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TWiV 176 Letters

Richard writes:

Hi Vincent,

Just listened to this weeks twiv, and the q dot dyes you mentioned are also used in electronics. There they are used as a ultra precise phosphor. In that application blue light from LEDs can be re-emitted as red, and green. This gives an ultra precise RGB light source, allowing highly accurate colour rendition on LED backlit TVs.

It's surprising how often these crossover applications crop up. Another good reason to listen to twiv. This should happen more and more, as the technology singularity approaches.

Thanks as always for the interesting podcast.

P.s. no replies regarding magnetotactic bacteria. Though there's time yet. If not then I might have to experiment. I'm guessing replication of near anaerobic conditions, and elevated CO2, with the correct nutrients (nitrates, nitrides?)

P.p.s Best coffee maker? Airobe airopress, simple but highly effective.

Andrew writes:

Hi TWiV!

I've been listening to the show for a long time and I love it.  It is great while I am working in the lab doing my plaque assays.  Keep up the great work.

I just wanted to say I second Matt's suggestion from episode 175 to Tessa about the program Papers for organizing references and PDFs.  In the new version you can also use it to cite while you right (kind of like EndNote).  I know Tessa wanted an online version, but personally I love papers.  It makes managing references really easy and it lets you highlight and take notes on articles you've read.  If you are student you can get a pretty good discount, and they have great customer service.

Sincerely,

Andrew

Neil writes:

Dear Vince, Rich, Alan, and Dick (or V-RAD),

I just listened to TWiV 171. I believe it was Dick who said something along the lines of "wouldn't it be cool if you could label single virions and watch them in real time" (my paraphrasing, hope I got it right). I wonder what the other people at the gym thought when I blurted "it's been done!" (or did I just think it?!) Anyway I'm pretty sure this has been done for HIV by Tom Hope (Northwestern University) and more viruses by others. Here are some links to related information:

-images and movies from the Zhuang lab at Harvard: http://zhuang.harvard.edu/virus.html

-review article by Dr. Hope: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3209483/pdf/nihms175435.pdf

-a related blog post: http://scienceblogs.com/purepedantry/2009/03/watch_hiv_t-cell_transfer_live.php

Anyway I think the technology is definitely out there!

Keep the great podcasts coming, I learn so much from them!

Neil

David Esteban writes:

Dear TWiV folks

This week, one of the founding editors of the Journal of Virology, Lloyd Kozloff, passed away.  His daughter, a professor of Film here at Vassar College, notified me of his death.  Although his name may not be familiar to many, he began his career at a very exciting time as a member of a group of phage biologists associated with Cold Spring Harbor, that included many more familiar names like James Watson and Max Delbruk.   I can only imagine how thrilling it must have been for a young biologist to work at such an important time in the history of virology and molecular biology.

I wrote a brief blog post, with links to some of his early papers.  Since you have discussed some historical papers on TWiV recently, I thought some listeners might be interested in seeing these as well.  JVI will be publishing a more extensive obituary.

http://blogs.vassar.edu/viva/?p=639

Cheers

Brenna writes:

Dearest TWiV Doctors;

How would you approach current, and future, problems of being "research snubbed"?

About two years ago I was asked to help on a project with another lab.  I was struggling to get my own research off the ground, so I had some time.  I showed the post-doc how to do plaque assays, but it was obvious he was more inclined to let me do them.  So we completed three experiments before my own research had to take priority over helping him.  When things had calmed down I contacted to post doc about resuming the studies, but he never contacted me again.  At the last experiment I got the impression that they had a new hypothesis about the experiment, and were eager to test it.

A few months ago I see that they have published a paper on that work.  Now, no ethics were breeched.  They never mention my work (although, to be fair my work likely gave rise to the studies actually shown in the paper), so there is no ethical issue.  Just a matter of pride, time, and supplies that were used during their initial studies.

I was talking to a peer and she said that being "research snubbed" was the reason she required everything in writing prior to working with another lab group.

Is that what science has come to?  There must be a contractual agreement to protect work and/or ideas? It worries me, because I love talking and sharing ideas.  However, I have already come across one professor "borrowing" (stealing) my ideas for a grant, being research snubbed, and hearing stories of a researcher stealing ideas from a grant (and obviously scoring the grant low so it wouldn't get funded) and later publishing the research. And I don't even have a PhD yet!

What is a young scientist to do?

