Transcript

'Secrets of the Dead: Killer Flu'

Dr. Jeffrey Taubenberger and Jared Lipworth
Chief of the Division of Molecular Pathology, Armed Forces Institute of Pathology; Executive Producer
Tuesday, November 22, 2005; 12:00 PM

"Secrets of the Dead: Killer Flu" on PBS follows Jeffrey Taubenberger and his team of scientists seeking to learn where the 1918 flu virus came from and what made it so deadly. Using fragments of undamaged 1918 virus found in lung tissue of a flu victim, Taubenberger and his team set out to map the genes of the killer flu.

Since the original broadcast of this program, Taubenberger's team has created a genetic sequencing of the 1918 virus and has resurrected the virus itself to study its effects on lung tissue. This fall the team announced a striking similarity between the 1918 virus and today's H5N1 avian flu virus. Their findings indicate that the 1918 virus originated as a bird flu. The updated episode includes new material and interviews with Taubenberger that reflect these new findings. Secrets of the Dead: Killer Flu aired on PBS on Monday, Nov. 21, at 10 p.m. ET. (Check Local Listings.)

Taubenberger and executive producer Jared Lipworth were online Tuesday, Nov. 22, at noon ET to examine the 1918 flu virus and to discuss this episode of Secrets of the Dead.

Since 1994, Taubenberger has served as chief of the division of molecular pathology at the Armed Forces Institute of Pathology in Washington, D.C. He received his M.D. and Ph.D. degrees from the Medical College of Virginia and completed his residency in pathology at the National Cancer Institute. His clinical activities involve diagnostic molecular genetics. He holds dual board certifications in anatomic pathology and molecular genetic pathology from the American Board of Pathology and the American Board of Medical Genetics.

As executive producer for science programs, Lipworth is responsible for commissioning and overseeing all science programs produced by Thirteen/WNET New York. Current projects in production or development include "War Plane," "Secrets of the Dead V," "The Human Spark," "The Mysterious Human Heart" and "Big Ideas II." Prior to becoming executive producer, he was the series producer for the department's technology series, "Innovation." In 2003, Lipworth was nominated for a writing Emmy for "Secrets of the Dead: Mystery of the Black Death."

The transcript follows.

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Salt Lake City, Utah: Please address the evidence that suggests to you that the 1918 Spanish Flu was likely to have infected humans directly from the avian population, rather than involving an intermediate mammalian host. Thank you.

Dr. Jeffrey Taubenberger: There may well have been an intermediate host involved in the formation of the 1918 pandemic, we just don't know. If there was, we don't know what species. Molecular evidence fits the historical picture that humans gave the virus to pigs, not the other way around; so it probably wasn't pigs. What we think is different about the 1918 pandemic compared to the 1957 or 1968 pandemics is that it doesn't look like a mixed or "reassorted" human-bird virus, but an entirely bird-like virus that adapted to humans.

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Charleston, W.Va.: Right now the H5N1 seems particularly virulent with a mortality rate between 33-50 percent. I have seen in print articles that, based on history, the virulence decreases as the virus causes a pandemic. Is that always the case? Would the decrease be due to a genetic mutation or recombination? It is hard to sort through all of the information available. Thanks!

Dr. Jeffrey Taubenberger: It is likely that virulence would decrease if a new virus, like H5N1 adapted to become transmissible to humans, although we cannot predict with certainty what will happen with any given pathogen. But in general, pathogens that kill a large percentage of victims quickly are thought to spread less well (for example Ebola) than those that can be spread by people who are not debilitated. These changes would undoubtedly be due to mutations in the viral genome. At this time we do not know which mutations are critical to allow an animal-adapted virus to become transmissible in humans. We know that the 1918 virus was very transmissible, and that the current H5N1 viruses are very poorly transmissible in humans. so, differences in their genomes are likely to be important in working out this process.

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Jared Lipworth: Hi everyone. Thanks so much for watching last night's Secrets of the Dead program and for joining us today in the chat. And a special thanks to Dr. Taubenberger for making himself available--I can only imagine how busy his schedule is these days...

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Arlington, Va.: Jared, when and why did you decide to update this film? Due to recent news/concerns expressed about the flu - or before that? Thank you.

