Marian writes:
Two virological comments regarding the listener who worried about the possibility of Ebola virus spreading within the US: I agree, as does Thomas Freiden, head of CDC, that the likelihood of human to human spread in the US is low because of our great health care system. However, since Ebola virus is zoonotic, I wanted to speculate why it also seems unlikely that Ebola virus would spread to US nonhuman animal hosts, perhaps bats, and become a reservoir here. Many viruses are found in American bats, but I believe no Ebola virus. Successful zoonotic viruses do not usually kill their nonhuman animal hosts, presumably because they have co-evolved with their host. An introduction of Ebola virus into western hemisphere nonhuman animals is more likely to be catastrophic to the animal, and not lead to establishment of a new animal reservoir, for the same reason that it is catastrophic in humans: it is not yet adapted.
My second comment is related to a comment that Dr. Freiden made at his press conference: it is a subtle virological point that may have been lost in the frenzy. (Parenthetically you may want to mention the new paper out
http://www.sciencemag.org/content/early/2014/08/27/science.1259657 and
http://www.nola.com/health/index.ssf/2014/08/qa_with_tulane_researcher_who.html, delineating 395 mutations in the outbreak strain (s). I think it’s not behind a paywall, maybe for humanitarian reasons.) Anyway, we know that this outbreak is more devastating because it is in a highly populated region, thus affecting more people. However, high levels of replication will permit more mutations to accumulate. This is discussed in the paper. Although it is not known yet whether this new strain(s) is more pathogenic, it may be that simply by occurring in a more densely populated region, unfortunately evolution of a more transmissible or more virulent strain may occur.
Christos writes:
Congratulations on reaching the 300 TWiV episode milestone!
I was listening to episode 298 yesterday. A listener was asking about the half-life of the ZMapp antibodies for Ebola and you mentioned that antibodies have a relatively short half life and don’t usually stay in circulation for more than a few weeks. Human IgG1 have a half-life of about 3 weeks. However, I would like to point out that Fc engineering is now used to change the interaction of antibodies with the neonatal Fc receptor (FcRn) and greatly prolong antibodies in circulation (see two examples of publications that mention such technologies http://www.jimmunol.org/content/184/4/1968.long and http://www.nature.com/nbt/journal/v28/n2/abs/nbt.1601.html). Also, antibody therapies against exogenous targets (like the ebola glycoproteins) have an advantage over antibodies against endogenous targets (eg tumor cell proteins) as there is no target mediated clearance, which also leads to improved half-life profiles.
I think these are important points because without the requirement for repeat dosing, one can start thinking of utilizing monoclonal antibodies and Fc engineering to use antibodies as vaccine alternatives.
Best wishes,
Christos
Howard writes:
Thanks for doing your usually excellent podcasts.
On this one, I thought the approach taken was incorrect. Too much of the time, you seemed to be assuming that only rich Westerners, behind secure borders, with top flight hospitals and virologists, with many thousands of dollars per infected person (payable by rich governments with national health services), were the appropriate subjects of the podcast. You did not adequately discuss how to stop the spread of Ebola virus in Africa, the second largest and second most populous continent, with more than 1 billion people.
Four days after your August 10 podcast, the World Health Organization said “Staff at the outbreak sites see evidence that the numbers of reported cases and deaths vastly underestimate the magnitude of the outbreak. . . . These steps align with recognition of the extraordinary measures needed, on a massive scale, to contain the outbreak in settings characterized by extreme poverty, dysfunctional health systems, a severe shortage of doctors, and rampant fear.”
August 28, WHO issued its Roadmap and said: “As of 27 August 2014, the cumulative number of Ebola cases in the affected countries stands at more than 3000, with over 1400 deaths, making this the largest Ebola outbreak ever recorded, despite significant gaps in reporting in some intense transmission areas. . . .
