TWiV 288 letters
It is 17 C here, two miles from Google’s main campus in Mountain View, California.
Alan’s pick for episode 287 was a site called “do not link” that prevents search engines from following outbound links to bad content. Google already solved this problem in 2005. Any link can be hidden from search engines by using the “nofollow” attribute (see below). The original intent was to combat spam comments on blogs, but there is no reason a blogger could not use it in the main body of a post.
Stool and somatic motor paralysis
Somatic motor paralysis can result in stool incontinence by affecting the innervation of the striated muscle of the pelvic diaphragm which includes the 2nd, 3rd & 4th sacral nerves (“S two, three, four: keeps the faeces off the floor”). This does not affect the autonomic functions that influence the viscera such as the gut.
The thoraclumbar outflow from the thoracic and lumbar segments of the spinal cord is the sympathetic component, and the craniosacral outflow (the 10th cranial nerve – the vagus nerve – plus the sacral segments of the spinal cord) is the parasympathetic component. These two components affect the viscera. They can be affected in such conditions as diabetic autonomic neuropathy, with resulting dysmotility of the gut blamed for disturbances in the flora and for diarrhoea (and also the absence of pain with heart attacks). That narrative is many decades old, and the gut part could well be outdated.
Does MERS grow in New World camelids? Llama farms can be found in the US. If it does, they can be used as live models.
Statistics and immunisations:
The older part of the brain, the reptilian or lizard brain, which includes the limbic system, is non-rational and non-verbal. It is associated with emotions (short timeframe) and values (long timeframe). The intellect, associated with the cortex, particularly in the frontal lobes, is verbal and rational, and appears to be in the driver’s seat. But what is generally not realised is that it is the chauffeur. It will find rationalisations to defend the positions taken by its lizard brain boss.
This is true even in the case of the most sophisticated of scientists, and hence the observation by Max Planck that
“A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die, and a new generation grows up that is familiar with it.”
– or the more colourful though perhaps apocryphal attribution “Science advances one funeral at a time.”
Politicians and advertisers understand that the way to change the behaviour of the masses is to address their emotions. If any numbers are used, they are cherry-picked, kept simple and aimed at the emotions.
Fancy statistics directed at the intellect will be effective only in those who are trained to digest them: it is like preaching to the choir. Among the rest, the monkey brain will use any statistics provided to the extent that they can support the agenda of the lizard brain.
If the objective is to get children immunised, the method is neither a deluge of numbers nor a freshet of rationalisations, but rather a display pictures of sick and suffering children with appropriate narratives. Dr. Dickson’s suggestion of videos of children with whooping cough is actually quite a good idea.
Next to the Coronamap site there is the website below on different parameters of the epidemic. From the graph of the case number vs time there might be some seasonality of the virus (nothing statistically significant I guess). Every April the cases go up (“rainy season” in KSA I believe). So it is worthwhile to talk about the weather
I also heard a new minister of health was appointed, which could also explain the increase in cases.
Thanks for the great podcast,
Dear Twivsters (sorry, no bingo points here)
First, I agree wholeheartedly with your reaction to the quote-unquote Ethical Research opinion piece. Even if the levels of lab accidents that the authors claim/make up were true, the response shouldn’t be to stop the work, but rather to improve biosafety precautions. It’s also odd that they talk about what is unsafe today by pointing to a nearly 40 year old (potential) incident—when biosafety precautions were still being developed.
But I have an (easy to address) critique. You were much harsher than called for responding to claims that the 1977 reoccurrence of H1N1 flu came from a lab accident. Too much was made of the word “thought”—which is a matter of style not substance. You criticized the use of the a review rather than research paper—but I think Lipsitch and Galvani chose that paper to make a sly attack on Kawaoka, one of the authors: “See, Kawaoka should have known better.” That’s yet another bad debating tactic (especially since, from skimming the article, it looks like the claim that the virus escaped from the lab occurs only in a caption; the body of the paper is far more circumspect), but it doesn’t negate that many scientists seem to think a lab accident is a strong possibility.
Thanks to paywalls, I haven’t been able to access many papers on the subject, but I can quote from http://www.virology.ws/2009/03/02/origin-of-current-influenza-h1n1-virus/ which comments on one such paper: “The suggestion is clear: the virus was frozen in a laboratory freezer since 1950, and was released, either by intent or accident, in 1977. This possibility has been denied by Chinese and Russian scientists, but remains to this day the only scientifically plausible explanation.” I realize that blog posts must rank below even review articles, but I tend to trust the author of this one.
