tag:theconversation.com,2011:/us/topics/bacteriophage-60403/articlesBacteriophage – The Conversation2024-02-22T13:42:50Ztag:theconversation.com,2011:article/2202832024-02-22T13:42:50Z2024-02-22T13:42:50ZBacteria can develop resistance to drugs they haven’t encountered before − scientists figured this out decades ago in a classic experiment<figure><img src="https://images.theconversation.com/files/575458/original/file-20240213-24-7w1h4o.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2048%2C1480&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Bacteria are evolutionarily primed to outpace drug developers.</span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/nihgov/28881401596/in/photolist-U4kMcq-c57xDd-L19JtW-c9uWe5-dYBMYW-a5tw3L-2joPCWz-2jfgs7P-9VPmA4-fuUV2g-fvxv6D-ot5Jyg-fvacBd-vughy5-7NapMs-7N7qSL-yrSV6f-7N5dpc-Mj3KFR-7Na6i5-ysPK3x-7Na5Wq-ftHb6n-ftXtfs-ftH7Vt-7Na6P5-tCCMPo-xvLN1S-ybiGai-yqtCoy-982F9z-ftHaAP-7N3qKg-7N674D-fvxufn-fvMDps-x2Btgv-ftHapZ-7Na6sy-7NaoHs-fuUUt8-fuUQjz-fvxptp-fuUXN2-7U2mNs-7N66b2-fvaabC-xtGans">National Institute of Allergy and Infectious Diseases, National Institutes of Health/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc/4.0/">CC BY-NC</a></span></figcaption></figure><p>Do bacteria mutate randomly, or do they mutate for a purpose? Researchers have been <a href="https://doi.org/10.1017/S0022172400017125">puzzling over this conundrum for over a century</a>.</p>
<p>In 1943, microbiologist Salvador Luria and physicist turned biologist Max Delbrück <a href="https://doi.org/10.1080/09332480.2010.10739800">invented an experiment</a> to argue that bacteria mutated aimlessly. Using their test, other scientists showed that bacteria could acquire resistance to antibiotics they hadn’t encountered before.</p>
<p>The <a href="https://doi.org/10.1080/09332480.2010.10739800">Luria–Delbrück experiment</a> has had a significant effect on science. The findings helped Luria and Delbruck win the <a href="https://www.nobelprize.org/prizes/medicine/1969/summary/">Nobel Prize in physiology or medicine in 1969</a>, and students today learn this experiment in <a href="https://doi.org/10.1128/jmbe.00161-23">biology classrooms</a>. I have been studying this experiment in my work as a biostatistician for <a href="https://doi.org/10.1016/S0025-5564(99)00045-0">over 20 years</a>.</p>
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<p>Decades later, this experiment offers lessons still relevant today, because it implies that bacteria can develop resistance to antibiotics that haven’t been developed yet.</p>
<h2>Slot machines and a eureka moment</h2>
<p>Imagine a test tube containing bacteria living in nutrient broth. The broth is cloudy due to the high concentration of bacteria within it. Adding a virus that infects bacteria, <a href="https://theconversation.com/viruses-are-both-the-villains-and-heroes-of-life-as-we-know-it-169131">also known as a phage</a>, into the tube kills most of the bacteria and makes the broth clear.</p>
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<a href="https://images.theconversation.com/files/426550/original/file-20211014-27-n6jugx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Illustration of bacteriophage structure." src="https://images.theconversation.com/files/426550/original/file-20211014-27-n6jugx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/426550/original/file-20211014-27-n6jugx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=1014&fit=crop&dpr=1 600w, https://images.theconversation.com/files/426550/original/file-20211014-27-n6jugx.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=1014&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/426550/original/file-20211014-27-n6jugx.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=1014&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/426550/original/file-20211014-27-n6jugx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1274&fit=crop&dpr=1 754w, https://images.theconversation.com/files/426550/original/file-20211014-27-n6jugx.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1274&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/426550/original/file-20211014-27-n6jugx.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1274&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Bacteriophages are viruses that specifically infect bacteria.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/flat-illustration-of-bacteriophage-royalty-free-illustration/1285360925">Kristina Dukart/iStock via Getty Images Plus</a></span>
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<p>However, keeping the test tube under conditions favorable for bacterial growth will turn the broth cloudy again over time. This indicates that the bacteria developed resistance against the phages and were able to proliferate.</p>
<p>What role did the phages play in this change?</p>
<p>Some scientists thought the phages incited the bacteria to mutate for survival. Others suggested that bacteria routinely mutate randomly, and the development of phage-resistant variants was simply <a href="https://doi.org/10.1128/jb.28.6.619-639.1934">a lucky outcome</a>. Luria and Delbrück had been working together for months to solve this conundrum, but none of their experiments had been successful. </p>
<p>On the night of Jan. 16, 1943, Luria got a hint about how to crack the mystery while watching a colleague hit the jackpot at a slot machine. The next morning, he hurried to his lab.</p>
<p>Luria’s experiment consisted of a few tubes and dishes. Each tube contained nutrient broth that would help the bacteria <em>E. coli</em> multiply, while each dish contained material coated with phages. A few bacteria were placed into each tube and given two opportunities to generate phage-resistant variants. They could either mutate in the tubes in the absence of phages, or they could mutate in the dishes in the presence of phages.</p>
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<a href="https://images.theconversation.com/files/575442/original/file-20240213-28-9m0ay7.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Illustration of six test tubes and and six petri dishes, a few of the dishes containing red dots" src="https://images.theconversation.com/files/575442/original/file-20240213-28-9m0ay7.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/575442/original/file-20240213-28-9m0ay7.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=277&fit=crop&dpr=1 600w, https://images.theconversation.com/files/575442/original/file-20240213-28-9m0ay7.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=277&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/575442/original/file-20240213-28-9m0ay7.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=277&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/575442/original/file-20240213-28-9m0ay7.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=348&fit=crop&dpr=1 754w, https://images.theconversation.com/files/575442/original/file-20240213-28-9m0ay7.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=348&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/575442/original/file-20240213-28-9m0ay7.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=348&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">This diagram of the Luria-Delbrück experiment depicts colonies of phage-resistant variants of <em>E. coli</em> (red) developing in petri dishes.</span>
<span class="attribution"><span class="source">Qi Zheng</span>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
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<p>The next day, Luria transferred the bacteria in each tube into a dish filled with phages. The day after that, he counted the number of resistant bacterial colonies in each dish. </p>
<p>If bacteria develop resistance against phages by interacting with them, none of the bacteria in the tubes should have mutations. On the other hand, only a few of the bacteria – say, 1 out of 10 million bacteria – should spawn resistant variants when they are transferred into a dish containing phages. Each phage-resistant variant would grow into a colony, but the remaining bacteria would die from infection.</p>
