• Nationality American

• Citizenship United States

• Alma mater University of Iowa

• Known for: Identified Shope papilloma virus and main cause of 1918 pandemic as Influenza A virus

• Spouse(s) Helen Ellis

• Children 4

• Awards

  • 1957 Kober medal

  • 1957 Albert Lasker Clinical Medical Research Award

    • U.S. Army Legion of Merit

• Scientific career : Fields : Virologist

• Institutions

• Rockefeller University

• National Naval Medical Center

[...] Richard Edwin Shope (December 25, 1901 – October 2, 1966) was an American virologist who, together with his mentor Paul A. Lewis at the Rockefeller Institute, identified influenzavirus A in pigs in 1931.^[1] Using Shope's technique, Smith, Andrewes, and Laidlaw of England's Medical Research Council cultured it from a human in 1933.^[1] They and Shope in 1935 and 1936, respectively, identified it as the virus circulating in the 1918 pandemic.^[1] In 1933, Shope identified the Shope papillomavirus, which infects rabbits. His discovery later assist other researcher to link the papilloma virus to warts and cervical cancer. He received the 1957 Albert Lasker Clinical Medical Research Award.^[2]

Career

In 1931 Shope worked as researcher and together with [Dr. Paul Adin Lewis (born 1879)] at Rockefeller University discovered that the cause of swine flue was virtually identical to bacillus influenza, a bacteria that had in 1892 been identified as the cause for human influenza. Shope and Lewis went on to identify a virus that also had links to influenza, putting into doubt the thesis that flue was caused by a bacterial infection. Soon after this controversial discovery, Lewis traveled to Brazil to study an outbreak of yellow fever. The 28 year old Shope had put himself forward for this research trip, but his offer was refused by Lewis. Instead Shope continued to research swine flue. Lewis did not return from the research trip, as he died of a yellow fever infection brought about by a laboratory accident.^[3]

Shope continued his work at the Department of Animal Pathology at the Rockefeller Institute for Medical Research in Princeton, New Jersey.^[4] In 1933 Wilson Smith, Christopher Andrewes, and [Sir Patrick Playfair Laidlaw (born 1881)] isolated the influenza virus. In 1935 Shope found that humans that had been alive during the 1918-1919 swine flue epidemic still carried antibodies against the swine flue virus.^[5] Throughout the 1930s Shope continued to research swine flue. While studying swine flue on farms in Iowa Shope discovered that virus infections caused the mad itch, also known as pseudorabies, in cattle. Scope also discovered that virus infection caused fibroma in the cottontail rabbits he had hunted in New Jersey, and that a virus infection was also responsible for the papillomatosis in the cottontail rabbits he had observed in Iowa. By the last 1930s Shope had established himself as a well-known expert with a reputation as a virus hunter.^[6]

Shope left the Rockefeller Institute to join a research team the Canadian Department of National Defence and the US War Department established to investigate rinderpest.^[7] The research team was based in Canada, but Shope could not commence research at the speed he was accustomed to, as he was also in active service as Commander in the US Naval Reserve.^[8] In 1943 Shope presented his team's research on rinderpest at a meeting hosted by George Merck.^[9]

Family

His son [Dr. Robert Ellis Shope (born 1929)] was also a virologist, who specialised in arthropod-borne viruses.^[10]

[...]

[Russell Currier] Yeah! I wanna just talk just briefly about One Health, and the, uh... Let's see, yeah, and those concepts, but before I even get into that, if you want, uh, some nice reading material, I've displayed a book called Zoobiquity there on that center table, and I got interested in that book when I had a subscription to the Sunday New York Times. The week in review section had, the front page of that section, 2/3 of it was on this book and then it continued inside, and it was two full pages, by Barbara Natterson-Horowitz and Catherine Bowers. One of them dated must've dated the editor there or something in years past. Because they just, they just went full hog on that thing, and it's very, very good. I've met these gals on several occasions, and they're delightful and very accomplished and, uh, you'll get a whole concept of One Medicine, you might say, or One Health, and she's just one of a few other key physicians that are working in the area. Let's talk just a little bit about One Health. A lot of people have a very narrow view of this and think it's just Zoonotic disease, which is, uh, somewhere around here. Let me see. Well, it doesn't make any difference. But it really embraces all the major disciplines, now includes environmental health and plant health, and it's incredibly important that if something happens in one area, it's gonna impact another. So, that comes to mind with one of the leaders in this movement, another physician, along with Barbara Natterson-Horowitz who I mentioned there, is Laura Khan, too, who's just published a book in the last year on antimicrobials in livestock production. So, that's, I see Zoonotic infections here now. So I mean, it's a big concept, and it's bigger than just Zoonotic disease. Let me say that it even brings in evolutionary concepts, and it calls for interdisciplinary investigations and cooperation, so that just gives you some idea of that.

[...] One Medicine thing goes back for hundreds of years, and you might say it peaked in about the 19th century. There was a lot of collaboration between physicians and veterinarians. Many physicians around the staff at veterinary colleges. In fact, the first veterinary college, established 1761, was staffed entirely by physicians. So, uh, it's kind of had a resurrection in just the last quarter-century, but the most depressing, minimal amount of effort in this area was actually in the inter-work area of the first half of the 20th century, from about 1915 through 1945. There were two exceptions to that, two exceptions, and here is the first of those two. This is Karl Frederick Meyer.

[Karl Frederick Meyer] was a veterinarian that was educating in Switzerland, and he accomplished just a number of major things. This is just a short list. It goes on and on, and he was, it's been said that, if it wasn't for World War 2 he probably would've been nominated for the Nobel Prize. So, he was quite the guy. And you notice that there's MD after his name. We'll get to that in a minute. If you want some reviews, and I think these slides are accessible through Donna or somewhere, a nice bio was written by him in, for the National Academy of Sciences, by Albert Sabin of polio vaccine fame, and there's a couple short little recent pieces by Pospischil and Konigsbaum, if I got that right, in the last few years on him. He's just a remarkable person. And it led to the awarding of the Laker Award, which we'll talk about, but he was the he was an incredible guy. [...] He got into trouble during World War Two. He was from the German part of Switzerland, and he had a heavy German accent, and he came under suspicious, you know, during the McCarthy era and he lost his security clearance and what have you. So, with that approaching, he had gotten an honorary MD degree from the College of Medical Evangelists of Yorba Linda, California for his work on saving the canning industry of California from Botulism, especially for olives and mushrooms. And so, in summary here, this is in bold type, Meyer was a veterinarian who masqueraded as a physician.

The second person is the topic of today's lecture, [Richard Edwin Shope, ] and he was a physician who masqueraded as a veterinarian. Just a remarkable person.

He was born December 25th, of course we all recognize that date as Christmas Day, and I would like to read a paragraph very quickly from his daughter's term paper in high school of 1952, largely dictator by Doctor Shope. "Christmas Eve night of the year 1901," "It was cold and snowy outside, but inside the Shope house" "at Riverview Street, Des Moines, Iowa, always warm and cozy." "There was a blazing fire in the old fireplace," "But the only two taking advantage of it" "Were Doctor Charles Cornelius Shope, prominent physician" "In Des Moines, and Julia Anderson, MD." "Both were quite nervous, still, for Mrs. Mary Hashille" "Was expected to bear his first child." "They left at 5 o'clock in the morning of December 25th." "Doctor Watson, the family doctor, appeared" "and announced that that the Shope's" "First child was a long, skinny boy." "A few days later, Doctor Watson examined Richard" "And said that he was jaundiced," "And would probably not live." "However, Richard did full through," "And in five months he weighed 17 pounds, he could get" "Up and walk at the age of nine and a half months." So that's a little bit about [his] birth.

