The Enemy of My Enemy

The Enemy of My Enemy

✇ Nearly 125 years ago, a British bacteriologist observed that the holy waters of the Ganges and Yamuna had curious bactericidal properties, limiting the spread of cholera. It took another 20 years before two microbiologists independently proposed the existence of viruses. Observing small clearings on a lawn of dysentery-causing bacillus on an agar plate, d’Herelle coined the term bacteriophage for the virus that devours bacteria; now affectionately abbreviated to “phage”.  

A Voracious Appetite: Found everywhere bacteria exist- in the soil, deep inside the earth’s crust, within the bodies of animals and plants, and densely packed in the oceans, there are an estimated 1×10^8 different types of phages, each infecting only a specific type of bacteria.  Almost comical in appearance, a phage has its genetic material tightly packed into the capsid head, that can be injected through the stalk-like tail into the bacterial cell. Once inside, it can stage a peaceful coup (lysogenic) or burst open the bacterium (lytic) when it multiplies. It is estimated that there are up to 10^32 phages in our biosphere, destroying half the bacterial population every 48 hours! 

Microbe Hunters: d’Herelle and his fellow scientists were quick to grasp the potential of phages as antibacterials. After consuming a preparation to confirm its safety, he administered the phage to a 12-year old boy with acute dysentery. The boy fully recovered. This set off a golden era in the commercial production and use of phages, centered largely in eastern Europe and Russia. In the 1940’s, companies like L’Oreal and Eli Lilly marketed products with catchy names like Bacté-coli-phage and Staphylo-gel! There were set backs (d’Herelle’s science partner in Tbilisi was executed by Stalin) and with the discovery of antibiotics in the 1940’s, Western scientists lost interest in this line of medical research. Unfortunately, most published studies (written in Russian or Georgian) are not accessible to the western world and clinical trials did not follow current protocols of controls, making them difficult to assess retrospectively. 

Evolutionary Arms Race: With growing resistance to antibiotics, a resurgence in phage therapy may be warranted. One advantage to phage therapy is that when bacteria develop resistance to a phage, we should be able to rapidly select (in a few days or weeks) for mutant phage versions in a tit-for-tat evolutionary arms race! Phage therapy is already around us in some form:the USDA has approved a phage spray (ListShield) that can be used on cheese, chicken, and processed meat to prevent infection with Listeria. Is this the start of a new phage in the way we treat bacterial infections? 🙂

REF: (1) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC90351/#B21

(2) http://cid.oxfordjournals.org/content/48/8/1096.full

Image: T-phage infecting E. coli , false-colored EM via http://goo.gl/fmDVCi

#ScienceSunday  

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115 Responses to The Enemy of My Enemy

  1. Rajini Rao says:


    Thanks. I sneaked in a pun at the end, too 😀


  2. I loved reading this and had never heard of phages but boy, do they ever make sense in my head now. It is grand to find one of the “unknown mysteries” as to why those waters were deemed so beneficial for many years.  Makes me wonder if other “miraculous waters” and spas also promoted growth of phages and thus more benefits.


  3. Great post, Rajini Rao! I am surprised and a little disappointed that I never heard of this before, but I like that we have a potential “new” weapon in our war against resistant bacteria.

  4. Scot S says:


    Are there Phages that are effective against “Drug Resistant Bacteria” strains? 

  5. Satyr Icon says:


    Yes, it’s a new phage, and I can’t wait to turn the phage when this book is finished being written 🙂

  6. Rajini Rao says:


    BJ Bolender and Michael Verona I’m glad I wrote this..thought it would be “old hat”! It’s possible the mineral-rich spa waters are a breeding ground for lots of microbes and phages, good point. I should add that there are challenges with phage therapy as well (the two references go over them in detail)..for example, we could generate neutralizing antibodies to take them out of circulation. Still, it would be great to see more effort directed towards this line of research. 