This Roadmap assumes that in many areas of intense transmission the actual number of cases may be 2-4 fold higher than that currently reported. It acknowledges that the aggregate case load of [Ebola Virus Disease] could exceed 20,000 over the course of this emergency. The Roadmap assumes that a rapid escalation of the complementary strategies in intense transmission, resource-constrained areas will allow the comprehensive application of more standard containment strategies within 3 months. This plan recognizes that a number of currently unaffected countries could be exposed to EVD, but assumes that the emergency application of the standard control strategies will stop any new transmission within 8 weeks of the index case.”
I suggest you agree the Roadmap assumptions are unrealistic, even with 20,000 cases. Why should the actual number of new cases be only 2-4 fold higher than the numbers “reported by the respective Ministries of Health of Guinea, Liberia, Nigeria, and Sierra Leone [at] 3069, with 1552 deaths”? Very large areas are under military, and poorly, enforced quarantine, including the Monrovia West Point slum of perhaps 100,000, in the capital city of 1 million. Do you even know what of the infected areas are quarantined areas, and the effects of inadequate food and water?
Why should “standard containment” (i.e. the kind of containment you might expect in the US) exist within 3 months? What chances do you give that any new transmission will end within 3 months plus 8 weeks?
You discussed how if this virus was transmissible as airborne aerosol, and I paraphrase, all bets would be off. A paper was published in Science, August 29, 2014. “Five of the paper’s more than 50 co-authors died from Ebola before publication. . .We’ve uncovered more than 300 genetic clues about what sets this outbreak apart from previous outbreaks,” said Stephen Gire, one of the study’s co-authors and an infectious disease researcher at Harvard.”
How do you know that mosquitos won’t puncture some of the horrifying Ebola pustules and begin spreading the disease? How do you know that the totally inadequate number of needles that someone might use repeatedly, after inadequate sterilization, to try to rehydrate Ebola patients, won’t spread the infection? How do you know that the WHO allowance of continued international flights will not spread the disease? How do you know that boatloads of Ebola refugees will not spread the disease to many countries?
I am sending you something I suggest you read in penance for ignoring a realistic discussion of present and future very large suffering and death from Ebola, a copy of Jean Raspail’s, The Camp of the Saints. This apocalyptic fiction published in 1973, envisions hundreds of thousands of sick and desperate refugees landing in a western country at once.
John writes:
Dear TWIVvers,
This is the first of two letters on the same theme. I think TWIV is absolutely great, and tremendously inspiring, and I tell everyone about it, so please accept the following criticism with love.
In episode #297, I was surprised at the narrow approach to analyzing the routes by which Ebola viruses might spread between humans. I cannot fault you, really, because none of you are clinicians, and, therefore, it is not in your nature to question dogma through the lens of human variability. I’d be interested to know what you think of the following.
First, there was discussion of the experiment with the Reston strain of Ebola, in which pigs transmitted the virus by air to monkeys. The conclusion seemed to be that, because pigs produce larger aerosol droplets than primates, primates cannot transmit the virus by the aerosol route.
But, what about situations where humans produce large, or especially virus-laden droplets? For example, people with a lung abscess can cough up chunks of lung tissue. More commonly, people with pulmonary tuberculosis will cough up blood. And what about a person who has a simple chest cold, with thick mucus, who is also coughing 100 times more than normal? Such co-existent conditions will not be uncommon in a population with poor underlying health. If tissue or blood or mucus, propelled by a cough (or maybe a pig-like grunt?), were to land on a healthcare worker’s cornea or oral mucosa, it would not be far-fetched at all if infection followed.
Mechanisms like this may explain the cases in which the infection of health care workers is otherwise mysterious. I believe, therefore, that you should say humans do not *classically* transmit Ebola viruses by aerosol routes, but there are circumstances in which it would be possible. Yes, it is still exposure to body fluids that is the key factor, but it is nevertheless via the aerosol route. And in the future, always be suspicious of absolute statements that “Humans cannot do X,” because there likely are pathological states where they can.
