Hello Dr. Racaniello,
On last week’s episode of TWiV it was suggested that it would be helpful to have timestamps associated with the episode links. I would be happy to assist TWiV by marking down the times that the links are mentioned. I already listen to TWiV on the day it is released, so I could quickly send the information back to you for the website.
I am an avid fan of TWiV and I would be happy to volunteer in other capacities if needed. I’m a second year PhD student of Dr. Palese’s and I was the one who shared our virus holiday cookies with the TWiV Facebook page last December.
Let me know what you think, I would be happy assisting TWiV in any way!
Graduate Student, Palese Laboratory
Icahn School of Medicine at Mount Sinai
I wanted to chime in on part of the discussion in TWiV 329 when you talked about PKR, which binds to dsRNA to phosphorylate and inhibit eIF2 to block protein translation. Dickson inquired about the relationship of this molecule to TLRs and other innate receptors, and Vincent rightly pointed out that PKR is an effector, while TLRs and other pattern recognition receptors (PRRs) are sensors. But this distinction is a bit confusing since PKR can bind to and apparently “sense” RNA, so why isn’t it a sensor?
I had this same conceptual confusion when I began my PhD in an innate immunity lab, and the question is by no means settled. In fact, some people would call PKR a sensor as in this paper (“The IFN-inducible protein kinase PKR is a unique, multifunctional molecule that is known to act as a PRR for dsRNA and to mediate several of the anti-viral effects of Type I IFNs”).
Vincent’s explanation that PKR is inducible is not quite complete, since many receptors (notably the NOD-like receptors) are barely present at steady-state, but are inducible by inflammatory cytokines, and many would consider these proteins PRRs.
My own opinion is the the sine qua non of a PRR is the ability to induce the transcription of pro-inflammatory cytokines. I can clarify why I think this is a useful distinction if you like, but the fact is that no matter how much PKR you activate, you will not get the production of something like TNFα without a legitimate PRR in the mix. I’d be interested to know if you agree with this distinction, or think there’s a better way to discriminate. All definitions seem to fail at the edges, but I think the ability to induce inflammation might be a useful conceptual dividing line.
A related question in the minds of some listeners might be: “why would effectors need to sense RNA if they’re only made in the presence of viral infection?” The explanation here has to do with an infection in the context of a tissue rather than in a petri dish. Virally infected cells produce IFNs, which can activate neighboring cells that aren’t yet infected. Those cells can then ramp up the effectors (like PKR), but wouldn’t necessarily want to shut down transcription until they sense the offending virus themselves.
Kevin (of Audiommunity)
My name is Kenny and I am a predoctoral fellow studying Infectious Disease at Rutgers Graduate School of Biomedical Sciences. Just wanted to respond to Kathy’s question this week regarding the Bio-Rad Science Ambassador Program. I signed up for the Bio-Rad program back in 2013 while I still lived in Bethesda, MD. I now live in Brooklyn, NY and still have not been contacted by Bio-Rad to teach a class.
I wanted to bring to your attention though that the New York Academy of Sciences has a fantastic, similar program where you can teach an Afterschool Life Sciences curriculum to underserved middle school classrooms. We do some great experiments with the kids, including a DNA extraction experiment, but with wheat germ, since NYC Public Schools won’t allow kids to take swabs of their inner cheek (they are worried about potentially sequencing the kids genome and getting personal information about them.) We also do ELISAs, patient zero exercises, and much, much more. Great experience for anyone interested in outreach and lives in NYC.
You can find more information about the program here: http://www.nyas.org/landing/afterschool.aspx
Thanks for reading me email! Love the show!
Department of Medicine
Rutgers New Jersey Medical School
Rutgers, The State University of New Jersey
Dear Vincent and friends,
I’m sure you have received other emails regarding your discussion on Episode 329 about ME/CFS and Dr. Lipkin’s latest paper, but as a long time fan of the show who has lived with ME/CFS for more than twenty years, I could not resist chiming in with my two cents.