  7. Rajini Rao says:


    Scot S , there should definitely be phages that target bacteria resistant to antibiotics. Here’s a news story of curing a gangrenous wound that was not responding to antibiotics using phage (keep in mind that it is a case study not a clinical trial): http://www.popsci.com/scitech/article/2009-03/next-phage?nopaging=1

  8. Rajini Rao says:


    Satyr Icon  haha, thank you for repunning 😉

  9. Jesse H says:


    I knew about this for some time Rajini. I only wish they would focus more attention on this. I never thought of spa waters being a breeding ground though. Great post.

  10. Rajini Rao says:


    Hot tubs were in “hot water” recently for harboring pathogenic bacteria, Jesse H . I’m guessing that’s less of a problem with natural hot springs. 

  11. Scot S says:


    Rajini Rao Big Pharma seems to have turned its back on Anti-Bacterial research. I believe the concept of “Portfolio Friendly Research Investment” trumps that of solving the problems Anti-bacterial misuse has caused. 

  12. Tom Lee says:


    Great info, good to know. I’m a cheese fan so I can feel better to eat the cheese. 🙂

  13. Rajini Rao says:


    Scot S there’s still a lot of enthusiasm for this form of therapy in Russia and some eastern European countries. I wonder if it is profitable there..if so, then it should be worth investing by US pharma too. 

  14. Jesse H says:


    I’m just thinking about all of those hot tubs people own and no idea what’s brewing in their own homes.

  15. Rajini Rao says:


    Tom Lee that’s gouda to know 🙂 There are still some holes in the arguments for this therapy, though. 

  16. Rajini Rao says:


    Susana M. shared a post on phages recently with some of my favorite images (aliens!!) and links to explore more: https://plus.google.com/u/0/117734150713820609627/posts/aUefTpisaXv

  17. Lacy Galtere says:


    Always love your stuff lady! 

  18. Rajini Rao says:


    Awesome, thanks- good to meet you Lacy Galtere 🙂

  19. Lacy Galtere says:


    Rajini Rao anything we can do to combat Multi-Resistant diseases is extremely prosperous. Those R plasmids are quite nasty.. so are spores. It’s amazing how they re-concoct the Flu immunization every year.

  20. Rajini Rao says:


    Agree! Why not harness the remarkable mutating power of viruses. I like biological warfare in this case..fighting bacteria with phages. 

  21. E.E. Giorgi says:


    wow, fascinating story, I had no idea that’s how they were discovered!

  22. Rajini Rao says:


    Shaker Cherukuri I believe that specific formulations can be patented, such as Intralytix’s “ListShield”. Interesting that you bring this up, because the Wiki article on this topic states, patent issues (specifically on living organisms) may complicate distribution for pharmaceutical companies wishing to have exclusive rights over their “invention”, making it unlikely that a for-profit corporation will invest capital in the widespread application of this technology.

  23. Rajini Rao says:


    E.E. Giorgi the historical part of this is what hooked my interest, actually 🙂


  24. It works. I have a acquaintance who broke his leg on motorbike. Unfortunately, at the hospital, he got a nosocomial infection and was having his bones slowly eaten by a kind of gangrene. Until Gorbachev came to power…


    My friend was from armenian parents and they decided to visit their remote family in Yerevan. There, they found the sickness of my friend ridiculous (it’s what he said). He was treated in a big hospital in Yerevan during more than a year, from 91 till begin 93, through multiple trips he made.


    I met him in 94 and till 2000, everything was ok. The french doctors didn’t like the idea of injecting some living virus and refused to follow him. But he is fine, till now.


    Now, I have a question for you, Rajini Rao, how specific are these phages ? Is it per family of bacteria or larger by Gram positive/negative ?


  25. Wish those phages could wear nano cameras. I’d love to watch how they attack from their view point. Bacteria reality TV!

  26. Rajini Rao says:


    Olivier Malinur thanks for that interesting anecdote! Re. your question, phages are considered to be highly strain specific. Polyvalency (ability of phage to display broad host specificity) is not common. On the other hand, a bacterial species may be targeted by up to 10 different phage types. 