<p>If bacteria develop resistance independently of interacting with phages, some of the bacteria in the tubes will have mutations. This is because each time a bacterium divides in a tube, it has a small probability of spawning a resistant variant. If the starting generation of bacteria is the first to mutate, at least half of the bacteria will be resistant in later generations. If a bacterium in the second generation is the first to mutate, at least an eighth of the bacteria will be resistant in later generations.</p>
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<a href="https://images.theconversation.com/files/575444/original/file-20240213-30-vbeqfp.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Four tree diagrams of green and red circles, with subsequent branches from red dots turning red" src="https://images.theconversation.com/files/575444/original/file-20240213-30-vbeqfp.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/575444/original/file-20240213-30-vbeqfp.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=340&fit=crop&dpr=1 600w, https://images.theconversation.com/files/575444/original/file-20240213-30-vbeqfp.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=340&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/575444/original/file-20240213-30-vbeqfp.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=340&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/575444/original/file-20240213-30-vbeqfp.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=427&fit=crop&dpr=1 754w, https://images.theconversation.com/files/575444/original/file-20240213-30-vbeqfp.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=427&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/575444/original/file-20240213-30-vbeqfp.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=427&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Mutations that confer resistance against phages (red) early on will spawn a large number of phage-resistant variants, while mutations that occur later on will spawn only a few resistant variants.</span>
<span class="attribution"><span class="source">Qi Zheng</span>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
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<p>Like small-prize cash-outs in slot machines, late-generation mutations occur more often but give fewer resistant variants. Like jackpots, early-generation mutations occur rarely but give large numbers of variants. Early-generation mutations are rare because early on there are only a small number of bacteria available to mutate.</p>
<p>For example, in a 20-generation experiment, a mutation occurring at the 10th generation of bacteria would give 1,024 phage-resistant variants. A mutation occurring at the 17th generation would give only four phage-resistant variants. </p>
<p>The number of resistant colonies in Luria’s experiments showed a similar pattern to that of slot machine cash-outs. Most dishes contained no or small numbers of mutant colonies, but several contained a large number of mutant colonies that Luria considered jackpots. This meant that the bacteria developed resistant variants before they interacted with the phages in the dishes.</p>
<h2>An experiment’s legacy</h2>
<p>Luria sent a note to Delbrück after his experiment was completed, asking him to check his work. The two scientists then worked together to write <a href="https://doi.org/10.1093/genetics/28.6.491">a classic paper</a> describing the experimental protocol and a theoretical framework to measure bacterial mutation rates.</p>
<p>Other scientists conducted similar experiments by replacing phages <a href="https://doi.org/10.1073/pnas.31.1.16">with penicillin</a> and with <a href="https://doi.org/10.1128/am.20.5.810-814.1970">tuberculosis drugs</a>. Similarly, they found that bacteria did not need to encounter an antibiotic to acquire resistance to it.</p>
<p>Bacteria have relied on random mutations to cope with harsh, constantly changing environments <a href="https://theconversation.com/antibiotic-resistance-is-not-new-it-existed-long-before-people-used-drugs-to-kill-bacteria-115836">for millions of years</a>. Their incessant, random mutations will lead them to inevitably develop variants that are resistant to the antibiotics of the future. </p>
<p>Drug resistance is a reality of life we will have to accept and continue to fight against.</p><img src="https://counter.theconversation.com/content/220283/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Qi Zheng does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>The Nobel Prize-winning Luria−Delbrück experiment showed that random mutations in bacteria can allow them to develop resistance by chance.Qi Zheng, Professor of Biostatistics, Texas A&M UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2163442023-11-03T12:45:40Z2023-11-03T12:45:40ZVampire viruses prey on other viruses to replicate themselves − and may hold the key to new antiviral therapies<figure><img src="https://images.theconversation.com/files/557327/original/file-20231102-23-pcztem.png?ixlib=rb-1.1.0&rect=0%2C0%2C4306%2C1431&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The satellite virus MiniFlayer (purple) infects cells by attaching itself to the neck of its helper virus, MindFlayer (gray). </span> <span class="attribution"><a class="source" href="https://doi.org/10.1038/s41396-023-01548-0">Tagide deCarvalho</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>Have you ever wondered whether the virus that gave you a nasty cold can catch one itself? It may comfort you to know that, yes, viruses can actually get sick. Even better, as karmic justice would have it, the culprits turn out to be other viruses.</p>
<p>Viruses can get sick in the sense that their normal function is impaired. When a virus enters a cell, it can either <a href="https://theconversation.com/viruses-may-be-watching-you-some-microbes-lie-in-wait-until-their-hosts-unknowingly-give-them-the-signal-to-start-multiplying-and-kill-them-189949">go dormant or start replicating right away</a>. When replicating, the virus essentially commandeers the molecular factory of the cell to make lots of copies of itself, then breaks out of the cell to set the new copies free.</p>
<p>Sometimes a virus enters a cell only to find that its new temporary dwelling is already home to another dormant virus. Surprise, surprise. What follows is a battle for control of the cell that can be won by either party. </p>
<p>But sometimes a virus will enter a cell to find a particularly nasty shock: a viral tenant waiting specifically to prey on the incoming virus.</p>
<p>I am a <a href="https://scholar.google.com/citations?user=T1I1sNAAAAAJ&hl=en">bioinformatician</a>, and <a href="https://erilllab.umbc.edu/">my laboratory</a> studies the evolution of viruses. We frequently run into “viruses of viruses,” but we recently discovered something new: a virus that <a href="https://doi.org/10.1038/s41396-023-01548-0">latches onto the neck of another virus</a>.</p>
<h2>A world of satellites</h2>
<p>Biologists have known of the existence of viruses that prey on other viruses – referred to as <a href="https://doi.org/10.1038/nrmicro2676">viral “satellites”</a> – for decades. In 1973, researchers studying bacteriophage P2, a virus that infects the gut bacterium <em>Escherichia coli</em>, found that this infection sometimes led to two different types of viruses emerging from the cell: <a href="https://doi.org/10.1016/0042-6822(73)90432-7">phage P2 and phage P4</a>.</p>
<p>Bacteriophage P4 is a temperate virus, meaning it can integrate into the chromosome of its host cell and lie dormant. When P2 infects a cell already harboring P4, the latent P4 quickly wakes up and <a href="https://doi.org/10.1128/mr.57.3.683-702.1993">uses the genetic instructions of P2</a> to make hundreds of its own small viral particles. The unsuspecting P2 is lucky to replicate a few times, if at all. In this case, biologists refer to P2 as a “helper” virus, because the satellite P4 needs P2’s genetic material to replicate and spread. </p>
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<figcaption><span class="caption">Bacteriophages are viruses that infect bacteria.</span></figcaption>