But all joking aside, I’m really curious about what we do and don’t know, and how much we really can know, based on the analysis of mutations. I’ll admit, I’m somewhat skeptical of molecular clock analysis, probably because I’m more familiar with its misuse in linguistics (historical linguistics often borrows from evolution, sometimes successfully).
I get that the similarities between 1977 H1N1 and virus from the 50s suggests that something odd was going on, but I have trouble (as someone outside the field) figuring how much can be hung on that fact and how much is just speculation. In another example, a recent article in PNAS, “Genesis and pathogenesis of the 1918 pandemic H1N1 influenza A virus”, used a molecular clock approach to reconstruct when that Spanish flu’s H1N1 emerged, and to understand the timing of its predecessors. I read the article, but the suggestion that molecular clock reconstruction explained the high mortality in younger adults seemed very speculative—I had a number of complaints, but mostly I found myself wanting to shout that correlation doesn’t equal causation.
I’d appreciate if you folks could respond to some of those issues. I imagine a whole episode could be spent discussing the implications of molecular clock analysis and similar studies, but I’d appreciate any insight you can offer if you don’t want to do that.
I realize this letter is already long, but I wanted to thank you for your great podcasts. I finally caught up all the TWIx podcasts and have started exploring other science podcasts; I haven’t found any that match your depth and expertise while making listeners feel a part of a conversation.
Great TWIV. Rich did a great job, and I agree: poxviruses are very cool!
Regarding Dick Moyer’s paper, you guys were wondering what would happen in humans if vaccinia virus would be injected into someone instead of using the regular scarification route. I can say that the lesions are very, very ugly. Unfortunately we had an accident in our lab in the past when a student was using a syringe to disperse virus. The needle made a scratch on her finger but there was some blood coming out of the wound.
Well, the whole story is told in the following paper:
I can’t say that all the severe effects we observed were due to the route of infection because we can’t tell the dose of virus that got into her finger, but it was not an injection per se. The needle was used by the student and she was removing it from the microtube when it scratched her skin, but it was not superficial such as scarification.
It’s always very good to listen to TWIV. I forwarded the link of this episode to my virology class so they can vote. We had a debate last week on this issue. The class was divided in two and one group was against and the other was in favor of destroying the remaining stocks of variola virus. They elected a leader of the group who was in charge of conducting the debate, directing questions to individuals of the opponent group. It was very nice and productive. At the end they could reveal their real opinion. The majority was in favor of keeping the stocks and reevaluate this issue in the future.
Congratulations for this nice work!
All the best,
Dick Moyer writes:
I listened to the TWIV that discussed my upcoming paper in JVI. First, let me say that I was extremely flattered that you chose our paper to present. Let me also say that Rich’s presentation of our work was very well done and that he covered the content very well. Since I know you guys are always interested in “factlets”, let me provide a little filler discussion.
First, why focus on rabbits as they are both cuddly and relatively expensive. When we first got interested in the field of poxvirus animal models the good news was that there was a lot of information on various models which it turns out was also the bad news. The models were terrible (like intracranial inoculation) probably because the models were developed at a time when there was little sophistication and assays were typically feet up/down.
As the science advanced, the gold standards became better and included a high degree of sensitivity to the virus and attention to models where infections mimicked the natural disease which is smallpox (to me). That led us to focus on the rabbit which of course as you now know is exquisitely sensitive to the virus. However, there is one additional, very, very, very important feature reproducibly found in the rabbit which is not appreciated and generally ignored. That feature is natural animal to animal spread via aerosol from ID infected animals. No fancy devices needed! I needn’t tell you that in the event of an outbreak that aerosol generated spread is critical. To further expand on this point for two more sentences, if I were working on antivirals, and wanted to get something through the FDA, I would test any and all antivirals for the ability to block dissemination and aerosol mediated spread. Doses required to block dissemination which is really the scary feature of the disease, would undoubtedly be lower and hence easier to get past the FDA. Anyway, the rabbit represents nearly the perfect host for smallpox because it mimics virtually all features of the disease whereas the mouse doesn’t.
Finally, Rich alluded to other unpublished work. That is true. For the last 2 years before closing the lab, I had the total and complete luxury of doing exactly what I wanted without worrying about NIH. That allowed me some time to investigate what I think is potentially one of the most unexplored yet interesting aspects of host-pathogen interaction; namely what genes of a given host render the animal susceptible or resistant to disease. Without going into detail we did a huge number of mouse genetic cross experiments with susceptible/resistant mouse strains using cowpox and vaccinia viruses. These experiments were designed to allow us to explore and potentially identify the host genes involved in animals infected by (1) 2 viruses via the same route and (2) in the case of cowpox virus host genes involved with one virus via two routes of infection. We were able to show some fascinating stuff. THAT is what I am struggling with now in terms of writing it up because some of the complex mouse genetics complications are really tough to understand and effectively communicate to others. Anyway, that should be coming out later this year.
