Seth Carus writes:
Dear Dr. Racaniello and colleagues,
I enjoyed your conversation with Jens Kuhn. His comments on the complexity of creating biological weapons were right on the mark and serve as a useful counterpoint to those who think it is easy to turn pathogens into effective weapons.
As a non-scientist, I always find your discussions interesting and enlightening, even when I don’t understand the science involved. Keep up the good work.
Many thanks for referencing a study I did nearly two decades ago, Bioterrorism and Biocrimes. The study was written while working for the U.S. government and thus has no copyright. Subsequently, someone (unknown to me) took it and starting selling print version through Amazon. There is no reason for anyone to pay for it: it is available free of charge as a pdf download at this url:
http://wmdcenter.ndu.edu/Portals/97/Documents/Publications/Articles/Bioterrorism-and-Biocrimes.pdf
One additional comment. Having spent considerable time researching the history of biological warfare, I have grown intensely skeptical of some of what is written about it, especially about its pre-modern history. The first incident for which there is definitive proof is the 1763 smallpox blanket incident at Fort Pitt. The evidence to support earlier examples is limited or nonexistent.
As an example, virtually every history of biological warfare will mention that the Greeks ended the siege of Cirrha by contaminating that city’s water supply with hellebore, thus incapacitating the defenders. Yet, there is no evidence that the city ever existed and some classicists believe that the whole story was fabricated. Indeed, the oldest account of the incident dates to 200 years after it supposedly took place.
Should you be interested, I wrote a new history of biological warfare, available for free (another government publication), incorporating the most recent scholarship. It is available at:
In addition, I reviewed the available evidence on the history of biological warfare in an article published in Health Security, unfortunately behind a pay wall (https://www.ncbi.nlm.nih.gov/pubmed/26221997).
Seth Carus
Emeritus Distinguished Professor of National Security Policy
National Defense University
Jeffrey writes:
As a student beginning a Master’s in Microbiology at McGill University – MacDonald Campus, where our illustrious alumnus dosed his roommates with Ascaris suum, I feel a need to point out that Sainte-Anne-de-Bellevue isn’t truly part of Montreal.
Fascinating episode on Bioweapons and another great discussion with Dr. Kuhn.
Keep up the good work!
Bob writes:
This was an awesome podcast. Jens Kuhn’s story of his odyssey to Russia is fascinating.
During the show Kathy Spindler said something like “Chapter 12 tells this story and it is worth reading… I will put a link to it in the show notes.”
But I cannot find what she was talking while looking thru the notes provided.
Perhaps it is in the (alas, paywalled) Nature article referenced?
Regards, Bob
Jason writes:
Dear Vincent, Rich, Kathy, Brianne, Dickson and Alan,
I wanted to thank you all for the great discussion about our manuscript on poxvirus membrane fusion last week. The whole lab (avid TWiVers) really enjoyed this!
I just wanted to briefly answer a few of the questions that came up during the episode.
The trade-offs between super-resolution (SR) and cryo-electron microscopy (EM) were briefly touched on. First, I’m a huge fan of cryo-EM and like to think of SR and EM as complementary approaches. Cryo-EM has been invaluable with regard to solving virus structure, and cannot be touched with regard to resolution. However, if you’re willing to take a bit of a hit on resolution there are two main gains with SR microscopy.
-First, because these techniques are rooted in fluorescence microscopy, you readily gain molecular specificity which is most important when mapping protein localization in complex or polymorphic viruses.
-Second, these SR techniques are compatible with live cell imaging. This means we can actually visualize virus assembly and maturation in real-time. In other words, we can add molecular specificity to the phenotypic descriptors provided by EM.
In fact, I think correlative cryo-EM / SR microscopy (exemplified by Kay Grunewald’s work), will provide the next paradigm shift in our understanding of virus structure and assembly.
It was asked if the fusion protein polarization was unique to poxviruses. As pointed out during the episode, a similar phenomenon has been observed with HIV. Given the energy barrier of full fusion, we suspect viral fusion protein polarization will be revealed as a common feature of enveloped viruses once other virus fusion proteins are visualized using SR techniques.
