Michael B.A. Oldstone, MD
(Author, Viruses, Plagues, & History)
3.7 – Aliens, Plagues, & Epidemics (9.8.11)
Viruses lie at the heart of some of humanity’s most pernicious and devastating diseases, such as AIDS, hepatitis, and influenza. Michael Oldstone, a recently elected member of the National Academy of Sciences and a professor of immunology and microbiology at The Scripps Research Institute in La Jolla, California, has devoted his career to a molecular understanding of how viruses infect cells, evade and manipulate the immune system, and cause disease. Oldstone studied the pathogenesis of lymphocytic choriomeningitis virus (LCMV) in its natural host, the mouse, for decades. Along the way, Oldstone overturned a deeply entrenched dogma about immunological tolerance, and made numerous observations that shaped fundamental concepts in virology, immunology, and infectious disease. In his Inaugural Article, Oldstone explores several of the lessons learned and concepts established through his studies of two viruses: LCMV and influenza virus.
Microbe Hunter in the Making
Oldstone was born in Manhattan, and when he was in junior high school he devoured the 1926 classic book Microbe Hunters, by Paul de Kruif. Inspired by the lives and work of scientists, such as Louis Pasteur, Robert Koch, Anton van Leeuwenhoek, and Sir Ronald Ross, Oldstone remembers thinking, “Wow, that’s what I want to do.”
Seeking a different climate and atmosphere far away from his native New York City, Oldstone attended the University of Alabama in Tuscaloosa. He received his bachelor’s degree in 1954, majoring in English and history, although he also took sufficient coursework in science so that he could later enroll in medical school. After a two-and-a-half-year stint as a lieutenant in the United States Army, stationed in Germany, Oldstone enrolled in the University of Maryland School of Medicine in Baltimore.
On his third day of medical school, as Oldstone waited in line with his classmates to dissect a cadaver, he was summoned to meet with Theodore Woodward, the school’s Chairman of Medicine and a renowned expert in infectious diseases. Woodward took Oldstone and two other students to visit a patient, who fluctuated between stupor and coma, and told them that without a diagnosis and appropriate treatment the sick man would die within a day. The students smeared a drop of the patient’s spinal fluid onto a microscope slide, stained it using a technique that aids the identification of bacteria, and examined the specimen under a microscope. Woodward informed them that they were looking at pneumococci, and began talking about many of the microbiologists Oldstone had read about in Microbe Hunters years earlier. Oldstone, who was somewhat ambivalent about medicine at that time, began to think that perhaps he had ended up in the right place after all. When Oldstone and his classmates returned the following day to visit the patient, who had been given antibiotics for his infection, they found him talking. “It was like Lazarus returning from the dead,” Oldstone says. “I couldn’t believe it.” Woodward invited Oldstone to see patients with him on Saturday afternoons, and later sent Oldstone to spend the summer working with his former mentor, Joseph Smadel, who was then the head of virology and virological research at Walter Reed Army Medical Hospital and Institute of Research in Washington, DC. Woodward also introduced Oldstone to Sheldon Greisman, a young clinician and professor at the University of Maryland who served as Oldstone’s clinical instructor during his second year of medical school. “I have, as most people who go into medicine, a very retentive memory,” Oldstone says, “and I could memorize what I was supposed to memorize, but I was disappointed in that there was limited knowledge about what the mechanism of these various diseases were.” He began to realize that he would not fully understand the causes of disease, or disease pathogenesis, just by going through medical school. ” I thought that if you want to practice medicine, you really have to understand the disease process and then how to treat it,” Oldstone says.
In Search of Research
To help ensure that he would gain the knowledge needed to better understand disease processes, Oldstone began working on a doctorate during his second year of medical school. He split his training between the University of Maryland and The Johns Hopkins University in Baltimore, Maryland. Oldstone furthered his knowledge of biochemistry by working in the laboratory of William D. McElroy, the chairman of Biochemistry at Johns Hopkins. He also spent time studying the secreted toxins of Rickettsia bacteria with Charles Weisseman, and in Greisman’s laboratory he examined a bacterial cell wall component known as endotoxin, which triggers a potentially lethal reaction called endotoxic shock. “One of the great advantages of working with Sheldon Greisman was that his wife was the roommate of the woman I [later] married,” Oldstone recalls. “So that’s how I met my wife, Betsy.”
As a result of his work on endotoxic shock, Oldstone was invited to spend the summer of his third year of medical school working at Beth Israel Hospital in Boston, Massachusetts, in the laboratory of Jacob Fine, one of the world’s leading experts on endotoxic shock. “That exposed me to high-powered science, which wasn’t done at the medical school I was at,” Oldstone says.
