Viruses are going to save our butts.

Okay, no big shock to any of you– bacteria are becoming resistant to our antibiotics. One of the many enteric bacteria (cause kids to poop to death), E. coli, is racking up antibiotic resistance genes like theyre McDonalds Beanie Babies.

What the hell are we going to do?

Phage therapy.

Bacteriophage are viruses that eat bacteria… lol… Bring in the gators to eat the snakes.

For a long time it was ignored as an option in the US (eh, Soviet medicine). It doesnt help that the Soviet ‘science’ behind phage therapy is murky– yeah, they have commercially available phage therapies, but virtually nothing published about the details of the clinical trials/bacteria/viruses behind them.

But our antibiotic options are dwindling. We need something different, even if its only for very specific infections (O127:K63 E. coli), or very specific diseases (bacterial meningitis), or even if we can only approve of its use in animals, not humans. The real science has started:

T4 phages against Escherichia coli diarrhea: potential and problems.

So Denou et al have made a realistic list of potential problems of using phage therapy, and have tried to address those problems in their experiments.


1– If you are feeding people bacteriophages to get rid of pathogenic bacteria, how do you know that the viruses wont kill off all your commensal bacteria too?
One of the problems/good things about phages is that they are super-specific for a particular bacteria. The problem side of it, is that if you feed a sick person the wrong phage, nothing will happen to the pathogenic bacteria. Which means you need to culture someones poo before you know what to treat them with. Antibiotics have broad effects– you can treat immediately. Phage, youd have to wait a couple of days, and you might not have that kind of time. Happily, it turns out that you could conceivably make a phage mix’, and youd be sure of catching a majority of potential enteric bacteria for a fast hit. But what are the side effects of this?
They fed healthy mice specific phages, or a cocktail of phages, and cultured their poo — same kinds of normal bacteria in virus(+) as virus(-) mice. Contrast that to the healthy mice that got regular antibiotics, whose normal flora was ravaged.
Phage therapy actually looked better for your normal flora than traditional antibiotics!

2– Okay, feeding people viruses. That means the viruses have to survive the stomach before they get to their targets in the intestines. Hows that going to work?
Denou went back to their healthy mice, gave em some phage, and dissected their digestive system to see where the virus ended up. Yeah… not a whole hell of a lot survived the stomach. There was hardly anything in the intestines, where you want the phage to work.
BUT!
When they fed viruses to mice infected with bacteria, there was 10-1000 fold more virus where you want it (there are some limitations to this particular experiment, small mouse models of enteric bacteria suck, which actually means the effect is probably greater in humans). This is because phage therapy would be a self-amplifying ‘drug’! Even if just one phage survives the stomach and latches on to a pathogenic bacteria in the intestines, that one infection will result in thousands of more viruses!

3– What are the side effects?

I never take antibiotics. Its not because Im a virologist and I know antibiotics wont do anything to my viral sniffles. Im not allergic to them. Its not because Im, like, totally natural and GMO free and dont want to contaminate mah bodeh with toxic pharmaceuticals.
Antibiotics make me puke. Whenever I like, really need antibiotics, I have to have them injected. Otherwise, I take a pill, and 30 minutes later Im puking. Violently. For hours. Yeah…
Would phages be any better? Well, in this paper they were! Denou fed normal, healthy mice a ton of phage. A ton. They put it in their water at 109 infectious viruses/ml. The mice that got phage in their water developed at the same rate, had the same weight, same behaviors, as the mice that got plain water. Nothing kooky happened. No puking or poopy mice. Even though phage therapy for anything is probably decades away, this result alone is enough to get me excited.

4– Well, youve mentioned before that pathogenic bacteria got their tricks from phages. How do you know phage therapy wont just spread virulence factors and make things worse?

Easy! Pick phages for the cocktail that dont have any known virulence factors! Dont have em, cant spread em. You also need to take other phage-factors into account when picking out which ones are putative therapies– You know how some human viruses are hit-and-run (influenza), and some are hit-and-stick (herpes)? Phages are the same way. Some infect bacteria, go latent, and dont wake up for a million years (phage DNA is inserted into the bacterias genome, kinda like our ERVs!). Some phages infect and immediately go lytic, making lots of babies and blowing up their host cell. The latter are the ones we want in our mix.

Phage therapy might just be a viable solution to some of our antibiotic-resistant problems!

Comments

  1. #1 Jerry Coyne
    August 25, 2009

    If you’ve read Sinclair Lewis’s (and Paul de Kruif’s) wonderful novel Arrowsmith — HIGHLY recommended though a bit purplish — you’ll see that phage therapy is an important part of Martin Arrowsmith’s work

    I still think this is the best novel about a scientist ever written. Oh, and don’t forget de Kruif’s The Microbe Hunters.

