Explorer, Nobel Laureate, Astrobiologist: Things You Never Knew about Barry Blumberg
2014; Mary Ann Liebert, Inc.; Volume: 15; Issue: 1 Linguagem: Inglês
10.1089/ast.2013.1401
ISSN1531-1074
Autores Tópico(s)Spaceflight effects on biology
ResumoAstrobiologyVol. 15, No. 1 TributeOpen AccessExplorer, Nobel Laureate, Astrobiologist: Things You Never Knew about Barry BlumbergCarl B. PilcherCarl B. PilcherSearch for more papers by this authorPublished Online:15 Jan 2015https://doi.org/10.1089/ast.2013.1401AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail IntroductionBaruch S. “Barry” Blumberg, winner of the 1976 Nobel Prize in Physiology or Medicine and founding director of the NASA Astrobiology Institute (NAI), passed away suddenly of a heart attack at age 85 on April 5, 2011, during a conference at Ames Research Center. That Barry spent his last day conceptualizing an International Research Park on the Moon befits the unflagging curiosity that characterized his life in general and his scientific career in particular.In this paper I trace Barry's scientific career, including his early formative years and the unexpected path that led to the Nobel Prize. I also show that Barry's perspective and approach to science in general made astrobiology a natural area to attract his attention after he had retired from medical research. Indeed, his priorities as NAI director reflect directly things that were important to him throughout his career.The Making of a Physician, Scientist, and AdventurerBarry was born in Brooklyn, New York, in 1925, a grandchild of eastern European immigrants. His father's career as a lawyer provided for a comfortable middle-class family life, even after the stock market crash of 1929. Nonetheless, Barry grew up a child of the depression and carried with him ever after a need for financial security he could generate by his own labor.His curiosity was developed and nurtured during primary education at the Yeshiva of Flatbush, a Jewish parochial school in Brooklyn, New York, where in addition to traditional subjects he studied Hebrew as well as the Torah—the first five books of the Old Testament—and the Talmud—extensive commentaries on the Torah written over the last two millennia. The fact-based argumentation of Talmudic study introduced him to an analytical thought process on which he would draw throughout his life (Blumberg, 2002, p 9). He subsequently attended Far Rockaway High School, whose graduates of the period included Richard Feynman, winner of the Nobel Prize in Physics in 1965, and Burton Richter, winner of the Nobel Prize in Physics in 1976, the same year as Barry's prize. Barry would later reflect that he did not encounter as great an intellectual atmosphere as Far Rockaway High until he reached Oxford over a decade later following medical school to study for his PhD in biochemistry (Blumberg, 2002, p 9).After graduating high school, Barry entered the Navy at age 17. The Navy supported his completion of a physics degree at Union College in upstate New York and then commissioned him a line officer serving on small amphibious ships, one of which he eventually captained (Fig. 1). The Navy taught him responsibility, forward planning with contingency options at the ready, and the importance of logistics and infrastructure. These were lessons he would later put to great use, particularly during the extensive fieldwork that formed a central part of his scientific career.FIG. 1. Ensign Baruch S. Blumberg in 1946 as executive officer on USS LSM-416.In 1947, after leaving the Navy, Barry followed the advice of his college mentor that he leave physics because he “didn't have the specific intellectual skill to be successful in that subject” (Blumberg, 2002, p 10). He entered medical school and graduated in 1951 from Columbia University's College of Physicians and Surgeons. In 1950, as a third-year medical student, he sought an opportunity to work in “the tropics.” Barry found the tropics fascinating, as did many of his generation. He had read extensively on the subject, and while working as a movie usher had seen repeatedly many of the films of the day that depicted the tropics, usually in a way that today we would find inappropriate at best, offensive at worst. He approached a professor of tropical medicine, who offered him the opportunity to work temporarily in Suriname, a country in north central South America then known as Dutch Guiana. Barry accepted the offer and spent 3 months serving in the hospital and public health facilities of Moengo, a town on the Cottica River and site of a bauxite mine that had provided a good part of the aluminum ore needed by the United States in World War II (Fig. 2).FIG. 2. Barry with a native family in Suriname, 1950. In addition to collecting specimens for the malaria, filariasis, and other surveys, Barry and another medical student conducted daily clinics under the supervision of the physician for the Moengo region.The mine workers were a heterogeneous mix of South American