Alan asked if it was possible to use these super-resolution techniques to map the protein architecture of smaller viruses. Briefly, the answer is Yes. dSTORM, a single molecule localization technique featured in the paper, can achieve resolutions of 20nm. If combined with single particle averaging using VirusMapper, one can couple that resolution with protein localization precisions of ± 5nm. So, while VACV is a VERY BIG virus, these techniques can work on viruses in the 50-100nm size range.
It was suggested that an add-back of soluble A27, to A27(-) virions may result in repolarization of the fusion machinery to the virus tips. Excellent suggestion! Although I suspect that the virus membrane will not be fluid enough to allow for fusion protein repolarization, A27 addback may partially restore fusion protein clusters and might even speed full fusion kinetics. We will for sure give this a go and keep you posted!
Thanks again for the great episode and all the best!
Jason
—
Dr. Jason Mercer
MRC-Laboratory for Molecular Cell Biology
University College London
Eric writes:
Hi Vincent – I finally figured out how to listen to podcasts on my car radio (welcome to the 21st century, right?) so I’ve been enjoying listening to TWiV (you may or may not remember that I was a guest on TWiV many years ago). On a recent episode, there was discussion about the clustering of viral envelope glycoproteins, and whether this had been reported for viruses other than vaccinia, and under what conditions. Indeed, HIV-1 Env has been reported to cluster in a manner linked to virus maturation. We reported a number of years ago (Murakami et al., JVI 2004) that HIV-1 Env-mediated fusion is suppressed in immature virions, but is activated upon virion maturation. The explanation likely lies in the observation, made by the Krausslich lab (Chojnacki et al., Science 2012), that virus maturation induces Env clustering. This presumably increases the number of Env trimers available for CD4/coreceptor binding and membrane fusion. Interestingly, as with our earlier observations on suppression of fusion in immature virions, the clustering is dependent on the long cytoplasmic tail of gp41, probably as a result of interactions between the cytoplasmic tail and the underlying Gag lattice.
Keep those TWiVs coming!
Best regards,
Eric
************************
Eric O. Freed, Ph.D.
Director, HIV Dynamics and Replication Program
Center for Cancer Research
National Cancer Institute
River writes:
Thanks a lot to introduce our paper on TWiV. I am very glad all of you like my movies.
I plan to make some new movies about Jelly-rolls based on my latest seminar talks about jelly-rolls. The topology of the beta-strands are really like the jelly-roll. As one of the hosts asking about the interactions among the proteins of giant viruses, we submitted a new paper showing that electrostatic interactions play important roles in the giant virus assembly and stabilization. We found three different modes of interaction between the pseudohexagonal capsomers (one mode within trisymmetron and two modes at the border/edge). Our final conclusion is mode 1 is the dominating interaction that stabilize the capsid and hold the trisymmetron much stronger than the border area. This is consistent to the 1969 paper (when the trisymmetron was discovered and named) that the trisymmetron still hold together when the viruses break apart.
Again, thanks a lot for introducing our paper! I am also excited that “Wolbachia warriors” are winning the war against Dengue Viruses.
Best,
River
Jens writes:
Dear TWiV team,
In Episode 507 you covered Ebola virus and related filoviruses. I thought I would weigh in a bit with everything you never wanted to know about these bugs…
- First, pronunciation: “Ebola virus” is actually pronounced [ɛ’bɒlə vɑɪrəs] (International Phonetic Alphabet) which is akin to eh-bo–luh vahy-ruhs in English phonetic notation. This is because the word Ebola is francophone in origin, i.e. the “E” in “Ebola” actually has an accent aigu, which however is not shown because the E is capitalized (i.e., it is actually Ébola). This pronunciation is in contrast to the word “ebolavirus” (the vernacular for one members of the genus Ebolavirus – one word), which is pronounced [iːˌboʊlə’vɑɪrəs] (IPA) – ee-boh–luh-vahy-ruhs 😊. This nitpickiness becomes important because of the “Ebola virus” (two words) vs. “ebolavirus” (one word) dilemma you mentioned – correct pronunciation of both words is the only way of properly differentiating between the two in oral proceedings.
- Please don’t say there a “multiple kinds of Ebola virus”. There are several ebolaviruses and they are as distinct from each other as Lassa virus is from LCMV. Ebola virus is one of them. Bundibugyo virus is another.
