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Letters

TWiV 170 Letters

Jim writes:

Honored Profs:

May I suggest a pick-of-the-week podcast that captures the difficult aspects of creativity and research that may help students of your craft understand the 90% perspiration part of your work. A download link of, http://www.econtalk.org/archives/2011/05/byers_on_the_bl.html , also describes the hour-long podcast as follows:

"William Byers of Canada's Concordia University and author of The Blind Spot talks with EconTalk host Russ Roberts about the nature of knowledge, science and mathematics. Byers argues that there is an inherent uncertainty about science and our knowledge that is frequently ignored. Byers contrasts a science of wonder with a science of certainty. He suggests that our knowledge of the physical world will always be incomplete because of the imperfection of models and human modes of thought relative to the complexity of the physical world. The conversation also looks at the implications of these ideas for teaching science and social science."

Regards,

Jim

Smithfield, VA

John writes:

Good day to the TWIV Nation:

I'm giving a shout out to Dr. Welkin Johnson from TWIV 168. He got us listening for a "Viruses, Genes, and Evolution" course at Boston College. The lectures on Virology 101 have been extremely helpful and refreshing. I got excited to hear he was a guest this past week. Be sure to keep him coming back so his students can eventually make him his own auto-tuned remix of his comments on TWIV and get it going "viral" on YouTube.

I was thinking about the vector immunoprophylaxis results by Baltimore's lab at CalTech and see them as very exciting (see reference below). Yet, provided these results may yield a future vaccine, it seems likely to me that the final product would only be administered to people in close contact with HIV-infected individuals and not everyone--perhaps those that are traveling or working with patients of HIV such as nurses or paramedics?

Furthermore, with HIV as the target, many new vaccines would be in development for other target surface proteins year after year. The difficulty surely lies in developing various vaccines that elicit specific immune responses effective against the many mutating strains particular to areas of the world. Is this feasible or is it worth investigating yet another mode of inhibition? Whatever the case, it's a stride all the more.

I do have a technical question about VIP. With the addition of the gene to a cell's nucleus via the adeno-associated virus, does the gene randomly insert itself in the host genome or is it only a functional gene for that particular cell? My thinking is that with cell division, that gene would be lost or could randomly insert in the genome and trigger complications? All the help and wisdom any of you could impart would be greatly appreciated.

Thank you!

John

Undergraduate at Boston College

Class of 2012

Reference:

http://www.nature.com/nature/journal/vaop/ncurrent/full/nature10660.html

Mark writes:

I had a few comments as I listened to this episode. You discussed Zinc Finger Nuclease (ZFN) technology [TWiV 144, probably], and I thought TWIV listeners would love this study:

http://www.ncbi.nlm.nih.gov/pubmed/17965707

Luigi Naldini's lab used an integrase defective lentiviral vector to express a ZFN and to provide the template DNA used for gene correction. So, they used a virus to provide both the scissors and the patch. This gives highly efficient gene transfer while the integrase deficiency allows transient episomal delivery from a lentivirus, at least in principle.

As a stem cell guy, I listened with interest to the portion of the show that discussed pluripotent stem cells. Alan rightfully pointed out that some people dispute whether pluripotent stem cells can make every cell type. For human cells, this is impossible to ethically prove since we cannot make chimeric humans. But for mouse, it has been shown that entire mice can be made from embryonic stem cells (or induced pluripotent stem cells) using a technique called tetraploid complementation.

The way this works is that a two-celled embryo is zapped with electricity to fuse both cells together. So your two diploid cells are now one tetraploid cell. This tetraploid cell continues to divide after the fusion and is competent to develop to the blastocyst stage, creating functional extraembryonic tissue. When combined with embryonic stem or induced pluripotent stem cells, the tetraploid cells provide the extraembryonic tissue but will rarely contribute to the embryo itself. Using this assay, it has been shown by many groups that mouse embryonic stem cells and mouse induced pluripotent stem cells can give rise to a mouse that is composed almost entirely from these stem cells.