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<p>Subsequent research has shown that most bacterial species have a <a href="https://doi.org/10.1038/s41396-018-0156-3">diverse set of satellite-helper systems</a>, like that of P4-P2. But viral satellites are not limited to bacteria. Shortly after the largest known virus, mimivirus, was discovered in 2003, scientists also found its <a href="https://doi.org/10.1038/nature07218">satellite, which they named Sputnik</a>. <a href="https://doi.org/10.1016/0042-6822(81)90531-6">Plant viral satellites</a> that lurk in plant cells waiting for other viruses are also widespread and can have <a href="https://doi.org/10.1007/s11262-020-01806-9">important effects on crops</a>.</p>
<h2>Viral arms race</h2>
<p>Although researchers have found satellite-helper viral systems in pretty much <a href="https://doi.org/10.1016/j.coviro.2018.08.002">every domain of life</a>, their importance to biology remains underappreciated. Most obviously, viral satellites have a direct impact on their “helper” viruses, typically maiming them but <a href="https://doi.org/10.1016/j.coviro.2018.08.002">sometimes making them more efficient killers</a>. Yet that is probably the least of their contributions to biology. </p>
<p>Satellites and their helpers are also engaged in an <a href="https://doi.org/10.1371/journal.pgen.1005609">endless evolutionary arms race</a>. Satellites evolve new ways to exploit helpers and helpers evolve countermeasures to block them. Because both sides are viruses, the results of this internecine war necessarily include something of interest to people: antivirals.</p>
<p>Recent work indicates that many antiviral systems thought to have evolved in bacteria, like the CRISPR-Cas9 molecular scissors used in gene editing, may have <a href="https://doi.org/10.1093/nar/gkac845">originated in phages and their satellites</a>. Somewhat ironically, with their high turnover and mutation rates, helper viruses and their satellites turn out to be <a href="https://doi.org/10.1016/j.chom.2022.02.018">evolutionary hot spots for antiviral weaponry</a>. Trying to outsmart each other, satellite and helper viruses have come up with an unparalleled array of antiviral systems for researchers to exploit.</p>
<h2>MindFlayer and MiniFlayer</h2>
<p>Viral satellites have the potential to transform how researchers understand antiviral strategies, but there is still a lot to learn about them. In our recent work, my collaborators and I describe a satellite bacteriophage completely unlike previously known satellites, one that has evolved a <a href="https://doi.org/10.1038/s41396-023-01548-0">unique, spooky lifestyle</a>. </p>
<p><a href="https://phages.umbc.edu/">Undergraduate phage hunters</a> at the University of Maryland, Baltimore County isolated a <a href="https://phagesdb.org/phages/MiniFlayer/">satellite phage called MiniFlayer</a> from the soil bacterium <em>Streptomyces scabiei</em>. MiniFlayer was found in close association with a helper virus called <a href="https://phagesdb.org/phages/MindFlayer/">bacteriophage MindFlayer</a> that infects the <em>Streptomyces</em> bacterium. But further research revealed that MiniFlayer was no ordinary satellite.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/557149/original/file-20231101-28-nu795n.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C1084%2C1097&q=45&auto=format&w=1000&fit=clip"><img alt="Microscopy image of a small round virus colored violet attached to the base of a larger round virus colored gray with a long tail" src="https://images.theconversation.com/files/557149/original/file-20231101-28-nu795n.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C1084%2C1097&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/557149/original/file-20231101-28-nu795n.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=607&fit=crop&dpr=1 600w, https://images.theconversation.com/files/557149/original/file-20231101-28-nu795n.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=607&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/557149/original/file-20231101-28-nu795n.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=607&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/557149/original/file-20231101-28-nu795n.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=763&fit=crop&dpr=1 754w, https://images.theconversation.com/files/557149/original/file-20231101-28-nu795n.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=763&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/557149/original/file-20231101-28-nu795n.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=763&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">This image shows <em>Streptomyces</em> satellite phage MiniFlayer (purple) attached to the neck of its helper virus, <em>Streptomyces</em> phage MindFlayer (gray).</span>
<span class="attribution"><a class="source" href="https://doi.org/10.1038/s41396-023-01548-0">Tagide deCarvalho</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
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<p>MiniFlayer is the first satellite phage known to have lost its ability to lie dormant. Not being able to lie in wait for your helper to enter the cell poses an important challenge to a satellite phage. If you need another virus to replicate, how do you guarantee that it makes it into the cell around the same time you do? </p>
<p>MiniFlayer addressed this challenge with evolutionary aplomb and horror-movie creativity. Instead of lying in wait, MiniFlayer has gone on the offensive. Borrowing from both “Dracula” and “Alien,” this satellite phage <a href="https://doi.org/10.1038/s41396-023-01548-0">evolved a short appendage</a> that allows it to latch onto its helper’s neck like a vampire. Together, the unwary helper and its passenger travel in search of a new host, where the viral drama will unfold again. We don’t yet know how MiniFlayer subdues its helper, or whether MindFlayer has evolved countermeasures.</p>
<p>If the recent pandemic has taught us anything, it is that our <a href="https://doi.org/10.1007/s00018-022-04635-1">supply of antivirals is rather limited</a>. Research on the complex, intertwined and at times predatory nature of viruses and their satellites, like the ability of MiniFlayer to attach to its helper’s neck, has the potential to open new avenues for antiviral therapy.</p><img src="https://counter.theconversation.com/content/216344/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Ivan Erill receives funding from the US National Science Foundation. He is affiliated with the Universitat Autònoma de Barcelona. </span></em></p>Researchers discovered a satellite virus latching onto the neck of another virus called MindFlayer. Studying the viral arms race between similar viruses could lead to new ways to fight infections.Ivan Erill, Professor of Biological Sciences, University of Maryland, Baltimore CountyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2044192023-05-03T11:24:28Z2023-05-03T11:24:28ZThousands of unknown viruses discovered in baby poo – why this is not necessarily a bad thing<p>An international team of scientists who spent five years studying the poo of <a href="https://www.nature.com/articles/s41564-023-01345-7">647 Danish babies</a> found something astonishing. The nappy samples contained 10,000 species of virus – ten times the number of bacterial species in the same children. Most of the viruses had never been described before. </p>
<p>This may alarm many readers. Viruses haven’t exactly had a <a href="https://ourworldindata.org/covid-deaths">good reputation</a> in recent years. But what many people don’t realise is that the overwhelming majority of viruses do not make people sick and do not infect humans or animals at all. </p>
<p>The viruses I’m referring to are bacteriophages. They exclusively infect bacteria and make up a large part of the human microbiome. It’s these bacteriophages that the researchers found so abundantly in baby poo. Indeed, around 90% of the viruses found in the nappies of the Danish babies were these bacteria killers.</p>
<p>The human gut microbiome is a complex collection of microorganisms, including bacteria, archaea, microbial eukaryotes and viruses. The viral component of the gut microbiome, or virome, is mainly made up of bacteriophages that help maintain a healthy and diverse microbiome.</p>
<h2>Atlas</h2>
<p>The researchers of this new study – a collaborative team from Denmark, Canada and France – looked at how many of these 10,000 viruses were new and how best to describe all this new viral diversity in an accessible form. </p>
