Fernando writes:

Hi TWiV team,
I was rather disappointed that TWiV 321 tiptoed around what is really going on in the discourse around “gain of function” experiments. You and your gracious guest failed to state the obvious, that Lipsitch et al are using language to achieve a political objective, the stoppage of research they object to. Belly-aching about inflammatory, inaccurate language is beside the point. That language is used purposefully, and achieved its goal, at least for the time being. Climate scientists learned painfully that engaging their opponents as if they were using language in a shared way was a big mistake. Scientific-looking language can be used for all kinds of purposes, from selling snake oil to influencing the wielders of state power, which is what we see with the moratorium.

Until the flu virology community is as deliberate about language use as their opponents, they will likely see a sustained shrinking of their research freedom. And arguments about the importance of unexpected results from basic research are exactly the kind of discourse naïveté that delights politically-motivated opponents. Sure, it is true, but to decision-makers and the general public it sounds like a dice throw that could as well engender a monster (sorcerer’s apprentice and all those tropes). Instead, flu scientists and their supporters have to be equally political in their choice of language and examples to convince about the huge risk of closing down research that is essential for developing better surveillance, prevention, and treatment. There were hints of that in Alan’s comments about passaging in vaccine development, but that has to be articulated much more strongly.

I listen to TWiV before all the other podcasts, but this episode was too wishy-washy for my taste.

Ramon writes:

At the very beginning of TWIV’ episode # 322 , Mr Despommier says ” I first pranded, then I posted” Sound recording of the last word was unclear. It’s a new meaning of the ancient Latin phrase “Primum vivere deinde philosophare” ? Could be a title for a future episode “Primum vivere, deinde poadcastare” ?

Ramón Canet, MD
Internal Medicine Dept
Hospital Can Misses
Ibiza, Spain

Johnye writes:

Measles humor a la The New Yorker.
Sent from a colleague and friend today. Best to all.

Johnye Ballenger, M. D., FAAP
West Cambridge Pediatric and Adolescent Medicine
Cambridge, Massachusetts

Sharon writes:

I listened to last week’s TWiV and noted the comment about editors not doing due diligence with preferred reviewers. I think most (I would hope) editors first check pubmed before inviting a preferred reviewer. The bigger challenge, however, is that some sneaky authors provide names of real reviewers, but make up bogus gmail addresses for those persons, which route the review invite back to them. The issue of bogus email addresses for real reviewers is not as easy to check, because many bona fide researchers have multiple email addresses, and in countries where their institutional email systems are not reliable, many scholars rely on their gmail/yahoo etc.. So the problem of authors recommending bogus reviewers is not as easily resolved by simply checking pubmed. When I’m using a preferred reviewer, for which a non-institutional email (.edu) is used, I first check if the reviewer is already in our system (and use the email we have for them), and sometimes do a google search on the email address itself, or check the reviewer’s website for the reviewer to verify the email address provided.


John writes:

Dear TWiVers,

As I write from Manhattan’s Upper East Side, it’s “unacceptable” degrees celsius and the barometer reads “stay inside and make hot cocoa.” My pet groundhog agrees.

On TWiV #322, a listener named Natalie wrote in citing my January article, “A Career in Science Will Cost You Your Firstborn Child.” Natalie rightly identified the cynicism of the piece as a stylistic choice made to support the position that science is in trouble, but lamented that despite my tone, the facts I shared still make the situation very bleak for new science trainees.

The facts she’s talking about are my least favorite thing about the piece. I found it very depressing to see how many people read my work and shared it with commentary like “well now what do I do with my life” or “oh god what have I done,” in the characteristic raw, punctuation-free emotionality of Internet commenting. I didn’t write that to hurl people into despair about their future.

Natalie asked if there was a path or advice that you could share for someone looking to get a PhD, or otherwise become a scientist. I liked how you answered her questions, but I also wanted to chime in with some of the things my more cynical tone didn’t emphasize.

Firstly, I wanted to say that I don’t think getting a PhD is a bad financial decision. Getting a PhD with the objective of becoming a tenured basic scientist is unrealistic, yes, but getting a PhD with another goal in mind? Your likelihood of employment, as well as your earning potential, are improved with a PhD. Furthermore, the opportunity cost is reasonable: $60,000-100,000 in lost wages in order to graduate with no debt, not even for basic cost of living? Better than an MBA.

The problem is the value you lose if you try for that tenured basic science career path after you get the doctorate.

So would I recommend that interested people still go for a PhD? Well, like you said–if you can imagine doing anything else, do that. But I don’t think that people who enter a PhD program with reasonable expectations are hurting themselves–as long as they take caution and realize that their endgame after graduating has to be something like going into industry, government, policy, consulting, or some other field.