natives, descendants of African slaves (one of the first successful slave rebellions in the New World occurred in Suriname in the mid 18th century), Europeans, Indonesians, and a few Indians, Chinese, and other nationalities. Barry observed a puzzling fact about this diverse population. Although they lived under the same conditions, different ethnic groups had very different susceptibilities to common tropical diseases such as malaria and filariasis, the latter a parasitic infection caused by threadlike roundworms. Field surveys of other areas of Suriname conducted during this period by Barry and a medical student colleague also showed great variation in disease susceptibility. This led Barry to formulate a simple question that would motivate much of his medical career: why do some people get sick while others, exposed to the same environment and infectious agents, remain healthy? Or more precisely, how do inheritance, human behavior, and the environment interrelate in the context of disease (Blumberg, 2002, p 19)?Barry's experience in Suriname was seminal in other ways as well. Barry was something of an adventurer. Early in medical school he had crewed on an ill-equipped sailing ship attempting an Atlantic crossing from the Netherlands to the United States. After much difficulty and a harrowing storm at sea, he found himself stranded in Portugal without a visa or seaman's papers. He narrowly avoided arrest before managing to ship out on a US freighter bound back for the United States (Blumberg, 2007, parts 6–8). So Barry was no stranger to challenging and even dangerous situations. In Moengo he found himself surrounded by impenetrable jungle populated, among other things, by huge snakes, with access only possible by means of a river rich in crocodiles. And by all indications he loved it. During his stay, he and a colleague traveled into the interior in a dugout canoe, traversing extensive rapids, to conduct a health survey of remote populations (Fig. 3). This was Barry's introduction to field research, and it would shape his career for decades to come.FIG. 3. Barry in the corrial, or log dugout canoe, that his small group used to travel up the Marowyne River to survey the Paramacanner nation, a remote people living in the interior near the border with French Guiana. Reprinted by permission of Princeton University Press (B.S. Blumberg, 2002, Hepatitis B: The Hunt for a Killer Virus).Barry wrote in his autobiography about another thing he learned in Suriname that was to shape his approach to science: It was there that I learned to rely on observations in the field; new observations led to new hypotheses that could not have been induced by laboratory-based experiments. The stark interplay of genetic differences and environmental effects was clear in the harsh tropics. But the field-work was, in turn, very dependent on laboratory techniques, and hypotheses were confirmed or rejected by experimental testing (Blumberg, 2002, p 19).This interplay between field work, laboratory studies, and theory would form another part of the foundation for Barry's scientific career.Disease Susceptibility and Genetic PolymorphismsAfter medical school, Barry interned for 2 years at Bellevue Hospital in New York City and then spent an additional 2 years as a clinical resident at Columbia Presbyterian Medical Center, a few miles uptown. Barry likened his experience at Bellevue—a city hospital that accepted patients from some of the most dreary and depressed areas of the city—to Dante's descent through the circles of Hell and eventual return to Earth (Blumberg, 2002, pp 21–22). But it was at Bellevue that Barry met and courted his wife Jean, to whom he would be married for 57 years, so all was not Dantesque.At Bellevue, Barry continued to observe great variation in the susceptibility of various populations to disease, particularly in the tuberculosis wards, which were very busy places at the time. After Barry moved to Oxford in 1955 for his PhD, he continued to be intrigued by questions of diversity in relation to disease stimulated by my experiences at Bellevue and in the jungle hospital in Suriname … Of particular interest are inherited differences among individuals and populations that result in differential disease susceptibility because these can often be detected before the person is exposed to the disease hazard. It was this notion that became the driving force in our research. If we could precisely identify the susceptibility factors before a person became sick, then we might be able to intervene to prevent the illness. The idea of a disease-free life—or, to be more realistic, a life with less disease—might be possible (Blumberg, 2002, p 31).Barry's turn toward research on inherited differences that result in differential disease susceptibility—one dimension of “human genetic polymorphisms”1—put him firmly in the camp of preventative medicine, a field that did not have high professional status at the time (and, some would argue, even today). Preventative