<p>Putting all of them in a large table would be a rather boring read. Instead, they created an “atlas of infant gut DNA virus diversity”, where they grouped the viruses into new virus families and orders based on how similar the genomes were to each other. They found 248 families of which only 16 were previously known. </p>
<p>The researchers named the remaining 232 newly identified virus families after children who took part in the study, such as Sylvesterviridae, Rigmorviridae and Tristanviridae.</p>
<p>An <a href="https://copsac.com/earlyvir/f1y/fig1.svg">interactive version</a> of the atlas is available online.</p>
<figure class="align-center ">
<img alt="Illustration of bacteriophages attacking a bacterium" src="https://images.theconversation.com/files/523793/original/file-20230502-1677-ej65zg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/523793/original/file-20230502-1677-ej65zg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=338&fit=crop&dpr=1 600w, https://images.theconversation.com/files/523793/original/file-20230502-1677-ej65zg.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=338&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/523793/original/file-20230502-1677-ej65zg.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=338&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/523793/original/file-20230502-1677-ej65zg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=425&fit=crop&dpr=1 754w, https://images.theconversation.com/files/523793/original/file-20230502-1677-ej65zg.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=425&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/523793/original/file-20230502-1677-ej65zg.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=425&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Bacteriophages attacking a bacterium.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/3d-illustration-bacteriophage-infecting-bacterium-1126283543">Design Cells/Shutterstock</a></span>
</figcaption>
</figure>
<h2>Unique viromes</h2>
<p>What is interesting about bacteriophages and other viruses in the gut is that every person has their own unique set, with <a href="https://www.sciencedirect.com/science/article/pii/S1931312819304767">almost no overlap between two different people</a>. </p>
<p>While each gut virome is unique, it is also stable over time in adults, meaning you carry with you the same set of viruses as you age. But right after a baby is born, this virome is very different from that of an adult and it only stabilises after a couple of years. </p>
<p>When comparing the approximately 10,000 viruses of this new study with extensive reference virome collections of healthy adults, the researchers found that only about 800 of these viruses had been found before. </p>
<p>That means that when babies are born and have the first bacteriophages colonise their gastrointestinal tract, these “baby bacteriophages” don’t all stay there, but gradually get replaced with “adult bacteriophages”. </p>
<p>This replacement could be partially linked to the bacterial hosts these bacteriophages infect. For example, <em>Bacteroides</em>, <em>Faecalibacterium</em> and <em>Bifidobacterium</em> were the most prominent hosts that were predicted for the baby bacteriophages. </p>
<p>I’d like to highlight <em>Bifidobacterium</em> species here, which are very important for infant health. These bacteria help with the digestion of breastmilk and so are important early in life, but become less abundant as we age. So it makes sense that the viruses that infect <em>Bifidobacterium</em> are found more in babies and less in adults. </p>
<p>Conversely, the most abundant group of adult gut bacteriophages, members of the order <em>Crassvirales</em> were not as prevalent in baby poo, meaning children acquire these bacteriophages as they age. </p>
<p>With the addition of these 10,000 new virus species and the many new families, from just one group of several hundred Danish babies, it becomes clear that there’s more that we don’t know about the virome than what we do know. But the scientific community is working on it, one baby poo sample at a time.</p><img src="https://counter.theconversation.com/content/204419/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Evelien Adriaenssens receives funding from the Biotechnology and Biological Sciences Research Council (BBSRC) and Medical Research Council (MRC). She is affiliated with the International Committee on Taxonomy of Viruses. </span></em></p>Babies guts found to have ten times as many viral species as bacterial species.Evelien Adriaenssens, Group Leader, Gut viruses & Viromics, Quadram InstituteLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1920282022-10-09T07:39:22Z2022-10-09T07:39:22ZNigeria’s missing virus hunters: university decline robs country of virologists<figure><img src="https://images.theconversation.com/files/488727/original/file-20221007-26-y700xw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><span class="source">shutterstock</span></span></figcaption></figure><p><em>Nigeria’s university system witnessed its <a href="https://www.jstor.org/stable/1166618#metadata_info_tab_contents">golden era</a> between the 1950s and 1980s. It produced globally <a href="https://theconversation.com/akin-mabogunje-nigerian-urban-geographer-who-mapped-the-origin-and-trends-of-african-cities-190378">celebrated academics </a> and <a href="https://theconversation.com/david-olufemi-olaleye-erudite-virologist-excellent-mentor-and-academic-giant-166199">virologists</a>. But the story has changed. Under funding of the university system, inadequate support for research and lack of commitment to the development of science and technology by the government are robbing the nation of quality academics. Virologists are among them. Renowned virologist, Oyewale Tomori, who graduated in the 1970s, sets out how it was then, why the country is where it is now and what it can do to restore its lost glory in science and technology education.</em></p>
<hr>
<h2>What’s the history of training virologists in Nigeria?</h2>
<p>Although modern virology began with the discovery between 1915 and 1917 of bacteriophages (that is, <a href="https://scholar.google.com/scholar?q=DOI:https://doi.org/10.1016/j.cmi.2018.12.003&hl=en&as_sdt=0&as_vis=1&oi=scholart">viruses that infect bacteria </a>, virology only became a discipline on its own in the last 50 years. </p>
<p>The discipline can be divided into the biology of viruses (molecular biology and biochemistry) and viral diseases (physiology, epidemiology, and clinical aspects of virus diseases). One branch deals with the study of the nature and properties of the virus, while the second is focused on the diseases caused by viruses and the interplay of the factors (human, animal, virus and the environment) that result in the emergence and reemergence of viral diseases. </p>
<p>Today, a thorough study of virology encompasses the <a href="https://www.cdc.gov/onehealth/index.html#:%7E:text=One%20Health%20is%20a%20collaborative,plants%2C%20and%20their%20shared%20environment">One Health concept</a>. This takes into account the interactions between humans and animals and the environment.</p>
<p>The first set of Nigerian virologists was trained outside the country. Local training of virologists started in the early 1970s, at the University of Ibadan. It was the sole training centre for virologists until the late 1990s. </p>
<p>Today, <a href="https://punchng.com/nigeria-has-only-200-virologists-expert-laments/">there are about 200 virologists in Nigeria</a>. Is this number enough?</p>
<p>Answering the question isn’t the same as measuring, for example, the ideal “doctor to patient” ratio. This is because virologists are researchers, so the headline number isn’t the main issue. Rather it’s whether those trained as virologists are functioning effectively and maximally. </p>
<p>Suffice to say that Nigeria needs more virologists given the size of the country, and the number of endemic viral infections prevalent in it. Annually, the country reports severe outbreaks of virus diseases, such as Lassa Fever, yellow fever and measles.</p>
<p>You need virolgists to be ahead of the emergence of viral disease outbreaks. </p>
<p>But the high cost of equipment and reagents, as well as other facilities for conducting virus studies have limited the output of trained virologists by the Nigerian university system. </p>