Long time listener, first time writer;

~Brenna

Tina writes:

I wonder if you are aware of the most recent study of MS and EBV. Whereas EBV has been a trigger suspect for MS since the 1980s, this new study shows that even if the virus is not actively replicating in the brain cells of MS patients, it is releasing chemicals that cause an immune system response.

I have a cousin with MS. I remember years ago finding out that MS is more common in subtropics compared to other areas. Some studies show it is important where you lived in your childhood and teenage years, as to whether you are at risk, no matter where you lived your adult years.

This and other studies prompted the theory that MS is caused by or triggered by a virus. A study in 2006 showed MS patients have an immune system overreaction to EBV. A 2009 study showed, after accessing 7 million blood samples, that those who had no infection of EBV did not get MS.

I find this very interesting as I am an ME/CFS patient. And MS has many similarities to ME/CFS. They both have post-exertional malaise or fatigue, much more pronounced in ME/CFS though. They both occur more in women. They both have a relapsing / remitting course for most patients. And they both have occurred in outbreaks. Lesions on the brain can also occur in ME/CFS patients, which – along with the similarity of symptoms – causes some with ME/CFS to be misdiagnosed with MS. (The lesions of ME/CFS are pinpoint, small white spots, but MS lesions are oblong.)

Ironically, ME/CFS has also been linked with EBV, even originally called “chronic Epstein-Barr virus syndrome.” Some have noticed increased EBV and other herpes virus titers in ME/CFS patients.

It is well established that many, not all, ME/CFS patients develop the disease after a case of mono, such that a study is onging, following people with mononucleosis to see who develops ME/CFS and possibly why.

EBV hides in B cells, which is why the drug Rituximab is sometimes used off-label in MS treatments. And, in October, a phase II double blind study in Norway found Rituximab, which kills B cells, brings moderate improvement to 2/3rds of ME/CFS patients. A few have seemingly been cured. Those physicians theorize that ME/CFS is autoimmune in the brain. Some others have theorized that killing B cells may reduce ME/CFS symptoms because EBV hides there and could possibly be causing a malfunction in the B cells, causing it to make autoantibodies. Kill the B cells and you kill EBV.

Could EBV behavior inside the cells be the cause of two autoimmune diseases, depending on what part of the central nervous system is being attacked by autoantibodies?

I would love to hear your thoughts on all of this. Ronald Glaser, PhD, has done studies on CFS, and the effect stress has on EBV. Might this be the thing that brings together those who see ME/CFS is triggered by stress and those who think it is triggered or caused by a virus?

Greg writes:

Hi guys,

Great podcast! I'm a PhD student at McGill and I work on HIV, but in more of a biochemical context than a virological one. Your podcast is great at rounding out my knowledge of the virus I work on, and of course many other viruses as well.  I'm sure this paper is on your radar, as it comes out of David Baltimore's lab, but I think gene therapy is an amazing technology and this seems like the perfect application in order to "cure" a difficult virus, HIV. (http://www.nature.com/nature/journal/vaop/ncurrent/full/nature10660.html)

Nature. 2011 Nov 30. doi: 10.1038/nature10660. [Epub ahead of print]

Antibody-based protection against HIV infection by vectored immunoprophylaxis.

Balazs ABChen JHong CMRao DSYang LBaltimore D.

Thanks!

John writes:

Dear TWIVvers,

I loved your Concerto in B episode (TWIV 161).  Your discussion left me with a bunch of questions regarding B cells and antibodies.

As I was listening to the discussion of affinity maturation, I kept trying to think of how this process interacts with existing memory B cells, and in particular, how it interacts with original antigenic sin.

What happens when you already have a good population of memory B cells to an antigen.  Do you get new germinal centers forming and the affinity maturation process going on again?  And if so, does it start with the B cells that have already been through that process, or does it start with new, immature B cells that responded to the soluble antigen?  Does that depend on how much new antigen is available (if you have an effective antibody response, does that keep this process from restarting?)

Do some mutations in the affinity maturation process close off the possibility of mutating back in some way that would be helpful later, or is all the raw material still around in a functional B cell after affinity maturation, so that you can get from a good antibody to the 2005 flu strain to a good antibody for the one you get in 2007?  It seems like there must be some impact of the existing stock of memory B cells on future affinity maturation, or you wouldn't observe original antigenic sin.  (And it seems like it should work the same way when there's antibody dependent entry of cells, as with dengue--is this right?)

Is this process the reason why some vaccines require three shots to get protection?  (I recall getting the Hep B vaccine many years ago in three doses--the second shot a month after the first, the third six months later.).  Or is this more a matter of getting enough antibodies, rather than getting higher affinity antibodies?

