TWiV 279 letters

Robert writes:

Hello TWIV docs,

I enjoyed the discussion of the zinc finger treatment paper. During the discussion the question was raised concerning the origin of the CCR5 delta 32 mutation. About 4 – 18% of people of European descent have at least one copy of the mutation. There has been some speculation that the mutation conferred selective advantage for people with the mutation during plague epidemics of the middle ages in Northern Europe. The current hypothesis is that it provided some protection against smallpox throughout Europe (Fraure E., Royer-Carenzi M., Infect. Genet. Evol. 8(6): 864-74, 2008). Also, there was a question about whether or not the CCR5 may be dispensable. This is most likely not the case as a study has shown that CCR5 is important in resistance to West Nile Virus infections in humans with people carrying the CCR5 delta 32 mutation being more susceptible to infection (Glass WG et al, Exp. Med. 203 (1): 35-40, 2006).

Weather here in Orange CA has been sunny with temperatures in the low to mid 70’s, light winds good for sailing. We did get a good shake last weekend from a 5.1 earthquake located about 30 miles inland from us along with several aftershocks in the 4.1 range.

Robert Kelley, Ph.D

Bill writes:

Vincent et al, I read slashdot daily. Today they had this article about PLOS, which you might like to read.

http://science.slashdot.org/story/14/02/25/2132234/major-scientific-journal-publisher-requires-public-access-to-data

and here is the front door portal. http://slashdot.org/

and the wiki

http://en.wikipedia.org/wiki/Slashdot

I made this comment as ‘aurizon’, my nom-de-plume on slashdot

A lot of people ignore the collateral functions of the ‘peer review’ system administered by the publisher. The publication must be read by someone who knows the subject passably well. If his first pass finds it acceptable, he must then select from a number of true experts in these matters (the peers or equals to the writer of the paper). He works for a living as a competent editor for that area of research. The peers he chooses are sent a copy of the paper to review and criticize, if not acceptable, the comments are passed back to the author for him to respond. After his responses to fix the flaws, it goes back to the panel and so on until rejected or published. The review mechanism is needed to avoid total BS being published. The publishers have created this niche and profit by it – some say excessively, and I agree. So some way must be found to pay for these. Page fees are the initial solution – the author pays a fee, and this is spread among the experts involved.

As for an Archive, in the USA, the Library of Congress can do this, as long as a proper indexing method is used so that the paper does not
become a needle in a haystack. It should be google indexed. Perhaps Google will fund this via ads, because all the biological supply houses will place biological ads, and the same with all the other disciplines.

In fact, this could become a gold mine for Google and at the same time serve PLOS and the research community very well. Large data bases of
terabytes of particle data would not be stored, the publisher would grant access to those who wanted to down load it (a precious few will want terabytes of particle data)

So why not someone who has a pipeline to google give them a whistle, they might leap at the chance. It is a natural fit.

Pavitra writes:

Hello TWiV,

This is in response to a letter you read on TWiV 273 where Bill asked about a way to make negative results available. I just wanted to bring to your attention a couple of journals that might be relevant. There are probably more, but here’s one in biomedicine (http://www.jnrbm.com/) and one for ecology and evolutionary biology (http://www.jnr-eeb.org/index.php/jnr).

I also remember reading about a journal of “serendipitous and unexpected results”, but it appears that their website (http://jsur.org) has been rather unexpectedly taken over by a Japanese company or spambot.

Pavitra
Seattle

Raihan writes:

Heyya fellas,

I came across this paper from PLoS One, showing negative results and rushed to show it to you guys with hopes to share the great news: You
can publish negative results!

This group started with the hypothesis: Harbor porpoises are a reservoir for influenza B viruses. And after serological analysis of 79 porpoises, no antibodies were found specific to influenza B (or A) viruses. Therefore, they concluded that their hypothesis was wrong.