<p>Currently, the country has more virologists specialising as molecular virologists, rather than experts on the epidemiology and clinical aspects of viral diseases. And poor collaboration between laboratory scientists, epidemiologists and clinicians has robbed Nigeria of getting the needed balance between molecular virologists and those studying viral diseases. There is a disconnect between the study of viruses and the diseases they cause. We have expert virologists with little knowledge of how to control the diseases caused by viruses. </p>
<p>Virologists who will be relevant and contribute to improving the health of the society, must use their knowledge and expertise to prevent and control viral disease, otherwise they become a precious ornament of little use to someone dying of a viral disease. </p>
<p>Nigeria, a disease ridden society, has no place for virologists who discover a virus but can’t decipher what it does. Or are unable to use their knowledge to mitigate the devastation of a viral disease outbreak. </p>
<h2>What’s different now in the training of virologists?</h2>
<p>When I trained as a virologist at the University of Ibadan in South West Nigeria, the training was comprehensive. It involved both broad-based field work as well as laboratory investigation. </p>
<p>In the past, in addition to employing available techniques (antigen-antibody studies and animal experimentation) to identify and classify viruses, a detailed epidemiological study of the diseases caused by the virus was also carried out. </p>
<p>This was a One Health concept that considered the pathogen, the person, the animal, and the environment in the study of viruses and the diseases they cause. This provided information needed for the control and prevention of the disease. </p>
<p>Today, the focus is principally on studying and dissecting the virus, using more modern and highly sophisticated techniques, like <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/genome-sequencing">genomic sequencing</a>. </p>
<p>A host of hurdles stand in the way of building a bigger cohort of virologists in Nigeria.</p>
<p>Firstly, the lack of modern facilities in laboratories and the poor state of basic infrastructure and other resources (such as electricity and reagents) are working against research development. You cannot run genetic sequencing or even sterilise your equipment using a candle as your source of power.</p>
<p>Secondly, budgetary allocation to education is generally poor – at all levels, including the secondary school system. </p>
<p>Thirdly, and unfortunately, the <a href="https://guardian.ng/features/despite-tetfund-intervention-research-in-tertiary-institutions-still-poor-experts-say/">Nigerian government is not committed to funding research</a>. Financial support for science and research remains pathetic. This has led to the deterioration in the quantity and quality of trained virologists at Nigeria’s universities. The oases of excellence in the Nigerian desert of research landscape are largely funded by grants from external bodies and agencies. </p>
<p>But for how long are you going to depend on external grants to fund your research and development? It is like Africa whining and crying for equity when, for example, COVID-19 vaccines were not available for our populations. You do not beg for equity, you fight for it. You use your resources responsibly to contribute to equity, and not just be a consumer of the crumbs of equity.</p>
<p>On top of this, we have corruption and examination malpractices undermining the very foundation of integrity and probity, the pillars on which science and research stand. Consequently, our university system is neither able to retain responsible academics, nor attract the right kind of prospective students imbued with responsibility. </p>
<p>Add to these hurdles the lack of interest of many students in science and technological education. </p>
<h2>What’s missing?</h2>
<p>Sustained funding, infrastructure, facilities (regular power supply), and national government support for and sustained commitment to research. </p>
<p>There is a general national disdain for science and technology. There is also a national failure to fully recognise that science and technology are needed for the socio-economic transformation of Nigeria.</p>
<p>The government should invest in science, technology, research and development. </p>
<h2>How has this affected Nigeria’s ability to produce cutting-edge research?</h2>
<p>Adversely. </p>
<p>We are a nation consuming other countries’ returns on investment in science, research and technology. Rather than investing in research and contributing to global development through science and research, we have resorted to begging for the crumbs of equity. </p>
<p>We are only ready to consume other people’s returns on investments on science and research. </p>
<h2>What needs to be done?</h2>
<p>Go back to basics. Invest in research, science and technology. </p>
<p>Nigeria should create an enabling environment for scientists to function effectively and maximally. The nation should commit to using research outcomes in science and technology as the medium for transforming our society to a developed nation. If Nigeria refuses to fund research especially in science and technology, we will remain at the blunt-edge, rather than the cutting-edge of research, science and technology. We will not have the body of knowledge that can help us to address the nation’s health and other challenges.</p><img src="https://counter.theconversation.com/content/192028/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Oyewale Tomori does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Financial support for science and research in Nigeria remains pathetic. This has led to the deterioration in the quantity and quality of trained virologists at universities.Oyewale Tomori, Fellow, Nigerian Academy of ScienceLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1899492022-09-15T12:25:40Z2022-09-15T12:25:40ZViruses may be ‘watching’ you – some microbes lie in wait until their hosts unknowingly give them the signal to start multiplying and kill them<figure><img src="https://images.theconversation.com/files/484664/original/file-20220914-25-l0cplf.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2309%2C1299&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Phages can sense bacterial DNA damage, which triggers them to replicate and jump ship.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/bacteriophage-infecting-bacterium-royalty-free-image/992263464">Design Cells/iStock via Getty Images Plus</a></span></figcaption></figure><p>After more than two years of the COVID-19 pandemic, you might picture a virus as a nasty spiked ball – a mindless killer that gets into a cell and hijacks its machinery to create a gazillion copies of itself before bursting out. For many viruses, including the <a href="https://doi.org/10.1038/s41579-020-00468-6">coronavirus that causes COVID-19</a>, the “mindless killer” epithet is essentially true.</p>
<p>But there’s more to virus biology than meets the eye.</p>
<p>Take HIV, the virus that causes <a href="https://doi.org/10.1002/eji.200737441">AIDS</a>. HIV is a <a href="https://doi.org/10.1101%2Fcshperspect.a006882">retrovirus</a> that does not go directly on a killing spree when it enters a cell. Instead, it integrates itself into your chromosomes and chills, waiting for the right moment to command the cell to make copies of it and burst out to infect other immune cells and eventually cause AIDS.</p>
<p>Exactly what moment HIV is waiting for is still an <a href="https://doi.org/10.1016/j.cell.2018.04.005">area of active study</a>. But research on other viruses has long hinted that these pathogens can be quite “thoughtful” about killing. Of course, viruses cannot think the way you and I do. But, as it turns out, evolution has endowed them with some pretty elaborate decision-making mechanisms. Some viruses, for instance, will choose to leave the cell they have been residing in if they detect DNA damage. Not even viruses, it appears, like to stay in a sinking ship.</p>