After a year and a half of research, Oldstone was certain that he wanted to work on the pathogenesis of infectious diseases. “Rather than complete my PhD, I thought it would be better for me to just get my MD degree, and then …work in a basic science laboratory.” After completing his medical degree in 1961, Oldstone applied to work as a postdoctoral fellow in infectious diseases in the laboratory of John Enders, who shared the 1954 Nobel Prize in Physiology or Medicine for his work establishing cell culture, which subsequently enabled in vitro study and propagation of viruses to generate vaccines. Although Enders accepted Oldstone as a fellow, he pointed out that Oldstone, who had grown vesicular stomatitis virus in laboratory dishes, already knew enough virology and suggested that Oldstone work with Frank Dixon, a major figure in immunobiology and immunopathology, at The Scripps Clinic and Research Foundation (now The Scripps Research Institute, referred to as such hereafter) in La Jolla, California. “He thought that the future lay in the melding of virology and immunology, and that if he was my age, that’s the area he’d go into,” Oldstone recalls.
Lessons Learned from LCMV
For his postdoctoral research, Oldstone proposed to isolate antigens that cause experimental allergic encephalomyelitis, an animal model of multiple sclerosis. Dixon agreed to let Oldstone pursue this project in his laboratory part-time, but because Oldstone had experience working with viruses, he suggested that Oldstone also investigate how chronic infection with LCMV could lead to kidney disease in mice. To learn how to work with LCMV, Dixon sent Oldstone to work with his collaborator, Wally Rowe, at the National Institutes of Health. Oldstone’s work with LCMV soon turned out to be so fascinating and important, he says, that he abandoned his multiple sclerosis project and devoted his full attention to LCMV.
Oldstone arrived at The Scripps Research Institute in 1966, and worked alongside a number of gifted postdoctoral fellows in Dixon’s laboratory who later became influential scientists, including Emil Unanue, Richard Lerner, Thomas Edgington, and Howard Gray. The first three scientists were, in time, elected to membership in the National Academy of Sciences, and all as members in the Institute of Medicine. “It was a very stimulating group,” Oldstone says. Furthermore, Karl Habel, a major figure in virology, relocated to The Scripps Research Institute from the National Institutes of Health in the late 1960s. “I spent time with Habel and that really helped me in terms of enhancing my knowledge of virology,” Oldstone says.
Dixon invited Oldstone to study the interactions between LCMV and the immune system of its natural host, the mouse. It was then generally recognized that an acute LCMV infection triggers a vigorous immune response as the animal attempts to rid itself of its infected cells; in contrast, mice that acquire the virus congenitally typically remain asymptomatic. The accepted dogma at the time held that persistently infected mice remained symptomless in part because they developed immunologic “tolerance” to the virus and thus were incapable of making antibodies that would help to purge their bodies of infected cells. In agreement with this hypothesis, the virus could be found in the blood and organs of persistently infected animals, but freely circulating antibody against the virus was not detectable. However, some studies demonstrated that chronically infected mice developed a type of kidney disease that resembled autoimmune kidney disease, which suggested that chronically infected animals were capable of generating an “auto” antibody, or perhaps antibody, response to the virus .
Oldstone sought to resolve these two conflicting observations, and found that mice with persistent LCMV infections accumulated significant amounts of virus-antibody immune complexes in the kidney that were involved in the pathogenesis of the observed kidney disease. He eluted, quantified, and identified the antibody as being specific to LCMV, and concluded that chronically infected mice made antibodies to the virus; others had previously failed to detect anti-LCMV antibodies in the circulation because the animals produced so much virus that the antibodies were bound to the virus in the form of immune complexes that were deposited in certain tissues, such as the kidneys. Within weeks of Oldstone’s publication detailing these findings, he received a letter from Enders, “who said that I certainly had made the right choice and I was on the right track for a career,” Oldstone says.
Oldstone then turned his attention to other murine viruses that were thought to establish persistent infections as a result of immune tolerance, such as Gross murine leukemia virus. Oldstone was again able to find immune complexes in mice chronically infected with this virus, and furthermore, he was able to recover the immune complex, dissociate it, purify the antibody, and show that antibody had specificity for the virus. Further studies revealed that these findings could be extended to many chronic human viral infections, such as with hepatitis B virus, cytomegalovirus, Epstein-Barr virus, and HIV, suggesting that immune complexes are a signature of persistent infection.
In Pursuit of Persistence
Following his postdoctoral fellowship, Oldstone remained at The Scripps Research Institute as an assistant professor, and within two years was granted tenure. He continued working with the LCMV mouse model, and began investigating the mechanisms of persistent infection and how such infections cause disease. Because LCMV is not cytolytic, unlike most viruses, Oldstone was able to clearly delineate any effects caused by the virus from those caused by the host immune system. He found that the virus could alter the function and biochemistry of the cells that it infected, including not only cells of the immune system, but also differentiated cells, such as neurons and endocrine cells, thereby promoting disease. For example, the virus dampened the expression of GAP43 in the neurons of mice, causing deficits in cognition and learning; LCMV infection also suppressed the production of growth hormone by endocrine cells, impairing mouse growth and development.