I know this paper might not be significant for a TWiV discussion, considering the other cool stuff you guys discuss, but you may remember
from a letter i wrote in a many many TWiVs ago, that influenza B virus is my BaBy. I can’t help But rush at any puBlication aBout it!

Hope this email gets read. Wishing you all the Best for TWiV!

http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0089058&representation=PDF

BBest Regards and BBest Wishes

Joseph writes:

Greetings TWiV Docs,

I writing to offer my two cents on the negative data discussion stemming from an email read on TWiV 273 as a substantial portion of my Ph.D. thesis was negative data! At the time, quite a number of good papers were published demonstrating that the macroautophagy pathway contributed substantially to the generation of peptide epitopes during an anti-viral T cell response. Because we were very interested in the pathways of antigen processing, we wanted to see if this pathway was important during influenza virus infections. Despite our best efforts, we could not find any significant contribution of macroautophagy to T cell activation. Sure, we could force it to happen with artificial constructs and controls thereby validating our detection methods, but the data indicated that this pathway did not contribute to T cell activation (at least at our level of detection anyway). This was difficult to get published, but after many revisions and rebuttals it was accepted at JVI. Looking back on this only after a few years away, I appreciate those revisions and rebuttals much more because the paper was much stronger at the end. Dr. Condit is dead on about the purpose of meetings and communication- I always found one or two other people at meetings that were making the same observations as us but also could not (or would not) publish their data.

I suspect that the phrase “negative data” leads many to conclude that the data is not important. As you all discussed, I think this couldn’t be further from the truth. Negative data can indicate that our procedures or techniques were wrong, the technology we used was inappropriate, or that our hypothesis needs revising. That’s really helpful information. Obviously not all of it is publishable, but helpful nonetheless. Maybe this inappropriate interpretation of negative data, particularly in the general public, is a result of how science and the scientific method is taught in schools. In the Introductory Biology classes (for non-majors) that I teach at a local university, I am always careful to explain the scientific method in detail as this description in most survey texts is incomplete and more or less depicts a negative result as the end of a line of questioning.

Two more quick points on this subject. First, what may be negative data today might be positive data tomorrow with advances in technology and the development of more sensitive techniques and procedures. Second, at least in my experience, there are also positive results that do not get published for a variety of reasons.

I have a pick of the week if I may- a website from UC Museum of Paleontology of the University of California at Berkeley called Understanding Science. It has a really nice overview of how the scientific method, and therefore science itself, works from screening the literature to collaboration with other scientists.

The main page: http://undsci.berkeley.edu/article/intro_01
The scientific method page: http://undsci.berkeley.edu/article/0_0_0/howscienceworks_02

– Joe

PS: The weather in lovely Doylestown, PA is 24F (-4C) with a light snow falling.

Joseph Comber Ph.D.
Postdoctoral Fellow
Immunotope Inc

John writes:

Dear TWiumvirate,

I’ve wanted to write to you guys for a long time. Your podcast started early in my time as a PhD student at Dr. Racaniello’s alma mater, and I’ve listened to it pretty regularly ever since. I don’t know why I’ve not lent fingers to keyboard until now, but I guess I haven’t really felt like I had much worth saying.

At the moment, the weather here on the East Side of Manhattan is one degree below celsius. As it is Friday morning, that probably matches the conditions for the recording of TWiV #275. What little snow remains is a sad reflection of its former self, embedded thoroughly with the schmutzdecke of New York life.

Awhile back, a listener sent in a piece I’d written, “Why You Don’t Actually ‘F&%#ing Love Science’” which was bought by Mashable, and you guys briefly discussed it—but that’s not what I’m writing to discuss.

What I wanted to write about this time is a theme that comes up from time to time during the course of the show: the publishing of “unpublishable” data. I mean negative results, results that are difficult to reproduce, etc. Recently, I remember someone wrote into your show about how publishing data like this would prevent wasteful investigations.