<p><a href="https://scholar.google.com/citations?user=T1I1sNAAAAAJ&hl=en">My</a> <a href="https://erilllab.umbc.edu/">laboratory</a> has been studying the molecular biology of <a href="https://doi.org/10.4161%2Fbact.1.1.14942">bacteriophages</a>, or phages for short, the viruses that infect bacteria, for over two decades. Recently, my colleagues and I <a href="https://doi.org/10.3389/fmicb.2022.918015">have shown</a> that phages can listen for key cellular signals to help them in their decision-making. Even worse, they can use the cell’s own “ears” to do the listening for them.</p>
<h2>Escaping DNA damage</h2>
<p>If the enemy of your enemy is your friend, phages are certainly your friends. Phages <a href="https://doi.org/10.4161%2Fbact.1.1.14942">control bacterial populations</a> in nature, and clinicians are increasingly using them to <a href="https://doi.org/10.1038/s41591-019-0437-z">treat bacterial infections</a> that do not respond to antibiotics.</p>
<p>The best studied phage, <a href="https://doi.org/10.1016/j.virol.2015.02.010">lambda</a>, works a bit like HIV. Upon entering the bacterial cell, lambda decides whether to replicate and kill the cell outright, like most viruses do, or to integrate itself into the cell’s chromosome, as HIV does. If the latter, lambda harmlessly replicates with its host each time the bacteria divides. </p>
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<iframe width="440" height="260" src="https://www.youtube.com/embed/ZWWH8ZxeV0E?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">This video shows a lambda phage infecting <em>E. coli</em>.</span></figcaption>
</figure>
<p>But, like HIV, lambda is not just sitting idle. It uses a special protein called CI like a stethoscope to listen for signs of DNA damage within the bacterial cell. If the bacterium’s DNA gets compromised, that’s bad news for the lambda phage nested within it. Damaged DNA leads straight to evolution’s landfill because it’s useless for the phage that needs it to reproduce. So lambda turns on its replication genes, makes copies of itself and bursts out of the cell to look for more undamaged cells to infect.</p>
<h2>Tapping the cell’s communication system</h2>
<p>Some phages, instead of gathering intel with their own proteins, tap the infected cell’s very own DNA damage sensor: LexA.</p>
<p>Proteins like CI and LexA are <a href="https://doi.org/10.1016/j.jmb.2019.04.011">transcription factors</a> that turn genes on and off by binding to specific genetic patterns within the DNA instruction book that is the chromosome. Some phages like Coliphage 186 have figured out that they don’t need their own viral CI protein if they have a short DNA sequence in their chromosomes that bacterial LexA can bind to. Upon detecting DNA damage, LexA will activate the phage’s replicate-and-kill genes, essentially double-crossing the cell into committing suicide while allowing the phage to escape.</p>
<p>Scientists first reported CI’s role in phage decision-making <a href="https://doi.org/10.1038/294217a0">in the 1980s</a> and Coliphage 186’s counterintelligence trick <a href="https://doi.org/10.1074/jbc.273.10.5708">in the late 1990s</a>. Since then, there have been a few other reports of phages tapping bacterial communication systems. One example is <a href="https://doi.org/10.1038/sj.emboj.7600826">phage phi29</a>, which exploits its host’s transcription factor to detect when the bacterium is getting ready to generate a spore, or a kind of bacterial egg <a href="https://doi.org/10.1023/A:1020561122764">capable of surviving extreme environments</a>. Phi29 instructs the cell to package its DNA into the spore, killing the budding bacteria once the spore germinates.</p>
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<iframe width="440" height="260" src="https://www.youtube.com/embed/MkUgkDLp2iE?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Transcription factors turn genes on and off.</span></figcaption>
</figure>
<p>In our <a href="https://doi.org/10.3389/fmicb.2022.918015">recently published research</a>, my colleagues and I show that several groups of phages have independently evolved the ability to tap into yet another bacterial communication system: the CtrA protein. CtrA integrates multiple internal and external signals to set in motion different developmental processes in bacteria. Key among these is the production of bacterial appendages called <a href="https://doi.org/10.1007/s12275-017-7369-4">flagella and pili</a>. Turns out, these phages attach themselves to the pili and flagella of bacteria in order to infect them.</p>
<p>Our leading hypothesis is that phages use CtrA to guesstimate when there will be enough bacteria nearby sporting pili and flagella that they can readily infect. A pretty smart trick for a “mindless killer.”</p>
<p>These are not the only phages that make elaborate decisions – all without the benefit of even having a brain. Some phages that infect <em>Bacillus</em> bacteria produce a small molecule each time they infect a cell. The phages can sense this molecule and use it to <a href="https://doi.org/10.1016/j.cub.2021.08.072">count the number of phage infections</a> taking place around them. Like alien invaders, this count helps decide when they should switch on their replicate-and-kill genes, killing only when hosts are relatively abundant. This way, the phages make sure that they never run out of hosts to infect and guarantee their own long-term survival.</p>
<h2>Countering viral counterintelligence</h2>
<p>You may be wondering why you should care about the counterintelligence ops run by bacterial viruses. While bacteria are very different from people, the viruses that infect them are <a href="https://doi.org/10.1128/MMBR.00193-20">not that different</a> from the viruses that infect humans. Pretty much <a href="https://doi.org/10.1016/j.virol.2012.09.017">every single trick</a> played by phages has later been shown to be used by human viruses. If a phage can tap bacterial communication lines, why wouldn’t a human virus tap yours?</p>
<p>So far, researchers don’t know what human viruses could be listening for if they hijack these lines, but plenty of options come to mind. I believe that, like phages, human viruses could potentially be able to count their numbers to strategize, detect cell growth and tissue formation and even monitor immune responses. For now, these possibilities are only speculation, but scientific investigation is underway.</p>
<p>Having viruses listening to your cells’ private conversations is not the rosiest of pictures, but it’s not without a silver lining. As intelligence agencies all around the world know well, counterintelligence works only when it’s covert. Once detected, the system can very easily be exploited to feed misinformation to your enemy. Similarly, I believe that future antiviral therapies may be able to combine conventional artillery, like antivirals that prevent viral replication, with information warfare trickery, such as making the virus believe the cell it is in belongs to a different tissue. </p>
<p>But, hush, don’t tell anybody. Viruses could be listening!</p><img src="https://counter.theconversation.com/content/189949/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Ivan Erill receives funding from the US National Science Foundation</span></em></p>Phages, or viruses that infect bacteria, can lie dormant within chromosomes until they’re triggered to replicate and burst out of their hosts.Ivan Erill, Associate Professor of Biological Sciences, University of Maryland, Baltimore CountyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1691312021-10-19T12:23:41Z2021-10-19T12:23:41ZViruses are both the villains and heroes of life as we know it<figure><img src="https://images.theconversation.com/files/426749/original/file-20211015-16-1e3elye.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2380%2C1252&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Bacteriophages are viruses that infect bacteria and play a potential role in the evolution of life.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/bacteriophage-on-bacterium-illustration-royalty-free-illustration/1191008746"> NANOCLUSTERING/SCIENCE PHOTO LIBRARY/Science Photo Library via Getty Images</a></span></figcaption></figure><p>Viruses have a bad reputation. They are responsible for the COVID-19 pandemic and a <a href="https://viralzone.expasy.org/678">long list of maladies</a> that have plagued humanity since time immemorial. Is there anything to celebrate about them?</p>
