I don’t consider myself a virologist or immunologist although I have learned a lot about these tangental fields in the life sciences. I am a molecular biologist who focused on basic issues surrounding the development of cancer. I guess this area of expertise was confirmed by my scientific peers when I received my first research grant from the American Cancer Society in the early 80s and then multiple grants from the National Cancer Institute. The grants came after I left the Bureau of Biologics of the FDA on the campus of the National Institutes of Health in Bethesda to move to the Pauling Institute in Palo Alto, California – another form of heaven. Going to NIH was like going to research heaven. I seemed to have unlimited funding to do research at the Bureau because I purchased the reagents when I needed them and no one ever said I couldn’t. If I hadn’t been at the Bureau and had ended up at one of the many NIH institutes, an unlimited budget would have been out of the question. I was even able to invite my brother Andy join me at the Bureau (albiet without pay) which I could not have done in one of the other NIH buildings. Later Andy was able to move on to a paid position at NIAID (Natl. Inst. of Allergies and Infectious Diseases).
When I took the job, my boss Frank Ennis made some suggestions about what I could work on related to vaccines but I was also able to continue with my interests in cancer research. Frank suggested that I look into why the Sabin polio vaccine caused polio in about one in a million vaccinated people. He also suggested that I try to figure out why Reye’s Syndrome was associated with viral infections complicated by taking aspirin. But the main focus of the Bureau was to regulate vaccine production especially the infuenza vaccine which I avoided like the plague.
The way Andy and I got started with these viruses was to grow them and examine their expression in normal and neoplastic human cells in culture. I was a hands on researcher who preferred to teach myself by doing experiments rather than learning out of a book (I have always been very dyslexic). I have recently learned that this is how naturalists of the 19th century like Darwin and Huxley learned when there was no federal funding for research per se. The 1st figure below shows how I started to learn about the flu virus. This was an influenza A strain (H3N2, I think) which I grew in a human fibrosarcoma cell line. This virus lytically infected all cancer cells I tested but did not lyse normal human fibroblasts. This is a picture of the structural proteins of influenza virus which I labeled with S-35 methionine and separated by their charge and molecular weight in a polyacrylamide gel. The pattern shows the simplicity of the virus – just 4 structual proteins. The proteins labeled HA0, HA1, HA2 are derived from one protein H0, the hemagglutinin surface protein that determines the serotype of the virus (H1, H2, H3, etc.). H0 is converted to HA1 and HA2 by a proteolytic enzyme in the infected cell. This proteolytic event which was not found in the one normal human fibroblast strain is required to activate the virus to infect other cells after its release from infected cells. The other antigen surface protein is the neurominidase (NA) that also determines the serotype (N1, N2, N3, etc.). The nucleocapsid protein is NP1/NP2 that surrounds the flu RNA genome. The matrix protein M surrounds the nucleocapsid/RNA genome complex inside the viral particle envelope. The Flu genome encodes only eight gene products (proteins). Not shown here are the three RNA polymerase proteins and another non-structural protein, NS.
Shortly after I arrived at the Bureau all the staff were tested for polio antibody titre in our blood since I was going to grow the live poliovirus. A titre of 1:8 to 1:32 (negative serum:immune serum) achieved by vaccination is thought to provide immunity to poliovirus. I had a titre that was basically off-scale (1:>>>5000). This finding confirmed that I had once had the natural infection. I believe that this was when I was four because I remember playing with my friend Judy (about 1950, 2nd picture; 1990s, 3rd picture; Judy and I have remained in touch) in our front yard at dusk. Judy went home with a fever and ended up in an iron lung. If you click to enlarge picture 2 you can see that Judy was wearing a leg brace on her left leg (her polio leg). I ended up with a flu-like disease with no paralysis. Today you don’t often see people walking around with leg braces due to polio but this was not that uncommon before the 1970s. One of my Ph.D. advisors, Garrett Ihler a brilliant scientist, wore one. I favor my right leg tremendously but this only shows up when skiing or skating. I have always felt that this came from my polio infection.
To finish up on polio, the 4th figure (click to enlarge) shows the decline in paralytic polio rates by year since the development of the Salk and Sabin vaccines (3 killed serotypes and 3 live serotypes, respectively). Yes, the Sabin vaccine is live and has been shown to cause rare cases of polio.
On to the reality part concerning flu.
The only way to confirm influenza is to perform a diagnostic test which can also determine serotype. The 5th figure shows the CDC’s estimate of annual deaths by Flu. During my two bouts with Flu I did not even think to go get the confirmatory test and I did not die. Most Flu cases are not confirmed. I think that the CDC’s estimate is a reasonable educated guess based on their expertise. The other way of compiling this data is by looking on death certificates which the doctor signs with an educated guess of the diagnosis in most cases. The death certificate diagnosis suggests that deaths by Flu is 1/10th to 1/30th of the CDC’s estimates (6th figure) averaging 1256 per year from 1979 to 2004 compared to about 30,000 on average based upon the CDC’s estimate. Again, the CDC’s estimate is closer to the truth. Furthermore, we hear a lot about the increased mortal susceptability of toddlers but the annual data in Figure 6 doesn’t support this and these cases are more likely to be confirmed with a diagnostic test. Seventy-seven percent of Flu deaths occur in people 75 and above, for which there is a wide array of underlying conditions. The four deaths that have occurred in Connecticut as of yesterday were in this later age-group.
The 7th figure displays the complexity of determining the cause of death. Deaths attributed to Flu are usually combined with pneumonia because the two cannot be distinguished without a diagnostic test and these two maladies often occur together. This data also confirms that while influenza is strongly suspected, no serotype was determined for most cases; the serotype would come out of a proper diagnostic test.
Figure 8 maps the decline in combined rates of infectious diseases for which vaccines have been developed from 1900 to 2000. These infectious diseases were declining before most vaccines were implemented. A major reason for our government’s concern about influenza is the Spanish flu, an H1N1 strain, that circulated between 1914 and the early 1920s.
“The 1918-1920 H1N1 influenza A pandemic caused unprecedented morbidity and mortality on a global basis. Within the span of two years, about 1/3 of the world’s population had sickened from influenza; in excess of 675 000 people died from “Spanish influenza” in the United States and as many as 50-100 million people died worldwide.” Brian Hoffman http://currents.plos.org/influenza/article/influenza-activity-in-saint-joseph-85l14ji6dt9z-2/ Hoffman BL. Influenza activity in Saint Joseph, Missouri 1910-1923: Evidence for an early wave of the 1918 pandemic. PLOS Currents Influenza. 2011 Nov 22 last modified: 2012 Mar 10. Edition 1.
There can be no question that this was a devastating strain of influenza. So, in 1976 when an H1N1 strain reappeared on the horizon (usually from China), the CDC recommended a nation-wide vaccination program against this H1N1 strain called the “Russian Flu” a label which made this strain even more scary to the public. The epidemic never showed up but adverse reactions from the vaccine were notable.
The FDA Bureau of Biologics was given more money by Congress. Because of good timing, I was hired as their first “Senior Staff Fellow” and later I was converted to a career civil service position. When the best boss I ever had decided to leave the Bureau to take a professorship at Umass Medical Center, I decided to leave research heaven and move to another heaven, Palo Alto CA, a move that I have never regretted.
Click to enlarge.