There are a lot of ways to use a PhD, and as our biological capabilities expand, our society finds itself in need of experienced, trained scientists to do jobs relating to the interaction of science with business or the public. PhD graduates still have a lower unemployment rate than the general population.

The problem is that most PhD students don’t want to be a regulatory official or a writer. They want to be a scientist creating experiments. While that’s possible in some places in industry without a postdoc, I don’t think I’ll get much argument if I say that it’s not possible outside of nonprofits or academia if you wish to become a basic scientist.

I’m carrying avulaviruses to Newcastle here, but let me just say that basic science is where we really change the future. Despite this, the humanistic value of basic science is as hidden in its data as the artistic value of Van Gogh’s work was during his lifetime. It is often many years before the impact of a basic scientific discovery can be digested and its real value revealed.

In general, if we knew what we were going to get when we began doing the research, it wouldn’t be science–it would be engineering. Basic science takes that idea to its purest form, and in line with that, it gives us the biggest surprises. And yet, there isn’t a clear path to a career in basic science because the only place it can even barely get funding is in academia, and that’s drying up, too.

That’s the main problem I was getting at with my piece–that we are making basic science impossible to do by making the impoverished “PhD–>postdoc–>Tenure Track” path the only place for a basic scientist, and that’s going to hurt science and society. There are other problems, yes, but I think not enough attention has been given to the human toll, both financial and psychological, of the basic science career path. Sometimes I’d rather cut my ear off than do a postdoc, sad as that makes me.

I outed myself under my real name at a recent scientific conference, saying that I’d written the article in question. To my surprise, a lot of PIs congratulated me and were incredibly supportive. This is a community that is ready for attitudes to change–but most people are at a loss for solutions.

To paraphrase one senior PI at the meeting, the piece is depressing because the data on careers in science are depressing, but awareness of the data has never hurt science–it only helps. Once awareness is high, we can start working on solutions. I’m doing that a little, behind the scenes, but I’m nobody–and I’m just ONE nobody. I want to see what other people come up with.

To summarize, I’d tell Natalie that there’s a good case for getting a science PhD. It confers skills and abilities–particularly if you are humble, smart, and dedicated–that you’ll only get from a PhD’s feet-to-the-fire training style. Furthermore, you will get the opportunity to make a real contribution to human knowledge. Even if your findings are later overturned, your contribution was real, and it added to the conversation–it cannot be taken away from you. Knowing you can walk into a dark tunnel and find the light will benefit you in any line of work that involves problem solving or risk.

But unless you’re uncharacteristically brave, lucky at levels of P<0.01, or independently wealthy, I would not recommend going from PhD graduation into a postdoctoral fellowship or planning on getting to a tenure track position. If your destiny is to be in a professorship, you’ll find your way to it eventually. And if not, at least outside of academia you will be able to pay the bills, and more.

I’ve gone on quite awhile, so I’ll close by wishing all of you, hosts and listeners, the best of weather, data, and discovery.

John Skylar, also known as Lee, a student at the Icahn School of Medicine

Ani writes:

Dear TWIV,

When I entered a Medical Lab Technician program two years ago, I introduced myself as someone who has always been in love with Pond Scum, (if only there was an electron microscope in my basement!). Since the fourth grade, I have been in love with the unseen world of microbial life. I am a shameless TWIV, TWIP, TWIM groupie.

I have lamented for years the obscurity of most clinical textbooks, with their incomplete indexes and material that usually gets too technical before building a base of understanding. I have had a few recent bouts with hateful texts which seem to conceal knowledge rather than yield it freely to eager minds. When I read, I just want to start with quick access to unfamiliar words in order to have a working understanding to decipher more complex ideas. One thing I found was a cycle where I would attempt to look up a word and it was not defined, but merely referred back to in the text! This is just one example of many. And I believe I know why books are written this way. They are not written for the student, but to other collegians. I suspect they want to gain and keep tenure or other accolades in the field, more than they want to relay information.

I grew up in an area where there are two major Universities, one of which is considered among the top ten in the country. I have known and been surrounded by many truly brilliant people. Most of my high school friends’ parents were among the tenured faculty at that University. I notice that people who are true intellectuals, LOVE to share their knowledge. I found among this group, true teachers who did not look down on those less educated, but rather their own love for the material was so infectious, that they could not help but to reproduce it in others.

As science based careers become more available to more diverse groups of people from various backgrounds, I feel that someone must stop and examine this issue. Books could be written to be more quickly understandable, (especially as many programs have become shorter) and this process could be made more palatable. After all, Education is a business and currently they are not serving their clientele as well as they could.