Dickson commented that patients with CFS are self-diagnosed, going to doctors who are prone to believing their symptoms. For the vast majority of patients, this is not true. The IOM report said that 800,000 to 2.5 million Americans may have this disease, but that 80-90% of them are undiagnosed. I have never met an ME/CFS patient who easily found doctors to believe them. Every single one of us has been dismissed or even ridiculed by one or more doctors. We’ve been told that we are lazy malingerers, that we have psychological problems, or that we just need to reduce stress. It is simply not the case that people “feel lousy,” as Dickson put it, go to the doctor, and come home with the CFS label.
As Alan noted, there is no doubt that the controversy over case definition has hindered progress in this field. Dickson was right to ask how many diseases are really included in an ME/CFS population, and he pointed out that absent an objective test, conclusions are preliminary. The IOM made recommendations to address that. First, the SEID criteria are no longer a diagnosis of exclusion. If a patient fits the criteria, then he or she should be diagnosed with the disease. The onus is put on physicians to make differential diagnoses, and physician education will be of critical importance if these recommendations are to succeed. Second, the IOM explicitly stated that their recommendations were based on current evidence and should be revisited in no more than five years. They anticipated that new evidence, such as Dr. Lipkin’s paper or the studies demonstrating brain inflammation, would change our understanding of the disease’s pathogenesis and perhaps validate biomarkers for diagnosis.
The Lancet editorial stated that the IOM was heavily and negatively lobbied for undertaking this study, but failed to acknowledge that there were legitimate scientific and political reasons for this opposition. First, at the time this study commenced, the IOM had never produced a disease case definition. There was no guarantee how many ME/CFS experts would be appointed to the panel, and the community feared this “definition by committee” would be created by people who knew nothing about the disease. Second, the ME/CFS field has upwards of twenty proposed definitions, so spending one million dollars to create the twenty-first seemed like a questionable strategy. Third, given the IOM’s prestige, we knew that we would likely be stuck with the results for a long time, and if the case definition was flawed then this would have long-term negative consequences. Fourth, the Department of Health and Human Services pursued this IOM study in secret. No ME/CFS experts were consulted about it, and the Department’s own CFS Advisory Committee was not informed of the plan. ME/CFS advocates discovered the contract by accident, and HHS completed the deal over the vociferous objections of advocates and researchers alike.
All that being said, it is not true that the entire ME/CFS community continued to negatively lobby the IOM after the study began. Certainly, some advocates did so and have continued to object (and not without reason). But many advocates, myself included, gave presentations to the IOM panel and provided written input. In fact, the public access file for the study, which contains all of the written materials submitted to the panel, totals over 5,500 pages. In my opinion, there is ample evidence that the panel listened to this public input.
The Lancet editorial also mentioned the PACE trial and the Cochrane review on exercise therapy. This brings me back to Dickson’s question about how many diseases are lumped together in the CFS category. Depending on the case definition being used, it could be more than one. The Oxford CFS definition, in particular, is overly broad, as it requires only six months of subjective fatigue. A patient population defined by only that subjective symptom is larger and less precise than a more narrow definition like the IOM SEID or the Canadian Consensus Criteria. In fact, a recent report from an NIH panel and a systematic evidence review by the Agency for Healthcare Research and Quality both recommend that the Oxford definition be retired because results from studies of this broad group cannot be accurately applied to the more specific ME/CFS group. This is important, because most of the studies in the Cochrane review on exercise in CFS were Oxford studies. The PACE trial also used the Oxford definition to enroll subjects. In fact, most of the studies purported to show that exercise is beneficial for patients with CFS have used the Oxford definition. In contrast, there is a growing body of work, such as this paper by Keller et al, showing that ME/CFS patients (defined more narrowly than Oxford) have measurable abnormal responses to exertion. The case definitions are not interchangeable, and research results should not be extrapolated from one group to the other.
Patients with ME/CFS do not just “feel lousy.” This is a serious disease with serious consequences. I have been housebound, and sometimes bedbound, for more than twenty years. The most severely ill patients suffer from numerous neurological symptoms, including ataxia and allodynia. This disease costs our economy billions every year in lost productivity, and yet NIH spends only $5 million a year on research. Even Dr. Lipkin has stated publicly that his grant application was denied after a reviewer claimed biomedical research was unnecessary because ME/CFS is a psychological disorder. The IOM report is an exceptionally well-referenced document, and states unequivocally that this is not a psychological disorder. It is my fervent hope that we can leave that controversy behind, and move forward with rigorous, well-funded research into carefully characterized patients. This is the only way we will find treatments and get our lives back.