[Richard Edwin Shope] went out to Iowa State College to enroll in a course in forestry, but the office was closed, so, and this is true, he hopped a freight train for IOC and enrolled in pre-medical studies here, and became quite a tremendous student. There he is as a student athlete, both for varsity football and for track and field. He ran the 440 and the Hertz, and did quite well in those areas. He entered the college after two years of pre-med. This is also his daughter Nancy's birthday. While in medical school, he was expelled for writing a makeup example of physical chemistry for a classmate. His period of expulsion lasted for his Christmas vacation, so the only actual penalty turned out to be a failure in the course despite straight A grades throughout the semester. He was also made ineligible for one year from competing in football and track. Furthermore, he was required to make up his course in physical chemistry during the Summer between his freshman and sophomore years. The remainder of his [...] school career was without serious consequence. His grades good, and in his senior year he was elected to Alpha Omega Alpha at the honorary Omega fraternity. He was also chosen president of his senior class, and overall the University of Iowa president. So he was quite the man. And, uh... One of the... Things that he had to do, you know, he was about 16 maybe going on 17 when he got here. There was a compulsory to be the same as ROTC today, it was called SATC, and so he was put in a special group of boys called the Saturday, what was it, Saturday Afternoon Tea Club, I think, for SATC, and did fairly well there. So, and in the year 1918, which includes this period, of course, several of those boys in that quasi-military group died from the influenza. So, it was pretty serious stuff. He remained in Iowa. You know, it's been said that medical schools are monsters that devour their own young. That was particularly true here in Iowa, because he nearly went on staff here and taught pharmacology, and did research of, on tuberculosis.

And then he [got] a call from [Dr. Paul Adin Lewis (born 1879)]. He was referred by his pharmacology professor to come to Princeton and work with Paul Lewis. [Dr. Paul Adin Lewis (born 1879)] was the, one of the two [first] scientists to work with the polio virus, but he had this research on animal diseases and that sort of thing. [Richard Edwin Shope] got married here. He married Helen Ellis of Lineville, Iowa, who's father was a physician, and actually Richard Shope did the practices for both his father and his father-in-law during the Summers when they were on vacation. He made extra money that way. And they, what was really interesting is that he had been a, he met his wife by, it was raining hard and she'd come to the overhang of their rooming house, and he thought it was his girlfriend at the time, and so he went out and he realized it wasn't. But he obviously liked what he saw. He asked her out the following Saturday and seven months later they were married. And then they took that big trip east. That trip took eight days in that $35 jalopy, and it was was covered with graffiti and sometimes, I think it was West Virginia or Pennsylvanian, it was crank-start. There was no electric start, and he couldn't get it started, and someone, a crowd of spectators came around there and watched that and they said, well, you know it says here painted right on your car to shake before starting. So he shook the car, and a quarter of a turn later it took off. So, things improved after that.

[Richard Shope ], as he was working on hog cholera at that time with Dr. Charles Murray, a professor over at Ames, asked him, "Why don't you look into something we don't know about" "Anything about: hog flu?" And Shope realized that if he could find the cause of hog flu, it might be the answer to human flu, too. And he received assistance from a practicing veterinarian here in IOC, Dr. Fred Crow, and the whole thing about the swine connection was very controversial. Cedar Rapids had a national swine show the last few days of September, and October, and there had been influenza-like illness in west central Illinois in August. Well, when you bring all these pigs in, lo and behold, it really took off. This show was actually shut down early because of that. At any rate, the... The fellow by Dr. Koen was actually on two sides, he says, "I have no apologies to offer of my diagnosis of flu." "Last fall we were confronted with a new condition," "If not a new disease." This was never in swine textbooks. "I believe I have as much to support this diagnosis in pigs" "As physicians have to support a similar diagnosis in men."

"The similarity of the epidemic among people" "And epizootic among pigs was so close, the reports so" "Frequent, that the outbreak" "in the family would be followed" "Immediately by an outbreak among the hogs." "Striking coincidence. It looked like flu," "It presented identical symptoms of flu," "It terminated like flu." "Until proved that it was not a flu," "I shall stand by that diagnosis." And that statement is in every review paper on the history of influenza, but it's very, very good. So, Shope had a natural interest in that.

Before we go on, I wanna talk just briefly about [Dr. Theobald Smith (born 1859)], because he was at the Rockefeller Center heading up this research in the final years of his long and productive career. But he worked originally, he was a physician, that originally worked for the Bureau of Animal Industry in the US Department of Agriculture, and he headed up the team under Daniel Salmon, that's who the genus salmonella's named after, to look at Texas cattle fever, and this was, needed a lot of work, and it was spreading, and it was a major problem with livestock production. And he worked with another veterinarian by Fred Kilbourne, and Cooper Kurtz who was both a veterinarian and a physician, and a crackerjack pair of cytologists. But they had worked out that indeed it was tick-transmitted, it was a... Protozoan by the name of babesia [see https://en.wikipedia.org/wiki/Babesia ]. And it was transmitted on by a tick called Boophilus annulatus. But this, I think, came out at around 1892, this report, and this opened up the whole field of inquiry of thinking about arthropods as vectors in disease. And so the work on malaria, Walter Reed on yellow fever and his team and on plague, on being flea-transmitted, was enabled by this. So this was really groundbreaking work, and that laboratory at the Bureau of Animal Industry, was so effective that the Marine US Public Health Service Marine Hospitals said that, you know, we need a laboratory too. Theyfor one in agriculture. You know it today as the National Institutes of Health.

So, Richard Shope had two inspirational figures. One was Paul Lewis, who later, shortly after the work here, isolated the flu virus, went down to work on yellow fever in Brazil, caught it in the laboratory and died just after a few days of illness.

So, Paul Lewis was a very unfortunate thing. So, the real big event occurred in 1930, and Shope was a lover of the fellow by the name of [Sir Patrick Playfair Laidlaw (born 1881)] from Britain to connect swine flu to the 1918 pandemic strain.

This is a little bit about Paul Lewis that I forgot about, but anyway, he worked with a fellow by the name of [Dr. Simon Flexner (born 1863) ] to find a vaccine for polio.

Well, they had one, and who he protected for the monkeys, and Simon Flexner was the brother Abraham Flexner who did the study at the medical schools, particularly here in Iowa, among others, to improve education and patterned after the Johns-Hopkins Model, and is uh, as um, Jim Hanson told me, you know, I was trying to discuss this with his, he says well, look Russ, I'm paraphrasing here, but he said, Johns-Hopkins was an example of a good medical school.

The University of Iowa was an example of a bad medical school. So, they'd really changed things around here. But that would be the brother of Simon Flexner.

Now, one of the real problems, Shope had three sons and a daughter, and the oldest son, Richard Jr., became a veterinarian, and the second son, Robert Shope, become an arbo-virologist who was charismatic, and almost was very effective and isolated a number of flu viruses and so forth.

But here's where our friendly New England Journal of Medicine, you know, with those eagle eye editors, they said, "The breakthrough came in 1931 when Robert Skype," "A veterinarian, transmitted the infectious agent" "Of swine influenza."

Well, first of all, the names are wrong. It should be Richard Shope, and he was a physician, not a veterinarian. So, um... And then, what Dick Shope did, he worked with a British team that was looking at this, too.

They had them doing research with ferrets on distemper which is very important, as you know, in dogs, but several other species as well.

So they had this colony of ferrets and got interested in this, and they tried to infect ferret intra-nasally, and they could not do it.

I think Shope's suggested that they anesthetize them, and uh... And still infected, that infective material with virus deeper, and they got infection all the time.

And ferrets now are identified as being exquisitely susceptible to all influenzas.

And they adapted it to then run it through a hundred times, then into mouse, and you could see the thing and finally got it to grow in pigs, and they blamed the vaccine that came out when, I think the late 40's, but that was quite an accomplishment.