Jared Lipworth: Really, as soon as we heard that Dr. Taubenberger had finished sequencing the 1918 genome we knew we had to update the film. When it originally aired, he was still working on it, and now we had the chance to see the sequence completed and to see firsthand what he had learned. The fact that Dr. Taubenberger could talk about the similarities and differences between the 1918 virus and today's avian strains made it even more relevant. Secrets of the Dead is always looking to make important connections between past events and our world today, so this was an excellent and important opportunity to do so.

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Arlington, Va.: Dr., what did you learn overall about mutation of viruses during your research? Applying what you've learned to what's going on today, do you think the avian flu will mutate? Thank you.

Dr. Jeffrey Taubenberger: We are trying to understand two basic things about the 1918 influenza - how did the pandemic virus form?, and why was it so virulent? Having the complete sequence is helping us to answer these questions. But even more importantly we are trying to understand the lessons of the 1918 virus to learn more general rules about how pandemics form and cause disease. for example we have found that the H5N1 viruses share some changes with 1918 that we think will be important for the virus adapting to humans. Whether the H5N1 virus will ultimately acquire the ability to become human adapted is an open question. Obviously we hope not, but we need to be vigilant about monitoring the virus for these kinds of changes.

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Vienna, Va.: I wasn't surprised at the discovery that the 1918 flu virus acted by creating a cytokine storm. The very symptoms (black feet and so on) was very similar to Ebola and hantaviruses, which also kill mostly due to the immune system's own overreaction. I'm in one of the few families that have a written history of those times, so I grew up knowing about the 1918 flu. I was amazed that so many of my generation had never heard of it... at least until a few years ago when the 1918 flu became a hot topic.

That said, what is the major age group that the current H5N1 virus is infecting and killing?

Dr. Jeffrey Taubenberger: We don't really know yet what made the 1918 virus virulent. The animal models do suggest a very robust immune response which may indeed have contributed to the progression of disease. Remember however that individual responses to the identical virus can very tremendously. Even in 1918, about a third of those exposed developed no symptoms, and of those made ill, the vast majority recovered. Case mortality rate in the U.S. was around 2.5%. What we need to figure out still is whether people of the young adult age group had this unusual "over-robust" immune response or another kind of unusual immune reaction to the virus relating to their previous exposure history to flu viruses. Unfortunately we do not yet know anything about the human influenza viruses that circulated before 1918.

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Ventura, Calif.: Temperature at which the virus thrives appears very important. As long as it remains high, avian, the disease appears to lodge in the lungs. Question, you envision the virus becoming more mammalian, thriving at cooler temperature, and thus lodging higher up the respiratory tract, and thusly more easily transmitted, ie, pandemic. How will this occur?

Dr. Jeffrey Taubenberger: Yes, the optimal temperature for viral replication is likely to be important for switching hosts. There are several mutations in the polymerase genes (encoding the proteins that copy the viral genetic material)that might be important because they change the temperature optimum of the polymerase complex. The genetic details of what needs to take place for a bird virus to adapt to a mammalian host are just not yet clear.

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Chicago, Ill.: When do you think we will have a vaccination for H5N1?

Dr. Jeffrey Taubenberger: Scientists at NIH have made an H5N1 vaccine and it has already gone through several rounds of testing. The problem with making vaccines for influenza is that the virus mutates very rapidly. so, one cannot predict the exact form a future pandemic virus will take until that particular strain emerges. What scientists hope to do now is work out the conditions necessary to make the appropriate vaccine as efficiently and quickly as possible once a pandemic strain emerges.

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Louisville, Ky.: Has H5N1 gone human to human yet?

Dr. Jeffrey Taubenberger: There are several instances in which localized human-to-human transmission have been reported with the H5N1 viruses, but it is clear that theses viruses cannot do this efficiently.

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Philadelphia, Pa.: During the 1918 epidemic, it became mandatory in many cities for people to wear masks. We also saw this during the SARS epidemic in Asia. How effective are masks at helping to prevent the spread of germs?

Dr. Jeffrey Taubenberger: Masks are helpful in reducing the spread of respiratory viruses, but cannot prevent spread completely. Simple things like frequent hand-washing are also very helpful in preventing the spread of viruses.