So, Vince, I apologize for this very verbose email, which when stripped down to essentials, is a thank you note from me, thanking you and TWIV for your interest in our stuff and for taking the time to discuss our paper on the air.
This is not a question about viruses, but more fact checking something I believe Rich Condit said. I am sorry I cannot direct you to a specific episode, but within the first 3-4 months of this year.
Referring to his own mortality, I believe he made reference to death as returning “to equilibrium with the universe.” I wanted to check if was something he said. The thought of one’s atoms equilibrating with the universe might actually appeal to some as an expression sympathy. The way I remember hearing it spoken conveyed a calm and peaceful sense of rational acceptance of death. This is where having a better grasp and understanding of the Laws of Thermodynamics would, not doubt, enrich my appreciation of the inherent beauty of the statement. I’ll have to research and review.
Thank you, all, for creating the most informative, engaging weekly program I know of. Your chemistry (and virology of course) are great. You’re better than any old, or new, radio or TV serial, ever!
Currently it is 12 C, with light winds (14km/h), mist and intermittent drizzle, in Boston, 11 C in Cambridge.
Best to all,
Johnye Ballenger, M. D., FAAP
West Cambridge Pediatric and Adolescent Medicine
Cambridge, Massachusetts, 02138-4627
Hi Vincent, naturally I thought of you today with the polio/CIA announcement!
I hope you are well and thriving!
Below is my view on why we should destroy Varicela stocks.
Thanks for listening, as always,
Yes; destroy the stocks immediately.
Our current risk management methodology is decisively inferior. Our closely interconnected systems are collapsing at an increasingly rapid rate; consider the two recent examples of Fukushima and the Great Financial Crash.
The top mathematicians in the world assured us that neither of those two events would happen more frequently than once every several million years, i.e. they were 12 sigma events.
But that was false and it was stupid. But most of the brightest risk management folks don’t know why. That portends danger for retaining such stocks.
One key point is that these models that say we have a 12 sigma chance (or thereabouts) of a catastrophic accident from a virus laboratory are making the same mistake made in both Fukushima and Goldman Sachs risk modelling.
To wit, proper risk assessment must take into account that these are complex systems of interconnected and layered probabilities. Additionally, any estimate of a very small risk contains a margin of error. That margin of error is often larger than the actual risk being estimated. When you layer those massive uncertainties, their products must be multiplied for an accurate risk assessment to be made.
These clowns are off by orders of magnitude. They do not employ what is known as metaprobability analyses.
Simply stated, we are too stupid as a species at the present time to continue research with smallpox.
The foregoing analysis is informed by pages 91-98 of a seminal new text on risk management to be published next year.
That text, entitled “Silent Risk” is available free of charge below. Virologists need to understand this so we don’t have a viral “Fukushima”.
Amgen’s oncolytic herpesvirus improved overall survival with p=.051:
Given the mild side effect profile in comparison to chemotherapy drugs, I hope the FDA will find it within itself to overlook the .001.
Actually, there were more serious adverse events for T-vec than the comparator drug;
“Serious adverse events occurred in 26 percent of talimogene laherparepvec patients and 13 percent of GM-CSF patients”
Hi TWiV Guys and Gal,
I am on my 3rd listen through on all the TWiV episodes, am up to #153 and have a couple of questions and a comment.
On the subject of using an engineered Zinc-finger nuclease to knock out CCR5 in HIV infected T Cells.
1. Will knocking out the gene for CCR5 in a cell only affect its daughter cells?, i.e. Haven’t the receptors already been made and they’re on the surface of the cell?
2. Aren’t the T-cells of an infected person already mostly infected with latent integrated HIV provirus? If so, won’t knocking out the entry-receptor be pointless?
On another topic. My sister has been diagnosed with Multiple Sclerosis and is considering undergoing Monoclonal Antibody therapy, but is very worried about the side-effects she has been warned about, particularly Progressive Multifocal Leukoencephalopathy (PML), due to re-activation of JC Virus. She has been tested for JC Virus and doesn’t have it, but if she were to undergo MAB therapy, is there a real risk that she could possibly contract the JC Virus and develop PML, even though she does not currently have the virus? (She works in a pharmacy, so see’s a lot of sick people)
I just finished watching Season 9 Episode 18 of the TV Series Criminal Minds entitled “Rabid” and thought you might find the plot line of this episode “interesting”. The show follows a team of profilers who track down serial killers. This particular episode involved a serial killer who had a rabid animal bite his first victim and then he would keep the victim until they developed symptoms and then have that person bite his second victim and so on, he would watch them die over a period of months and film the results. They described the virus as having an incubation period of 24 hours after which time post-exposure prophylaxis was futile. They even mentioned the Milwaukee case of the woman who was put into a medically induced coma that survived the virus.