Finally, listening to the description of the germinal centers, it seems like they should run out of antigen, since they're using it up each time a B cell tries to take up and present antigen to the T cells.  Is there some mechanism to recycle the antigen?  Is the supply of antigen the limiting factor in this process, or is there plenty--maybe my intuitions at this scale are just all wrong?

Anyway, thanks for your wonderful podcasts, and for answering my amateur immunology questions.

Gabriel Victora answers:

Hi Vince,

Please congratulate you listener, these are all excellent questions. Unfortunately, I don't think we know nearly as much about these things as we should. Vaccine development has historically been mostly empirical, and regimes are usually based on what works best rather than on immunological considerations (most vaccines were actually developed by microbiologists). Part of the difficulty in addressing these issues is technical - it would be very difficult and costly to serially determine the affinities and specificities of B cells responding to antigen during consecutive immunizations of the same individual (or animal).

I've written some ideas about what might be going on below each question.

Hope this helps,

Gabriel

What happens when you already have a good population of memory B cells to an antigen.  Do you get new germinal centers forming and the affinity maturation process going on again?  And if so, does it start with the B cells that have already been through that process, or does it start with new, immature B cells that responded to the soluble antigen?  Does that depend on how much new antigen is available (if you have an effective antibody response, does that keep this process from restarting?)

>> The original antigenic sin phenomenon is most likely related to the rapid elimination of antigen by existing antibody or by antibody produced soon after the second challenge by existing memory cells. The novel (ignored) determinant would not be capable of priming naive B cells because it would be bound by circulating antibody and complement and eliminated before it ever had a chance to do so. As to new GCs, emerging data suggests that some memory cells (those that haven't switched their antibody isotype) can make it back into GCs upon second exposure. I would expect that a secondary GC would therefore contain a mixture of B cells derived from naive and memory precursors. Many factors could influence the composition of this putative mixture, including competition between B cell clones for limiting amounts of antigen or T cell help.

Do some mutations in the affinity maturation process close off the possibility of mutating back in some way that would be helpful later, or is all the raw material still around in a functional B cell after affinity maturation, so that you can get from a good antibody to the 2005 flu strain to a good antibody for the one you get in 2007?  It seems like there must be some impact of the existing stock of memory B cells on future affinity maturation, or you wouldn't observe original antigenic sin.  (And it seems like it should work the same way when there's antibody dependent entry of cells, as with dengue--is this right?)

>> I think this is mostly a matter of the extent to which the existing memory cells recognize the newcomer variant. If it is enough to trigger an "original antigenic sin"-type phenomenon you would probably not generate new germinal centers, in which case you would get no further affinity maturation. However, naive B cells are constantly being turned over (dying and being re-generated in the bone marrow). Therefore, the likelihood of a "hole" in the repertoire in 2007 arising due to all flu-specific B cells having gone the 2005 way is negligible. But theoretically it is possible that an unswitched 2005 memory cell could re-enter a GC in response to 2007 viruses, and in this case, it is conceivable that some cells could be impaired by 2005-specific mutations, but these would be unlikely to last in the highly competitive environment of the GC.

Is this process the reason why some vaccines require three shots to get protection?  (I recall getting the Hep B vaccine many years ago in three doses--the second shot a month after the first, the third six months later.).  Or is this more a matter of getting enough antibodies, rather than getting higher affinity antibodies?

>> The three shots of vaccine have probably more to do with attaining high titers of circulating antibody in blood than with improving affinity. Serum antibody affinity already increases quite dramatically (up to 10,000 fold) within the first immunization, although serum antibody titers (a composite measure of affinity and amount of antibody) only really really go sky high after one or two booster shots. The idea is that whereas the first contact with antigen generates germinal centers and affinity-matured memory cells, the booster doses "reap the profits" of this germinal center reaction by triggering the ensuing memory cells to proliferate vigorously and differentiate into large numbers of antibody secreting cells within a few days. What the role in vaccination is of GCs emerging during booster doses is not clear (at least as far as I know), but could conceivably involve the recycling of unswitched memory B cells back into GCs for further affinity maturation.

Finally, listening to the description of the germinal centers, it seems like they should run out of antigen, since they're using it up each time a B cell tries to take up and present antigen to the T cells.  Is there some mechanism to recycle the antigen?  Is the supply of antigen the limiting factor in this process, or is there plenty--maybe my intuitions at this scale are just all wrong?

