Friday, January 21, 2011

17 Video: How bacteria "talk" and how to make them shut up

Another interesting TED talk today.

This one is by Bonnie Bassler, who discovered how cell populations use chemical powwows to stage attacks, evade immune systems and forge slimy defenses called biofilms. For that, she won a MacArthur "genius" grant.

At the beginning of Bassler's slideshow, she displays Lyme Disease as one of the bacteria we are in a war against, and she proceeds to explain how bacteria communicate with one another to invade us.

Once bacteria reach a certain population level after dividing, they release a chemical message that triggers their virulence. This communication is known as "quorum sensing" and many bacteria do it.

There is also another bacterial communication method known as "efficiency sensing" which is not mentioned here, but worth investigating.

I highly recommend taking 18 minutes out of your day to watch this video, and think about the implications of her research for Lyme Disease patients - as well as for anyone needing to treat bacterial infections in the future.



Additional Resources:
Bonnie Bassler's Homepage: http://www.molbio.princeton.edu/index.php?option=content&task=view&id=27

17 comments:

  1. Wow, I never heard of possible antibiotics from this.

    Did you read the persister cell article from Kim Lewis?

    John S

    ReplyDelete
  2. Yes, it's fascinating, and Bassler is an entertaining presenter. I hope everyone who comes through here clicks "play".

    Sorry, John S, I haven't had a chance to read the article yet. I will take a look at it tonight.

    ReplyDelete
  3. persister cells
    quorum sensing
    round bodies
    blebs
    biofilms made of borrelia
    biofilms made of a mix of pathogens
    symbiosis in all its forms and iterations
    intracellularity
    the cascade of genospecies and strains
    quiescence and dormancy
    transfections
    borrelia stuck in B cells with CLIP attached
    the role of toll-like receptors&inflammation
    the growing list of possible co-infections
    xmrv
    new view of PANDAS that goes way beyond strep...
    molecular mimicry

    guess I'll stop here but I could go on --you just need a little proof: not just proof it is happening but proof that treating it will end the illness. that's the problem.

    ReplyDelete
  4. Anonymous, that's a good list of things that bear mentioning, absolutely - and I intend to discuss them here over time. It is rather like unpeeling the layers of an onion over time, and not even a static onion - many different factors are involved at different points in time.

    The first thing that needs to be communicated to the media and the world at large is persistence. Proving persistence and what Borrelia can do is the most important thing that will help Lyme patients in securing treatment.

    The second most important thing is research into coinfections and synergy due to them. Right now, many doctors don't even know to look for coinfections, and could dodge some of the politicization of their jobs around Lyme while still providing care for their patients if they worked to diagnose, test, and treat coinfections.

    The research dollars have to go towards helping people who have been harmed and into learning more about the organisms themselves rather than into vaccine development. In fact, not knowing as much about Borrelia or their clinical trial subjects as they should have is part of what makes the vaccine scene a raw deal.

    The trick, of course, is convincing those with the money to put it in the right places. At the moment, vaccines are considered far more profitable than new antibiotic development. But if we change the way antibiotics go through the R & D and certification process, they can be profitable, too.

    If I have to live in a capitalist society and this profit is the driving force for technological advances, I'd like to see it put to use in antibiotic development sooner rather than later.

    It seems to take longer to get a number of good solid vaccines together for pathogens outside of the flu than it takes to develop a new antibiotic. Many years later: Still no Syphilis vaccine, no HIV vaccine, and others. In that same time period, a number of new antibiotics came into being. I know where I'd rather invest.

    ReplyDelete
  5. In other words, prove what is happening first, then come up with treatments.

    Part of what has harmed progress in this area for Lyme patients has been quoting the same 4 clinical trials pointing out "longterm antibiotic treatment doesn't work" when longterm antibiotic treatment and persistence are two separate issues.

    ReplyDelete
  6. Don't you think that looking at persistence in isolation could be futile, given the large number of people treated for years without cure? Persistence could be the imperceptible spark that incites an immune tsunami. What if it is easier to treat the tsunami --by its nature outsized and blatant and in your face-- than the spark which, though present and incendiary, we cannot find? Is it possible that the yin and yang nature of the fight has prevented a view of the system overall? What if a tiny amount of infection has caused a huge inflammatory response? What if that infection is hiding in B cells because a glitch in the system has prevented T cells from recognizing the foreign invader, and thus, from finishing the job? What IF to get rid of the persistent infection, you must treat immune dysfunction first? So no ...I don't think it is as simple as you say, or that by conceiving the issue along the old paradigms of the fight, raging fruitlessly for 30 years, you will get what you want ... unless of course, it is really as simple as you suggest. I mean, what if you prove persistence, but it still won't bring a cure?