    I found this reference (a free read) useful to get a sense of how many types there are: http://jb.asm.org/content/186/12/3677.full

  27. Rajini Rao says:


    Carmelyne Thompson , finally a type of reality TV that I could watch! 😀


  28. Second question, is there a reverse, some “predators” of virus ?

  29. Rajini Rao says:


    Olivier Malinur no free living predators of viruses. However, host cells can fight back by targeting viral genetic material for destruction, etc. 

  30. Rajini Rao says:


    Actually, good coloring Samoya O’meally 🙂 The picture itself is an electron microscope capture of a real bacteriophage. 

  31. Gaythia Weis says:


    Great post, Rajini Rao !


    I think that it is important to note that “natural” hot springs which might historically been just fine, may now (as with any springs) be contaminated by human activity elsewhere.  Or, as with hot tubs, by too many people in the water.  Also, many commercially operated hot springs now use considerable purification methods making them essentially the same as ones with a tapwater source.  Odorous sulphur is often removed, as well as other constituents now considered harmful. 


    And the water may be treated with chlorine or other disinfectants.

  32. Rajini Rao says:


    Good points, thanks Gaythia Weis .

  33. Vlad Levin says:


    This sounds so promising. I would think in India, with its already more widespread problems with antibiotic resistance, this would be actively pursued. 

  34. Ryan Aslett says:


    I’ve always hoped that someday there would be research into phages for the bacteria that cause dental caries.  Im sure the whole dental industry would be alarmed at a the potential for them to be made mostly irrelevant.

  35. Rajini Rao says:


    Ryan Aslett interesting that you bring up the potential of viruses in dental health. I just read this news story that mentioned there are 100 million phages per ml of saliva. The story went on to describe how we could use the viral biome in our mouth to diagnose diseases and possibly treat them: http://www.popsci.com/blog-network/under-microscope/we-may-one-day-go-viral-perfect-smile


  36.  I never heard of this before.Thanks Rajini Rao !! 

  37. Chad Haney says:


    Great post Rajini Rao. I was gardening instead of working on a #ScienceSunday post. We are supposed to get a storm this afternoon.

  38. Mary T says:


    Fantastic post Rajini Rao :-).


  39. I was under the impression that a large amount of the phage research carried out in Russia, and not a few of the scientists who had worked on them, were bought out by a few Western companies in the 90s? I remember reading that at the start of the 00s somewhere and wondering we were likely to see some trials appearing.

  40. Rajini Rao says:


    It’s always #sciencesunday here enjoy the calm before the storm Chad Haney 🙂

  41. Rajini Rao says:


    Cod Codliness , if you can recall any names, I’ll look them up. Intralytix is based in Baltimore, MD. The companies I mentioned, Eli Lilly and L’Oreal, were involved in the heyday of phage therapy..not sure if they are invested in this now. 

  42. Rajini Rao says:


    Here’s a handy table of companies invested in phage therapy: http://www.nature.com/nbt/journal/v22/n1/fig_tab/nbt0104-31_T1.html


  43. Rajini Rao Do you know the results of this interesting research? ☺ >>


    http://www.nature.com/nature/journal/v494/n7438/full/nature11927.html


  44. Subsequently, phage therapy was “rediscovered” by the English-language literature starting with the work of Smith and Huggins in the 1980s. This western phage therapy renaissance gained momentum only in the 1990s, however, as access was increasingly gained to the rich trove of Soviet and Polish work. The field finally began maturing from those heady “wild west” days of the 1990s starting approximately in the year 2000, a progression that was coupled with an explosion of genomics and broad ecology-based phage research, with this latest era of phage therapy research as well as application continuing to this day.


    From the very long article at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278644/#R20

  45. Rajini Rao says:


    annarita ruberto an evolutionary arms race indeed! The bacterial CRISPR/Cas system (which has taken the research field by storm because of the tremendous practical applications) evolved as defense against phages. So there is a counter to that too! Nice find, thank you! 