It should be noted that it is almost impossible to prove that 100% of the cells are from the stem cells. And there is data to suggest that not every single cell is derived from the stem cells. But I'd say that, at least where we can do the experiment, there is pretty strong evidence that embryonic stem cells and induced pluripotent stem cells are capable of making nearly every cell in the body.

Our being able to recreate all of those cell types in a dish is another issue entirely. But this experiment, I believe, demonstrates that the potential exists. Our current challenge is to understand the developmental biology required to get to each cell type. We attempt to translate how different pathways are activated and silenced over the course of time from model organisms to a human developmental timeframe. One such success just happened next door to my lab: Lorenz Studer's group has recently demonstrated the derivation of transplantable midbrain dopamine neurons from human pluripotent stem cells:

http://www.ncbi.nlm.nih.gov/pubmed/2205698

Mark Tomishima, Ph.D.

Head, SKI Stem Cell Research Facility

Kent writes:

Dear Jed-Vri masters,

First I wanted to thank you for the yeoman's effort all of you put into making a great podcast. I subscribe to over a dozen podcasts, and over the past year or so TWIV has become one of my favorite. As a self described "science geek" I can say that the show you produce is truly one of the best science podcasts that can be found. I am a computer consultant by trade, but I have a decent background in biology and a soft spot in my heart for microbes and virii of all kind (which would probably sound strange to most people, but I think you all feel the same way). I have learned quite a bit listening to you on a weekly basis for the past year, so my thanks to each of you.

You may have covered this recent development in the XMRV world already, (I must confess I am a few weeks behind on my podcasts), but if not I thought this might be a good opportunity for you to address what seems like the nail in the coffin (for now) of the the XMRV to CFS Link.

I'm sure you have seen this: http://news.sciencemag.org/scienceinsider/2011/12/authors-pull-the-plug-on-second.html

It appears that the much disputed evidence for the link between XMRV and CFS may have all but disappeared at this point. As a somewhat educated layperson on this subject thanks to your outstanding podcast discussions on this topic, I am left with a few questions at this point:

1) What, if anything, went wrong in the vetting process for the papers that were published in support of the XMRV/CFS link? Obviously the reviewers can't be expected to reproduce every experiment, but were there warning flags that should have kept these papers from being published in the first place or is this just the sometimes messy process of scientific inquiry sorting itself out pretty much according to plan, or a bit of both?

2) Did any of the individuals involved act inappropriately during this process, either scientifically or ethically? For example, did Harvey Alter just misspeak at the Croatia conference in 2010 or should he have been much more circumspect with his declarations given the evidence he had at the time? (of course hindsight is 20/20, which is why I caveat it with the "at the time")

3) My sense is that much of the furor over this XMRV to CFS link may have been due to scientists who were well intentioned but over eager to publish results that in hindsight (and perhaps even in forward-sight) should not have been published or at a minimum that they should have been much more cautious with their public declarations. Additionally, this combined with a small but (understandably) fervid group of CFS sufferers who latched onto what seemed like a promising explanation and pushed for a premature acceptance of this causal link in the public sphere.

I'd be very interested in hearing everyone's take on this subject. Thanks again for the great work, I know I'm not alone when I say how much I appreciate your efforts.

Sincerely,

Nicholas writes:

Dear Vince, Alan, and Rich,

I absolutely love your podcast and hope you never stop producing it. I count on the three of you to keep me up to speed on some of the most interesting virus research being published and look forward to downloading the podcast every Sunday evening. I also really appreciate the fact that you continued producing TWiV through the holiday break. I wanted to bring a paper to your attention that you might consider covering on TWiV. It just came out in the journal PLoS Pathogens and I thought it was really creative. Basically the group engineers a Dengue virus to be targeted by microRNAs that exist only in macrophages and dendritic cells. While the virus replicates normally in other cells, it is completely blocked wherever this specific microRNA is present. They then use that virus to infect mice and demonstrate that, without the availability of replication in macrophages and dendritic cells, the virus cannot spread in the animal. I found this strategy a really unique way to study the function of particular cell types in response to infection.

Keep up the good work,

Nicolas

If you're interested in the paper, it can be found here:

http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1002465

 

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