medicine was the province of government-employed public health officers. It was not a focus of either medical training or practice, because “If everything works well, nothing happens. No one gets sick; no blood, no rushes to the emergency room with tubes dangling from arms and legs, masses of equipment covering the patient. It's hard to make a dramatic TV episode out of a no-action scenario” (Blumberg, 2002, p 32). Human genetic polymorphisms weren't so much a part of medicine at the time as they were a part of forensics (think of modern DNA evidence), paternity determinations, and anthropological population studies.This line of research was countercultural in another way as well. It would require study of diverse populations, an idea that appealed to Barry's sense of adventure. The research…would require travel, working with populations outside of Western culture, and the prospect of active searching in the fashion of the explorer-scientists of previous centuries. I would dredge up the geographic knowledge I had amassed in my youthful hobby of stamp collecting in the selection of locations for field trips (Blumberg, 2002, p 40).But population studies were considered to be inexact, particularly in comparison to the more conventional reductionist laboratory approach to biological science which sought to explain all in terms of chemistry and physics (Blumberg, 2002, p 57).So Barry was “swimming against the stream” both by studying human genetic polymorphisms and by using population studies to do so. Nonetheless, he was able to get support for his research, first at Oxford and then at the National Institutes of Health (NIH) in Bethesda, Maryland, where in 1957 he joined the Division of Clinical Research at the National Institute of Arthritis and Metabolic Diseases (NIAMD). Between 1956 and the early 1960s, Barry led field studies in the Basque country of Spain; in Nigeria, Greece, and the Pacific Islands; among Native Americans; in Mexico and South America; and in the American Arctic (Fig. 4). Barry and his team studied blood proteins, since the recombinant DNA techniques to study the genes coding for those proteins would not become available until much later. In many cases their studies piggybacked on other health studies and surveys that involved obtaining blood samples, so that additional invasive sampling was not required. The studies were conducted without a specific hypothesis but within the broad framework that they would find genetic differences between different populations, living in different environments, at risk for different diseases. “Our primary intent was to make observations in the field and in the laboratory in the expectation that we would observe relationships with health and disease that would generate hypotheses that could be tested more directly in subsequent studies” (Blumberg, 2002, p 54).FIG. 4. Barry in August 1958 in Anaktuvuk Pass in the Brooks Range, northern Alaska. He was dressed for a meeting with Inuit village leaders to explain the research program and the purpose of their visit. Reprinted by permission of Princeton University Press.This was true exploration, both geographic and scientific. Barry and colleagues went out to see what they would find, confident that the data they were acquiring and the questions they were asking would lead to productive outcomes. But what outcomes they couldn't say. Since they were seeking associations between genetic polymorphisms and disease, it is not surprising that they found some, or in some cases were able to formulate testable hypotheses. Their most notable discovery was probably what they named Ag, a polymorphic system affecting low-density lipoproteins and associated with diseases of the heart, stroke, and diabetes (Blumberg, 2002, pp 65–71, 73–74).But this work was to take an unexpected turn that would lead to the Nobel Prize. Before describing that turn, an explanation of the technique they were using in the field studies is helpful. The technique of gel electrophoresis, familiar today to any microbiology student, was first introduced in 1955. It replaced paper electrophoresis, which was only capable of distinguishing a few proteins from one another. In gel electrophoresis, a sample, for example of blood serum2, is placed in a small well in an agar gel, and an electric field is applied. The blood proteins contained in the serum migrate through the pores of the gel, separating according to their charge, mass, and shape.In 1960, Barry and the colleague who had introduced him to genetic polymorphisms, Tony Allison, decided to use a variant of this technique called double diffusion. Its use was based on a principle involving patients who had received multiple blood transfusions. It had become clear by that time that there were genetic variations between individuals and populations and that those variations led to variations among blood proteins. If a patient received several blood transfusions, it was likely that he or she would receive a variant of some protein