  46. Greg Gilbert says:


    Huh, and I worried about ritual bathing in the Ganges.

  47. Rajini Rao says:


    Greg Gilbert probably a bunch of pathogens in those rivers too 😉

  48. Rajini Rao says:


    Cod Codliness another excellent review, thank you. I completely agree with their conclusion:


    Phage therapy has a long history, though for most of that history this approach has been neglected by the English-speaking western world. We show here, however, that there is much more in the literature than has generally been realized, with many studies demonstrating that phages as natural and self-amplifying antibacterial “drugs” could be used to safely and effectively treat or prevent many common human diseases of bacterial etiology. Especially in light of concerns regarding the serious menace of antibiotic resistance, as has been recently stressed by the World Health Organization (http://www.who.int/world-health-day/2011/en/), we believe that there is enough of at least semi-anecdotal evidence of efficacy to strongly recommend continued evaluation of this alternative antibacterial approach.

  49. gage payton says:


    This is a good story that u put o on line

  50. Kevin Clift says:


    If it hasn’t already been mentioned phages have their own .org http://phages.org/ which was in the additional links section when I posted a BBC article on phages: http://goo.gl/36ufAu

  51. Bill Collins says:


    Most intrigued. It would be nice to see the research opened up for the world to benefit from. 

  52. J Stasko says:


    А почему это знание не доступно Западу?

  53. Rajini Rao says:


    Exactly, J Stasko 🙂

  54. Marta Rauch says:


    Thanks for the interesting post, Rajini Rao.


  55. Just wondering Rajini Rao are there also viruses that “eat” other viruses and that could also be used in this “battle”?


     Good post by the way 😉

  56. Rajini Rao says:


    al pistacchio not that I know of (so far, anyway)! Probably because viruses are quite inert outside their hosts, so another virus  or organism cannot really do much with them.  Bacteria fight back against phages, of course. 


  57. Oh I see… Rajini Rao very clear (like when the phog has lifted) thanks a lot Rajini Rao 😉


  58. Very cool story about bacteria killers. A fun (and dramatic :-)) factoid on a Sunday! 🙂

  59. S Ikhwan says:


    Very informative

  60. James B says:


    I will have to look into that


  61. This sounds wonderful.

  62. Rob Kook says:


    I expect the big pharma taking over as soon as scientist discover a useful way of phage tuning. With patent lawyers in the first line.


  63. Ooh, what a cute picture. And I loved the pun!


    I heard about this in the 70s, from my biology teacher in school–that the Ganga water does not smell bad upon prolonged storage because it has phages. We all thought then that phages were cool but kinda scary (after all, virus, for which no known cures existed then, except interferon). I kept a jar full of Ganga water for a month, to see if it stank or it was all a myth. To be on the safe side, I added plant matter (leaves, and stuff), to give the bacteria full scope for growth. A month later, the jar was as non-stinky as ever. QED to my satisfaction (yeah, yeah, no controls, single sample, blah blah).


    Also, I read on G+ some time back that mucosa attracts phages. Different mucus linings attract different phages. I promptly wondered if the extra mucus generated in, say, colitis is actually a defense mechanism from the body’s side. If so, we should not be so keen on suppressing it.


    Ditto, is the allergic reaction of dry nostrils a failure of the body’s defence mechanisms? After all, allergy is an auto-immune disease, so this is likely, no?


    A little knowledge is so dangerous. 🙂

  64. James Haynes says:


    Interesting read. This story has opened my eyes


  65.               Loved To Read This. Thanks for sharing info. 


                  May India be the country who would give the solutions for the improvisation of the water quality. 


    I knew a little about this but you gave us some more dept information as a reliable knowledge source. 🙂 🙂


  66. Viruses can be dangerous and unpredictable which is why many scientist avoid them. While they are technically not alive they have the ability to mutate into something that could be far worse than bacteria if chronically exposed to the human environment.