    ReplyDelete
  7. regarding the four trials cited, they do in fact show benefit to retreatment for fatigue and pain --and thus, in fact do not match with the wording of the conclusions rendered or (in the case of two of three authors) forced down those authors throats by the powers that be. There is actually ample evidence in these trials to suggest a benefit to retreatment and longer treatment --and in the case of the Klempner trial, serious issues with methodology. But as you say, the outcome of these trials must be detached from pathophysiology --what is the mechanism of the benefit? That question the trials do not address.

    Still, to detach infection from immune response is just plain wrong-headed. We are 10% by weight bacteria, and most of those organisms are beneficial. The question is --which are the pathogens, and how do those pathogens do us in? In every case, inflammation and cellular immunity are going to play a role.

    ReplyDelete
  8. In response to the first Anonymous comment following my last comment:

    You bring up good questions. I don't think persistence can completely looked at in isolation - I've indicated that elsewhere in this blog, stating that if in studying persistence immune dysregulation was revealed as part of the cause for patient symptoms that would be useful.

    I've made basic statements about what needs to be proven, but know that the scientific research behind proving them is anything but simple. So far my writing on persistence has been more of a rant about needing to prove it rather than about what is required as proof. Perhaps methods of acquiring this proof is something I could address in this blog in more detail.

    So far I've been treating this space like a blog and not a book - I write what comes to mind at a given moment. I also think about providing an overview or survey of different topics first then branching out or drilling down as I go. But largely, I'm playing it by ear.

    Re inflammation and the immune response... Looking at inflammation causing patient symptoms alone is problematic. Inflammation can come from different sources. Is inflammation coming from membrane lipoproteins on Bb, triggering B-cell mitogens and cyotkines? Is it coming from somewhere else - some comorbidity? What happens if the host has an impaired immune response and is infected but doesn't produce a solid antibody test result? What if the host has neuroborreliosis and the inflammatory response is compartmentalized to the CNS?

    Too many factors. Each has to be untangled and its implications examined in the host as well as the infecting agent. Virulence, genotype, pathogen, synergy - all these come into play with the invading organism(s). The host's genetic profile, host immune response, and previous antibiotic exposure that modulates that immune response also are examples that play a role in fighting off pathogens.

    What if the inflammation alone is treated (say with anti-inflammatory agents and steroids) and there is still a latent or persistent infection in host tissues which begins to wreck havoc? Steroids induce immune suppression, and can leave the patient open to other infectious agents with greater ease. So I would be very careful with pursuing this as a sole cause and would have to consider other factors.

    You said, "I mean, what if you prove persistence, but it still won't bring a cure?" Well, from where I sit, if the entire medical community knew there was persistence and it was proven, that would at least be progress. Then the next step could be to work on solutions for treatment - if not a cure.

    The tone and nature of your comment suggesting this is not so simple is correct - it is not. One has to start somewhere.

    ReplyDelete
  9. In response to the second Anonymous comment just above my previous comment:

    I agree with your assessment that the outcome was that patients had improvements in fatigue and pain from prolonged treatment, and that the conclusions often cited do not match or mention this. I do think that these same four trials are cited too often including the Klempner trial and that more studies are needed including more double-blind controlled studies with larger populations.

    Putting together more well-designed studies is going to require solid testing and methodology, as well as subjects who have a clear case definition and proven serology/culture going in. And sometimes control subject health profiles are not completely healthy or Bb response-free and thus skew the data... Accurate serology is an issue for test subjects as much as it is for patients.

    You said, "We are 10% by weight bacteria, and most of those organisms are beneficial. The question is --which are the pathogens, and how do those pathogens do us in? In every case, inflammation and cellular immunity are going to play a role."