Second, there was no discussion of the possibility of super-spreaders, despite the jaw-dropping statement that the virus can persist in semen for 61 days. This suggests that either some people can tolerate a more chronic infection, or that there are immunologically privileged sites in the body where the virus may remain. (The prostate is known to be such a site. The lens of the eye is another.) Recall that Typhoid Mary was able to harbor salmonella typhi bacteria in her gall bladder without harming herself, and there are certainly lots of precedents for chronic viral infection of a specific tissues.
If one person in a thousand can become a super-spreader or chronically infected, it would not be surprising that none has been detected in past outbreaks, which have all been much smaller than that.
Finally, why was there no discussion about the mutation rate in Ebola viruses? Right now there are trillions of virus particles in densely populated cities. Unlike the past Ebola outbreaks in lightly populated areas, a mutation that allows aerosol transmission would certainly find a susceptible human host nearby, with consequences too horrible to contemplate. It would be interesting for me (and perhaps the rest of your audience) to understand, at the molecular level, why Ebola viruses are not classically transmitted through air, and to hear your estimation of how much alteration the virus would require to become air-transmissible. Of course, that would be a road map to a potent bio-weapon, about which I’ll say more in the next letter.
I realize that avoiding panic is important, and that communicating the nuanced probabilities of the above considerations will be difficult. Admittedly, they are statistically minor factors. But we cannot afford to be dogmatic, and we must realize that improbable events can kill people unprepared for them. If anyone can rise to the communication challenge, it’s TWIV.
Regards,
John
Marcie writes:
Enterovirus D-68 has been all over the news in the last few days. I thought “entero” meant intestines but this causes primarily respiratory symptoms. Am I confusing two similar words?
What do you know about this virus? It seems to cause severe respiratory symptoms in those with other respiratory issues. Is it a relatively new virus or is the current outbreak just worse than usual?
Thanks, Marcie from Pittsburgh where it is currently 74 degrees F and sunny. Dewpoint is 56 degrees.
Dallas writes:
Dear TWIVERs,
Your comments on TWIV 294 on the formation of the Cambridge Working Group is probably highly understating the risk to basic research posed by their activities.
As our scientific understanding of the world continues to increase, the real complexity becomes more apparent and individuals, including the best scientists, only have fractional knowledge in smaller and smaller subdomains of all human knowledge. The days of “renaissance man” are long past. This means that even very brilliant people like yourselves, who I hold in awe for the depth and breadth of your knowledge, will make errors in comments outside your range of expertise.
Under these condition of individual information/knowledge limits, it become very easy for someone with Chicken Little “the sky is falling” type thinking to get great traction using simplified pseudoscientific vocabulary that can only be contradicted by getting into the technical weeds way beyond the understanding of most people. I am afraid that the Cambridge Working Group is just the innocent sounding start of what we have seen evolve to ultimately kill research and innovation in other areas. At the present time, they are somewhat reasonable scientists, but once funded and staffed organizations, rules, policies, agencies with bureaucrats and lawyers obtain power over approvals, permits and grants there will be an evolution towards zero risk by saying NO to everything that has any risk of finding out anything new, especially something unexpected. A bureaucrat who approves an experiment that turns out bad, even with trivial impact, will be faulted, but if he just asks more questions and delays for a decade or two, he has a career and retirement. Every imaginary “could”, “can”, “may” and “concern” of an active imagination, no matter how improbable, becomes an unacceptable risk.
For a lesson in this type of evolution, one could look at nuclear energy or areas like climate change, where opposing activists have obtained significant control over policy and research. For anyone outside the specific technical areas, they don’t have enough basic knowledge to rationally evaluate the science. As most of the TWIV group probably already “believe” the science of CO2 and climate change and discount the beliefs of the deniers, I will use nuclear energy as an example of organizational/social evolution leading to ultimately research starvation and detrimental outcomes for society.
