I was a physical chemistry major, and that was a very lucky choice. Of all my education preceding medical school, the physical chemistry and math courses were the most valuable in understanding the biological processes and homeostasis I was later to study in medical school. In fact, Hopkins had very good preclinical courses, and with the help of a solid background, I got quite a bit from them—with the exception of gross anatomy. I spent virtually the entire 10 weeks of anatomy lying on my back in a dark dorm room, staring at the ceiling and trying to force myself to do an evening's worth of study.
I began to understand why Harvard's application wanted one's first-year organic chemistry grade on the front page: high ratio of memorization to understanding. Hopkins did not give out grades to medical students, ostensibly to prevent us from becoming as competitive as stereotypical premed students. That was very effective for about a month, until we had our first biochemistry exam.
During the lab before the first exam, graduate assistants and others circulated through the class and would pull a few of the students off to one side to whisper something in their ear. After their pallor had returned to their normal pink color, these students were interrogated by their classmates, who learned they had been put on notice about failure if their test scores weren't excellent. With that settled, we competed hardily even without markers of station. However, in the fourth year, we were faced with choosing an internship site without knowing our grades.
The process was to sit with your advisor, who had a set of your grades concealed as though they were a poker hand in a high-stakes game. That pissed me off, because I had spent a summer and free quarter doing research there and thought their clinical program was at least as good as I had seen at Hopkins or in brief interviews elsewhere.
I chose Parkland and felt justified; I have seen the major textbooks in many specialties come out authored by the guys I studied under when they were assistant professors although the profs at Hopkins were frequent contributors in the years before. I also made another landmark friend, Jay Sanford, who turned clinical medicine and infectious disease into a calling that could be entered only if one attempted to do his best in history taking, physical diagnosis, and knowledge acquisition from minute to minute and week to week.
He also had a high regard for zoonoses and patterns of disease, which probably started me along my path. I didn't learn my actual Hopkins grades before I was in the second year of fellowship and flirted with Frank Dixon's secretary until she let me look at my transcript. I made an A in microbiology but only a C in pediatrics; subsequently, my wife would let me treat the kids only if it looked like an infectious disease.
In any case, in those ancient times, every graduating physician after internship was guaranteed a uniform, usually olive drab. I interviewed with several laboratory chiefs, and it finally came down to either an NIH intramural lab in the Panama Canal Zone, which promised tropical virology, a foreign culture, and Karl Johnson as a boss, or Al Kapikian's lab, which promised another first-rate mind to train with, lessons in vaccine development, and a rigorous National Institute of Allergy and Infectious Diseases NIAID environment. I had written the PHS several times asking for a different reporting date and mode of transportation than given in my orders air, the day after ending residency.
I never got an answer, so I assumed they would be flexible and it would be fine for me to disregard my orders as written and drive, rather than fly, and report for duty when I arrived. The trip down was tremendously interesting and, by chance, was at a time when there were no really nasty guerrilla wars or drug cartels active, but I was ready to get to work.
The hotel was run by a fellow who believed in inexpensive, plain, basic, clean housing. I should have begun to suspect something when an attractive young Panamanian woman knocked on my door a couple of hours later and asked if Jorge was there and was I lonely. I hurried down to the pharmacy and looked up Karl's phone number in their Canal Zone phone book separate from the Panama City book, which was the only one available in the Ideal. The only microbiological discovery I made initially was that if you ate in enough cheap places in Central America you could get hepatitis A.
My project was to take two different colonies of Calomys callosus , the mouse-like reservoir for Machupo virus—which causes Bolivian hemorrhagic fever BHF —and study their responses to infection with two arenaviruses: Machupo virus and Latino virus.
Latino virus was an arenavirus isolated from about km or so south of the BHF endemic zone. It turned out that nothing came out as predicted, but the results were explained 30 years later. Terry Yates and I collected some Calomys from a Machupo epidemic in a town overrun with infected and uninfected Calomys. The chromosome preps made on site, as well as later mitochondrial DNA testing, established that the actual reservoir for Machupo virus was another species called Calomys hildebrandii.