    Good question. There is a complex ecosystem inside each one of us. I couldn't even really say that all organisms are beneficial under all circumstances. Some organisms are neutral and have a symbiotic relationship with other beneficial organisms and some participate in mutualism; some organisms have no marked negative effect on us until they achieve a certain population threshold.

    The more I learn, the more I learn that there's a lot I don't know... and there's more that everyone else doesn't know, either. Regardless of how much anyone knows, though, it is good to continue the pursuit of knowledge.

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  10. It is a very complicated problem, as you say.

    It is TRUE that if you suppress inflammation infection would spiral out of control: The murine studies on borrelia and toll-like receptors show that to be right.

    But here's the thing: Most researchers, even most of the IDSA researchers, don't actually deny that organisms can persist. They just deny that those quiescent remaining organisms are driving the continued symptoms --they say these persisting borrelia are too few, and too dormant. And they would cite the research on quorum sensing to support their case.

    As I see it, it is not really persistence you need to prove, but rather, the mechanism by which persistence at the low level research suggests drives the disease. Inflammation is not the only immune mechanism --cellular immunity or dysfunction thereof can play havoc, too, and persistent infection could drive it in an endless loop.

    Also: Treatment studies without knowing more about pathophysiology can work against you, because --hell-- they are just empiricism on top of empiricism, more wandering in the dark.

    I contend you need more basic biology to target such studies, strategically. If you were to move forward without that, you would need an elaborate methodology with many variables and large enough numbers of patients to test for many possibilities and separate the data from the noise. And with Lyme patients still so ill-defined, with no test extant for active infection ...

    Makes my head spin. A hundred million dollars would help.

    ReplyDelete
  11. Anonymous - small request: Can you please give yourself initials or some identifier so as to prevent future confusion if more than one anonymous poster responds and I can address their comments a bit more easily? Thanks.

    I've gotten the impression that while IDSA researchers have said the organisms persist, they don't think that their presence is significant. Not all researchers think so, though.

    Have you seen this study by Barthold?
    http://aac.asm.org/cgi/content/full/52/5/1728?view=long&pmid=18316520
    I'm looking for studies along these lines.

    Research is needed on pathophysiology and basic science. Willy Burgdorfer has made similar remarks about this and the need to go back to the drawing board on serology. I think improving serology is helpful for early detection and diagnosis, but it's not so useful for treatment esp. where there are resistant organisms. And some genotypes of Borrelia are more resistant than others to specific classes of antibiotics - including ones doctors typically use to treat LD.

    If Barthold's study is correct, and PCR and serology tests can't be relied upon for determining how successful antibiotic treatment is, and lipoproteins from the remaining spirochetes are what is causing symptoms in patients - then at least there is a clearer target to aim for in further studies.

    I'm hoping with a better understanding of these infections and proof that they are causing patients' symptoms will lead to fewer medical professionals telling patients they need antidepressants and their symptoms are all in their heads. Even if it isn't fully understood what is happening yet.

    Sure, a hundred million dollars would help. Less than that could do some good, too. Someone just has to decide what is a priority that will help more people - preferably sooner rather than later. The longer the wait for effective treatment, the greater number of people there are with greater disability and suffering.

    BTW, thank you for posting your comments and discussing the role of immune response and cellular immunity/dysfunction in persisting symptoms. Some people are afraid to mention the immune angle of this disease for fear it will mean that they're on the "bad guys" side. I don't think mentioning it means this at all. I think it's likely a combination of factors give rise to ongoing symptoms, but persistence of the organism seems to be a necessary precursor and ongoing contributor in the process.

    More dialog like this is needed. Let's consider all the angles.

    ReplyDelete
  12. Other,

    My comments refer specifically to the Barthold work, with which I am extremely familiar. Barthold's findings of small numbers of dormant, quiescent spirochetes within collagen across the range of mammalian species following treatment have been well-known inside the mainstream (though published only recently) for decades. There is no great rush to debunk Barthold, whose research really is beyond dispute --Barthold himself being an especially meticulous and careful scientist. What his critics say, however, is that these spirochetes are not active enough and not numerous enough to cause disease. (to wit: issue of quorum sensing.) Barthold theorizes otherwise, contending that the small numbers of chetes may provoke an outsized --but heretofore undetected-- cytokine cascade that causes the disease. Barthold would classify this cascade under the heading of INFLAMMATORY response. This is his theory --and a powerful one that should be explored.