  67. Rajini Rao says:


    TANVIR HUSAIN ZAIDI you may need to re-read this post. Nobody is pushing river water as a therapy. The reference to the Ganges and Yamuna relates to the historical discovery of bacteriophages, published in 1896: Hankin E H. L’action bactericide des eaux de la Jumna et du Gange sur le vibrion du cholera. Ann Inst Pasteur. 1896;10:511. 

  68. Rajini Rao says:


    DeAngelo Mckinley , bacteriophages are viruses that can only use bacteria as host and are therefore harmless to us. Not all viruses are the same. Please do check out the references in the post. They are free and quite easy to read, even for a lay person. Let me know if you have questions after reading them. 


  69. I tend to agree with J Stasko . Due to communist ideology, scans (or at least photocopies) of the old soviet papers should be easy to obtain (they had no Elsevier or nature.com over there requiring $30 for viewing an article onscreen 24 hours). If the stuff is really important, it should not be too hard to pay a few students of Georgian origin to translate the papers (maybe hire even people inside Georgia).


  70. Rajini Rao actually I’m not a lay person which is why I posted that. Viruses including bacteriophages can mutate to infect other species, the likelihood of jumping from prokaryotes to eukaryotes is small, but does exist. Also you have to consider the possible antigens bacteriophages may produce. Not trying to rain on anybody’s parade, just food for thought.

  71. Rajini Rao says:


    DeAngelo Mckinley , excellent! Then you already know that a virus that infects E. coli cannot mutate to infect Staphylococcus. The specificity barriers for infection arise from co-evolution of host and pathogen. This is because multiple host/virus adaptations are involved such as binding sites on the bacterial cell wall, phage enzymes that commandeer host resources, etc. The analogy is that HIV virus infects our immune cells whereas the West Nile or dengue virus infects mature red blood cells, but neither can mutate to cross infect the other cell type. The evolutionary barrier is too large.


    Bacteriophages are considered safe to humans because they cannot infect our cells, no matter how much they mutate.  If you know of exceptions, DeAngelo Mckinley, I would love to see a reference so we can continue this discussion!  To quote from an excellent review (http://goo.gl/Qe9X4q): Indeed, bacteriophages are considered as “intelligent antimicrobials” due to the specificity of their action. They infect the target bacteria without any effect on commensal flora and are naturally eliminated along with the complete eradication of pathogenic bacteria (Kutateladze and Adamia, 2010; Jenny, 2011).


  72. Rajini Rao About this argument, I found a pdf  document  from Nunzia Nocerino, Ph.D. in Production and Health Food of Animal Origin-XXIV cycle, University of Naples Federico II. Unfortunately the paper is in Italian, but at its end there is a rich bibliography in English >>


    http://www.fedoa.unina.it/8507/1/Nunzia_Nocerino_XXIV.pdf


    In the paper there is too an abstract in English.


    It seems to me that this paper looks after phage therapy and immunity…and much more. 

  73. Rajini Rao says:


    Thank you, annarita ruberto. From the abstract, the paper you found is looking at a specific phage, called MSa, and its target bacterial host, S. aureus. It shows how the bacteria can become resistant to the phage by altering its cell surface proteins. This is part of the ‘arms race’ between host and virus to which I’ve referred. It occurs within specific host/virus pairs. 


    The confusion in this thread arises from people thinking that these viruses can mutate to infect human cells. To do this, the virus would have to acquire entire sets of genes (which is not possible by mutation). Even if phage DNA/RNA was injected into a plant or animal cell, it would not be able to replicate because it does not have the genes necessary to tell the host cell what to do (and vice versa, the host cell may not be able to make the viral proteins from the information provided). That’s why we are not infected by viruses that attack our rose bushes or make our dogs sick. 


  74. Rajini Rao Yes, I am following the discussion in this thread. Your presentation of content is very clear and comprensible.