According to other studies by mammalogists, the Calomys callosus distribution stopped about where the second Calomys colony had been derived. The original identification of C. This type of data gave me the idea to go through the list of arenaviruses with assigned hosts, and sure enough, Amapari virus, an arenavirus from Brazil, had been isolated from both Neacomys guianae and Oryzomys capito multiple times.
A discussion with the scientist who found the virus and did initial studies on its ecology revealed that the original isolate had been compared with other known arenaviruses by neutralization tests, considered to be the most specific serology for distinguishing arenaviruses.
Later isolates were usually identified by complement fixation tests, known to be much less specific for an arenavirus species.
I obtained additional isolates from the Brazilian lab and showed with neutralization tests that the viruses from each rodent species were distinct one from another. While working on arenavirus serology, I developed an indirect fluorescent antibody IFA test for Machupo virus, cross-tested it against New World arenaviruses to explore specificity, and tested serial sera from BHF patients to confirm its diagnostic utility.
I used this same test to demonstrate an antigenic relationship to lymphocytic choriomeningitis virus LCMV , leading to a more solid relationship to New World arenaviruses and supporting the creation of the family Arenaviridae. The IFA test became the standard for serology of Lassa fever that showed unusual neutralization characteristics and for grouping arenaviruses.
In —71, Venezuelan equine encephalitis VEE caused a major epizootic that began in Costa Rica and moved north through Mexico, finally reaching the Texas border. Karl, with his usual prescience, had sent two PHS fellows to Costa Rica before the epidemic so that he would have a good baseline. Fortunately, as the epidemic began to move north from Costa Rica, one of my PHS colleagues in the lab was attending to a wife in the final stages of pregnancy, and the other was dealing with a wife mounting an insurrection after being left alone too much in a strange place.source url
Forty Years with Emerging Viruses
A coworker Gerry Eddy and I were volunteered to temporarily replace them actually Karl didn't give us an option, but he correctly deduced we both wanted to go. We laid a ground for pursuing a long-shot bet. The early epidemic transmission according to serology and local reports was along the Atlantic coastal plain, and Karl took this info and organized an on-site trial of TC, a human vaccine developed by the US Army because of the major biological warfare threat posed by VEE.
It proved efficacious in horses and thus capable of stopping mosquito infection and transmission after about 7 days. The USDA is an interesting organization, in that their attitudes have been shaped by their exemplary success in the eradication of foot-and-mouth disease FMD in the United States. FMD is a positive-strand RNA virus, is naturally spread by aerosol and fomites, is latent in cattle, occurs in multiple serotypes, and rarely, if ever, causes human disease.
By contrast, VEE is a negative-strand RNA virus, is spread by mosquitoes, and causes fever, headaches, and occasionally encephalitis in humans. It can be lethal in the very young, the elderly, and the immunocompromised. They had no interest in a live-attenuated vaccine like TC, which they felt could revert to virulence and would leave antibody-positive animals that could not be moved or exported. Administrators at the top of the USDA did not seem to think very often about the possibility of residual live virus in putatively inactivated vaccines.
Ironically, when Scott Weaver solved so many VEE puzzles, by extensive sequencing and reverse genetics using historical and contemporary strains, the best fit to the data was that incompletely inactivated vaccine had led to the epidemics in South and Central America. TC replaced the virulent strains that had been used to prepare the inactivated vaccine a belt-and-suspenders approach , and the epidemics greatly decreased in frequency. Later emerging epizootic viruses were found to have evolved from previously known enzootic strains.