    You may have noticed that NIH has begun to test the Barthold work with a study of xenodiagnosis, but patients are protesting that study for fear that the ticks used might not be as naive as claimed: And really, given the confusion over pathogens involved, who knows?

    Other theories of persistence to pursue include the impact of round bodies AND the work of Newell, who finds Borrelia stuck inside B cells because of a dysfunction in MHC.

    In the case of Newell, especially, the notion is that persistent infection can never be cured without correcting the recognition dysfunction of MHC. In other words, even though the disease is driven by persistence, Newell says you have to correct the immune problem first.

    And by the way, both she and Barthold insist you can never entirely clear borrelia infection with antibiotics alone --you need the immune system to do the final kill, and so you must have an immune correct FIRST, even if the driver is persistence.

    Or it could be the round bodies... but whatever it is, it is complicated --and simply fueling the fight of persistence versus immunity isn't helpful.

    There is a difference between what patients use to get well right now --the ax in the form of huge quantities of endless suppressive antibiotics-- and what they should want for the future --the chisel, which could well be an immune correction that allows infection finally to be resolved. There should be a divide between the effort to protect a Lyme doc in the here and now and the direction of research for the future --but it is hard for a lot of people to understand this.

    I agree with you that if we knew the mechanism we would have a target --and that is why I am so equivocal if not outright squeamish about the continued treatment trials some patients are calling for.

    What are they treating? --and if they don't really know, there is a big risk that study could bury them deeper and darker than ever before. anonx

    ReplyDelete
  13. anonx,

    It seems like a combination of immune system repair/replacement plus antibiotic use together would be the best approach - a two-pronged solution.

    In absence of other treatment and based on what we do know, I think LLMDs need to continue to treat patients with antibiotics but that shouldn't stop research in immune factors.

    As a Lyme/coinfection patient myself, I've never been completely comfortable with the idea of open-ended treatment, and periodically I have to stop treatment due to digestive problems (even with extensive probiotic treatment and dietary restrictions) or allergic reactions to the drugs.

    I'd like to know there is a way to totally eradicate the infection and its effects - not just have periods of remission and relapse. But after stopping the antibiotics for a while - and feeling nearly normal - the symptoms do eventually return.

    What do you suggest for the next set of trials if not treatment trials? I'm curious.

    You asked, "What are they treating?" and that deserves a closer look. A better map of the terrain of possibilities needs to be spread out before us, and the most promising candidates selected.

    ReplyDelete
  14. Given current state of knowledge immune treatments could backfire, big time --as the literature shows. If you look at the work on toll-like receptors you find a genetic curve for inflammatory response to borrelia ranging from almost nothing to off-the-charts and everything in between. That is just one immune parameter, and there are many others. These parameters could vary for every infection or strain and every person. Therefore it is possible with current state of knowledge that suppressive abx are really the best we have... there needs to be a crunching of data to understand what we are looking at --otherwise, it is just stumbling in the dark. The amazing thing is that the IDSA crew has gotten away with such a grotesquely oversimplified story of this disease for so long --and that to explain it, they perpetuate the explanation that it is a psychosis instead of a complex spectrum of infection and immune response. But by giving an oversimplified rejoinder, patients have hurt their cause, too.

    In a gross way one could do a study treating infection, treating immune issues or treating both: but this would be very crude without more data up front.

    anonx

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  15. And it could be that they are persisting in biofilms and they haven't been looking in the right place there either.

    John S

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  16. John S, both you and anonx have given me much to think about. I'm working on a post on issues of persistence and suspect it will end up being an ongoing issue or multi-part post. It's going to take a while to write it out and I'm considering an overview of the issues first then drilling down.

    In the meantime, I'm not entirely doing well here (well, I'm usually anyway, it's a matter of degree) and am not sure how often I will be able to post. I may post noteworthy material from other sources if I am unable to get something of my own together soon enough.

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  17. The disease symptoms can be lessened with antibiotics, but then return when the drugs are stopped, as I have experienced. Therefore they aren't just remaining dormant. What is the mechanism they use to do this is question. My opinion is that Lyme is probably using biofilms and persister cells, as in Kim Lewis's theories.

    Is an immune response involved? Who knows, but I tend to believe not.

    John S

    ReplyDelete

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