- You asked about specifics on the Marburg virus outbreak in Belgrade in 1967. I thought this is a good opportunity to point out that the original publication on this outbreak is almost never cited (but should be!):
Тодоровић, К., Мирјана Моцић, Радмила Клашња, Љ. Стојковић, М. Борђошки, Ана Глигић, and Ж. Стефановић [Todorović K., Mocić Mirjana, Klašnja Radmila, Stojković Lj., Borđoški M., Gligić Ana, Stefanović Ž.]. 1969. НЕПОЗНАТО ВИРУСНО ОБОЉЕЊЕ ПРЕНЕТО СА ИНФИЦИРАНИХ-ОБОЛЕЛИХ МАЈМУНА НА ЧОВЕКА [Nepoznato virusno oboljenje preneto sa inficiranih-obolelih majmuna na čoveka]. With English abstract: Todorović K., Mocić Mirjana, Klašnja Radmila with collaboration of Stojković Lj., Bordjoški M., Gligić Ana, Stefanović Ž. AN UNKNOWN VIRUS DISEASE TRANSMITTED FROM INFECTED GREEN–MONKEYS TO MEN. CCLXXV(22):91-101 [Serbo-Croatian].
This publication (attached FYI) is behind a pay-wall, behind a language-wall (as it is in Cyrillic Serbo-Croatian), and behind a search strategy wall. This publication is actually indexed in PubMed (PMID: 4991421), but you would never find it if you didn’t know a priori what you are looking for as the only search terms that would locate it are “monkey” and “disease” (which of course will give you thousands of hits). Other important papers like these are not even indexed in PubMed. It is amazing to me that 20-30 years back, authors managed to properly cite foreign scientific literature such as this paper in the absence of computers and search engines, whereas today people seem to think proper citation is just finding “something” in PubMed without checking whether whatever was retrieved is actually a primary and the first publication for a particular statement.
By the way, the three Marburg virus disease outbreaks in Marburg, Frankfurt, Belgrade were connected via the infected grivets these three places received from the same primate supplier in Uganda.
- A little bit of self-promotion: you asked about how many filovirus disease outbreaks there were. I actually made a what I think is a very nice figure of all human filovirus disease outbreaks and sporadic cases for the filovirus chapter in the latest edition of Harrison’s Principles of Internal Medicine (Kuhn, Jens H. 2018. Ebolavirus and Marburgvirus Infections, p. 1509-1515. In Jameson J. Larry, Fauci Anthony S., Kasper Dennis L., Hauser Stephen L., Longo Dan L., Loscalzo Joseph (ed.), HARRISON’S PRINCIPLES OF INTERNAL MEDICINE, 20th ed, vol. 2. McGraw-Hill Education, Columbus, Ohio, USA. ISBN: 978-1259644030). This chapter is also behind a paywall, but the figure (205-3, attached) may give you something to discuss in particular in regard to the question of CFR and whether one virus is worse than another… Please note that the latest COD (DRC) outbreaks are not yet included in this figure.
- You said “often they can identify bushmeat as the source” of Ebola virus disease outbreaks. That is not correct. Interviews with index cases often revealed that they were hunting in the forest (and caught certain animals), but that is where the connection ends. One might as well say “trees are the source” because people walked through the forest. This is important as “bush meat” is an important food source in many areas (not unlike shooting deer in the US is “bush meat” by the way) and therefore discouraging contact with bush meat might have negative consequences (as in “no food”). The discovery of a new ebolavirus, Bombali virus, in bats indicates that the source of ebolaviruses may indeed be mammals/bats, but in the reports about past outbreaks the “bush meat” association was made in regard to nonhuman primates, not bats…
In short, we do not know how ebolaviruses spill into the human population.
- Kudos to you for saying “grivet” instead of “African green monkey”! Most people do not appreciate the complicated taxonomy of “African green monkey”, which is a term that actually should not be used anymore.
- Nomenclature/capitalization etc.: The members of the genus Morbillivirus (capitalized and italicized one word) are called morbilliviruses (not capitalized, not italicized, one word). Likewise, the members of the genus Ebolavirus (capitalized and italicized one word) are called ebolaviruses (not capitalized, not italicized, one word). This is, admittedly, an unfortunate genus name as ONE of the five members of the genus Ebolavirus is called “Ebola virus” (capitalized, not italicized, two words). I would love to change the genus name to get rid of this confusion, but that requires majorities in committees…
Best,
Jens
Sam writes:
Hello TWIV! It’s been a real hot day in Tucson, with a high of 112 F or nearly 45 C, and a humidity of 21%. The good news is monsoon season is in full swing, we have 20-60 percent chance of rain forecast each day for the next week, and with the rain will come some wonderful cool 96 degree weather. Our evening skies have been filled with towering clouds rising over the mountains and being lit by the sunset.