    I love your field of research and always follow your posts. After earning my master’s degree in Physics, I studied Biology at the University for two years, but I had to stop due to too many commitments: teaching, marriage, children, etc…

  75. Rajini Rao says:


    Wow, annarita ruberto …Biology and Physics! Not to mention your art, teaching and everything else. Count me as a fan 🙂


  76. Rajini Rao So honoured! I’m your fan all along. ☺


  77. Rajini Rao The reason I say this because the way attenuated vaccines are made. The attenuated flu virus that people take every year is made by introducing a live flu virus into a foreign body such as an animal. Eventually a virus will develop a mutation that allow it to infect that animal and in doing so loses its ability to infect humans. This virus is then harvested and that’s what you get in a flu vaccine.

  78. Rajini Rao says:


    Sure, DeAngelo Mckinley . However, viruses that infect plant, animal and bacterial cells are completely distinct. We don’t get infected by plant and bacterial viruses, period. Besides, bacteria are prokaryotes and have different cellular machinery for the phage to exploit. A phage that infects bacteria cannot infect us. This post is about phages, not the flu virus. Observations about the flu virus are interesting, of course (and welcome!) but not relevant to the point of this post! 


  79. Very interesting! You injected the right amount of fascinating information and humor. I’m going to have to keep an eye out for more phage therapy now.

  80. Rajini Rao says:


    Nature News just came out with a story on phage therapy: http://www.nature.com/news/phage-therapy-gets-revitalized-1.15348   Phages can be engineered to destroy a bacterium’s antibiotic resistance gene using the CRISPR/Cas9 system. They also bring up patenting issues. A good read via MicrobiologyBytes .


  81. A great post, Rajini. Thank you.


  82. May not be right today

  83. Rajini Rao says:


    Ranjit Bhandari I’m not sure what you mean, please clarify, thanks.

  84. Chad Haney says:


    Tomorrow, on the other hand, will be absolutely right.


  85. I had no idea that phage therapy had been used in the past and is actually a product in the present. Very interesting. 


  86. Phages drive bacterial evolution which in turn are the reason why animals, like humans, exist. No phages means the end of life as we know it.

  87. gamer shaju says:


    Thnx for informing

  88. Rajini Rao says:


    I’ve not read the book, Marius Piedallu van Wyk , perhaps I should! Did you read the English translation? Here is the Wiki entry on the book in case anyone is curious: http://en.wikipedia.org/wiki/G%C3%B6del,_Escher,_Bach

  89. Rajini Rao says:


    Thanks for the inside review. I’ll look for it and give it a go! 

  90. Vishnu RR says:


    Thanks for your brillant work


  91. There are a series of case studies at http://sciencecases.lib.buffalo.edu/cs/  on cholera.  By the end of last year, but students became exasperated and exclaimed “why are we still talking about cholera!?”    I may have gone overboard.   

  92. Rajini Rao says:


    Haha, I guess they needed exposure to more diseases? 🙂


    Did you bring up oral rehydration therapy? That’s a nice story of how a simple salt and sugar can circumvent the nasty cholera toxin. It turns out that the toxin targets chloride absorption but has no effect on sodium-coupled transporters. By giving patients sodium and glucose in equal parts, the sodium coupled glucose transporter SGLT can keep working. Water follows the salt/glucose passively and water loss from diarrhea is curbed. 


  93. Thanks, Rajini Rao , I’ll add that bit of information for next year.   I can also tease my graduated students by sending this update to them, I’m sure their missing all of our cholera talks by now.  

  94. Rajini Rao says:


    Oops, did I inadvertently inflict more diarrheal drivel information on them? 🙂


  95. Very nice nd intersted story ….

  96. Khalid Kyle says:


    Rajini Rao nice post, just discover ur informative page, spend my whole day reading ur page lol,  keep posting awesome informative posts ok, have a nice day 🙂

  97. Rajini Rao says:


    Thank you so much for your encouraging comments, Khalid Kyle . All the best to you, cheers! 

  98. Alex J says:


    Rajini Rao 😀 


  99. Jetzt sind sie gekommen die Alien

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