<p>Many <a href="https://scholar.google.com/citations?user=T1I1sNAAAAAJ&hl=en">biologists like me</a> believe there is, at least for one specific type of virus – namely, <a href="https://www.ncbi.nlm.nih.gov/books/NBK493185/">bacteriophages</a>, or viruses that infect bacteria. When the DNA of these viruses is captured by a cell, it may contain instructions that enable that cell to perform new tricks.</p>
<h2>The mighty power of bacterial viruses</h2>
<p>Bacteriophages, or phages for short, keep bacterial populations in check, both on land and at sea. They kill <a href="https://dx.doi.org/10.1002%2Fbies.201400152">up to 40% of the oceans’ bacteria every day</a>, helping control <a href="https://doi.org/10.1111/j.1574-6976.2010.00258.x">bacterial blooms and redistribution of organic matter</a>.</p>
<figure>
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<figcaption><span class="caption">Bacteriophages are viruses that kill specific types of bacteria.</span></figcaption>
</figure>
<p>Their ability to selectively kill bacteria also has medical doctors excited. Natural and engineered phages have been <a href="https://dx.doi.org/10.1038%2Fs41591-019-0437-z">successfully used to treat bacterial infections</a> that do not respond to antibiotics. This process, known as <a href="https://dx.doi.org/10.4292%2Fwjgpt.v8.i3.162">phage therapy</a>, could help fight <a href="https://dx.doi.org/10.1179%2F2047773215Y.0000000030">antibiotic resistance</a>.</p>
<p><a href="https://doi.org/10.1093/nar/gkab773">Recent research</a> points to another important function of phages: They may be nature’s ultimate genetic tinkerers, crafting novel genes that cells can retool to gain new functions.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/426550/original/file-20211014-27-n6jugx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Illustration of bacteriophage structure." src="https://images.theconversation.com/files/426550/original/file-20211014-27-n6jugx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/426550/original/file-20211014-27-n6jugx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=1014&fit=crop&dpr=1 600w, https://images.theconversation.com/files/426550/original/file-20211014-27-n6jugx.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=1014&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/426550/original/file-20211014-27-n6jugx.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=1014&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/426550/original/file-20211014-27-n6jugx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1274&fit=crop&dpr=1 754w, https://images.theconversation.com/files/426550/original/file-20211014-27-n6jugx.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1274&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/426550/original/file-20211014-27-n6jugx.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1274&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Bacteriophage caspids can carry extra DNA that the virus can tinker with.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/flat-illustration-of-bacteriophage-royalty-free-illustration/1285360925">Kristina Dukart/iStock via Getty Images Plus</a></span>
</figcaption>
</figure>
<p>Phages are the most abundant life form on the planet, with <a href="https://dx.doi.org/10.1128%2FAEM.01465-08">a nonillion – that’s a 1 with 31 zeroes after it – of them floating around the world</a> at any moment. Like all viruses, phages also have <a href="https://doi.org/10.1128/JVI.00694-10">high replication and mutation rates</a>, meaning they form many variants with different characteristics each time they reproduce.</p>
<p>Most phages have a <a href="https://dx.doi.org/10.1007%2Fs00018-007-6451-1">rigid shell called a capsid</a> that is filled with their genetic material. In many cases, the shell has more space than the phage needs to store the DNA essential for its replication. This means that phages have room to carry extra genetic baggage: genes that are not actually necessary for the phage’s survival that it can modify at will.</p>
<h2>How bacteria retooled a viral switch</h2>
<p>To see how this plays out, let’s take a deeper look at the phage life cycle.</p>
<p>Phages come in two main flavors: temperate and virulent. <a href="https://dx.doi.org/10.1038%2Fismej.2017.16">Virulent phages</a>, like many other viruses, operate on an invade-replicate-kill program. They enter the cell, hijack its components, make copies of themselves and burst out.</p>
<p><a href="https://dx.doi.org/10.1038%2Fismej.2017.16">Temperate phages</a>, on the other hand, play the long game. They fuse their DNA with the cell’s and may lay dormant for years until something triggers their activation. Then they revert to virulent behavior: replicate and burst out. </p>
<p>Many temperate phages use DNA damage as their trigger. It’s sort of a “Houston, we have a problem” signal. If the cell’s DNA is being damaged, that means the DNA of the resident phage is likely to go next, so the phage wisely decides to jump ship. The genes that direct phages to replicate and burst out are turned off unless DNA damage is detected.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/426559/original/file-20211014-19-1g3475j.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Diagram of lytic and lysogenic cycles of bacteriophages." src="https://images.theconversation.com/files/426559/original/file-20211014-19-1g3475j.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/426559/original/file-20211014-19-1g3475j.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=423&fit=crop&dpr=1 600w, https://images.theconversation.com/files/426559/original/file-20211014-19-1g3475j.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=423&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/426559/original/file-20211014-19-1g3475j.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=423&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/426559/original/file-20211014-19-1g3475j.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=531&fit=crop&dpr=1 754w, https://images.theconversation.com/files/426559/original/file-20211014-19-1g3475j.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=531&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/426559/original/file-20211014-19-1g3475j.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=531&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Virulent phages follow the lytic cycle of viral reproduction, destroying their hosts as soon as they complete replication. Temperate phages, on the other hand, follow the lysogenic cycle and stay dormant inside their host’s DNA until they’re triggered to burst out.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Figure_21_02_03.png">CNX OpenStax/Wikimedia Commons</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>Bacteria have retooled the mechanisms controlling that life cycle to generate a complex genetic system that my collaborators and I have been <a href="https://erilllab.umbc.edu/">studying for over two decades</a>.</p>
<p>[<em>Research into coronavirus and other news from science</em> <a href="https://theconversation.com/us/newsletters/science-editors-picks-71/?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=science-corona-research">Subscribe to The Conversation’s new science newsletter</a>.]</p>
<p>Bacterial cells are also interested in knowing if their DNA is getting busted. If it is, they activate a set of genes that attempt to repair the DNA. This is known as the <a href="https://doi.org/10.1111/j.1574-6976.2007.00082.x">bacterial SOS response</a> because, if it fails, the cell is toast. Bacteria orchestrate the SOS response using a switch-like protein that responds to DNA damage: It turns on if there is damage and stays off if there isn’t. </p>
<p>Perhaps not surprisingly, bacterial and phage switches are evolutionarily related. This prompts the question: Who invented the switch, bacteria or viruses?</p>