In , we heard about cases resembling BHF but occurring not in the low-lying tropical Beni Department the endemic zone but rather in the town of Cochabamba, located in an Andean valley south of the known endemic zone. The Machupo laboratory at MARU was maintained at negative pressure, and denizens wore scrubs and showered out, but generally there was nothing resembling modern containment inside, and so work on Machupo virus was confined to those who had been infected and survived. Patricia was in Bethesda being treated successfully for some unknown type of lymphoproliferative disorder, and the only other scientist with immunity was at the University of Wisconsin completing a PhD.
Karl explained the situation to me and pointed out that this outbreak might well bear no relation to BHF at all the last similar outbreak turned out to be plague , and that the epidemiology, with interhuman transmission, jaundice, and no known Calomys in the area, meant that a nonimmune could go with no more risk than an immune.
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He offered me the opportunity, but actually he would have had to tie me to the lab bench to keep me away. I packed a footlocker and loaded up a liquid nitrogen tank with dry ice soaked in liquid nitrogen to avoid the problems with transporting liquid nitrogen. We were all a bit cavalier in those days, and when I poured the liquid off on a floor with no one else around, I got some on the soles of my sandals, which cracked while frozen but didn't contact my feet.
I flew Braniff Airways to La Paz can't do that anymore because Braniff disappeared from commercial aviation and met up with Luis Valverde, one of Karl's colleagues from the original investigations, to obtain the samples that had been sent to him from Cochabamba. After deplaning and walking briskly toward the terminal, I quickly found out that at 13, feet I was not in shape.
It was a shock; the marble steps leading up to the impressive entrance were worn down about 2 to 3 inches by who knows how many people's feet. Luis's office was high ceilinged and lit from the sun but was drab, containing one desk, two wooden chairs, and a locked Revco freezer, period. My sadness for the woeful extent of the infrastructure was matched by my admiration for Luis bearing this burden with so little support.
A day later I boarded a Lloyd Aero Boliviana flight an airline that, like Braniff, today flies only in the imagination and memory of a few bound for Cochabamba, leaving behind the thin and depressing atmosphere of La Paz. I was surprised to be met at the airport in Cochabamba by Bob LeBow, a classmate from medical school who was serving as a Peace Corps physician and who regularly rounded at the three largest hospitals in the city.
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The second was the Seguro Social hospital, filled with rabidly anti-American, Soviet-styled communists. The third was a private Catholic hospital that also cared for some indigent patients through US church support. It was fortunate that Bob had been assigned to Cochabamba, because he served as a communication link among the three major hospitals.
Although each of them had experienced cases of the recent outbreak, the institutions spoke to one another only rarely. Bob, his wife, and I went to their house and discussed things over dinner, which consisted of tough beef and vegetables washed in dilute bleach to eliminate the various pathogens, including typhoid, which they had both suffered from.
Bob had been under terrible stress: He and a couple of nuns were the only people who would enter the room of the last remaining patient, and Bob was thinking about who would care for him if he became ill. The town was somewhat panicked, and the airlines were threatening to cut off service. The Catholic hospital pathologist was hospitalized there on an otherwise unoccupied wing, tended by volunteer nuns and Bob. The next day, I worked with the local physicians to organize blood sampling from all the contacts for later testing. Mercado, like many working health ministry members I have met all over the world, was a sincere physician knowledgeable about local diseases.
Mercado had traveled all over Bolivia, sometimes on muleback, and was side-by-side with local physicians in surveillance and other efforts. The WHO representative was largely clueless and topped this off by contacting Geneva by shortwave the only communication we had and demanding to be evacuated because he had been exposed and felt ill.
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Many ham radio operators all over the world were listening on our frequency, and this spread rumors about the status in Cochabamba. In fact, he hadn't been anywhere near any patient or any samples, but Mercado and I went to the airport to see him off—not because we would miss him, but to be sure he got on the flight. Bob had borne the brunt of working with D. There were a number of French-trained physicians around, and they wanted the prestige of caring for D.
Each day, they debriefed the nuns and proceeded to write their orders without seeing the patient. Then I examined D. This spared D.