And here, Shope wanted his name to identify with Shope Fibroma and also Shope Pappilloma, and here's an example of the, an artist's rendition of the Pappilloma, and it almost looks like they have horns.

Taxidermists had a ball with these things.

What they would do is, with jack rabbits, the taxidermists would, and attach antelope horns pheasant wings on the side and call 'em flying jackalopes 'til they were a postcard entity of Walldrug and places like that out west.

The next thing is, is that this actually helped with the development of Gardacil vaccine.

I put that picture of that bunny rabbit there, is from a New York Times article which I have here, and I'll just read you the first two sentences.

It says, "Nuns and Jews, cow warts and rabbit horns." "The common link: They are all crucial elements to the" "search for the world's newest vaccine."

And, uh, I won't get into all the detail on that, but Shope's work was foundational in terms of dealing with that. [...]

This is Camp Dodge, Iowa, during World War I, and there were 18,000 men grouped there to form the Statue of Liberty. That was a very, very active base at the time, and uh... They had an influenza episode there in the fall, and one of the interesting things, and Shope pointed this out in a review article which I'll be talking about a little bit later, but they were struck, uh, the 2nd Infantry Regiment was in Hawaii in the Spring. In June, were... Affected by the first wave of that flu. That was actually some of the big nature's vaccine scream. They were transferred to Camp Dodge in August, and then in September, October of, I mean, they almost needed trucks or something to cart away dead soldiers because it killed 6.8%. But virtually none of the men in Hawaii in June became ill with this 1918 thing. In subsequent research, uh, when... When Shope got to really working with this, he had a mild case of influenza in swine, and he gave that term a name called Filtrate Disease. And then he finally discovered that they also needed a cold pathogen called Haemophilus influenzae suis, and this, uh, was that, and the full-blown flu in which it had this funny, whooping-type breathing called thumping. Pigs that were affected by this were called thumpers. So he, you know, he basically identified what a complicated thing, and up to this time, the human influenza was assumed to be due to or Haemopilus influenza, a little different strain. But Shope was a student, certainly, of the disease. So anyway, um... One of the things that puzzled Shope was that there was just no hog flu almost all year 'round, and then the first cold wave of weather in Autumn each year, which was a stressor, these swine would just all break out with this disease. So, how did it occur? How did it maintain itself? And this where he went down somewhat of a controversial thing, and he postulated that lung worms, that swine were affected by, lay eggs in small bronchials that are coughed up and swallowed to go out with the feces, and then eggs are consumed by earth worms, and later the worms are eaten by pigs. A delicacy for them. Pass through the stomach into the, and then came out. They go through three stages in the worm, earth worm, and two stages in the swine as they're migrating back to their This cycle was never fully confirmed, but I for some reason put this in to show this... Basically. It's kind of gross, transparent look at pigs. And he postulated that the virus ran intostate or masked state, that's sometimes used, where you can't isolate it no matter how many earth worms you grind up. Well, Christopher Andrewes isolated the first human influenza virus, and he and Shope became just very good friends, and they traveled back and forth across the ocean to see each other. In fact, Shope took him up to Woman Lake, Minnesota, where his family's cabin is, and worked with, uh, Anyway, Andrewes and his co-investigators Smith, Wilson, and Laidlaw, were later knighted for this accomplishment. And uh... In those years, Shope basically said that the human and swine influenza were remarkably the same and have a lineage. He also worked with some other things, like mad itch, or pseudorabies, which we've heard about because of the program with he Iowa Department of Agriculture eliminated that, but generally it's a mildly, not of major consequence, at least to older swine. But they still got rid of it. But in cattle, it just devastating, and he showed that. The first big swine diseases textbook, called Dunn Swine, by an editor by the name of Dunn, it, he wrote the chapter on wolf influenza, Shope did, in probably the second as well as this pseudorabies. So, he was quite the guy you'd ask for. A lot of the emphasis from his work identified him as being a veterinarian. He also worked with swine pox here, and showed it could be, although not necessarily, transmitted by the agency of pig-swine-lice. On viruses and cancer, we've already talked a little bit about this. I'm jumping around a bit. This changed the, uh, in domestic rabbits, it's very serious. It was rare in wild rabbits, and he got busy with other work. He then worked with a fellow by the name of [Dr. Francis Peyton Rous (born 1879)], and he had been working with chickens, sarcomas in chickens, and uh... And his work from, the hand-off work form Shope, enabled him to get the Noble prize. Rous had been nominated for this both before and after World War II, I think he finally got it '66. Probably Shope was no longer alive. But he was the, tied with someone else with being the oldest recipient to receive a Noble prize, and that is... Anyways, we get into the 1940s, of course World War 2 happens, and Shope was assimilated into the Navy, and the first thing the Navy did was assign him to the Army. A special project to develop a Rinderpest vaccine. This is cattle plague. The Rinderpest is a take-off of a German word. It was a joint Canadian-US project on Grosse Island in the Saint Lawrence River, and it took them 19 months, but here they adapted that virus through, into, uh, hens' eggs, and it was protective against... That. Later in the 1950's, a Doctor Walter Plowright, due to using bovine kidney cells, developed a vaccine. Well, it was improved. It was so improved that it really enabled the uh... Eradication of Rinderpest, which was a big problem with African livestock, and he was honored, and I went to this ceremony in Hoyt Sherman in Des Moines in 1999. He world the World Food Prize for that work. Well, after that project on Rinderpest was done, he was transferred back to the Navy. He was transferred to Guam and Okinawa after an assault began, and started to study tropical diseases. And he had a curious thing happen to him. He found a mold growing on the covering of his wife's photograph on his desk, and he scratched off some of that, grew it, and found that the, trying to recall the name of... Doesn't make any difference, but it was mold. And he it in vivo antiviral properties, and he named it after his wife Helenine. It was a nucleoprotein that stimulated interferon production. In fact, the journal CA, if any of you wanted to look that up, it's a two-page article here, talks about that, and there was an interesting quote, gotta find it, of course, here, because I'm getting off-script... Here's the paragraph from it. "Doctor Shope's discovery of Helenine" "And its antiviral effects might be considered an accident," "But for the creative mind discovery is never completely" "An accident." "It is the mind which finds the significant significance" "In the insignificant." "Mystery in the commonplace." "A scientific achievement is, in reality," The next logical step in the never ending process" "Of adding one new observation to another, building" "On those that have been made before." So, it was quite the deal. When he got back, he got busy, and... Developed an effective vaccine to a South American rat disease that was delivered and they introduced it to Great Britain. You know, I don't know if you are aware of this, but if you get to certain insular cysts, rats just take off. We all think of Australia, but when I was in the I went to Puget Sound to, um, exercise those two, um, what are they called? Yeah, Friday harbor. I went there and rode the jeep around and what have you, and our commanding officer says, you can't step anywhere in thisexcept under the right reasons. You know, it was just that bad. I got back for a visit a few years ago, I asked the, uh, a clerk in the store, it was kind of interesting, he said, ah, yeah I grew up here and we just ate a lot of rabbit. She saysyou know, because there were just so many. But, when they start drilling into fields, that's like, you know, gophers in southern Minnesota, you know, it'll affect farming equipment and what have you. Well, this virus got into France where they had domestic rabitries for food use, food pro, er, meat production, and the vaccine that he developed for this actually saved the French rabbit industry. He also, in the 1950s, isolated a second benign-tumor virus. He also was the first to isolate and identify the hemorrhagic disease virus of deer. And in our southern counties, every year, especially if it's a hot semi-dry year, hemorrhagic, I mean, the flies just come out and harass the heck out of the deer, they get this disease and it's very often fatal. Really, really bad news. So he had really worked across the board. So, later when Rockefeller closed the Princeton branch, he had a little job on his farm there, he decided to leave and go to work for Merck in New Jersey. That did not last long. So, he returned to Rockefeller in Manhattan and he rented a right across from the institute, and lived that way. He later died from a pulmonary fibroma in 1966, and during his lifetime he had two serious illnesses. One was lymphocytic choriomeningitis, which would be a small, robotype disease, and also eastern equine encephalomyelitis. That's not one I ever wanna get. The human fatality rate, I believe, is 40 to 50% for eastern equine. So, he had plenty of neurons, so maybe he lost a few, I bet. But anyway, I'm sure it wasn't a pleasant experience. If you want embellish yourself with some reading, in the wake of the 1957 Asian flu, he wrote a review paper on it, and he used, he focused on three pandemics, and in his introductory paragraphs he discusses a little bit about the Asian flu, but he talks about the '19 episode and a couple in the 19th century, and uh... Many articles in that issue are dedicated to the Asian flu, which if you don't know, are, uh... Was seeded into the United States of America from Grinnell, Iowa. The presbyterian youth camp had a big conference there with over 1,700 people, and it was written up by me and veterinary heritage will get yourself a copy of this. I gotta plug myself here, I'm sorry. At any rate, what happened is a student from Davis went to a state conference, presbyterian, I guess, and you just can't trust those Calvicals, but anyway, uh... He had flu, and so he got there and it just spread like wildfire. And several of those teenagers were hospitalized in Vermont, and then everyone got on the buses, a few cars and trains, and fanned out over the rest of the country. That was in June. And what they did was infect their siblings when they got home, who then went to Valley Forge where 58,000 youngsters were at the Boy Scout National Jamboree. And that seeded the virus into the US in, really, by August and early September. It actually peaked in October, so by time they got the vaccine, got it ready to go, hell, it was too late. It just, it didn't do any good. So, that's reviewed in subsequent papers over in the Iowa Heritage if you'll care to take a look at it. Sir Christopher Andrewes was very close to Dick Shope, and, you know, they did part company on the lung worm theory. He made the comment that, look Dick, uh, basically the earth worm is not native to North America, and neither were pigs, and the swine virus just evolved, and almost overnight you're saying that these three are linked in a complex cycle? He just couldn't believe it, and Dick Shope gave him a can of earth worms to take back to England, and couldn't infect pigs there with them, so. It was controversial, but I can say with a fair degree of confidence that Doctor Shope adhered to that theory, and even though it was somewhat of a moot point as husbandry changes and what have you, but anyway here's kind of a touching tribute. He received many honors, he was elected to the American Philosophical Society and National Academy of Sciences. He got honorary degrees from the University of Utrecht, which was a DVM in that case, so, he could've been the reverse of KF Meyer, and then, I don't know, I was listed there. I contacted the dean here last week at the veterinary college. I would've bet next month's social security check against $5 that I asked the veterinary college to confirm an honorary DVM. They haven't. So, I was just crushed by learning that. So, he was uh, but the important one's on the bottom. That Lasker award is America's nobles, if you will, and a high proportion of people who get the Lasker award go on to get the Noble award. Here's a little trivia from an editorial of the Journal of the Veterinary Association, which a It says the second time this award has been given to a physician for contributions to the health of domesticated animals.

