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    • CommentAuthorKosmopolit
    • CommentTimeMar 10th 2011
     (8634.1)
    I suspect some people would shift to snorting other psychoactive dugs.
  1.  (8634.2)
    That kind of blows my mind. Cocaine is not a big molecule and it is lighter than sucrose. How do you make your neuron receptors capable of blocking something that small without fucking up a larger process? Cocaine plugs into the dopamine transporter proteins so they can't drain the good stuff. It is basically Dennis the Menace who confuses the teacher so that all the rabbits get loose and it is a party. Is it really a good idea to make my macrophages eat Dennis the Menace?

    That's not really a virus question though. And the article was paygated so I've only read the abstract. Did they measure negation of cocaine's effect in any matter other than how much the mice moved around? Maybe the mice were still feeling good but just in a mellow way. Cocaine like everything that touches a protein has more than one pathway. Just thoughts.
  2.  (8634.3)
    I don't know; maybe not. Don't people get addicted to lots of things simultaneously: you know, drink, cigarettes. drugs, gambling, etc.?

    Well, I meant cocaine addiction alone. Gambling isn't going to be something we can really make a vaccine against, but artenshiur's right that there are different types, and different levels, of addiction. Cocaine and crack are very difficult habits to break because of their inherent qualities as dopamine agonists. Even people who want to get clean have a lot of trouble doing so. This vaccine provides another tool to help them.

    However, just a note about cigarettes: I have heard of some work being done to make antibodies to nicotine, similar to this. We'll see if it goes anywhere.

    I suspect some people would shift to snorting other psychoactive dugs.

    The key part here is the "some." If this works to help some people get clean from a drug addiction that's hurting them, it's fulfilled its purpose.

    But, remember...the same vaccine strategy that worked for cocaine could work for other drugs as well.

    Did they measure negation of cocaine's effect in any matter other than how much the mice moved around? Maybe the mice were still feeling good but just in a mellow way.

    There isn't really a way to measure mouse emotions, just behavior. Still, the mouse response to cocaine is well known, and this kind of antibody vs. cocaine treatment has been tested in humans before. Instead of a vaccine in that case, it was just a prepared antibody, so "immunity" was not permanent, but it definitively reduced the potency of the high. That effect in humans corresponded to the same changes in mouse activity that were observed in this paper.

    When they say they measured how much the mice moved around, they don't mean a small effect. Looking at the figures, the mice that were high ran all over the area like frenetic little junkies for the duration of the experiment. The mouse trackers are almost black with the tracings of their routes. The control mice, like all normal mice should, hugged the sides of the enclosure and moved far less. It's such an extreme effect that it seems pretty clear that one group of mice was high, and the other was not.

    How do you make your neuron receptors capable of blocking something that small without fucking up a larger process?

    I saved this for last because it's a cool question.

    The thing about this strategy is that it uses the antibody response. By using antibodies, it can get the cocaine to be pulled out of the bloodstream before it ever reaches the brain, and so there doesn't have to be any interference with normal neural processes. The brain is, so to speak, surrounded by friends in the bloodstream who take away its keys so it doesn't make a mistake.

    Also, because it's an antibody response, it's specific to cocaine and cocaine alone. Antibodies are cool like that.


    Finally, one point that some of my colleagues brought up is that this could lead addicts to just try and take more cocaine in order to overcome their immunity. While that's true, after every challenge to the immune system on a specific antibody response, there's a jump in the level of that antibody. So if I try to get high one night and it doesn't work, then I take double the next night, the spike in my antibodies might prevent that too.

    The problem is...if I keep trying too hard, I might take way too much cocaine and die, either from an extreme immune response, almost like an allergic reaction, or from the cocaine itself. That problem *should* be mitigated by the antibodies, which ought to keep the cocaine from damaging anything, but since they didn't test OD dosages on the mice, we don't really know.
    • CommentAuthorFan
    • CommentTimeMar 11th 2011
     (8634.4)
    By using antibodies, it can get the cocaine to be pulled out of the bloodstream before it ever reaches the brain, and so there doesn't have to be any interference with normal neural processes.

    I see. That is cool.

    Do you have any idea what the smallest molecule is that could be targeted: alcohol?

    By the way, did you know, on the subject of 'impulse control': sometimes, a Parkinson's patient wants to tell their body to do something, but it doesn't do it (so they're unable to do that). To counter-act that, a typical Parkinson's med is a dopamine agonist: for which, the side effects can include excessive shopping, gambling, etc.
  3.  (8634.5)
    Do you have any idea what the smallest molecule is that could be targeted: alcohol?

    That's pretty complex, actually. Antibody targeting isn't easily understood and there are still a lot of open questions. You tend to hear people throw words around like "heft" or "bulk," because the size of the molecule doesn't seem 100% important, it's more like a combination of volume and mass, so something like "density." I'd call cocaine a pretty hefty small molecule.