I don’t really think we should prevent those investigations. Just because someone has gone looking for a finding in the past and failed doesn’t necessarily mean that the case is closed. Negative data is always weaker than positive data, which is exactly why it’s so hard to publish! There’s no telling why an experiment might show nothing, and it’s not always because the hypothesis was wrong. Sometimes it was just a bad month for that postdoc’s experiments.

That said, I think that it pays to have the ability to look up what others have done in the past and use it to inform future investigations. Knowing what methods failed in the past—and being able to update them—presents a starting point for anyone else who might want to try their luck.

Of course, as TWiV has discussed in the past, peer reviewed journals are reluctant to publish negative data, because it’s difficult to be sure that the negative result is due to reality rather than experimental artifact. Negative data has a lot of trouble in peer review.

My question, and solution, are therefore: why bother with peer review of negative data? The point of peer review is to ensure that what we know about science fits with the understanding of fellow scientific experts. I think that mostly is important for positive data. If you base an experiment on incorrect positive data, you might spend years chasing your tail when it doesn’t work. On the other hand, an experiment based on incorrect negative data, when it reveals the true positive information, will just lead to a novel result. The problems that peer review is supposed to solve don’t necessarily apply to negative findings.

Why not just dispense with peer review of negative data and have an online database of informal research reports on ideas that didn’t work? It seems to me that this could be a valuable resource for investigators, study sections, and others. Everyone would treat it like a conference abstract book: out in the open, but not necessarily sound in its foundations, a sort of guiding light for investigations towards peer reviewed publications.

As it is, this kind of informal information is shared among colleagues within a given institution or among people who have made connections with each other over the years. This rumor mill isn’t efficient, though, and while it may seem to be a sort of tactical advantage to have insider knowledge that others lack, this “advantage” comes at others’ expense. Too many people waste their efforts because there was no mechanism for them to learn what you know. That, in turn, hurts the overall scientific community.

The thing is, I have no idea how someone would set up such a database. I don’t know how it could be funded, who would do the work of keeping it running, or how it would be publicized. Fortunately, you folks have done all of these tasks with the TWiX podcasts…so I thought I would run the idea by you.

So, what do you think?

Thanks for your time, and for TWiV,

John Skylar

Michael writes:

Dear Vincent and colleagues:

I am a regular listener of TWIV and know that you visited my institute (BSRI) in SF previously to discuss my colleague Eric Delwart’s work on viral metagenomics. Of note, my colleagues at BSRI (particularly Graham Simmons) and I were quite active in refuting the alleged discovery and clinical associations of XMRV, authoring several papers in Science and other journals including the lead and senior author of the Science paper from the Blood Safety Working Group that was linked to the Science Editorial Decision to retract the Lombardi et al paper (attached).

I am writing in reference to the brief discussion during the preamble of session 273 on whether successful vaccines prevent infection (i.e., are “sterilizing”, precluding viral entry and any evidence of virus in blood or anamnestic adaptive immune responses) or allow viral inoculation and local replication but block or blunt dissemination of viral infections, yet are highly effective at preventing chronic infection and disease.

I think data on efficacy of HBV vaccination is illustrative of these issues. Although HBV vaccines have proven extremely effective at preventing chronic HBsAg+ carriers and consequent clinical hepatitis, cirrhosis and liver cancer, long-term follow-up studies of vaccinated populations have demonstrated modest rates of anti-HBc seroconversion as vaccinated children reached ages when they experience sexual or parenteral exposures to HBV, indicating that HBV infections have occurred in successfully vaccinated recipients, albeit at reduced rates relative to historical controls. Several papers documenting the clinical efficacy but low rates of anti-HBC SC are attached.

Relevant to my area of focus and expertise (international blood safety and efficacy, with broader interest in virology, emerging infectious diseases, and transfusion and transplantation medicine), we have detected HBV vaccine breakthrough infections in blood and plasma donors screened using highly sensitive nucleic acid amplification technology (NAT) assays. Several papers including a seminal paper in NEJM describing such cases, now observed in blood screening programs worldwide, are attached.