The previous recipient was Dr. Theobald Smith, who we visited about earlier in this talk. [Dr. Francis Peyton Rous (born 1879)] gave really a touching thing, he says, Dr., I don't know if he was, he might've been deceased by this time, I'm not sure. No, he was there, yeah. Dr. Shope's theme throughout his scientific life has been the meaning of animal diseases for mankind, though he would never say so. Yet not alone from this theme has he drawn his wisdom and strength. He knows human nature well. How does he value his fellow creatures including ourselves? Much as he does the lower animals, with understanding, indulgence, humor and love. So, as an epilogue, I just want to inventory the family. Of course, we've already talked about Richard and Helen Shope. They had four kids. Dick Jr. was a veterinarian that got a PhD in virology at the University of Minnesota, and that's where I roamed, because during my vet school days I'd see him smoking a small cigar and working on things. And his, he also, Dick Junior was enlisted in the Navy and became a pilot, and he just got his wings when the World War 2 ended, so he, I think, discharged and then he went to, all of them went to Port Wenn for their educations, because they had an inside track for admittance. And then Robert, who, like I say, he was a charismatic figure with I mean, people talk in reverational tones about him, and he really was an incredible abrovirologist, and sadly both of them are deceased. And Robert pretty much had pulmonary fibroma like his dad, and it somewhat affected Dick Jr., but he was, of course, older. The youngest of the family was Tom, the baby, he was an academic pediatrician. He went through the CDC EIS program about the same time I did. I think it was after me, but his whole was career in pediatric infectious disease with emphasis in virology. So that DNA from his daddy went into those three people. And Nancy was the equestrian wife of a Colorado rancher, and they lived happily ever after. Here's the family. I was gonna get that photoshopped out, but that's a neighbor girl, so-- And I decided, alright, I'll leave her in. But this is the Shope family about 1940, '49. But this is Nancy Shope, who gave me a lot of information, and this Dick Shope's mother Mary, and this is Dick Jr., a very tall guy, and that's Helen, and this is the baby of the family, Tom, who is that infamous pediatrician in Anarbor, and that's Robert, the very distinguished, and I think he even had a lung transplant at the end, it just didn't work out. And there's Dick, Dick Shope himself. And there's me and Dick Jr. We had gone to the Lexington restaurant, a good place to eat, it's been closed a few years but I heard it's re-opening. It ran at the avenue of Lexington and St. Paul. We had a nice dinner and a few libations to go with it. The server was gracious enough to photograph us. Just a great guy. These are references for your use, and all the references, the early references mentioned as well as these, I have PDFs, so you know, if, my email is ruscorrier, with one s, @yahoo.com. If you want a shortcut to the circuit, I can send you any one of them, send you all of them I guess. And, um, the... The one by Gert Williams is really neat, 'cause he talks about a lot of different scientists, but the one on Shope is just absolutely precious. Andrewes wrote a nice memoir for the National Academy of Sciences, and he does inventory all his publications by year. Just very, very nice. And then I, of course, I mentioned him in that thing as well. So, there it is. And my question right now, just being rhetorical, I don't wanna embarrass anyone, but I kind of have to end on a half-summary note. How do we remember Dick Shope at the University of Iowa? Can anyone tell me about a hall or a meeting room? A custodian closet named after him? We don't. And... In my naivety, I corresponded to President Sally Mason at the time about doing something, and really got nowhere, and I kinda read between the lines, and they'd like a lot of money. So I wrote to all the vaccine producers of influenza vaccine saying, hey, we're kind of passing the hat here, we'd like to make a request to Iowa to name under in honor of Dick Shope. Got nowhere. Well, I grew up, I mean I lived in Irvingdale, and when I first moved there, my next door neighbor, not next door, but the neighbor across the street down five homes, was John He once gave me a ride to work in a snowstorm, and his daughter once babysat for us, and... I thought, hey, I'm gonna get something named after Richard Shope. Well, I got the same thing. Anyway, I didn't think he wanted any money, but he just kinda couldn't be bothered. So, anyway, my challenge to you, it's a healthy challenge, that a lot of time has been under the bridge, and you're kind of tied with AMES at the veterinary college, which may be even be more appropriate that literally nothing is named in honor of this guy here. Just a remarkable person who plowed new ground, and like I say, he was right at the Nobel level in terms of all of his life's accomplishments, and he really was part of, as Tom Brokaw said, America's Greatest Generation. So, I believe that, to you, is a quite little challenge between us folks and if you could influence anyone and you wanna contact me for supporting information or what have you, I'd be happy to do that. I think we're about out of time, anyway. That's the substance of my formal remarks, and I would entertain a question or comment or two if I could be able to help. Yes, sir? -

[Audience Member] In your earlier slide, you mentioned the effectiveness of the polio vaccine. Is that before Salk and-- -

[Russell Currier] Both, by almost four, five decades at least.