>> This is a good question. Antigen appears not to be limiting, since it can be detected on FDCs many months after the GC reaction has faded, though how available this antigen is at this point is not clear. Many hypothesis exist for why the GC response ends; these include competition between B cells and circulating antibody (which would sequester the antigen available on FDCs) and exhaustion of GC T cells (perhaps through their regulation by GC-resident regulatory T cell populations). I tend to favor the latter, but this is still a topic of fervent investigation.

John writes:

Hello,

Attached are my two questions. I found your podcast even before the death of my sister during the 2009 H1N1 pandemic of ‘09. She died 14 Oct 09 from bilateral pneumonia as a result from a confirmed case of H1N1.

I received both the seasonal and H1N1 vaccines, as I’m not stupid, and not influenced by celebrities or former playboy bunnies (Ref. jenny mccarthy – Name intentionally lower case out of disrespect). I prefer my medical advice from a doctor, imagine that!

I’m sure I’ll have more questions as I make it through the episodes.

Very respectfully yours,

John

Raihan writes:

Hello ...insert cool way of addressing you guys....,

In one of your previous twivs you guys mentioned about how after the H1N1 pandemic, the prevalence of Flu infections dropped, suggesting a 'boost' in herd immunity.

If you don't mind I would like to chirp in to this discussion.

I am a grad student studying influenza here in Singapore. In my confirmation presentation (which was at the end of the H1N1 scare),I presented the following chart taken from the Ministry of Health (Singapore)'s website.

ifegbcfg

The pink bar (pandemic H1N1) shows a decrease in size over time, corresponding to the end of the pandemic.

But what is interesting is that while pandemic H1N1 dwindles down, the incidences of seasonal flu A strains and  flu B increases.

I am curious as to whether or not the same trend is observed in the US. You guys seem to suggest that after the pandemic the incidences of seasonal flu and flu B were not as prevalent, this is obvioulsy not the case here in Singapore.

http://www.cdc.gov/flu/weekly/weeklyarchives2009-2010/09-10summary.htm

On a separate yet related topic, I have to express my dismay in your podcast for not highlighting other types of Influenza. When you guys talk about flu, you exclusively talk abt flu A. This frustrates me  as I am studying influenza B. I have only noticed influenza B Being mentioned only aBout 2-3 times in the course of your podcast, and it was always in passing. The only discussion aBt flu B was By Peter Palese where he suggested that flu B could be potentially eradicated due to its lack of an animal reservoir.

Pls dont get me wrong, guys are doing a Brilliant joB with the podcast, But flu B is my BaBy, would love to hear your insights aBt flu B as well.

My take aBout the 'Are viruses alive or not?' deBate;

I've Been thinking aBt this for quite some time and I totally agree that this is not exactly a biological proBlem as much as it is a philosophical one. As early as I can rememBer amongst the first few things taught in Biology is that the cell is the Basic unit of life. I think this is quite an agreed upon definition and no one would disagree with it, most of us would see this in Biology textBooks in all levels. Therefore since viruses are not classified as cells, it would Be impossiBle to define them as alive as much as organelles are not alive.

Hope my email did not Bore or Bother you guys. Just take my earlier complaint aBout Flu B as the rantings of a PhD student trying to come in terms with his lack of publishaBle data.

Marcie writes:

Dear TWIVers,

I am listening to episode 164 "Six Steps Forward, Four Back" and as you were mentioning the fact that you wished you could reach everyone it occurred to me that the podcast title, This Week in Virology is a little intimidating to people who may only have a high school knowledge of science.  I am not suggesting that you change the name of the main show, but maybe you could do an occasional single-topic, explain--it-to-the-layman show when there are hot topics like the HPV vaccine, the H1N1 spread, or the H5N1 publication controversy.  These could be the short ~15 minute shows that target a broader audience than your regular shows.  The name would need to be something general, so as to cast a wide net (all of microbiology/immunology--you certainly have sufficient connections that you can recruit experts to do bacterial or fungal topics)  if not broader  ;-).  It would also need to be non-threatening to the average person (think "Idiot's guide to...") so it would need to avoid words like Virology and Microbiology.   Maybe  something like "Hot Topics in Health and Disease."

Marcie

Pittsburgh, PA

Where it is currently 50 degress F, and overcast.

Sven-Urban writes:

Ave, magi virorum!

(That ought to put me pretty high on the list of creative/obscure greetings!)