Mechanistically our paper just published in JID (last attachment) documents the blunted viremia which was associated with early engagement of the innate immune responses and anamnestic anti-HBs SC that we were able to characterize based on study of longitudinal samples from donors with vaccine breakthrough infections evidenced by very low-level HBV DNA in the presence of vaccine induced-anti-HBs but absence of HBsAg and anti-HBc.

We believe these data demonstrate mechanisms underlying vaccine efficacy in the absence of sterilizing immunity. As we note in the conclusion of the paper “Further studies of viral control and immune response in the context of pre-existing vaccination are needed to fully understand mechanisms underlying vaccine breakthrough infection such as incomplete seroconversion, waning anti-HBs, or prevalence of diverse HBV genotypes. Finally, studies elucidating consequences of vaccine breakthrough infection should be conducted to determine if there is persistence of HBV after breakthrough infection and if these individuals are susceptible to reactivation in the context of immunosuppression as in classically resolved HBV infections.”

Finally I have attached an excellent commentary in Nature Medicine on “Lessons from Vaccine History” that makes the point of the need to understand the mechanisms underlying clinical efficacy of established vaccines as we struggle to advance vaccines for HIV and other viral and non-viral pathogens.

Sincerely,

Mike Busch
Michael P. Busch, MD, PhD
Director, Blood Systems Research Institute
San Francisco CA 94118

Robin writes:

MERS virus in dromedary snot
Has been around long and a lot
Human may end up dead
But fortunately don’t spread
So long as no mutants get hot.

Martin writes:

Why didn’t you mention this?

“All of the students who were tentatively diagnosed with mumps had been vaccinated,” ABC News reported. “Vaccinations do not offer 100 percent protection.”

Learn more: http://www.naturalnews.com/044087_vaccinated_students_mumps_outbreaks_Fordham_University.html#ixzz2uVbkLL6H

Dave writes:

Vincent et al,

Have you seen this paper?

http://www.nature.com/modpathol/journal/vaop/ncurrent/full/modpathol2013198a.html

If confirmed this would be huge in the field of pulmonology. Idiopathic pulmonary fibrosis is a devastating disease affecting about one in a hundred thousand people. It progressively destroys the lungs and has a median survival of two years. There is no effective treatment or any real insight into what causes it. The hypothesis advanced by this paper has some biological plausibility. Unfortunately I’ve seen nothing further published on this so I’m concerned that other groups are having difficulty replicating the findings. It’s reminiscent of XMRV.

But why I really wrote is to let you know that I’ve now caught up and listened to every TWIV. TWIP is next. And it’s currently -26.6 C (-16 F) in central Minnesota.

Best regards,
Dave

Anne writes:

Hello TWiV Team,

First, many thanks for all of your efforts with the podcasts on virology, microbiology, and parasitism. I was delighted to find your podcasts last year, and while I am nowhere near being caught up on the virology podcasts, I look forward to listening to them when I can.

My college-age daughter recently experienced an episode of the Epstein-Barr virus which results in glandular fever (mononucleosis). She was diagnosed by her school’s clinic, and I encouraged her to have them confirm (through a blood test) that that was indeed the actual cause of her illness.

While she went through about a 2-3 week period of chills, fever, and great fatigue, she recovered without having to miss a lot of school (her class load at school is lighter this term, but she does have some intense classes in biochemistry, physics, etc.).

At any rate, in researching EBV on the interwebs, I found a few things that led to more questions. Apologies if you’ve covered these questions before; I did a quick search for EBV in the podcasts but didn’t come up with anything.

1) One of the things I read is that children exposed to EBV suffer from milder (inconsequential?) side effects – runny nose, low fevers, etc. Since the occurrence of the virus is more serious in adolescents and adults, why not expose children to the virus at a young age? Why does the virus cause more serious complications in adolescents and older people?