[Audience Member] Why didn't anything happen after that? -

[Russell Currier] I don't know. I've never pursued it that much, but they had a vaccine that protective against, uh, in monkeys. But it took a long time, because you know it, it was a difficult vaccine to produce in primates in the first place, and then to make sure it was inactive. And then we got into problems with the so then even when did have the Salk vaccine, the laboratories was really primarily a veterinary group, but they latched onto this vaccine and got a big chunk of it out, and that's what really helped cement the epidemic intelligence service at CDC, under Dr. Alex Wagner. But I don't know what the problem was. And I would also say, you know, in terms of these memoirs though, the one by Sabin, Sabin comes to mind, and really they should call it the Kaprowski vaccine, but Sabin was old school, quote unquote, and they let him get the glory because these guys didn't want to be bothered with the press and everything, but... To Sabin's credit, he wrote a very touching memoir of... I'm trying to think of his name. KF Meyer. One of the things I forgot to mention as I was flipping through here, I gotta read this to you, I told you, since the polio question prounced me to it, this is a quite from Kaprowski who wrote this chapter on polio, but also edited a book entitled Micropunners, Then and Now. This is on page 146, one short paragraph, immunization travel, this is polio, of children in Sonoma Valley, California was made possible through active collaboration of Karl F Meyer, the director of the George Williams Hooper Foundation at the University of California. authority on infectious disease, Meyer had a veterinary degree from the University of Zurich, and an honorary degree from the College of Medical Evangelists in Yorba Linda. He liked to use his MD title and once after, and I told you the rationale for that, and once after presenting the results of our polio trials in California, a not-very-friendly member of the audience asked him, "Is it true, Dr. Meyer, that you are a veterinarian" "And not an MD?" It is true, answered Meyer. Are you sick? That ended the exchange. Anyhow... Boy, oh, yes sir. -

[Audience Member] Your slide said that he had honorary degrees at just a number of places, it said Iowa. Yet I wonder, was it University of Iowa or Iowa State that was-- - [Russell Currier] I'm sure it was here. I didn't research it, but, someone, if you wanna get back into the archival thing, then shoot me an email and let me know. Probably was a doctor of science, or something like that. But I uh... You know, you give these talks. I've had a horrendous week where I'm doing other work, too, so I just couldn't nail down every detail, but that was one I actually thought of, oh, I thought GoogleIowa, but I really didn't, and apologize for that. But, this is, in terms of great American scientists, this guy here was a giant. And when you figure what he accomplished, and Dick Shope, like KF Meyer, were not desk-type scientists, or bench-type scientists. They got out in the field. And one time they did a horse's head, and I think that was his first diagnosis for western equine encephalitis. He wanted, there was a horse ailing, and it wasn't gonna make it anyway, and he wanted to buy from the horse from the farmer and euthanize it and remove its head, and he wouldn't agree to it. He was talking to the farmers wife and he said, you know, when you go to bed tonight, he goes to sleep, raise the shade, or some, there was some signal he worked out with here, and soon as that happened, and he was smoking his pipe hiding out there in a ditch or something, he went in and he gaveI think or something to horse, removed its head, threw it in a gunny sack and took it back to San Francisco. That was the type of guy KF was. Now, he was the same way. He just had to, he just had to dig up to his elbows in a puddle of guts on pigs and stuff like that, in working, getting samples. A good example, I talk to an old professor yesterday at AMES who said he was a graduate student, this was about '48, '49, or 1950, and it was a hot Summer in Iowa and there was a muskrat die-off, uh... And he was in the diagnosticthe only guy, it was just quiet, and he taking apart this, doing a necropsy on this muskrat. In walk this tall well-dressed guy who identified himself as Richard Shope, and he knew of course who he was. I mean at that point he knew who he was. And he says, "You mind if I look over your shoulder?" He says, no. So, there was some liver lesions there, and he says, this is from Bill Shweisser's, the veterinarian we're talking about, he wanted of that liver, do you mind if I take some samples and take it back? I'll give you a report. Which he did, and there was some factor, I don't fully understand, but it actually helped out later on with lesion errors diagnosis. So, just that type of remarkable guy. He'd go hunting and, you know, if there was a wart on that rabbit, he would study it. He was just that type of guy. This was a family that subsisted on two big things, the Shope family, one was wild game and the other was laboratory pork. He didn't throw all of those dead pigs away. He just removed the lungs and fed the family with the rest. He knew what he was doin'. You gotta be resourceful. Remember that $35 jalopy, you know, he had some lean early years, I'm sure, as he was starting his family and what have you, but he was an incredibly great human being, and all four of his children as well. And like I said, Robert had meeting her too, speaking, but I didn't. Didn't have any personal relationship. And then I corresponded with Nancy and Tom, the two youngers, and they, she said, we were really two families, because I can't remember my father until after World War 2. I was so young when he left, and then they come home and established that relationship. So, in your subconscious, I wanna bury that thought. Let's get something named after him, and I'll see what I can do over names with the College of Veterinary Medicine, 'cause it's long overdue. [...]

Summary of Richard Edwin Shope Contributions to One Medicine/Health

Richard E. Shope MD (Dec 25, 1901 – October 2, 1966) was one of the pioneer microbiologists to investigate a variety of human and animal diseases and merits recognition for his many accomplishments that supported later research that continues to this very day. Dr Shope graduated from medical school at The University of Iowa in 1924 and immediately remained on staff there to teach pharmacology and work on the chemotherapy of tuberculosis. Shortly afterward he was invited to join the laboratories of the Rockefeller Institute at Princeton to work with Dr Paul Lewis, the discoverer of polio virus. Subsequently in 1928, he left tuberculosis research to investigate hog cholera in the field where he observed his first outbreak of swine influenza. Later research on influenza resulted in isolation of the virus from pigs and its co-pathogen Haemophilus influenzae suis, and subsequent research that postulated that the swine virus was related to the human 1918 pandemic virus.

Dr Shope acknowledged the influence of the legendary [Dr. Theobald Smith (born 1859)], at the Rockefeller Institute, on his own career and observed that Smith “although possessed of great imagination and … uncanny foresight, was a meticulously methodical worker, who abhorred the waste of anything – time, material, or animals.” This set a pattern for Shope’s career and an informal distillation of his key accomplishments are summarized in the bullet form.

From Bernard Easterday, 4th Int’l Symposium on Emerging and Reemerging Pig Diseases, Rome June, 2003: “It remained for Shope to present the first reliable experimental evidence that influenza is caused by a virus (15). [Year 1931.] He demonstrated that he could reproduce swine influenza under strict experimental conditions by inoculating both filtered and unfiltered material from affected pigs into the respiratory tract of normal pigs. The disease produced by the filtered material was mild (later sometimes referred to as “filtrate disease”) but it could be transmitted repeatedly in this manner. Subsequently, Shope would describe swine influenza as a “… disease of complex etiology, being caused by infection with the bacterium H. influenzae suis and the swine influenza virus acting in concert.” Three years after Shope reported the viral nature of SI, Andrewes and Laidlaw (15) would report the viral nature of influenza in human beings. [Ref: Shope, RE 1964 Swine Influenza, In Diseases of Swine 2nd Ed. Ed by H.W. Dunne. P. 109-126.] Note: Shope and Christopher Andrewes became very good friends and Shope collaborated with the UK investigators on techniques to isolate virus which they subsequently did utilizing ferrets and Andrewes and co-investigators, Smith and Laidlaw, were later knighted for this accomplishment.

1936-1937. Shope postulated linkage between human and swine influenza. [Laidlaw also advanced same idea at same time.]