Thank you for continuing the conversation about this disease. Vincent, I also send you best wishes for your son’s recovery.
Dear TWIV team,
It is a lovely day here in the Bay Area, 65F/18C. I am a bacteriologist/immunologist by training but started listening to TWIV recently during my 1h commute in the craziness of Bay Area traffic. I was inspired by an avid listener from my postdoc era at UT Austin. I’ve been listening to the podcasts randomly and happened upon 230 today. The reason I decided to write is because I now work for the company that produces instruments for microscale thermophoresis that you mentioned in that episode, small world… It is not uncommon for people to be a little intimidated by this technique but it’s actually quite simple. You can think of it as electrophoresis but using heat instead to drive the movement of molecules in a temperature gradient. Unbound molecules will move differently from the complex and that’s how dissociation constants can be obtained. Anyway, I have really enjoyed listening to your discussions and opinions on various matters including alternative careers for PhDs and also have a much deeper appreciation for viruses. Keep up the good work!
Hello Vincent and and allies,
I’ve just come to face to face with two of TWiV’s recurring themes at once. I’m essentially a lab technician at a major research university, although I spend most of my time in the zebrafish facility rather than in the lab itself, and this facility holds fish for four different labs that work together. Unfortunately I’ve just been laid off because not one of the four labs was able to secure their R01 grant, and they’ve been forced to shed all their paid employees (one technician is moving onto grad school, but none of the labs she’s looking at have funding either). This is in spite of the fact that just a few months ago we had an old grant that we had to spend several thousand dollars from on equipment, or else we’d lose it. You’d think that with the hundreds of thousands of dollars we have invested in equipment and animals the university would have an interest in keeping its labs productive through funding slumps, but along with the recent privatization of the campus parking system I get the impression that the university is not terribly concerned with with the fiscal long term.
As long as I’ve been listening to you complain about it, I’ve agreed that the structure of American academic research is unsustainable, but now that it has personally affected me I’m moved to take action. What sort of steps can I even take as a random American schlub? Are there petitions I can sign, advocacy groups I can become a member of, an awareness campaign about the pyramid structure of post-graduate research? I’m almost afraid of what would happen to science funding generally if this became a national political issue, considering the contempt politicians already have for basic research. If solid research having some amusing aspect to it (hello shrimp treadmills) is considered evidence that basic research is overfunded, imagine the damage the budget hawks could do if they latched onto genuine problems as an excuse to axe the whole enterprise.
For the second issue, while I’m between jobs I’m going to have to watch the cost of my medication and might have to switch from an under-patent drug back to a less-effective generic (without naming names, the older drug is a prodrug, while the newer drug is the pharmacologically active metabolite of the prodrug, effective at lower doses and with fewer side effects). Like fantasizing about winning the lottery, I’ve fantasized about paying less for medication, and I’ve thought about different incentive structures other than the patent model. My idea is to take the current patent system and stretch it out entirely into the long tail: instead of a drug’s inventor holding a monopoly on its sale for a decade or two, anybody is free to manufacture it. Instead, generic manufacturers must pay a small (0.5-1% of gross sales) royalty fee to the drug’s inventor. This fee lasts as long as the patent holder wants it to, potentially forever, leaving the drug profitable for the inventor long after the patent would have expired under the old system.
I can imagine problems with this system, primarily that it would be biased in favor of large corporations with well-funded legal teams (though what law isn’t?) and that wealthy corporations could engage in rent-seeking by buying the rights to mature drugs. I imagine rent-seeking could be mitigated by having the royalty rate drop every time the rights change hands, perhaps with some allowance for small inventors selling the rights immediately to a larger company with the resources to enforce their right. Another issue is that by slowing down the rate of return you’d discourage the development of incremental improvements, which I know from personal experience can nevertheless still be substantial improvements. On the other hand, this works similarly enough to the current system that it should work without drug companies or national governments suddenly becoming more altruistic and setting aside billions to trillions of dollars for the betterment of humanity with no immediate return.