    Alcohol's real tiny though. I honestly don't think anybody knows what the definitive answer to this would be, which to me means you've just found an experiment that needs to be done.
    •  
      CommentAuthorBrianMowrey
    • CommentTimeMar 12th 2011 edited
     (8634.6)
    Finally, one point that some of my colleagues brought up is that this could lead addicts to just try and take more cocaine in order to overcome their immunity.
    Or put a tube in their skull to inject cocaine directly behind the blood-brain barrier? *Edit actually I am going to go ahead and use the subsequent story idea I added to this comment, nvm*
    • CommentAuthor256
    • CommentTimeAug 15th 2011
     (8634.7)
    @John - this might not be sufficiently exotic to warrant resurrecting the thread, but I wondered if you had any comment on MIT's release about a general-purpose anti-viral drug.

    Is this really radical and game-changing, or more like an incremental improvement? It's always hard to get a good picture outside your own field. Any speculative consequences of a Whitechaplain nature?
    • CommentAuthorRenThing
    • CommentTimeAug 15th 2011
     (8634.8)
    @256

    I wondered about that article because it seemed to cause almost as a kerfluffle among my friends list as that idiotic "Scientists cure cancer and NO ONE TOLD ABOUT IT" post that went around a few months back.
  4.  (8634.9)
    It should be a legit important thing.

    With antibiotics, for example antibacterials, the trick is finding a place in the bacteria's workflow that makes a unique marker and homing in on that for the attack. The limitation is that the not all bacteria have the same workflow, and finding molecules to hit just that process without side-effects is expensive and hard, and bacteria are mega hardy even aside from selection-based resistance.

    For dsRNA, the perfect detector molecule that activates on contact is already something our cells have been making all this time. The MIT drug, by their report, doesn't need to do the heavy lifting, it just straps a bomb onto the mechanic.

    The big question is: why does our immune system have a device to intercept viruse workflow with 100% efficiency that was leading to a weak defense process instead of agressive cell destruction? Our cells have some splaining to do :(
    •  
      CommentAuthorNygaard
    • CommentTimeAug 15th 2011
     (8634.10)
    @BrianMowrey I have vague recollection of someone claiming that 100% immunity is generally not selected for - the evolutionary pressure is actually toward partial immunity; can't even remember if "immunity" in this context applied to individuals or populations now. Aaagh. Tired and confused. Maybe I can track it down later...
  5.  (8634.11)
    You might be right.

    On the other hand we aren't aware of it, but our immune system already includes some total warfare stuff built in. For example, in a microscopic environment one of the most important concerns of a cell is iron acquisition. If a bacteria is floating around in our blood, it needs to get iron or can't be productive. When our bodies go into immune response, our liver chemistry changes and iron becomes immediately scarce. So by default, are a harsh and awful environment for bacteria to grow in. But lots of bacteria have amazing kung fu iron-stealing technology already. Our blood is like a desert and bacteria are like irrigation farmers. So we still get sick. My point just being, the immune system isn't pulling any punches on the iron resource front.

    So why is it phoning it in with dsRNA response? From the MIT article, we learn that the dsRNA targetor sets off a complicated defense mechanism that many viruses know how to block. Why such a shitty defense? It is an intersting question maybe.
    •  
      CommentAuthorJohn Skylar
    • CommentTimeAug 15th 2011 edited
     (8634.12)
    I was debating sharing that paper in this thread, but I have serious reservations about it.

    What they have done here is quite remarkable. This is in my field, as I generally focus on host sensing of viral RNA. I think it's quite courageous of the authors to call this a therapeutic, however.

    It's a protein, not a small molecule. That's a big deal in drugs. It means it can't be delivered orally, for one thing. It probably can't even be delivered in the bloodstream. Your body could also potentially see it as a nonself molecule and make you immune to its activity (though I believe they have skirted that issue).

    So, you can see that the mice in this paper had to be injected intraperitoneally in order for the thing to work. That's disappointing. I don't personally want to get gut-stabbed any time I have an RNA virus infection. Now, for something like Ebola, I'd take the gut shot. Rhinoviruses I think I'd wait out.

    Furthermore, viruses readily evolve defenses against just this kind of killing mechanism. Escape mutants (read: resistant mutants) are probably easy, as the proteins that they used are just bits of host proteins stapled together with recombinant genetics.

    So it's weak to escape mutants, difficult to impossible to deliver, and it uses a mechanism that many viruses can already evade effectively. I don't give this a lot of points for calling itself a "therapeutic." It's an interesting proof of concept, though. Now what they really need is a small molecule that activates the same pathway but during a virus-specific condition.
  6.  (8634.13)
    It's a protein, not a small molecule.
    ...
    It's an interesting proof of concept, though

    Exactly. Like how in antibacterials, every targetable process is a potential array of drugs grouped by action mechanism, the advent of DRACO is also the advent of later things that have a better way of doing the same thing. Right?