1941. Shope postulated linkage of “masked or occult” viral infection of pigs with swine lung worm and its intermediate host, earth worms. This was very controversial and was not entirely corroborated. The issue became a moot point as husbandry of pigs was changing that precluded importance of this postulated cycle. From Sir Chrotopher Andrewes biographical memoirs: “In 1930 Shope’s attention was drawn to “mad itch” [aka pseudorabies], a violent distressing and fatal disease of cattle in the Midwest. He showed that it was caused by a virus transmissible to rabbits, and that it was endemic among pigs, in which it was comparatively harmless. Cattle contracted infection through contact with pigs. He finally proved the identity of cattle ‘mad itch’ with psedudorabies, a disease prevalent in parts of Europe. Later he studied another disease of pigs – swine pox – and showed that it could be, though it was not necessarily, transmitted through the agency of pig-lice. He also published evidence that hog cholera virus might persist, as swine flu virus appeared to do, in lungworms. Ref: Biographical Memoirs vol 50 (1979), p 353-375, © The National Academy of Sciences. Shope’s three most outstanding discoveries followed each other in rapid succession: swine influenza in 1931, the rabbit fibroma in 1932, and rabbit papilloma in 1933.” Andrewes again, “The work [masked rabbit papilloma virus studies by Shope] gained a new dimension when it was found that in many tame rabbits the warts progressed and became carcinomatous [sic]. This change, though common in domestic rabbits, was rare in cottontails. Shope at this time, was busy with many problems, so he generously gave the material to [Dr. Francis Peyton Rous (born 1879)]. What Rous did with the rabbit cancers during the next thirty years is a matter of history.” [Peyton Rous received Nobel Prize for Medicine in 1966 for work demonstrating viral etiology of cancer.]

Viral etiology of cancer. Shope described papilloma in jack rabbits and the pathological condition bears his name “Shope papilloma [or fibroma]”, and in urban legend mode affected bunnies were referred to as “jack-a-lopes.” He prompted a colleague at Rockefeller Institute, [Dr. Francis Peyton Rous (born 1879)], to extend his inquiries to mammals. Rous had already demonstrated transmission in chickens but not mammals. During WW II, Shope was attached to the US Army and detailed to a joint Canadian-US project on Grosse Isle in St Lawrence River to develop a rinderpest vaccine for cattle. There was concern of biowarfare and deliberately introduced rinderpest would be a food production catastrophe. From Andrewes, “Here Shope, with a staff of five other scientists, worked in strict isolation, and in the course of nineteen months produced an effective vaccine by growing and attenuating the virus in hens’ eggs. This has since been used on a large scale in the field.” Shope was then transferred back to the Navy. He was in first party to set up a lab to study tropical diseases on Guam and on Okinawa after assault began. Shope was actually fired on. He found mold from Guam growing on photo of his wife Helen. He isolated a substance from this mold with in vivo antiviral properties and named it after wife “Helenine”. Later found to be nucleoprotein that stimulated interferon production. Approximately two years after WW II: Shope developed an effective vaccine to a South American rabbit disease that was deliberately introduced to Great Britain to reduce population and extensive burrowing of rabbits in farm fields. Inadvertent introduction in France however resulted in decimated rabbit populations and adverse effect on commercial rabbitries. Shope’s vaccine saved the rabbit industry in France. Circa 1950s: Shope isolated a second benign-tumor virus from deer. Also isolated the deer “hemorrhagic disease” virus. Later when Rockefeller closed the Princeton branch, Shope decided to leave and go to work for Merck in Rahway NJ. Subsequently he returned to Rockefeller in Manhattan [rented room during weekdays!] Later died from abdominal cancer October 2nd, 1966.

During lifetime had two serious viral diseases, lymphocytic choriomeningitis and eastern equine encephalomyelitis.

Andrewes, “ Shope received many honors. He was elected to the American Philosophical Society (1944) and the National Academy of Sciences (1940). He received honorary degrees from the universities of Utrecht, Rutgers, Giessen, Chicago, Pennsylvania, Iowa, and Yale, as well as many prizes and awards..[...]”

“On May 8, 1957, the Association of American Physicians awarded the Kober Medal to Dr Richard E Shope, the second time this award has been given to a physician for contributions to the health of domesticated animals. The previous recipient was [Dr. Theobald Smith (born 1859)].”

[See Harvard Magazine, July-August 2009] Dr Shope acknowledged influence of individuals on his career specifically Theobald Smith, who worked out arthropod transmission of disease and Paul Lewis who discovered/isolated polio virus and died of yellow fever while studying the same disease in South America. “Dr Shope then paid tribute to a veterinary practitioner, Dr Fred J. Crow of Iowa City Iowa, “who permitted me to spend … time with him in the field…and who guided me during my initial experience with swine influenza…He got me my first case of swine pox and … of pseudorabies and …served as the connecting link between the practicality of the field and science of the laboratory.” Ref: JAVMA, Nov 15, 1957, p 486-487. The following excerpt is from the Souvenir Book published by the Eastern Iowa Veterinary Association on their 25th Anniversary (1913-1938). It was written by Richard E. Shope MD, of the Rockefeller Institute for Medical Research, Department of Animal and Plant Pathology, Princeton, New Jersey. “In the summer of 1928, I was in Iowa doing blood counts in hog cholera and other swine diseases with the cooperation of a number of veterinarians in eastern Iowa. During that time I had occasion to go to Ames to see Dr Charles Murray and it was he who first called my attention to the existence of swine influenza. Returning to eastern Iowa, arrangements were made with Dr Fred Crow for the collection of material from typical cases when the epizootic should appear during the autumn. Dr Crow telegraphed me on November 13 saying, ‘Plenty of hog flu – come at once.’ I took the first train west, and on arriving in Iowa City found that there was indeed plenty of ‘hog flu.’ Through the friendliness and cooperation of a number of eastern Iowa veterinarians and their clients, many swine autopsies were obtained and material from the best cases was shipped back to Princeton. At that time, because we had no idea as to how fragile or easily killed the causative agent might be, we packed our infectious material in iced thermos jugs and sent it by air mail from Cedar Rapids. After several unsuccessful attempts to establish swine influenza in our experimental pigs in Princeton with the various samples sent, one batch finally ‘took.’ This had been obtained by Dr Crow on the Probst Brothers’ farm near Iowa City. Dr Lewis, my chief, wired me of his success in establishing the disease experimentally and to return to Princeton as soon as possible.” [...] Finally a quote from Dr Peyton Rous’ on the occasion of conferring The Academy Medal to Richard E. Shope, M.D. at the Annual Meeting of The New York Academy of Medicine, January 7, 1965: “Dr Shope’s theme throughout his scientific life has been the meaning of animal diseases for mankind, though he would never say so. Yet not alone from this theme has he drawn his wisdom and his strength. He knows human nature well. How does he value his fellow creatures including ourselves? Much as he does the lower animals – with understanding, indulgence, humor, and love.” [...]

The similarity in the pathogenic properties of human and swine influenza virus for ferrets led Elkeles (1) to attempt the transmission of the human agent to swine. He found that very young pigs (2 to 6 weeks old) , developed a mild illness when the virus from man was given intranasally under light ether narcosis. At autopsy these animals sometimes showed scattered dark red bronchopneumonic areas of consolidation in the upper lobes of the lung. When cultures of either swine or human influenza bacilli were added to the virus at the time of its administration, the swine developed a more severe illness. The clinical picture was characterized by a low grade fever, apathy, loss of appetite, and sometimes cough. At autopsy varying degrees of bronchopneumonia were encountered. Virus, pathogenic for ferrets,

could be recovered from the pneumonic lungs. It thus appeared that Elkeles had produced a disease somewhat resembling swine influenza by the administration to young pigs of human influenza virus mixed with influenza bacilli of either human or swine origin. This observation made more credible the theory that swine influenza may have arisen as the result of the infection of swine in 1918 from human sources (2 - 4).