2) I know EBV is a member of the herpesvirus family, and that my daughter will now have this in her system for the rest of her life. Do you have a podcast devoted to this class of viruses, and the mechanism of their persistence in the organisms they invade? I know I heard a recent podcast that addressed how the herpes viruses are able to hide out in the body, but any pointers you can provide to podcasts or articles would be appreciated.

3) I read that young adult exposure to EBV increases the risk of Hodgkin’s lymphoma. Has there been any study to explain why this might happen? Does the persistence of the EBV virus in younger children who have been exposed to the virus also include a higher risk for Hodgkin’s lymphoma? What about other the herpes viruses, e.g., those that cause chicken pox/shingles, cold sores/genital herpes, etc. – do these include a higher risk for the disease, or for other diseases?

4) I haven’t yet taken your Virology course, and look forward to doing so. Feel free to omit this question if it’s redundant with material covered in the course. I read/have heard that an immune system challenged by viruses and bacteria is “better”, and made stronger by these repeated challenges. I heard a discussion on a recent podcast (apologies, I did not note which one) where you spoke about the amount of energy required by the body to respond to immune challenges. Is there a “cost” associated with the generation of a strong immune response and/or strong immune system? Does genetics play a part in an individual’s immune response?

Thanks again for all your efforts, and for entertaining questions from your audience,
Anne

Marion writes:

http://zometool.com/

I’ve known about this for so long, that it never occurred to me that this had not been picked. Zome tool is a toy like tinkertoys, with sticks (struts) and joints (nodes), but the joints have 5-fold, 3-fold and 2-fold axis of symmetry. It is simple to build structures with icosahedral symmetry, such as a dodecahedron, and icosahedron and a virus (which has both). It was developed by a childhood friend of mine. They sell many kits, for example, “bucky ball,” “DNA” and (my favorite) “crystallography,” which includes a brochure about virus structure, written by me. The toys may be used to model many natural structures, as well as for beautiful art.

I’ve pasted some images, but this is a just a small sampling of the possibilities.

http://blog.andreahawksley.com/zometool-0/

http://momath.org/home/math-monday-01-18-10/

Kevin writes:

Dear Doctors TWiV, TWiM and TWiP,

I’m a graduate student in the immunology program at Harvard, and I love the TWiX series of podcasts. It’s great to hear the perspectives and papers from other fields, especially as I can listen to them on my commute to and from lab or while doing mind-numbing pipetting and tissue culture work.

In fact, some fellow graduate students and I were inspired by TWiX to create a podcast about the immune system called “Audiommunity.” Your audience is our target audience, and anyone that listens will see that we’ve clearly drawn inspiration from your shows, but we’re covering topics from a different angle, and we’ll be talking about a lot of topics that you guys don’t (though we do have a virology grad student on the payroll).

All three of us are also passionate about education, and we’re hoping to use the podcast as a tent-pole for all kinds of other educational content about the immune system. We’ve already got some graphics and even a couple of animations that we (actually, mostly Matt Woodruff) created that are associated with our episodes. For example, our second episode is about efforts from Michel Nusseinzweig’s lab to create HIV therapies based on broadly neutralizing antibodies, and we have a graphic of antibodies (showing V, D and J segments), and some animations showing VDJ recombination as well as my personal favorite: HIV infecting a cell.

Right now, we’re building these resources associated with the episodes we’re doing, but ultimately we’re hoping to have a library of graphics, posts and podcasts that anyone can use to understand the immune system. If you’d be gracious enough to share our efforts with your audience, everything can be found at www.emmunity.org and the podcast is also on itunes.

If it’s too selfish to ask that my own project be submitted as a listener pick, I thought I’d offer this paper from a few years ago suggesting the use of a phage targeting lactobaccili as a viable strategy to combat beer spoilage. Seems like all the normal objections to using phage as antibiotics in animals (like immune recognition, off-target effects etc) are irrelevant in this case.

Thanks,
Kevin Bonham (and Matt Woodruff and Kate Franz)