Humans infected with the rabies virus were making animal sounding noises and trying to bite everything, which I don’t think is very accurate.
Luckily I get my information about Viruses from TWiV, not Hollywood.
It is a beautiful day here in Sunny Queensland, Australia 27 degrees C, with white puffy clouds.
Keep up the great work on your series of podcasts and am loving your (Vincent’s) excellent Coursera course.
I suspect you got a dozen (or more) responses about the CCR5 mutation already, but just in case you did not: It has been suggested that the delta32 CCR5 deletion spread in northern European population in response to bubonic plague about 700 years ago. And as far as the phenotype, it’s been linked to more severe flaviviral diseases, especially dengue.
Yegor Voronin, PhD
Senior Science Officer
Global HIV Vaccine Enterprise
Hi TWiV crew,
As a follow up to my previous email about MAB Therapy and MS, I have a habit of fighting pseudoscience everywhere I find it, and there is a Natural MS support group that is advising my sister that dairy products can trigger MS:
“Dairy is best removed from your diet if you have MS, two proteins found in dairy trigger the immune system to attack myelin. Remember dairy is for baby cows… Not humans”
She did the right things and asked if they had any evidence, which they provided me enough information to do a literature search and I found these articles which they seemed to get their information from. (I can only read the abstracts)
After reading through the abstracts, it seems they may have a point. I don’t know enough about the field of immunology to make a judgment one way or another, but if “Milk triggers MS”, like they are claiming, surely it would be more widespread knowledge by now.
Hello esteemed TWiV Doctors,
First and foremost, I’d like to communicate my deep and sincere thanks for all of your incredible work in science and scientific outreach. Hearing experts discuss new and exciting research in the field of virology every week helps to keep me motivated during long days at the bench, in the hood, or behind a desk. I especially enjoyed recently hearing about Dr. Racaniello’s formative years, and I hope that Drs. Condit, Despommier, and Spindler will follow suit.
I’m writing today seeking some practical advice about something which I’m very much still figuring out: what makes a good scientific presentation. After over a year of hard work, one of my projects is finally ready to share, and I’m happy to say that our abstract was accepted for a talk at this year’s ASV! This will be my first oral presentation at a peer-reviewed conference and although I’m excited and honored, I’m also anxious and filled with questions. So, my question for you is simply – what are some aspects of successful scientific presentations? Can you offer any tips specific to ASV?
Thank you all again for all of your hard work, I can’t wait to see the live podcast!
I just listened to TWiV 279 and though that you did a good job addressing the question/statement about individuals immunized with MMR not being protected from infection with mumps during recent outbreaks. I just thought I would pass around an interesting paper that attempts to model the effectiveness of the MMR vaccine by dose using mumps outbreaks in Canada. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3114893/)
The conclusions show the importance of having very high vaccine coverage, especially if the vaccine has lower efficacy in an individual. The rates of vaccine coverage required to prevent community transmission of mumps are very high using their model with 88-98% of people needing 2 doses of vaccine.
It is also worth pointing out that while many of the people infected with mumps were vaccinated, most of the cases of measles are occurring in unvaccinated individuals. In both cases, the outbreaks would likely be much more widespread in an unvaccinated (or less vaccinated) population.
Hello TWiV Team,
Many thanks again for your engaging and illuminating podcasts. I want you to know I was inspired by your podcast to sign up for a course in immunology on EdX.org, and what I am learning is helping me keep up with your discussions, as so many immunological aspects of viruses are discussed. The course a lot of work, but it’s been a good course so far, and I hope it will help prepare me for the next iteration of Prof. Racaniello’s virology course on Coursera.
I’ve attached the link to an article by Ezra Klein, formerly at the Washington Post, and now writing at his own site, Vox. I would be interested to hear the opinions of your team of the assessment by law professor Dan Kahan, who investigated why people stick to a belief even in the face of evidence that disproves or weakens the argument of the belief. He says that the science community “doesn’t have a communications team at all,” referencing the HPV vaccine rollout debacle.