that was different from the one he or she had inherited. If the protein variant was detected by the patient's body as “foreign,” it might induce an immune response, that is, the generation of an antibody3. Such a foreign protein is called an antigen (from antibody generator). The blood serum of a patient having received multiple transfusions was thus likely to contain a large number of antibodies to a range of different antigenic blood proteins.In the double diffusion technique, Holes are cut in a thick sheet of agar cast on a glass plate. The serum from the transfused person is placed in a central well, and sera from the [subjects under study] are placed in adjacent wells around the center. Antibodies [from the transfused person's serum] diffuse into the agar. The proteins from the other sera in the peripheral wells also diffuse into the agar, and if the protein specific to the antibody is present, the combined proteins come out of solution and form a line of precipitation in the gel. The precipitation arc can be visualized, or the precipitated proteins can be stained for later study (Blumberg, 2002, p 67).Use of this technique led to the unexpected turn; it took the form of the “Australia antigen.”The Australia Antigen and Hepatitis BIn 1964, Barry moved from the NIH to the Institute for Cancer Research (ICR—now the Fox Chase Cancer Center). He left the NIH because of a problem. My main problem at the NIH…was fitting what I wanted to do into the discipline-determined rigidity of the constituent institutes.4 My research ranged over several disciplines. In addition to the laboratory work, I had to understand the anthropology of the populations we were studying and do field work and epidemiology. I was interested in how the environment and the host interacted to affect the risk of disease, and I didn't even know what disease I would be dealing with. In addition, there was a strong clinical component to the research. At ICR I would have the freedom and the funds to organize my research group in the way that I preferred. Even though ICR was dedicated to cancer, we were fundamentally a basic science organization, and we were, at least at that time, never asked what relation our research had to immediate cancer applications (Blumberg, 2002, pp 72–73).Shortly before the move, a researcher in Barry's laboratory ran an experiment that produced a precipitin (the product of a reaction between an antigen and an antibody) different from those observed previously. The antigen was from the blood serum of an Australian aborigine; the antibody with which it reacted was from a New York City hemophilia patient who had received many transfusions. The newly discovered antigen was rare in sera from the general US population but common in the sera of people from Taiwan, Vietnam, Korea, the central Pacific, and Australian aborigines (Fig. 5; Blumberg, 2002, pp 79–81).FIG. 5. The first published image of the precipitin reaction in agar gel between Australia antigen and the antibody against it. The two circles are wells in an agar gel. The bottom well contains the serum from a patient with leukemia who was a carrier of the Australia antigen. The top well contains serum from a hemophilia patient who had received many blood transfusions and contains antibody against Australia antigen. The precipitin, i.e., the combination of the antigen and antibody, forms a curved downward-facing arc between the wells. Figure 1 in Blumberg, Alter, and Visnich (1965) “A ‘New’ Antigen in Leukemia Sera,” JAMA 191:542. Copyright © (1965) American Medical Association. All rights reserved.They gave the new antigen the neutral working name of “Australia antigen” (Au). After moving to ICR, Barry built up a team and started a systematic study of the disease and geographic distribution of Au. They found that Au was common in Asia, the Pacific, Africa, and eastern and southern Europe. They naturally sought to interpret their data in terms of an inheritance model, so their initial studies focused on families. They found the expected familial relationships—for example, if both parents had Au, then all their children would as well—but there were some surprising exceptions (Blumberg, 2002, pp 85–88). Perhaps most interesting, they found that most patients in the United States (where Au is rare) who were positive for Au had been transfused! This provided their first inkling that Au might be a blood-transmitted infectious agent. Two subsequent “normal population” studies in the United States showed one instance each of Au-positive individuals, one diagnosed with hepatitis, the other someone who had just received a transfusion (Blumberg, 2002, pp 91–92).Although these results were indicative of an infectious agent rather than an inherited condition, it was a study of Down's syndrome5 patients that led the team to conclude that they had indeed found an antigen associated with the infectious agent of serum hepatitis, or hepatitis B. The focus on Down's syndrome patients was the result of the