  2. #2 Alex Besogonov
    August 25, 2009

    “Even though phage therapy for anything is probably decades away, this result alone is enough to get me excited.”

    That’s totally wrong! Phage therapy is routinely used in the USSR since 1930-s. In fact, phage therapy was developed BEFORE the antibiotics.

    And I know about it personally, my brother got the phage treatment for the festering burn wound.

  3. #3 JohnV
    August 25, 2009

    “Which means you need to culture someones poo before you know what to treat them with.”

    There are culture independent, fairly rapid tests that can be used to identify bacteria, especially if you have a guess. If you used some RT-qPCR sort of assay it wouldn’t be cheap but it would be powerful and a lot faster than culturing.

    “Pick phages for the cocktail that dont have any known virulence factors!”

    I guess I can come up a really nit-picky reason or two why that might not be enough BUT you should still be ok due to extreme specificity of phage.

  4. #4 Divalent
    August 25, 2009

    And a battle royale of evolution. Bacteria evolve resistance to one phage strain, phage evolves to evade resistance, repeat. (plus bacteriophages are way cool looking)

  5. #5 JohnV
    August 25, 2009

    I’ve seen people give presentations about phage therapy where they tried to get Staphylococcus to evolve resistance to a specific phage and they couldn’t do it. In their particular experiments, the binding target of the phage was apparently so vital (some cell wall thing) that resistance never appeared.

    Not like that would always be the case or anything, but if some turn out to be “unresistible” that would be pretty handy.

  6. #6 Peter Beattie
    August 25, 2009

    12 years ago, there was a BBC Horizon episode on phage therapy in Tbilisi, Georgia. Apparently, they’ve been working with phages as antibiotics for decades. Why is the West so reluctant to use them?

    If anyone’s interested, I could probably dig up that episode and make it available as a torrent.

  7. #7 Pockets
    August 25, 2009

    Would this method have an impact on other bacteria that would be really hard to kill? (think MRSA)

  8. #8 John Phillips, FCD
    August 25, 2009

    Peter Beattle, I remember that episode as well and have often wondered since, what with all the talk about antibiotic resistance flourishing, why we weren’t hearing more about them.

  9. #9 Optimus Primate
    August 25, 2009

    I hope I don’t come off as too cynical (or ignorant) here, but I have to wonder if the resistance to using phages might have something to do with profitability, in addition to the fact that the science has been questionable until recently.

    I mean, can you patent a phage? A certain type of treatment, sure, I can imagine patenting that — but the phage itself?

  10. #10 SVN
    August 25, 2009

    I approve of this post. The pharmacy college invited Dr. Wolcott to come in and talk about phage therapy last year. http://www.phagetherapycenter.com/

  11. #11 Epicanis
    August 25, 2009

    “That means the viruses have to survive the stomach before they get to their targets in the intestines. Hows that going to work?”

    I was coincidentally pondering that very question this weekend as I cared for a dog with a putative Clostridium gastrointestinal infection that seems to recur about the same time every year for no good reason…

    There was a recent paper on encapsulating probiotic bacteria to help them survive passage through the stomach better (I did a recent podcast on it…) and was wondering if a similar process could be used for phage therapy.

  12. #12 Ubiquitous Che
    August 25, 2009

    “Why is the West so reluctant to use them?”

    I think there’s more negative emotion attached to ‘virus’ than ‘bacteria’. The idea of ‘good’ bacteria vs. ‘bad’ bacteria is alive in the general population. The idea of a ‘good’ virus jars in my mind.

    That is to say: Intellectually, I know that there can be such a thing as a ‘good’ virus. But emotionally, I find it a bit of a contradiction in terms.

    To those less educated (yes, I’m an arrogant intellectual elitist, fuck you too), the emotional response would probably swamp out everything else.

    It annoys me how everything eventually boils down to PR.

  13. #13 SimonG
    August 25, 2009

    Optimus Primate:
    Various genes and cell lines have already been patented, so I don’t see why a bacteriophage couldn’t be. (Not saying that’s necessarily a good thing…)

  14. #14 Bryan Elliott
    August 25, 2009

    Have you read about / watched Kary Mullis’ TED talk on using DNA aptamers to attach alpha-1,3-galactosyl-galactose to microbes, thus rendering them immunologically tasty?

    Not saying that bacteriophages are a bad idea – just mentioning another option.