A New Lab Tech

Tim writes:

Dear TWIV friends,

Listening to the podcast yesterday night while attempting, and somewhat succeeding, to break loose 8″ of frozen cow manure from a pad of concrete that had accumulated thanks to the subzero weather over the past couple weeks I found myself agreeing out loud to your discussion on whether science is hard or not. Being a lot like Rich in my thoughts that science is easy but with the qualifier that I’ve been at it for a while may not be giving those without a spatial or systems thinking sort of mind due sympathy because without those abilities, visualization of concepts either too small or massive to “see” would be awful hard. It’s funny reflecting on my love of science when I think back to how little joy I found in it during high school. The forced memorization followed by regurgitation onto a test with precious little context for the information of pre-college science courses takes most of the fun and excitement out of learning or at least it did for me. I wonder if a better system of learning science wouldn’t be through more contextual discussions like the case study approach Dickson is so good at where terminology and application are learned through frequency of encounters as well as context. That’s the approach I’ve taken with teaching my own children science where we discuss a scientific topic that comes up at dinner at length, working in new terms among known ones and asking them lots of questions that require critically thinking about the subject. Just my thoughts I felt I’d share with you mostly out of passion for spreading the joy of science, curiosity and critical thinking. Have a great week and I look forward to you joining me next week through my headphones as I bounce along in my skidloader doing chores.

Lance writes:

Dear family TWiVidae,

Many thanks for your excellent coverage of the South American dengue vaccine trial. You did a particularly good job of discussing the aspects of the paper which are outside the usual TWiV topics, like intention to treat analysis versus per protocol analysis, things which are very important for those of us who have to make treatment decisions based on the results of clinical trials.

I wanted to add a note of caution to the interpretation of the results of this, and the 2 large Asian dengue vaccine trials. I am probably being over cautious here, but for me, the question of whether or not these vaccines could predispose to more severe dengue disease is not yet adequately answered. This is because the highest risk of severe dengue disease occurs on the second infection, therefore the group about whom we are most concerned about becoming predisposed to severe disease are those who were dengue naive at the point of vaccination. Based on the numbers given in the three trials (details below), 5430 people who are dengue neutralising antibody negative have received at least one dose of vaccine (extrapolating from the percentage of the vaccine group that was antibody negative at baseline in the immune endpoint subsets from each trial). If you take only those were conclusively shown to be neutralising antibody negative the number falls to 741. Both these sample sizes are likely to be too small to reliably detect an increase in severe dengue.

The situation is further complicated by the fact that absence of neutralising antibodies at least in some prospective studies does not seem to equate to being completely immunologically naive. For example, in a study by Anderson et al (attached PDF) in Northern Thailand, 76% of subjects who were neutralising antibody negative at the baseline of a three year follow up period in fact showed memory responses when they had their first flavivirus infection during the study period (very high anti-flavivirus IgG early in infection). Furthermore, in the first Thai phase 2b dengue vaccine trial, there was no efficacy against dengue 2 despite the presence of neutralising antibodies in conventional assays. This perhaps means that the neutralisation assays are measuring something which correlates with protection after natural infection but not after vaccination.

Lastly, there is considerable variation in the ratio of symptomatic to asymptomatic infection between years of infection, serotype and geographical location leading to significant uncertainty in the numbers of severe dengue cases expected in any given time period (for example see the attached Endy et al PDF, the data are derived from from the same Thai cohort as Anderson et al).

The CYD tetravalent dengue vaccine contains the prM and E (envelope) genes that together make up the outer part including the surface of the viral particle. There is evidence that the phenomenon of antibody dependent enhancement thought to be responsible for severe dengue is due to antibodies against prM exposed on the surface of immature dengue viral particles (Dejnirattisai et al 2010 – PDF attached). What might be a viable alternative vaccination strategy is a subunit vaccine based on E protein homodimers that can induce broadly neutralising antibodies. This work from Gavin Screaton’s group was just published in Nature Immunology and Vincent mentioned it in your episode – I look forward to hearing more discussion on this on TWiV! You can see more about exactly how these antibodies bind the E protein in bewildering detail here: http://www.nature.com/nature/journal/vaop/ncurrent/full/nature14130.html (behind a paywall unfortunately).

So if there does turn out to be a problem with this vaccine and severe dengue, we have another approach up our sleeve. That said, we should still recognise the enormous effort it has taken to get this vaccine as far as it has got and undertake these hugely complex trials.

A quick comment on why there are four dengue serotypes: this is thought to represent four separate introductions of different viruses to humans from the sylvatic cycle (Wang et al 2000 – PDF attached). This isn’t really my field, but I understand from colleagues that dengue 3 is diversifying a lot – more so than the other dengue viruses – and it’s possible this may give rise to serologically distinct viruses. Can’t give you a reference on that one I’m afraid.

The weather in Liverpool is 4C and sunny right now – but alternating rapidly between sun/rain and maybe even some snow who knows!