The question of the pathogenicity of human influenza virus for swine was of such importance that it seemed to warrant further investigation. The present paper reports our experience in the transmission of human influenza virus to swine.

Experimental - The Infection of Swine with Human Influenza Virus Alone

The PR 8 (Francis (5)) and WS (Smith, Andrewes, and Laidlaw (6)) strains of the human influenza virus were used in our experiments. No diflqculty was encountered in establishing either strain in swine 6 to 14 weeks of age. Older or younger animals were not tried. All animals were inoculated intranasally using the same methods employed in earlier studies of swine influenza (7, 8). The instillations were made with a Luer syringe without needle by pressing the tip of the syringe into the external nares. It was not necessary to anesthetize swine in order to induce infection with human influenza virus alone, although animals infected under ether narcosis exhibited somewhat more extensive pulmonary lesions at autopsy than those inoculated without anesthetic.

The WS virus was transferred 2, and the PR 8 virus 5, serial passages in swine before the experiments were discontinued. 10 per cent suspensions of infected mouse lung (5, 9) in physiological saline served as the source of virus for the first swine inoculation in each of the passage series and, after the first swine passage, similar suspensions of infected swine lung were used to inoculate swine of subsequent passages. 6.5 cc. of virus suspension was administered to each animal.

The disease produced in swine by human influenza virus was clinically very mild and, apart from a transient and indefinite malaise, no constant symptoms

were observed. It was sometimes difficult to be certain on antemortem examination that the animals had actually been infected. In most cases there was no significant elevation in temperature though a few had fever on the afternoon of the day following inoculation. 4 animals were kept under observation for 3 weeks or longer and made uneventful recoveries. 8 others were killed either by stunning and bleeding or by chloroforming on the 3rd or 4th day after inoculation and these exhibited the following picture at autopsy. There was a scattered, patchy, lobular atelectasis of one or more of the anterior lobes of the lung (Figs. 1 and 2). On cut section the involvement about the bronchi was seen to be more extensive than was apparent from the uncut surface. The involved lung was a reddish purple in color, beefy in appearance, felt rubbery, and was moist. A rather scant glassy tenacious mucous exudate could sometimes be pressed from the cut bronchi.

Histologically in involved areas of lung the alveolar walls were folded, greatly thickened, and infiltrated with large numbers of mononuclear cells (Figs. 3 and 4). Capillaries in the alveolar walls were dilated and packed with red blood cells. The partially collapsed alveoli themselves were either free of cells or contained at the most an occasional desquamated epithelial cell or a few lymphocytes. Polymorphonudear leucocytes were conspicuously absent. There was a pronounced perlbronchial round cell infiltration. The bronchial epithelium was, in places, fragmented and partially desquamated, and the cilia were either denuded or badly matted together. Some bronchi contained a scant, mixed lymphocytic and polymorphonuclear leucocytic exudate. Lymph channels in the interlobular septa were sometimes dilated and the septa themselves thickened and loosely infiltrated with mononuclear cells.

The trachea, bronchi, and lungs of swine infected with human influenza virus were in most instances bacteriologically sterile. The few animals from whose respiratory tracts organisms could be cultivated showed no evidence that their disease had been modified by the bacterial contaminant.

Influenza virus was demonstrated in the lung lesions of all passage swine by the inoculation of mice (5, 9). No evidence was obtained that serial transmission of the virus in swine modified its pathogenicity for mice. Also, the pathogenicity of the virus for swine appeared to remain constant through the number of serial passages to which it was submitted. It was of interest that the areas of swine lung that appeared free of lesions were also free of virus.

The symptoms and pathology observed in swine infected with human influenza virus were indistinguishable from those of the filtrate disease (10) produced in swine by the intranasal administration of swine influenza virus alone.

The Infection of Swine with Human Influenza Virus and H. influenzae suis

Sixteen swine have been inoculated intranasally with mixtures of human influenza virus and the bacterium, H. influensae suis (11). These animals were included in two serial passage experiments. One series, started with virus from infected ferret lung (6), was continued for 5 passages, and the other, initiated with virus from infected mouse lung, was carried through 3 passages in swine before being discontinued. 6.5 cc. of 10 per cent virus suspension to which had been added 0.5 co. of a 24 hour horse blood culture (11) 1 of H. influenzae suis, strain 18, was given intranasally to each animal. It was known from other experiments conducted at the same time as those under discussion that this culture of H. influenzae suis, in combination with swine influenza virus, was capable of producing characteristic influenza in swine (10).

In 11 of the 16 swine inoculated with mixtures of human influenza virus and H. influenzae suis the resulting illness was definitely more severe than that caused by the virus alone. This enhancement was evident both clinically and at postmortem examination. The temperature reactions were similar to those seen in swine influenza although nsuaHy the fever was less persistent. Seldom was it maintained for longer than 3 days, whereas 5 to 6 day fevers are not uncommon in swine influenza. Fever, while it lasted, was high, exceeding 41°C. on 1 or [...]

[...]

Summary

Swine inoculated intranasally with human influenza virus alone develop an ill defined, mild, and usually afebrile illness of short duration. At postmortem the anterior lobes of the lungs of such animals contain scant, scattered areas of lobular atelectasis. Transmission of the virus for 5 serial passages through two groups of swine

failed noticeably to enhance its pathogenicity for this species. The disease produced in swine by infection with human influenza virus alone is indistinguishable clinically and pathologically from that caused by infection with swine influenza virus alone. Transmission of human influenza virus from swine to swine by contact succeeded in only one of four attempts.

Swine inoculated intranasally with a mixture of human influenza virus and H. influenzae suis usually develop a febrile, depressing illness similar to mild swine influenza. The pneumonia encountered in such animals at autopsy is similar to but less extensive than that seen in swine influenza. In some animals H. influenzae suis fails to become established and the disease then seen is identical with that caused by human influenza virus alone.

The human influenza virus recovered after 5 serial transfers in swine was immunologically the same as that with which the experiments were begun.

Shope papilloma virus

Virus classification

(unranked): Virus

Realm: Monodnaviria

Kingdom: Shotokuvirae

Phylum: Cossaviricota

Class: Papovaviricetes

Order: Zurhausenvirales

Family: Papillomaviridae

Genus: Kappapapillomavirus

Species: Kappapapillomavirus 2

Synonyms^[1]

• Rabbit papilloma virus

• Rabbit (Shope) papilloma virus

• Cottontail rabbit papillomavirus (Shope)

• Cottontail rabbit papillomavirus

The Shope papilloma virus (SPV), also known as cottontail rabbit papilloma virus (CRPV) or Kappapapillomavirus 2, is a papillomavirus which infects certain leporids, causing keratinous carcinomas resembling horns, typically on or near the animal's head. The carcinomas can metastasize or become large enough to interfere with the host's ability to eat, causing starvation. Richard E. Shope investigated the horns and discovered the virus in 1933, an important breakthrough in the study of oncoviruses. The virus was originally discovered in cottontail rabbits in the Midwestern U.S., but can also infect brush rabbits, black-tailed jackrabbits, snowshoe hares, and European rabbits.^[2]

History

Richard Edwin Shope discovered the Shope papillomavirus

In the 1930s, hunters in northwestern Iowa reported that the rabbits they shot had several "horn" protrusions on many parts of their bodies including their faces and necks.^[3] The virus is also a possible source of myths about the jackalope, a rabbit with the horns of an antelope, and related cryptids such as the wolpertinger. Stories and illustrations of horned rabbits appear in scientific treatises dating back many years, such as the Tableau encyclopédique et méthodique, from 1789.