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Washington, D.C.: What's next for Secrets of the Dead? How did this episode do compared to others? Thanks.

Jared Lipworth: The next episode of Secrets of the Dead is on Wednesday night at 8 PM (check local listings), and is called Voyage of the Courtesans. Its the story of a ship full of female convicts that were sent from England to Australia in the early days of the Botany Bay penal Colony. The women were sent as "breeding stock" for the struggling colony, but took matters into their own hands and went on to become the founding mothers of modern Australia.

Killer Flu did very well last night. Clearly, it's a very relevant topic and because it's a Secrets of the Dead, it has both a strong historical angle and a strong science angle. So it appealed to audiences who like both or either.

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Staten Island, N.Y.: If/when the next pandemic hits, will our advances in treatment of symptoms offer any relief that might make this pandemic less deadly than the 1917 outbreak?

Dr. Jeffrey Taubenberger: Certainly we have lots of things available to us today that we did not have in 1918: 1) A good surveillance system to track and analyze viruses from people and animals 2) vaccines 3) anti-viral drugs and 5) antibiotics to treat secondary bacterial pneumonias (the biggest killer in 1918). But we also have several factors which may make things worse - the world is more crowded and people can move around much faster than they did in 1918 which could make the spread of a new pandemic even faster than in the past.

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Anonymous: I understand that the 1918 flu pandemic killed people from ages 20 to 40 mostly. Why do you think that is?

Dr. Jeffrey Taubenberger: This is still a mystery. We think that people over the age of 35 or so probably had some protective immunity against H1 subtype influenza virus due to circulation of a related virus in the mid-1800's. Children often have a milder outcome to viral infection than do adults (for example measles or mumps). So, the young-adult age group may not have had any protective immunity and had a bad outcome to a virulent virus. Alternatively however, this age group may have had an unusual immune response to the virus based on their previous exposure history to flu viruses (for example, being born right about the time of the last pandemic in 1889-1892. This may have contributed to the higher mortality. We don't know yet because we don't have the pre-1918 virus to study or antibodies from those age groups from before 1918.

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Pittsburgh, Pa.: The origin of the 1918 pandemic strain is still controversial. However, the vast majority of the polymorphisms in the 1918 pandemic strain can be found in human and classical swine H1N1 isolates of the early 1930's.

Doesn't that data indicate that 1918 was a recombinant between a human and swine H1N1 virus?

Dr. Jeffrey Taubenberger: The 1918 virus was the likely ancestor of both the human H1N1 and "classical" swine H1N1 viral lineages that were first identified in the 1930's with the isolation of influenza viruses from people and pigs. The data suggest not that the 1918 virus is swine-like but that 1930's classical swine viruses were more 1918-like than 1930's human viruses, because the human lineage evolved faster (more and longer-lived population immunity). The historical data suggests that swine influenza was a novel disease in 1918. The silent nucleotide changes that make 1918 less bird-like are retained to a significant degree in the the viruses directly descended from the 1918 virus -human and swine.

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Midwest: I've been fascinated with your work, Dr. Taubenberger, since I read Gina Kolata's book. Thank you so much for your work.

Dr. Jeffrey Taubenberger: Thanks you for the compliment. It is a very fascinating topic and I continue to be really fascinated and amazed by what happened in 1918 and to try to understand what more about influenza ecology in general. Here's a virus present in dozens of species, birds and mammals, with this tremendous capacity to mutate and evolve. It is not just an interesting question, but one with real, practical implications.

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Geneva: A collegiate of yours, Prof. Peter Palese Phd (Mt Sinai SM) recently presented at International Virology Symposium in Marburg, Germany last weekend. He discussed the "Reconstruction and Characterization of the 1918 Influenza Virus." However, what apparently what caused quite a stir was the presentation by Dr. Masato Tashiro on "H5N1 AI as a threat of a great pandemic" that accuses the Government of China of suppressing much higher numbers (300+) of infected and sick humans ( including H-H ). In fact it was reported as a highlight of the Symposium by the Frankfurter Allgemeine. What is your reaction to this development?

Dr. Jeffrey Taubenberger: I did not hear Dr. Tashiro's talk so I cannot comment about what was presented.