You mentioned in response to a letter in TWiV 279 how requests for data can be used to harass scientists. This happened on a fairly large scale with regards Australia’s legal wranglings over plain packaging of tobacco products. As part of this Philip Morris International demanded, via a freedom of information request, ALL data, published and UNPUBLISHED (including in progress) regarding advertising and merchandising of tobacco products from the tobacco research institute at the University of Stirling in Scotland. This was presumably to hopefully find a ‘smoking gun’ (sorry for the pun) to support their at the time legal wrangling in Australia.
I read (although can’t find the reference at the moment) that the data requested under the FOI request was to include not just raw data, but also all notes made between colleagues, telephone conversations and interview data.
Three key issues were: 1) the interviewee data was taken in some case from the young whom agreed on the basis it would ONLY be used for legitimate research, so even anonymised would undermine the promises of researchers.
The second issue was the fact that all the data was required a mass of work involved in collecting everything!
Finally the major issue was that all this data was being requested before any publications on the specific matter and they wanted EVERYTHING from the department!
In the end they dropped the request, albeit very quietly, assumed due to the up-raw from the public and the community, so never got to full legal challenge I the UK. But creates a bad president that it could be attempted. Anyone know of any attempts to actually do so much on such a grand scale?
12oC, bright and sunny, with a with a Beaufort of around 3 outside my work window.
While we are on the subject, I think I recall Dickson Despommier fairly recently saying how only America and Britain still use Fahrenheit. I am afraid that is no longer the case. I’m 28 and cannot recall a weather forecast even _mentioning_ Fahrenheit since I was in single digits and even then it was alongside Celsius. In schools Celsius is the only measure used. In fact the only place imperial measurements are used is legal road speeds and road distances on maps & road signs, wind speeds in non-scientific environments may be in mph but scientifically and in the Met Office knots or m.s-1 or now standard, electrical screws are often still based on the British Standard screw thread, and occasionally milk will be an even pint instead of an even litre (however it has to also have the metric equivalent and be sold as such, unless buying direct from the farm door of course which would be un-policeable).
Just to touch base on this. I announced the Minecraft virus competition during my talk at The Archer Acadamy and gave them a link to the twiv website so they could get some ideas on virus structures. The teachers at the school will announce the competition formally to the rest of the school (150 children in total) after the Easter break. They will be given until the last week in May to submit their entries. Three book tokens are to be awarded. In the first instance they will send the entries to me. I will collate them and send them on to you.
The talk to the children went very well indeed. I think there may have been some budding virologists in the audience. Even the teachers said they were inspired and were surprised that viruses were not alive! I like the way Khan describes viruses on Khan Acadamy “left to its own devices it will just sit there-like a book” (https://www.khanacademy.org/science/biology/tree-of-life/v/viruses). Thanks for your suggestions I used them all!
BTW (just in case you missed this) did you know you were cited in “Brain on fire” by Susannah Cahalan. www.virology.ws/2009/07/03/adaptive-immune-defences/
I liked your latest podcast on endogenous retroviruses. Mind blowing-there is so much to know! By the way pig endogenous retroviruses (PERVS) have also been described in the literature .
Best for now
Dear Vincent and friends,
I’m listening to twiv 279 and I heard Alan start a thought with “…one of the things running around in my head was…” and he proceeded to raise the question of how you evolve a system where HERV-H makes itself essential for embryonic development so recently. A discussion followed.
But what I really thought Alan was going to ask was whether lnc activity could be part of the life cycle function of other (many? all?) retro-elements, including retroviruses. If so, there could be a whole new dimension to retrovirus interactions with host cells that we don’t know about.
Careening toward retirement, which I am sure will be made more enjoyable by twiv,
David J. Spector, Ph. D
Professor of Microbiology and Immunology
Department of Microbiology
College of Medicine
Penn State Hershey
Hello TWIV hosts,
I would like to suggest the following paper for discussion on TWIV.
Michael Worobey et. al., A synchronized global sweep of the internal genes of modern avian influenza virus. Nature, Feb. 15, 2014.
I read a short article on this paper in an email I receive as a graduate of the University of Arizona. I also read the full article as I have a subscription to Nature. I think it would provide a good learning experience for the TWIV audience with respect to the phylogenomic methods used in these types of studies. Maybe Harmit Malik could also participate?
Weather in Orange CA today is sunny, 68 F, 20 C, humidity 58%, dew point 52 F, and pressure 29.95″. We are supposed to get some rain this week with 2 to 3 feet of snow in our local mountains. If it happens it will be welcome for sure.
Thanks for the great show,
Dr. Robert Kelley (Bob)