    Yayyy

    What was really news to me though was the article said all animal viruses have a dsRNA production stage -- because, that's a broad spectrum action mechanism just by definition. I usually glaze over the molecular part of the textbook when I am pretending to be a biology student, but I know viruses have lots of variety in what format they choose to store their code in in their actual virons. I had never read anything about them universally using dsRNA during replication. But are you saying it would be easy for animal viruses to workaround that? Or, that actually lots already don't need a dsRNA stage for replication, and the article exaggerates the broadness there?
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      CommentAuthorArtenshiur
    • CommentTimeAug 15th 2011
     (8634.14)
    @Brian, I'm no expert, but just off the top of my head it doesn't seem necessary for a virus to circumvent the dsRNA stage to develop a resistance to DRACO if, for example it can inhibit apoptosis.
    •  
      CommentAuthorJohn Skylar
    • CommentTimeAug 15th 2011 edited
     (8634.15)
    If this is the first step of a new class of antivirals, they will either have to be small molecules that activate an extant DRACO-like protein (unlikely, but possible) or there will have to be some new development that allows rapid and effective delivery of protein-based drugs (this may be easy to do with a nanoparticle, so perhaps that will happen in the next few decades? I hope so!).

    To address more, I'd say it's not strictly true that all animal viruses have a dsRNA stage. There is a paper that says DNA viruses produce dsRNA species through some weird RNA polymerase III-mediated mechanism, but...I dunno. That idea has always seemed weird to me, and it's a pretty new idea anyway.

    Artenshiur has a point that viral evolution tends to involve the quickest path to resistance (I was tempted to say "path of least resistance" but then realised that this analogy might be very confusing). I was referring to evolving an inhibitor of apoptosis, or an inhibitor of DRACO itself. Most animal viruses already have proteins that inhibit things like the proteins that inspired DRACO, so it wouldn't be very difficult (well, I imagine it wouldn't be) for those proteins to evolve a broader specificity and function against this construct.
    • CommentAuthor256
    • CommentTimeAug 17th 2011
     (8634.16)
    Cheers for the comments, John - always good to hear from someone who knows their stuff.

    Depressingly, the nuttery has begun.
  7.  (8634.17)
    So, anybody seen CONTAGION?
    •  
      CommentAuthorJ.Brennan
    • CommentTimeSep 16th 2011
     (8634.18)
    @John: I saw Contagion the other day. I went with friends and hadn't heard anything about it besides the name. I was pleasantly surprised that it wasn't another Outbreak. It felt far more realistic than any other disaster movie I can think of. It showed the strata of response, impact, and the actual time it takes to deal with an event as massive as a pandemic. I came across an awesome TED Talk on preventing pandemics via AICN of all places while reading a couple interviews with the director and writer.

    I'd like to say I found the Jude Law character a bit of an overly heavy-handed swipe at anti-vaccination proponents, but given what the CDC has been documenting lately I don't think that swipe can be too heavy at all. Rather frightening when thinking about some of the nastier things that are normally vaccinated against.

    But my opinion is that of a layperson, I'm very curious about what people in the fields portrayed thought of it.
    •  
      CommentAuthorJohn Skylar
    • CommentTimeSep 16th 2011 edited
     (8634.19)
    I felt that while all of the science occurred at movie-speed, it was the most scientifically accurate and realistic portrayal of such an event that I've ever seen.

    I happen to study the virus that the movie's MEV-1 was modeled after. It's called Nipah virus, and basically, this movie could have happened when it first appeared in 1999. It would've worse than in the film, then.

    While they sped up the science in the movie, they also sped up the virus. Nipah virus can have about a week of incubation period, as well as two weeks of profoundly horrible disease before either resolution or death (in 40-70% of cases). However, Nipah doesn't display sustained human-to-human transmission. Thankfully.

    I think Jude Law's character was an accurate portrayal of the kinds of people who pop up around genuine information about virology all the time. There's always someone out there who was once looking for answers, but then latched onto the answer that stood to benefit them the most. They are either fooling themselves, or aware of it, and either way they end up playing to people's fears. There were people who advocated that Chronic Fatigue Syndrome patients should take anti-HIV drugs when one study said a retrovirus similar to HIV might maybe cause CFS (this was later found to be a lab contaminant). There were people who said you should overload your body with zinc when you get a cold because one study showed zinc could kill rhinovirus in a tissue culture dish (later, it didn't work in mice). There is a measles virus epidemic (incidentally, measles and nipah viruses are somewhat related, sequence-wise) in the UK because parents believed it would cause autism (disproven by numerous studies). Measles virus has a reproductive coeffcient (r-naught) of 15, and you can get it by being within 100 feet of a patient. All of these things are damaging, dangerous, and harmful, not just to the patient but to others around them. They are also all refuted by science.

    But there is no science that can compete with the heartrending emotions of a mother toward her child, or the basic instinct that encourages you to take control of your life when you feel it's threatened. And because of that, this sort of person will always be looking for answers, and the ones who don't find those answers in science, will find them in all the wrong places.
  8.  (8634.20)
    Dusting this thread off because damn this thing is WEIRD. Weird, weird, weird. People are calling this a possible "fourth domain of life." There are genes in this thing that literally share NOTHING with the rest of life on this planet. I can't believe I'm actually typing those words and believing myself. I super need to read this paper, but damn.

    Giant viruses open Pandora's box
    Genome of largest viruses yet discovered hints at 'fourth domain' of life.