The Iowa reports led cancer researcher Richard E. Shope to investigate, and he discovered the virus in 1933.^[4] He separated the virus from horny warts on cottontail rabbits, and made one of the first mammalian tumor virus discoveries.^[4] Shope determined the protrusions were keratinous carcinomas due to the infection of CRPV. Shope's research led to the development of the first mammalian model of a cancer caused by a virus. He was able to isolate virus particles from tumors on captured animals and use these to inoculate domestic rabbits, which then developed similar tumors. This has contributed to our understanding of fundamental mechanisms in neoplasia, or the formation of a new, abnormal growth of tissue.^[4] The virus was sequenced in 1984, showing substantial sequence similarities to HPV1a. It has been used as a model for human papillomaviruses both before and after this discovery. The most visible example of this role is the HPV vaccine, which was developed based on and incorporating research done using the virus as a model. Similarly, it has been used to investigate antiviral therapies.

Genome

There is a lack of specific data about the reproductive cycle of papillomaviruses. Research is not conclusive about which coding regions are expressed before or after replication of viral DNA. The E1 region should carried the DNA required for cis and/or trans. E1 is the largest Open reading frame, which is the set of codons in the genome that code for proteins, encoding a 602 base protein. E1 is similar to COOH-terminal domain of the Simian virus 40, plays a role in viral DNA replication maintaining plasmids within a cell. Results have found that CRPV and BPV1 are found in the same location of the genome, which indicates that papillomaviruses likely have similar methods of replicating their genomes outside of a chromosome. A notable difference between the genomes of the four strains is that the E6 protein is almost twice as long in the CRPV as in any of the other strains of papillomaviruses. The E6 protein is somewhat homologous with a family of ATP syntheses that are found in mitochondria of cattle. The homology is significant enough to imply an evolutionary relationship between E6 and the beta chain of the ATP synthase family; however, they do not have the same function or enzyme activity. The E2 protein overlaps with the E4 open reading frames in the other papillomaviruses. These differences in the E2 proteins likely determine how oncogenic a virus is. The noncoding region has a homologies with BPV1. Other homologies exist, such as the fact that all papillomaviruses have repeated sequences in the noncoding parts of their genomes. CRPV has some notable repeats, some as long as 32 base pairs. Many pairs up stream of the transcription locations are homologous with promoter sequences in of SV40.^[5]

Life cycle

Replication cycle and transcription

The papillomavirus life cycle begins with cells actively multiplying in epithelial cells of basal and parabasal layers. The differentiation of these cells is necessary for this virus to complete its life cycle. Transforming proteins E6 and E7 induce the S-phase in the lower epithelial layers.^[6] Viral replication proteins E1 and E2 are also required to form the papilloma and keep the episomal viral genome replication low. Genome amplification will be restrained until viral replication proteins increase and several viral proteins are co-expressed. The infected, differentiating cells travel towards the epithelial surface during the viral cycle's late stage. In the upper epithelial layers, the promoter activity is altered during the virus’ production. E4 proteins are expressed, and viral DNA amplification starts in the differentiated cells. Following this, the L1 and L2 viral capsid proteins are expressed and the infectious virions begin to assemble.^[7]

Expression of the papillomavirus E4 protein correlates with the onset of viral DNA amplification. Using a mutant cottontail rabbit papillomavirus (SPV) genome incapable of expressing the viral E4 protein, it has been shown that E4 is required for the productive stage of the SPV life cycle in New Zealand White and cottontail rabbits.^[6]

Assembly and release

The virus particles are assembled in the upper epithelium. The virus capsomere icosahedral shell is packaged with an 8000 base pair genome, 360 L1 protein copies, and 12 copies of L2 proteins inside. L2 proteins gather at PML body nuclear structures and recruit L1 proteins during virus assemblage. L2 proteins are not necessary for assemblage, but it is possible that they augment packaging and infectivity. Capsid proteins have been thought to also gather at the PML bodies during packaging.^[6]

Transmittance of the Papillomavirus requires release from the infected skin cell at the epithelial surface, as they are non-lytic. They are resistant to desiccation, enhancing their survivability during extracellular transfer between hosts. Cornified squame release from the surface of epithelial cells may also contribute to their survival. Immune detection of the virus in the host may also be hindered by antigen retention until the virus reaches upper epithelial cells.^[6]

Modulation of host processes

When Richard E. Shope began his research on SPV, little was known about the natural transmission of the virus vectors and interactions of the virus on its hosts. In the lab setting, Shope worked with the virus’ natural host, the cottontail rabbit.^[4] Particularly, he worked with the cottontails of Iowa and other western states of the United States. He worked with these species because it was discovered that SPV had a restricted geographic range and was confined to the high plains of the western United States.^[4] Therefore, the major host species of SPV is the cottontail rabbit of the western United States. Cottontail rabbits in Shope's lab usually were infected with the virus through parasites such as rabbit ticks.^[4] When infected with SPV, hosts develop papillomas on hair-bearing skin, usually around the face and neck.^[4] Shope found through his research that rabbit epidermal cell transformation by SPV requires interaction with mesenchymal cells. It was further found that mesenchymal types support papillomatous transformation.^[4] Shope's research also investigated how vitamin A deficiencies or excess might affect host susceptibility to SPV. Shope found that deficiencies in vitamin A did not affect the relative growth of the papillomas, but in cases where there was excesses of vitamin A Shope papillomas were inhibited.^[4] Therefore, when SPV infects a host, vitamin A plays an important role in the host/virus interactions.

Location in the host

Fluorescent antibody study identified the locations of viral antigens in wild rabbit papillomas. They were present only in the nucleus of keratohyaline and keratinized layer cells, and not deeper down in proliferating epithelial cells. In domesticated rabbits, the viral antigens were present in much smaller quantity in only superficial, keratinized layers. The investigation proposed that the virus is only present in proliferating cell nuclei during early development, containing a deficient amount of proteins and mostly nucleic acid. The proteins may be immunologically specific in order to keep its transmissibility, making it a masked virus.^[8]

Associated viruses

Most homologous papillomaviruses are actually CRPV and HPV1a. This is possibly because both of these viruses target the skin. From an evolutionary perspective, CRPV and HPV1a could have diverged recently, or they could have converged due to their similar target. CRPV is a member of the papillomaviruses so it is related to all viruses in this family.^[5]

Tropism

Infection of a rabbit's follicular cell, often occurs in locations including ears, nose, eyelids, and the anus. The infection first appears as a red and swollen area on the skin, followed by development of circular papilloma warts and keratinized horny warts. Although transmission between rabbits is high, the tumors themselves do not contain the infectious virus. 25% of Papilloma infections become malignant and form squamous cell carcinoma. Metastases can form in the lungs and lymph nodes, and if it advances further, can develop in the kidneys and the liver.^[2]

Rabbit Papilloma displays tropism for the cutaneous epithelium. Warts are made up of nearly homogenous vertical tissue strands. Their outer coloration is typically black or greyish, and cut sections are usually white or pinkish white with a flesh-like center. Dark coloration is due to abundant melanin pigment. The warts are made up of several tight, branching, threadlike epidermis processes connected by narrow tissue cores. These growth structures indicate that the growth occurs simultaneously at several different centers, causing the surrounding tissue to bulge from the growth's lateral pressure. The normal epithelium abruptly transitions into a narrow zone of rapidly thickening epithelial layers, made up of rapidly multiplying cells.^[3]

Rabbits re-infected with the virus exhibit some or complete immunity, and can transmit the virus to other wild rabbits, and from wild to domestic rabbits. A domestic strain cannot transmit it to another domestic rabbit, however.^[3]

Immunologically, the papillomatosis virus is not related to fibroma or myxoma in rabbits.^[3]

See also

• Oncovirus – cancer virus