Back in the 40’s, 50’s and 60’s there was fantastic progress in both science and applications of nuclear energy being made, along with some mistakes. As it was easy to create a truly catastrophic images, sloppy science by people like Ernest Sternglass MD, with claims of weapons testing “causing” infant mortality using cherry picked data sets and excluding known relevant parameters, were able to achieve great political traction. (published in Science) That and other scientific “concerns” was combined with an excellent movie “China Syndrome” with Jane Fonda followed by the Three Mile Island accident. This recast Jane Fonda as a real expert in nuclear power providing testimony to congress about the huge unacceptable risks. After than, forget any new power plants or research as the labs at major universities closed and their reactors decommissioned (many major universities like UCLA had working reactors on campus and active teaching, undergraduate lab section for all engineering students and research programs).
Now that close half a century has passed, we can ask how accurate the risks analysis and hyperbolic claims were and what were the “unseen” and unpredicted consequences of those decisions. In the US, the actual impact of three mile island was a billion dollar class cleanup and even when you add in Chernobyl (a thermally unstable design) with about 4 thousand or so mortalities and Fukushima (20,000 killed by tsunami, zero by radiation) the cost to humanity of the alternative power supply of coal and oil makes those numbers look trivial. The blocking of nuclear power increased coal and oil use with very dispersed, but far more deadly impacts to much larger numbers of people (24,000/yr in the US — W.H.O.).
Virology experiments such as gain in function or any modification of viral genes put all virology in the political target zone. You can hypothesize all sorts of “sky is falling” scenarios. You have almost all the conditions for a Cambridge Working Group to evolve into a movement to stop the crazy scientists with their BSL4 labs who will destroy humanity. The researcher will counter with regulations, policies and procedures but the activists will want “independent” regulators and a place at the table (and lifetime income that comes with that) to review all proposed research.
Once the opposition to this “dangerous” research congeals into a movement with cash and a staff, some research article showing a lab modified gene in some virus causing a health problem and the research will be effectively shut down. Even when the article is proven false and retracted, the impact will stay and research will be destroyed. Note that after half a century of medical progress and natural exposure variations of factors of 10 to 100, our knowledge about the impacts of low levels of radiation hasn’t significantly improved. Money is being spent, but progress is stalled.
If you think, as I do, we don’t have have enough low direction research for pure exploration, wait until you have non-expert “risk managers” sitting on grant review committees. These regulatory system, formally driven by the “precautionary principle” evolve into doing nothing with anything that has any possible or even imaginary risk. The applicant would than have to “prove” the concern isn’t real, but that is proving a negative that can’t be done without the experiment being completed.
Good luck in preventing an anti-biotechnology/virology activism from effectively killing creative research along with the use of BSL-4 facilities anywhere near anything or anybody.
Dallas
Dallas E. Weaver, Ph.D.
Scientific Hatcheries
PS: As the above is already too long winded, I have put the following experiences with a well “evolved” scientific regulatory agency into a PS that can be cut.
If you think I am joking or exaggerating about “imaginary” risk, I witnessed the following as chairman of the Aquaculture Disease Committee in California. A mussel farmer wanted to import cherry stone clams from Florida so he could increase his sales per stop, when distributing his mussels. Existing food distributors were importing the same clams and holding them in tanks discharging to sewer system that discharged into the ocean, without disinfection of any kind. In Florida, they have a harmful algae species (K. brevis) that the “experts” (Ph.D. level scientists) of the Calif. Fish and Wildlife thought was a threat to our oceans, independent of temperature differences (surfer wear wet suits in Surf City — Huntington Beach —in the summer). However, live algae don’t stay in clams, they are digested, so the “experts” postulated a spore stage existed for this species, which had never been seen in this highly studied algae species. Since the farmer had installed a $25,000 chlorination/dechlorination system for the discharge from his holding systems using specifications, hardware and design that the Department used for its disease research quarantine facility, which would kill almost most all pathogens, the Department “expert” then hypothesized that the imaginary spore stage of this algae could withstand 200 ppm of chlorine for 15 minuets. The “experts” with their “imaginary” life stage with “imaginary” super chlorine resistance of a warm water algae species that “could” invade California and destroy our cold water ocean resources and that the observation that half a century of ballast water from the Gulf and all the ocean discharges of seafood distributors, that were outside the control of the Fish and Wildlife Department, had not created an invasion, they still had “concerns” and said NO. As it was impossible to “prove” the nonexistence of this chlorine resistant imaginary life state, the regulator only need a “concern” about its “possible” existence to legally win.