Oldstone also discovered that under some conditions, the immune response generated against viruses could cross-react with host proteins to cause autoimmunity, a phenomenon termed “molecular mimicry”. As a proof-of-principle, Oldstone generated transgenic mice that expressed a LCMV protein in the insulin-producing β-cells of the pancreas. Subsequent generations of these mice, whose immune systems were trained to recognize the viral protein as “self,” were then infected with LCMV. Oldstone found that the immune response generated by the viral infection not only destroyed LCMV-infected cells, but also eliminated the β-cells engineered to express the LCMV protein, thereby impairing insulin production and causing diabetes.
Oldstone has also teased apart some of the molecular details of how persistent infections evade the host’s immune system. During a typical immune response to a viral infection, the immune system generates a variety of factors called cytokines and chemokines that potentiate the immune response. At the same time, the body also generates negative regulators that help to keep the immune response in check so that it does not damage healthy tissues. Oldstone found that during the establishment of a persistent LCMV infection in mice, the virus induces a negative regulator of the immune system (called IL-10) that diminishes the function of T cells, which would ordinarily help to clear the virus. Moreover, by blocking IL-10 function using genetic approaches or an antibody against the IL-10 receptor, Oldstone showed that the immune system’s ability to clear the persistent infection could be restored. These findings suggest that negative regulators of the immune system may be promising therapeutic targets in the treatment of persistent human viral infections.
Oldstone’s career has been “mostly married to LCMV,” he says, although he admits to “having affairs with other negative-stranded RNA viruses,” such as measles. Most recently he has turned his attention to influenza virus, working in collaboration with fellow Scripps researcher Hugh Rosen, a medicinal chemist. In contrast to LCMV, influenza virus is cytolytic and causes an acute infection that is often accompanied by a hyperaggressive immune response called “cytokine storm,” which can cause severe injury to tissues and organs, potentially resulting in death. Using mice and ferrets infected with the human pathogenic H1N1 influenza virus, Oldstone and his colleagues found that sphingosine-1-phosphate receptor 1 agonists could prevent cytokine storms. Furthermore, these chemicals were more effective at protecting the animals from the tissue-damaging and lethal effects of influenza virus infection than a commonly prescribed antiviral drug that blocks viral replication. Their findings not only established that cytokine storms directly contribute to the pathogenesis of influenza infections, but also suggest that the sphingosine-1-phosphate pathway may be a promising therapeutic target for diseases accompanied by cytokine storms, such as those caused by Hanta virus, SARS viruses, and certain autoimmune disorders.
In addition to his research, Oldstone takes great pride in the cadre of postdoctoral fellows he has trained, many of whom have gone on to enjoy successful biomedical careers. Of the 77 postdoctoral fellows he has trained, most are in full-time academic research pursuits at universities or research institutes.
In his spare time, Oldstone enjoys fly fishing with his son in Montana, and going to the opera and Broadway shows with his granddaughters. He spends two weeks a year at the University of Alabama undergraduate school in Tuscaloosa as a resident professor in the College of Arts and Science. He recently wrote the book Viruses, Plagues, and History, which united his love of English and history with his passion for research. He envisions the work as a continuation of Microbe Hunters, and hopes that it will seduce others to go into research. The book, like Oldstone’s career, has been a resounding success, with more than 40,000 copies sold in six different languages. “My mother would have been proud of me because the book was reviewed in the New York Times book review section,” Oldstone says. “She didn’t care much about [my other accomplishments], but she would have been happy about that.” 
The story of viruses and humanity is a story of fear and ignorance, of grief and heartbreak, and of great bravery and sacrifice. Michael Oldstone tells all these stories as he illuminates the history of the devastating diseases that have tormented humanity, focusing mostly on the most famous viruses.
Oldstone begins with smallpox, polio, and measles. Nearly 300 million people were killed by smallpox in this century alone and the author presents a vivid account of the long campaign to eradicate this lethal killer. Oldstone then describes the fascinating viruses that have captured headlines in more recent years: Ebola, Hantavirus, mad cow disease (a frightening illness made worse by government mishandling and secrecy), and, of course, AIDS. And he tells us of the many scientists watching and waiting even now for the next great plague, monitoring influenza strains to see whether the deadly variant from 1918–a viral strain that killed over 20 million people in 1918-1919–will make a comeback. For this revised edition, Oldstone includes discussions of new viruses like SARS, bird flu, virally caused cancers, chronic wasting disease, and West Nile, and fully updates the original text with new findings on particular viruses.
Viruses, Plagues, and History paints a sweeping portrait of humanity’s long-standing conflict with our unseen viral enemies. Oldstone’s book is a vivid history of a fascinating field, and a highly reliable dispatch from an eminent researcher on the front line of this ongoing campaign.