I have just enjoyed episode 169, where You all discussed the question from Sophie on how to read scientific papers. I fully enjoyed and appreciated Your learned views, all of them very valid for You as scientists. However, not all readers of scientific papers need be or become scientists, so perhaps You might let me add one layman's perspective.

Just to give You the general picture, I am a Software Quality professional with a 30 year old M.Sc. in computer science. Out of general curiosity and for personal entertainment I occasionally read science papers from other disciplines, mainly from the section Evolutionary Biology in PlosONE. Many of the intricate details in those papers, whether they be on primatology, paleontology, ecology or (particularly) biochemistry, are usually beyond my grasp and knowledge. That’s fair, scientific papers aren’t written for laymen, and Alan's way of describing a paper as a highly compressed packet of information for transmission over distance was very instructive. What I look for, and hope to find, is something reasonably digestible at the “beginning” and “end”. As Dickson pointed out the pictures and graphs are very important, as they may aid, or sometimes hinder if badly designed, the intuitive understanding of the data, and here too good handiwork might aid my understanding. With well worked out introductions, discussions and illustrations I, the layman, should be able to grasp the general problem/question/hypothesis, as well as the general result/conclusion/implications. And that’s my main point, on some level a scientific paper ought to be accessible also to the non-initiated – if it’s not, the paper and science is in some sense poorly or obscurely presented. (On the other hand, if science papers were always graspable by the populace Alan would be out of business pretty soon...) Of course, as a layman not understanding the details I have no way of assessing the validity of the results presented, but that is of less concern as I am not using the information gleaned for anything else than maintaining my image as an “incurable intellectual” around the coffee pot at work!

Searching my bookshelves for a listener pick-of-the-week I found something that at least distantly tags in with the main theme of the episode. I suggest two highly accessible books on how we tend to overly rely on noisy, possibly meaningless, data, how we tend to extrapolate trends ad infinitum and how we can not disprove the odd/unknown/unobserved phenomenon: ”Fooled by Randomness” and “The Black Swan”, both by Nassim Nicholas Taleb.

Thanks for Your continuing effort!

Sven-Urban

P.S. The greeting supposedly means “Hail Ye, mages of viruses”; kudos to Internet if I’m right, shame on me if I’m wrong...

Colm writes:

Sirs:

I have been listening for a while and finally have enough disjointed comments to merit hitting send, I hope.

First, you frequently make references to temperature conversion. Born and raised in the United States, I have a poor understanding of Celsius as it relates to real life. I know my incubators are at 37, and that's toasty, and the lab is in the low 20s and that's "Room Temperature." I wonder if yo know of a weather application for iOS or Android that displays C and F side by side, for building those associations. I think it would be an amazing feature.

Secondly, I am not a Redditor, but I was recently made aware of their 'Ask Me Anything' threads where experts/insiders field questions from the community in long-running dedicated threads. For example, George Pelecanos, a writer and producer for The Wire and Treme recently answered dozens of questions in such a thread. It  would undeniably be a massive time sink, but may be a useful way to disseminate Virology to the public.

Third, and finally, you mentioned in this week's epidemiology TWiV that BSL-4 facilities seem to be predominantly government run affairs. That is generally true, but I am aware of at least one privately operated US BSL-4 in San Antonio at the Texas Biomedical Research Institute. The More You Know.

Best.

Diane writes:

Because I have CFS, I learned about you and your various podcasts during all the XMRV hoopla.  After many years of struggling, I have been able to teach part time for several years now.  I teach biology at a junior college, both a majors and a non-majors course, and I thought you would appreciate something that happened early on this semester.

I always start my classes with what I call “bioliteracy topics.”  I will briefly introduce something in the news that is both interesting (I hope) and usually controversial.  So of course I chose as one topic the H5N1 controversy.  At the time, my understanding was that the mortality rate was near 60%.

Meanwhile, I had decided to listen to all the current TWIVS, TWIPS, and TWIMS, and to slowly go back and listen to all of the old episodes.  So of course you know that I had to correct myself with my students the very next class!  It actually helped me to make a point that I love to make – that science is not merely a collection of facts to memorize, it is a process.  Those who undertake science  must maneuver through this process, and the public needs to understand that, at any given time, the information they have may not be the final word, and in fact, what they are hearing in the media may be misleading or simply incorrect.

I allow my students to earn some bonus points by responding to the bioliteracy topics on exam days and several chose to write about the H5N1 controversy.   I’m pleased I was able to provide them with information beyond the headlines – thank you for that!!

 

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