  15. #15 Ubiquitous Che
    August 25, 2009

    Holy crap! I just realized…

    Can you imagine what the anti-vax wackaloons would make of phage therapy?

    TEH DOCTAH WAN PUT VIRUS IN MAH BAYBAY????!!!!!!1111111eleven

    *shudders*

  16. #16 Optimus Primate
    August 25, 2009

    SimonG,

    Good point, and I definitely considered that, but it seems to me there has to be a staggering difference between patenting a gene or a cell line and patenting something that not only has the potential to, but certainly will, evolve.

    It definitely raises questions: Would they have to patent one specific and complete genome? At what point do you say, “This is no longer the thing you have patented”?

  17. #17 Divalent
    August 25, 2009

    Optimus said: “…there has to be a staggering difference between patenting … a cell line and patenting something that not only has the potential to, but certainly will, evolve.”

    Cell lines that can’t/don’t evolve? (I don’t think you understand the mechanism of evolution.)

  18. #18 Optimus Primate
    August 25, 2009

    Divalent,

    I do understand the mechanisms of evolution; I’m pretty ignorant about patented cell lines, though, so maybe you could nudge me along in learning about the subject.

    I can understand patenting a cell line, because I assume you can always point to an original culture and say, “we own the patent to any and all descendents (if that’s the right word) thereof.”

    I’m having a lot more trouble understanding how you would patent a bacteriophage, though. It seems a lot messier to me. It seems to me that it would be infinitely harder to keep tabs on who owns what, and when it’s sufficiently different enough to no longer be covered under the same patent. But maybe I’m missing something obvious here. You’re certainly not going to hurt my feelings by disabusing me of my ignorance, so, by all means, edumicate me.

  19. #19 Azkyroth
    August 26, 2009

    Do you mean to tell me you’ve made a virus that’ll disable their shields?

  20. #20 Stephen Bahl
    August 26, 2009

    In Soviet Russia, data publishes you.

  21. #21 BAllanJ
    August 26, 2009

    Does the treatment have to survive the stomach? You know, there are 2 access points to the intestines and only one of those is the stomach.

  22. #22 qbsmd
    August 26, 2009

    Discover Magazine had an article about this a while ago. They seem to be claiming that phages aren’t that specific, and can actually transfer genes from one bacterial strain to another. Could you respond to the accuracy of the article, and how it relates to your post?

  23. #23 Peter Beattie
    August 26, 2009

    If you know how to use a torrent, the BBC Horizon documentary is contained in this one:

    http://tinyurl.com/BBCHorizon

  24. #24 Peter Beattie
    August 26, 2009

    Although this one seems to be more responsive:

    Torrent

  25. #25 JohnV
    August 26, 2009

    qbsmd, the short answer is they looked at transducing phage an the problem would be avoided by not using transducing phage.

    Some phage can grab a piece of the chromosome on their way out of town (sort of), these are transducing phage and this phenomenon was (is still?) used in microbiology research.

    Presumably anything used for phage therapy would also be tested for host range prior to use.

  26. #26 Bill Riedel
    August 26, 2009

    Just finished reading a paper from experts in Poland and England on phage therapy – it answers most of the questions posed above and gives current status of phage therapy worlwide. You can find it at:

    pdf: http://www.ncbi.nlm.nih.gov/pubmed/19649921

    text: http://209.85.229.132/search?q=cache:949ZyYebEpIJ:www.biomedcentral.com/content/pdf/cd-1029603.pdf+/search%3Fhl%3Den%26q%3D%2Bsite:www.biomedcentral.com%2B%2522Bacteriophage%2Btherapy%2Bfor%2Bthe%2Btreatment%2Bof%2Binfections%2522&cd=1&hl=en&ct=clnk&gl=uk

    Bacteriophage therapy for the treatment of infections
    Current Opinion in Investigational Drugs 2009 10(8):766-774

  27. #27 Bill Riedel
    August 26, 2009

    I recently gave a talk to an annual gathering of MENSA entitled: Superbugs, phage therapy – getting beyond bullshit.

    Below is my summary and the websites should help readers find more information:

    Superbugs, Phage Therapy: Getting Beyond Bullshit!

    The following headlines might have appeared in Canada:

    1917: Canadian microbiologist, Felix d’Herelle, discovers natural nanotechnology, bacteriophage therapy, that can cure and prevent superbug infections and foodborne bacterial disease.

    2008: Canadians continue to suffer and die unnecssarily from superbug infections and foodborne disease because Canada is too venal to approve and use natural nanotchnology, bacteriophage therapy, discovered by Canadian microbiologist, Felix d’Herelle in 1917.