On a lighter note, I have a couple of listener science picks, two very accessible computer games about space exploration.
First is Space Engine (en.spaceengine.org). It’s a seamless scale model of the universe with most of the good bits modeled, from planets and comets, to clusters and nebulae, to galaxies and black holes. There isn’t much to do but zip around and look at gorgeous vistas, but it gives you a visceral feel for the phenomenal scale of the universe in a way I haven’t gotten anywhere else. Be warned you’ll need a pretty beefy computer if you want to run it at the highest detail level. It is currently freeware.
Second game is Kerbal Space Program (www.kerbalspaceprogram.com). Minimally-competent but expressive green aliens build rockets out of junk and try to explore their universe. It’s got two main parts, the Vehicle Assembly Building where you slap together a rocket of your own design out of modular parts, and a flight simulator, where you fly your rockets and hopefully accomplish missions with them. It’s a great hands-on way to learn about rocket science and orbital mechanics without having to do any math, and when you get bored you can build a hulking monstrosity entirely out of solid rockets and crash it into things. Full version is $30, but there’s a free demo that’s essentially just an earlier build of the game and it’s not missing any essential features. There’s also a classroom edition that makes the physics more explicit, but I don’t know much about it.
Love your shows, though I’ve still got a year left to work my way through!
Dear TWIV team members,
I have been listening somewhat randomly to past TWIV episodes, so I am not quite sure which episode contained a discussion of the politicization of science and its reporting. I was fascinated to see it played out in a recent set of reports regarding the finding of the select agent, Burkholderia pseudomallei in macaques at Tulane National Primate Research Center.
USA Today broke the story (and did a nice job of science reporting, in my opinion. )
Deadly bacteria release sparks concern at Louisiana lab
But it was the AAAS coverage which caught my attention.
Escape of dangerous bacterium leads to halt of risky studies at Tulane
Starting with the title, the report is, at best, biased. Note that the title itself characterizes the studies on select agents themselves as risky, not just the bacterial agent. I found it even more telling that the brief and biased report was concluded with a basically superfluous dig at “gain of function” studies in viruses.
“And in October, U.S. officials halted new federal funding for 18 projects that tweak the influenza, SARS, or MERS viruses to make them more pathogenic or likely to spread among mammals. Federal officials and outside experts are now reviewing the risks and benefits of such “gain-of-function” studies to decide whether they should be allowed to resume.”
For what it’s worth, regardless of what side one is on, they were excellent illustrations of how science reporting can easily reflect and attempt to propagate bias.
Anne Lewis, DVM, PhD
In TWIV 328, there was some talk of providing the time location of different topics. Why not crowdsource this? Ask listeners to post the time of different topics in the comments.
Also, it’s much easier to find specific spots in the audio by downloading the MP3 file and then using a standard player program to listen. The in-Page player is very convenient, but is a little iffy when it comes to finding a specific spot.
On a separate note, a measles denier in Germany lost in court:
German biologist who denies measles virus exists ordered to pay
Varun CN writes:
Recently I happened to have read an article on Ebola transmission in mBio. The article several times brings down the plausibility of aerosol transmission. I find from previous TWiV discussions that there isn’t compelling scientific evidence for assuming that there has been a undetected Ebola aerosol transmission. This seems to be a very troubling point. Being one of the “most read articles”, It worries me of what the paper finally is trying to impress.
The issue has been discussed in great length in the TWiV Ebola series. However, I would like to know the TWiV hosts’ opinions on how far could we weigh the arguments made in this paper. Or is it that I have missed some crucial point in the paper?
Thank you for clarification.
I also have a science pick to share. I’m not sure if this has been picked up before. It’s is a neuroscience book called Incognito, by David Eagleman. In the simplest sentence, the book is “awesome”.
Thank you for the ever-continuing public education.
Varun C N
Junior Research Fellow
Department of Neuromicrobiology