and the NIH Blood Bank rapidly transformed to an all-volunteer donor service. I then studied the effect of this transformation, as well as the introduction of a home-brew assay for identifying what by then was called the HBsAg. Ironically, because there was no commercial assay, I went back into the agar gel business, and, for a short time, my old friend Ouchterlony was utilized for screening blood donors. The combined effects of changing blood sources and introducing first-generation HBsAg testing was as astounding as it was gratifying. TAH incidence fell precipitously from 30% to approximately 10%.5 No intervention we have ever taken since that time, including hepatitis C virus (HCV) testing, has had as dramatic an effect on hepatitis transmission by blood transfusion. When highly sensitive assays for HBsAg were developed in 1973, we went back into stored samples and were able to show, somewhat to our surprise, that hepatitis B accounted for only 30% of total hepatitis and that some non-B entity was the primary cause. In 1975, Feinstone, Kapikian, and Purcell,6 at the NIH, discovered the hepatitis A virus (HAV) using immune EM. We immediately sent our non-B hepatitis sera for testing, and not a single case proved to be HAV related.7 It was then, in a brilliant display of deductive reasoning, that we decided that if these cases were not hepatitis A or B, we would call them non-A, non-B hepatitis (NANBH).7 We considered calling it hepatitis C at that time, but Purcell insisted on the more amorphous term because we had not yet proven it was a virus and, if so, how many agents might be involved. We were also pretty confident that we would discover the NANB agent(s) in a relatively short time and then apply the proper nomenclature. This was a confidence that was shattered over the next 15 years of intensive—but vain—effort. Our first task was to prove that the agent of NANBH was transmissible. To do this, I utilized samples from patients with acute and chronic hepatitis and from asymptomatic donors who had been implicated in NANBH transmission. We inoculated 5 chimpanzees and all 5 manifested alanine aminotransferase (ALT) elevations at appropriate postinoculation intervals, had histologic changes of mild hepatitis, and showed peculiar tubular structures on EM that became characteristic of NANBH in chimpanzees.8 Similar transmission studies were simultaneously performed by Tabor et al. at the FDA.9 The next important event was identification of a patient with severe acute NANBH from whom I obtained an apheresis unit on the upswing of the ALT curve, which subsequently peaked at 2,112 IU/L. This patient, Mr. H, became critical to my research and provided more information on NANBH than any other patient in the world, because Purcell performed infectivity titers in chimps and vialed a large dilution series, samples of which were disseminated globally. Importantly, the infectivity titer in chimps (106.5 CID/mL) was almost identical to the genomic titer in the patient (107 copies/mL). Having both a proven infectious inoculum and the chimpanzee model allowed for further characterization of the agent. Steve Feinstone performed chloroform extraction studies that showed that the NANBH agent contained essential lipid and hence was an enveloped virus.10 Li Fang He, a fellow in Purcell's lab, then performed filtration studies, which indicated that the agent was between 30 and 60 nm in diameter.11 I have always been impressed with what we knew before we knew what we know now. Long before cloning and before any validated assay, EM visualization, or culture system, we knew that the agent was small and lipid encapsulated, that it was blood transmissible, that it could be transmitted by asymptomatic "silent" carriers, and that it caused persistent hepatitis in the majority of those infected. Unknown then was the severity of the ensuing disease. Many thought NANBH was merely an innocuous transaminitis, but our collaborative studies with Marvin Berman, Jay Hoofnagle, and Adrian DiBesceglie in the Liver Service of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) showed that 20% of our patients developed cirrhosis and that half these patients died directly or indirectly from their chronic liver disease.12 This was the missi