You will no doubt hear of this paper by Ulrike Löber el al in PNAS many times, but it’s too cool for me not to flag it.
www.phys.org/news/2018-08-ancient-virus-defends-koalas-viral.html
Koalas have come up on TWIM, regarding chlamydia I seem to recall? So interesting to hear that a virus may be involved!
Congratulations on 500 episodes!
John writes:
I appreciate the work you all do and the discussion you bring to the airwaves.
I will add that I stand with Bob’s letter. I understand it’s difficult to remain objective when there is a nonstop media spin with an agenda. Alas we are all human, but if anybody has the pedigree to parse out the relevant points it is all of you.
A couple of other points.
The Outbreak exhibit at the Smithsonian is phenomenal.
The Gladwell podcasts were fascinating. I was pleased to hear that it was one of your picks.
Keep up the good work and bring forth your efforts to see the forest from the trees.
Funds donated to show my appreciation for your work.
Take care
jt
Ben writes:
Dear Team TWiV,
With regards to the discussion on episode 507 I had to write in because this may be the only time that my professional experience is directly relevant to a discussion on TWiV. As an artist and teacher of art at the tertiary level I’m guessing that I’m in a rather small minority listeners to the TWiX family of podcasts so I feel compelled to add some thoughts regarding the relationship between art and science.
I wanted to pick up on Rich’s comment on how he felt that his work refining technique in the lab was a kind of art. I reckon that this comment is spot on in a way that a lot of people in both the arts and sciences don’t fully appreciate. Art as a form of investigation depends on the ability to reliably repeat specific relationships between materials, techniques and processes. Repeatability is as important to art as it is to science. I understood Rich’s comment as relating to the art of the physical process of doing science, something that is a kind of embodied cognition that is not completely dissimilar to say playing a musical instrument.
Alan’s comment about the art on cave walls was really important here too. I love the idea that the cave wall was our first kind of peer reviewed publication and that communicating important relationships with the environment and our fellow organisms on this planet is part of the shared work of both art and science, in a way that we can relate to those cave paintings.
I think it’s really useful and important to think about the parallels and distinctions between the practices of art and sciences. One of the parallels that I often discuss with my students is the difference between basic, curiosity driven research and more applied forms of investigation. This is a useful distinction for artists to think about. One way to describe this is in relation to materials and representation. On a basic level as artists we want to know what our materials can do, their limits, and where we might find interesting thresholds where the materials cross over from doing one thing to doing something quite different. This requires rigorous material experimentation and, like curiosity driven research in the sciences, can be an end in itself, (recently I’ve done this sort of work using laser diodes to burn marks into particular kinds of paper with a robotic drawing machine). This material research might then be applied to the task of representing something or evoking a feeling.
I think there are any number of parallels that we can draw between art and science at the level of process. Another of these is the task of interpreting and communicating experiments which I see as being fundamental to both disciplines. If, as artists, we don’t spend time reflecting on and interpreting the material that we’ve created we quickly lose direction and experiments become just experiments without any useful or communicative outcomes. While there’s all these questions of process where we can find parallels between art and science there are some places where our disciplines diverge, perhaps less when it comes to the means and more when it comes to the ends. Whereas manipulating results to better fit our we feel about the subject has no place in a scientific publication artists do this all the time when they exhibit their work by selecting only the works that evoke what they’re looking for in a particular subject. And while a powerful sense of mystery might drive the scientific endeavor forward in art a powerful sense of mystery might be the end in itself.
All the best,
Ben Denham
Lecturer in Drawing
National Art School
Sydney, Australia
River writes:
I went over an article, a little bit old, that might be interested for your podcast listeners, particular scientists.
I really like the opinion of curiosity is the main force that drives science advance. I like the saying of “It has been said that the great moments in science occur not when a scientist exclaims “Eureka!” but when he or she murmurs “That’s strange.” I also really like another sentence “Because it is politically expedient to sacrifice the future, which does not vote, to the consumption of government services by those who do, America is eating its seed corn.”
River