    While 8000 to 12000 Canadians are dying from antibiotic-resistant superbug infections annually the joke is on us, as some countries still practice technology discovered by the Canadian, Felix d’Herelle in 1917. Phage therapy uses highly specific viruses, bacteriophages, which are harmless for humans, to treat bacterial infections. Phage therapy is not currently approved or practised in Canada. According to a letter signed by a former federal health minister it can be made available legally to Canadians under the Special Access Program of our Food & Drugs Act! A discussion of phage therapy is currently very timely because of the release of the Canadian film: Killer Cure: The Amazing Adventures of Bacteriophage and the book by Thomas Haeusler entitled, Viruses vs. Superbugs, a solution to the antibiotics crisis? ( see http://www.bacteriophagetherapy.info ). Both references are available at Ottawa libraries.
    This file has dramatically changed because the US Food and Drug Administration has amended the US food additive regulations to provide for the safe use of a bacteriophages on ready-to-eat meat against Listeria monocytogenes (see http://www.fda.gov/OHRMS/DOCKETS/98fr/02f-0316-nfr0001.pdf ). Also http://www.cfsan.fda.gov/~dms/opabacqa.html . The idea that ready-to-eat meat can be treated if contaminated with Listeria bacteria while a doctor could not get a pharmaceutical grade phage therapy product when faced with a patient suffering listeriosis strikes this author as absurd especially considering the recent massive recall of ready-to-eat meat in Canada due to contamination with listeria. Information is available on phage therapy treatment in Georgia , Europe ( http://www.phagetherapycenter.com ), or Poland – ( http://www.aite.wroclaw.pl/phages/phages.html ) or more recently at the Wound Care Center, Lubbock, Texas ( http://www.woundcarecenter.net/ ) .
    Canada should establish ‘The Superbug Victim Felix d’Herelle Memorial Center for Experimental Phage Therapy’ to provide phage therapy to patients when antibiotics fail or when patients are allergic to antibiotics.

  28. #28 Amplexus
    August 27, 2009

    I was under the impression that phage therapy didn’t work because the actual amount of bacteria compared to the body as a whole is so ridiculously low.

  29. #29 Damitall
    August 27, 2009

    How quickly does the patient mount an immune response of neutralising antibodies to the bacteriophage? It seems to me that even if the ‘phage does its job quickly in the first instance, any further attempts to treat a recrudescent infection with the same virus (or even a related bug with a related ‘phage) may be brought to nought by the patients antibodies to the (non-self) ‘phage

  30. #30 Stephen Wells
    August 27, 2009

    The bacteriophage infects bacteria, not human cells, so it shouldn’t trigger an immune response, should it?

  31. #31 damitall
    August 27, 2009

    Stephen, the bacteriophages are “foreign” protein that will get picked up and recognised by the immune cells in the gut during whatever time they spend between being released from the host bacterium at the culmination of the lytic cycle, and finding new host bacteria.
    I guess one would aim at giving an enormous dose of ‘phage to kill as many of the pathogens as possible before any immune respose kicks in – probably takes a few days anyway.
    I know the Russions have been using phage therapy for decades, but haven’t seen any reports on its efficacy or otherwise.

    Also, if I remember correctly from years and years ago doing phage typing of staphylococci, some staphs could mutate to phage resistance very quickly.

  32. #32 qbsmd
    August 27, 2009

    qbsmd, the short answer is they looked at transducing phage an the problem would be avoided by not using transducing phage.

    Some phage can grab a piece of the chromosome on their way out of town (sort of), these are transducing phage and this phenomenon was (is still?) used in microbiology research.

    Presumably anything used for phage therapy would also be tested for host range prior to use.

    Posted by: JohnV

    If it were that simple, I can’t believe anyone would be concerned enough to write an article about it. Why were they looking at a type of phage no one would use? How do you ensure that a non transducing phage doesn’t evolve that ability? Also, even if it were specific to one bacterial strain when applied, how long would it take to evolve away from that specificity?

  33. #33 JohnV
    August 28, 2009

    The resident phage expert at work is on vacation so I’m waiting for an email back from him about some specifics qbsmd.

    The really short and not purposefully glib answer is “i have no idea why they chose to use transducing phage for their experiment but perhaps that is all that are currently available for S. aureus.”

  34. #34 Snoof
    August 30, 2009

    I’m curious – how does one make certain that a given phage will eliminate a bacterial infection? Wouldn’t there be a possibility of achieving some kind of bacterium/virus equilibrium?

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