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Salt Lake City, Utah: I seem to recall a bit of information suggesting that one of the genetic mutations in the 1918 virus may explain its virulence. Could you speak to that and to the larger issue of virulence factors at the time?

Dr. Jeffrey Taubenberger: Virulence is a difficult issue to study, in that viruses may behave very differently between hosts. For example, there are examples of highly pathogenic viruses which kill 100% of chickens but will not cause any disease in ducks. The mutation that makes the virus deadly for chickens is known, but even with that mutation, it is not lethal for another species of bird. That said, mouse models do suggest that the 1918 virus encodes virulence factors in several of its genes - certainly the hemagglutinin gene - and the polymerase complex genes. What exact mutations are not yet known, but we hope to perform experiments to map these changes in the future.

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Alabama: I understand the 1918 flu took a big toll on the young and relatively healthy. Going further back in history, the Black Death of 1361 also took a larger toll on the young, compared to the more famous outbreak in 1347-1350. Does anything in a virus predispose it to attacking people in their 20s and 30s?

Dr. Jeffrey Taubenberger: We just don't yet understand the unusual age-mortality in 1918. for example it might be that this virus induced a very robust immune reaction in the healthiest age group, meaning that if another virus having similar features were to appear it would have a similar effect. Alternatively, this age group in 1918 may have been particularly susceptible to a bad outcome after exposure to the 1918 virus based on their previous exposure history to other influenza strains, in a way unlikely to be repeated in the future. It is very important to know which of these possibilities is correct to draw the appropriate lessons from 1918.

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Ojai, Calif.: You said, Chicago, Ill.: When do you think we will have a vaccination for H5N1?

Dr. Jeffrey Taubenberger: Scientists at NIH have made an H5N1 vaccine and it has already gone through several rounds of testing. The problem with making vaccines for influenza is that the virus mutates very rapidly. so, one cannot predict the exact form a future pandemic virus will take until that particular strain emerges. What scientists hope to do now is work out the conditions necessary to make the appropriate vaccine as efficiently and quickly as possible once a pandemic strain emerges.

So, why not develop a Flu Forecasting model, using sequence data at GeneBank and models such as recombination and reassortment to predict probabilities and prepare them for quick conversion to commercial production and distribution?

Dr. Jeffrey Taubenberger: That is exactly what the WHO network does for the annual influenza vaccine production cycle - using all available serolgic, antigenic, and molecular data to make predictions about the direction of influenza evolution. In regards a future pandemic this is much more problematic - we don't know when a new pandemic strain will emerge, where, or what subtype it will be. The NIH program that has made the pilot H5N1 vaccine seeks to make seed-stock vaccines for a more rapid commercial production from all known influenza subtypes (currently 16 different hemagglutinin forms and 9 different neuraminidase forms). This will help significantly for the future.

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London, UK: Is there any scope to sequence/recreate any other previous influenza strains in history?

Specifically, has there or can there be any attempt to sequence the swine flu or avian flu samples that came just before or during the 1918 outbreak?

Or is the genetic material of that period in time now exhausted?

Dr. Jeffrey Taubenberger: We are working hard to identify human influenza cases from before 1918 and also from the 1920-1930's. This will be crucial to understand how the 1918 pandemic formed and how it evolved after the pandemic. We have also done some sequencing of bird influenza viruses from circa 1918 using preserved museum specimens. So, there is material around, it's just a matter of finding it and then doing the molecular analysis. This is unfortunately a very time-consuming project and much, much, much slower than genetic analysis from contemporary virus isolates because of the poor quality of the genetic material from this sort of sample.

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Jared Lipworth: Thanks again for joining us today and please make sure to tune in to PBS on Wednesday night at 8pm (check local listings) for another spectacular edition of Secrets of the Dead. This film, Voyage of the Courtesans, tells the incredible story of a ship full of female convicts that was sent from England to Australia during the early days of the Botany Bay penal colony. The destitute women, banished to "parts beyond the seas," turned exile into opportunity and went on to become the founding mothers of modern Australia. It's a fascinating story and a beautiful film, so check your local listing and tune in to Secrets of the Dead. And for more information on past and upcoming programs, please visit our web site at http://www.pbs.org/wnet/secrets/

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