I can go on about the same department blocking importations of live shrimp into zero discharge biosecure quarantine systems miles from the oceans, to prevent some very nasty shrimp virus from infecting our oceans, while at the same time allowing imported frozen shrimp, with these same virus to be used as bait in the ocean. They knew that there were many journal articles demonstrating the viability of these virus in imported frozen shrimp and that the smaller sized lower cost frozen imports were often “emergency harvested” and really loaded with virus, because “white spot” or one of the many other virus was going to kill the whole pond.
Richard writes:
Dear Twivers,
Hello from Sedona, AZ. It peaked out at 102°F today with very clear skies and little wind, but, as we Arizonans say, it’s OK because the humidity is low: 11%. However, it should be pointed out that we have had increasingly hot summers over the many years my wife and I have had the great privilege of living in this beautiful place. At least from the perspective of this little corner of the world, there is no doubt about climate change.
For a few months, I fell behind on TWIV but am now catching up. I have comments on two podcasts from a few months ago.
First, I would like to nominate TWIV 275 (Virocentricity with Eugene Koonin) for induction in the TWIV Hall of Fame. I believe it is certainly among the most elegant, provocative, humane and visionary TWIVs. I have listened to it twice and am now reading Koonin’s recent papers. They are stunning in their brilliance. Koonin’s ideas are of great importance to all of biological science and perhaps even more broadly. Vincent’s and Rich’s interview of Koonin was superbly done. Thank you. I have two questions: You brought out the differences between the views of Koonin and of Claverie and Abergel, but you didn’t express your own views. Big to small or small to big? What do you think? Also, did viruses precede cells in the evolution of life? What do you think?
[rc: I’m with Eugene: Origin of giant viruses from smaller DNA viruses not from a fourth domain of cellular life.]
Second, TWIV 277 (My Podcast Vinny) was tremendously enjoyable and it is very good that Vincent agreed to the interview. You are to be congratulated for the discussion of condoms and their quality testing. Condoms represent one of the most important technologies for public health today. They allow millions of couples to help determine the number and spacing of children. They help millions more protect themselves from infectious viral diseases such as HPV, HBV, HIV, and from other sexually transmitted diseases. The assurance of their quality is an essential step in their production as with any human health technology. While “condom testing” may evoke certain smile-provoking images, the testing of these products according to high standards is an important undertaking. One of the important contributions of PATH (a non-profit biotechnology organization based in Seattle where I worked for many years) was to develop improved methods for condom testing that helped reduce condom failure and thus unwanted pregnancies and disease transmission. Thanks for bringing up this important topic in TWIV.
TWIV has become an important medium for science communication worldwide and you are all to be congratulated for your tremendous contributions.
All the best,
Rich
Kay writes:
Dear Vincent et al,
A few weeks ago, you picked the book “Viral Entry into Host Cells” which at that time was downloadable for free from the Springer web site. As you will have noticed, they now charge $149 for the download.
However, there is another interesting option to get this book for free: it is part of the Landes Bioscience Open Access Collection – actually Landes and Springer are both listed as publishers of this book. The link is http://www.landesbioscience.com/books/special/id/958/
I browsed the list of books in the open access collection and found several interesting titles with relevance for virology and microbiology.
Unless it has been picked before, this collection would probably make a good pick in its own right. It is accessible from http://www.landesbioscience.com/special
Thanks for the great show!
Best Wishes,
Kay