Total vaccinated:
Sabchareon et al (Thai phase 2b): 2666
Capeding et al (Asia phase 3): 6848
Villar et al (Latin America phase 3): 12 574
Total: 22 088

Percentage of vaccine group that is seronegative at baseline:
Sabchareon et al (Thai phase 2b): 30%
Capeding et al (Asia phase 3): 32%
Villar et al (Latin America phase 3): 19.4%

Extrapolated seronegatives:
Sabchareon et al (Thai phase 2b): 800
Capeding et al (Asia phase 3): 2191
Villar et al (Latin America phase 3): 2439
Total: 5430

Numbers actually shown to be seronegative:
Sabchareon et al (Thai phase 2b): 59
Capeding et al (Asia phase 3): 423
Villar et al (Latin America phase 3): 259
Total: 741

Lenn writes:

Hi Vince and Everyone at TWIV,

I had a rather disturbing experience last night on Twitter that I wanted to share with you. I received a tweet from someone who was re-tweeting another user’s message basically saying that vaccinations had harmed her son. She did not specify what had happened, but was obviously trying to convince people not to get vaccinations.

Being a big advocate of vaccinations, I replied with the following message:

“vaccines save far more lives than they harm. Without them, millions of people would die every year.”

I received the following response from the person who had originally re-tweeted the message:

“A speculative belief based on falsities & absurdities. Be Gone.”

And then the person blocked me on Twitter.

There are two things that bother me about this. First is the idea of this user blocking me rather than engaging me in reasonable discussion about the actual facts of the matter. I was prepared to cite three cases in which vaccinations have been very important for human health and have saved many lives. These are as follows:

1. Smallpox — Before the advent of the smallpox vaccine, smallpox killed many millions of people and blinded and disfigured many of those who survived. The vaccine effectively eradicated the disease and eliminated a huge amount of human suffering.

2. Polio — Before the creation of the polio vaccine in the 1950s, polio infected thousands of people, mostly children, every year, both in the United States and around the world. It killed a number of these people and paralyzed many others. The polio vaccine effectively eliminated it from most of the world, again eliminating a huge amount of death and human suffering.

3. Yellow Fever — Finally, I was going to cite the yellow fever vaccine, which I understand to be highly effective and prevent about 99 percent of deaths from yellow fever among those who’ve had the vaccine. Many people still die of the disease, however these are almost entirely among non-vaccinated populations (if I have been informed correctly).

To me, simply to block my messages without engaging in a reasoned and factual conversation about why we both believe the way we do, is indicative of someone who is operating at a purely ideological level and will not even consider the facts in forming and maintaining an opinion.

Secondly, when the person writes, “A speculative belief based on falsities & absurdities,” this seems to me to be broad generalization that is used to justify dismissing everything another person is saying, regardless of the facts presented. It is something that I have noted as a debating tactic in politics and culture in the last several years, but certainly goes back many more years Simply put, a person can make a broad statement like that, without any supporting evidence and then simply dismiss everything the other person is saying, again without the slightest shred of evidence. I hear the term, “you can’t trust the government,” used regularly in this regard. Many people think that if they say those words (or similar ones), then they do not have to believe anything the government says.

Where I am going with all this is as background to set up four questions I would like to ask all of you, as follows:

1. Are the three examples I gave, above, accurate and reasonable to use in conversations with vaccination deniers?

2. What are some other examples and arguments that can be used in this type of situation?

3. How does one counter this type of broad dismissal of ones position?

4. Do you have any idea of specifically what this person meant when they said, “A speculative belief based on falsities & absurdities?” To me, either the vaccines work or they don’t… either they have detrimental effects or they don’t… there’s relatively little room for ambiguity.

Anyway, to close, the temperature here in Smyrna, Georgia, is 18.8 C (66 F) and mostly cloudy. Thanks again for all you guys do. The podcast is wonderful and I hope that you all have many more episodes ahead of you.

Gretchen writes:

I found this video about how to cut a cake based on a mathematicians method that was published in Nature. It seemed like something the TWiV hosts and listeners would enjoy.


Thank you for all the effort and time that you all put into the podcast,

Leslie writes:

Dear TWiV show hosts,

I have been listening to TWiV and the other TWiX shows for almost two years now. I’ve come to enjoy your shows very much! My compliments on the above-average audio quality that you have for your podcast.

The “Listener Pick” I would like to contribute is….
“Principles of Virology: Molecular Biology, Pathogenesis, and Control” Copyright 1999, 2nd Edition by Flint, Enquist, Racaniello, and Skalka.

I will admit, I’m not a scientist by training, but I do enjoy learning new topics. I am recommending the 2ndEdition because it is affordable and a great way for the seriously curious “lay person” to better understand what you are talking about in the podcast. I probably won’t study it cover-to-cover, but I can look up most of the viruses and jargon you discuss on the show. This edition is about $13 including shipping on Amazon.com and in my opinion, money well spent!

Keep up the great work, and I hope that research moratorium gets lifted very soon.


Leslie in Ashland, OR

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