observation that Au was common in patients with leukemia. Down's syndrome patients were at high risk of developing leukemia, so it was natural to ask if they might also have a higher prevalence of Au (Blumberg, 2002, p 94).Experiments quickly showed that they did. What's more, studies of institutions of different sizes housing Down's patients6 showed that the prevalence of Au was correlated with institution size; that is, the more patients were in contact with one another, the more likely they were to have Au in their blood. This was clearly consistent with an infectious model. So was the case of one Down's syndrome patient who had tested negative for Au several times and then suddenly tested positive. It was found that he had a mild case of hepatitis, a strong clue that Au and hepatitis are associated7 (Blumberg, 2002, pp 96–99).This observation led to a focus on testing the sera of hepatitis patients for Au. By mid 1967 the conclusion was clear: Au was significantly elevated in patients with acute hepatitis. At this point Barry and his team did what any good group of scientists would do: they wrote a paper on their results and conclusions and submitted it to a peer-reviewed journal. The paper was rejected! The reasons for this rejection, and Barry's response, are interesting and important to this narrative.Hepatitis was a well-known and long-studied disease at this time. There are recorded references to hepatitis epidemics as long ago as 2000 B.C. (National Academy of Sciences, 2000). Its most obvious symptom is jaundice, a yellowing of the whites of the eyes and possibly the skin caused by the buildup of bilirubin in the blood. There was a well-established community of hepatitis researchers who had been searching for the cause of this disease, and Barry and his team were not members. None of us was a virologist, we had not been formally trained as epidemiologists, nor did we have any special expertise as hepatitis clinicians beyond our ordinary experience as physicians (Blumberg, 2002, p 102).The reviewer who actually rejected the paper confessed that he had deemed ours to be just one more in a series of reports claiming that the hepatitis virus had been found. In his experience, previous findings had been subsequently refuted when tested by other investigators. He didn't want to risk another false claim for the identification of the elusive virus; and, erring on the side of caution, he had recommended the rejection of our article (Blumberg, 2002, p 100).Barry and his team were surprised at the apparent hostility their claims engendered from the hepatitis community (Blumberg, 2002, p 102). It was around this time that Barry read Thomas Kuhn's The Structure of Scientific Revolutions (Kuhn, 1962) and realized that his team was on the cutting edge of a grand paradigm shift of the sort described by Kuhn. As Kuhn pointed out, the prevailing paradigm is not easily dislodged. As data accumulate that undermine the prevailing paradigm, its adherents resist. Only when the data become overwhelming, and a new paradigm is available to replace the old, does the scientific community swing quickly to a new way of thinking. This is what Kuhn termed a “scientific revolution.” So Barry and his team were not only explorers, they were revolutionaries as well. And although revolutions may erupt quickly, it generally takes a much longer time for the effects of a revolution to become the new normal. And so it would be for the effects of this new understanding of hepatitis.Saving LivesBarry was not deterred by the rejection of their paper on the association of Au and hepatitis. “If such rejections are taken too seriously, they can lead to an attitude of martyrdom and of opposition to a recalcitrant establishment…We may have harbored unhappy sentiments for a while, but they didn't last, and the rebuff didn't slow us down” (Blumberg, 2002, p 100).An earlier paper (Blumberg et al., 1967) with less definitive conclusions about the Au-hepatitis association had been accepted by the same journal that rejected the later paper, so the basic claim was in the literature. But this wasn't enough proof that Au could be equated with the hepatitis virus. At this point, Barry did something that characterized his approach to science and to life in general. Barry cared most that things get accomplished. He didn't much care whether or not he got credit as long as the work got done. So he gave away the results of years of research to anyone who could make good use of them.In October of 1968 we began to distribute—gratis, to scientists who requested them—reagent kits consisting of a serum containing Australia antigen and a second serum containing the antibody against it. This was one of the best steps we could have taken to move the research forward and speed its application. For years afterward, I met scientists in many parts of the world who recalled how these reagents allowed them to start research immediately without spending a year or more trying to find the reagents by themselves…During the next few months and years a growing understanding of the virus emerged. Some of this work was done at Fox Chase Cancer Center, but most of it was accomplished in laboratories spread throughout the world (Blumberg, 2002, pp 112–113).One important observation made at the Institute for Cancer Research/Fox Chase Cancer Center was that a highly purified fraction of Au, isolated from the blood of Au-positive individuals, was not infectious when injected into laboratory animals. But less-purified material did lead to infection. Barry and his team also knew from electron microscope imaging studies that Au particles appeared to be hollow and that the purified fractions did not contain nucleic acids. This indicated that Au was not the virus itself but a part of the virus.The understanding of the virus that developed from this research around the world is shown in Fig. 6. The Australia antigen turned out to be the protein coating the surface of the virus, designated HBsAg for hepatitis B surface antigen. Beneath this surface coat is the core protein, HBcAg, which forms the viral capsid. The capsid in turn contains the viral DNA (which comprises only four genes), a DNA polymerase, and a reverse transcriptase (a portion of the virus's life cycle involves reverse transcribing an RNA, making the hepatitis B virus a retrovirus, like HIV). This is a very simple virus whose behavior is far from simple (Blumberg, 2002, pp 113–115).FIG. 6. The structure of the hepatitis B virus, showing the surface antigen (HBsAg) that surrounds the whole virus and the core antigen (HBcAg) that surrounds the circular DNA strands. The strands are double, with a large gap in the inner (positive) strand. The outer (negative) strand is complete. The DNA polymerase acts on the DNA strand. The overall size of the virus is 42 nm. Reprinted by permission of Princeton University Press (Blumberg, 2002, p 114).Figure 7 shows an electron micrograph of hepatitis B (HBV) particles, illustrating an important characteristic of these particles in the blood of infected individuals: the Australia antigen, HBsAg, vastly outnumbers (by roughly 1000:1) active virus particles. This fact enabled two life-saving applications of the research.FIG. 7. An electron micrograph of HBV particles. The small circular particles and the elongated particles with the same width are the surface antigen. The small circular particles are about 22 nm in diameter. Three whole virus particles are visible in this image, two near the lower center and one at the top to the left. Reprinted by permission of Princeton University Press.The first application was eliminating hepatitis B virus from the blood supply. Before the discovery of Au, there was no way to detect the hepatitis virus in the supply of blood used for transfusions. With the explosion of surgery—particularly open-heart surgery, radical cancer surgery, and kidney transplants—that followed post-World War II developments in anesthesia and antibiotics, the need for blood had greatly increased. Hepatitis B infection had become a common and serious problem associated with these surgeries. In the late 1960s, there were more than 150,000 cases per year of post-transfusion hepatitis in the United States alone. But although Barry and his team recognized the potential to reduce and even eliminate post-transfusion hepatitis by eliminating Au-positive blood from the blood-banking system, others had yet to come to the same conclusion. The understanding of the virus described above had not yet been fully developed, and there was resistance to a new idea that upset the established model.We were told that the medical and blood-banking community would not change their practices based on the available evidence. In addition to the changes required in their day-to-day operations, there would be increased costs that could cut into profits for the entrepreneurial blood bank supplier and impact the economies of the not-for-profit health institutions. We needed to plan a research project that would compel the blood-banking community to take notice (Blumberg, 2002, p 120).That project began in late 1968 at the Philadelphia General Hospital, with which Barry and some of his colleagues were affiliated. It involved monitoring patients who had been transfused with Au-positive blood in comparison to a control group transfused with blood lacking Au. If the former developed hepatitis at a higher rate than the controls, it would be the evidence needed to move to the next step of screening and eliminating blood containing Au from the blood supply. While this project was underway, but before it had produced significant results, Barry and his team were informed of a similar study in Japan that had demonstrated a statistically significant correlation of Au-positive blood with post-transfusion hepatitis. They decided they could no longer ethically continue the study, that is, allow some patients to be transfused with Au-posit
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