<p>Our previous research and <a href="https://doi.org/10.1046/j.1365-2958.2003.03713.x">work by other researchers</a> indicates that phages got there first. In our <a href="https://doi.org/10.1093/nar/gkab773">recent report</a>, we discovered that the SOS response of <em>Bacteroidetes</em>, a group of bacteria that <a href="https://dx.doi.org/10.3390%2Fnu12051474">comprise up to a half of the bacteria living in your gut</a>, is under control of a phage switch that was retooled to implement the bacteria’s own complex genetic programs. This suggests that bacterial SOS switches are in fact phage switches that got retooled eons ago.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/426739/original/file-20211015-57123-3pn3x.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Diagram of bacterial genetic switch capture process." src="https://images.theconversation.com/files/426739/original/file-20211015-57123-3pn3x.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/426739/original/file-20211015-57123-3pn3x.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=394&fit=crop&dpr=1 600w, https://images.theconversation.com/files/426739/original/file-20211015-57123-3pn3x.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=394&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/426739/original/file-20211015-57123-3pn3x.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=394&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/426739/original/file-20211015-57123-3pn3x.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=495&fit=crop&dpr=1 754w, https://images.theconversation.com/files/426739/original/file-20211015-57123-3pn3x.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=495&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/426739/original/file-20211015-57123-3pn3x.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=495&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">When a temperate phage infects a bacterial cell and integrates its genome with the cell’s DNA, it typically lays dormant until it’s triggered to burst out of the cell. But once the phage’s DNA is part of the bacterium’s, mutations can disrupt the phage’s genetic material and render it inactive. This means that when DNA damage occurs, the phage won’t be able to reform itself and burst out. Over time, the bacterium may adapt the phage’s switch to control its own SOS response genes.</span>
<span class="attribution"><a class="source" href="https://doi.org/10.1093/nar/gkab773">Miquel Sánchez-Osuna/Created with BioRender.com</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc-nd/4.0/">CC BY-NC-ND</a></span>
</figcaption>
</figure>
<p>It’s not just bacterial switches that appear to be phage inventions. Beautiful detective work has shown that a bacterial gene needed for cell division also arose through <a href="https://dx.doi.org/10.1016%2Fj.cub.2019.04.032">“domestication” of a phage toxin gene</a>. And many bacterial attack systems, such as <a href="https://doi.org/10.2217/fmb.11.124">toxins</a> and the <a href="https://dx.doi.org/10.1128%2FMMBR.00014-11">genetic guns</a> used to inject them into cells, as well as the <a href="https://dx.doi.org/10.1128%2FMMBR.68.3.560-602.2004">camouflage</a> they use to evade the immune system, are known or suspected to have phage origins. </p>
<h2>The upside of viruses</h2>
<p>OK, you may think, phages are great, but the viruses that infect us are certainly not cool. Yet there is mounting evidence that the viruses that infect plants and animals are also a major source of genetic innovation in these organisms. Domesticated viral genes have been shown, for instance, to play a key role in the <a href="https://dx.doi.org/10.3389%2Ffmicb.2012.00262">evolution of mammalian placentas and in keeping human skin moist</a>.</p>
<p>Recent evidence suggests that even the <a href="https://doi.org/10.3389/fmicb.2020.571831">nucleus of a cell, which houses DNA, could have also been a viral invention</a>. Researchers have also speculated that the ancestors of today’s viruses may have pioneered <a href="https://dx.doi.org/10.1098%2Frstb.2015.0442">the use of DNA as the primary molecule for life</a>. Not a small feat.</p>
<p>So while you may be used to thinking of viruses as the quintessential villains, they are arguably nature’s powerhouses for genetic innovation. Humans are likely here today because of them.</p><img src="https://counter.theconversation.com/content/169131/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Ivan Erill receives funding from the US National Science Foundation</span></em></p>Viruses have gotten a bad rap for the many illnesses and pandemics they’ve caused. But viruses are also genetic innovators – and possibly the pioneers of using DNA as the genetic blueprint of life.Ivan Erill, Associate Professor of Biological Sciences, University of Maryland, Baltimore CountyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1543372021-02-24T13:28:52Z2021-02-24T13:28:52ZEngineered viruses can fight the rise of antibiotic-resistant bacteria<figure><img src="https://images.theconversation.com/files/385365/original/file-20210219-21-1mfowzt.jpg?ixlib=rb-1.1.0&rect=62%2C12%2C8234%2C4117&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Bacteriophage (yellow) are viruses that infect and destroy bacteria (blue). </span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/bacteriophages-infecting-bacteria-royalty-free-illustration/1155266155?adppopup=true&uiloc=thumbnail_same_series_adp&uiloc=thumbnail_same_series_adp">Christoph Burgstedt/Science Photo Library,Getty Images</a></span></figcaption></figure><p>As the world fights the SARS-CoV-2 virus causing the COVID-19 pandemic, another group of dangerous pathogens looms in the background. The threat of <a href="https://www.who.int/news-room/fact-sheets/detail/antibiotic-resistance">antibiotic-resistant bacteria</a> has been growing for years and <a href="https://cddep.org/publications/tracking-global-trends-in-the-effectiveness-of-antibiotic-therapy-using-the-drug-resistance-index/">appears to be getting worse</a>. If COVID-19 taught us one thing, it’s that governments should be prepared for more global public health crises, and that includes finding new ways to combat rogue bacteria that are becoming resistant to commonly used drugs.</p>
<p>In contrast to the current pandemic, viruses may be be the heroes of the next epidemic rather than the villains. Scientists have shown that viruses could be <a href="https://doi.org/10.2147/IDR.S234353">great weapons</a> against bacteria that are resistant to antibiotics.</p>
<p>I am a <a href="https://www.kevindoxzen.com/">biotechnology and policy expert</a> focused on understanding how personal genetic and biological information can improve human health. Every person interacts intimately with a unique assortment of viruses and bacteria, and by deciphering these complex relationships we can better treat infectious diseases caused by antibiotic-resistant bacteria.</p>
<h2>Replacing antibiotics with phage</h2>
<p>Since the <a href="https://www.pbs.org/newshour/health/the-real-story-behind-the-worlds-first-antibiotic">discovery of penicillin in 1928</a>, antibiotics have changed modern medicine. These small molecules fight off bacterial infections by killing or inhibiting the growth of bacteria. The mid-20th century was called the <a href="https://doi.org/10.1038/nature17042">Golden Age</a> for antibiotics, a time when scientists were discovering dozens of new molecules for many diseases. </p>
<p>This high was soon followed by a <a href="https://doi.org/10.1016/j.mib.2019.10.008">devastating low</a>. Researchers saw that many bacteria were evolving resistance to antibiotics. Bacteria in our bodies were learning to evade medicine by evolving and mutating to the point that antibiotics no longer worked.</p>
<p>As an alternative to antibiotics, some researchers are turning to a natural enemy of bacteria: bacteriophages. <a href="https://theconversation.com/are-viruses-the-best-weapon-for-fighting-superbugs-111908">Bacteriophages</a> are viruses that infect bacteria. They outnumber bacteria <a href="https://doi.org/10.1002/bies.201000071">10 to 1</a> and are considered the most abundant organisms on the planet.</p>
<p>Bacteriophages, also known as phages, survive by infecting bacteria, replicating and bursting out from their host, which destroys the bacterium. </p>
<p>Harnessing the power of phages to fight bacteria isn’t a new idea. In fact, the first recorded use of so-called phage therapy was over a century ago. In 1919, <a href="https://doi.org/10.4161/bact.1.2.15845">French microbiologist Félix d'Hérelle</a> used a cocktail of phages to treat children suffering from severe dysentery.</p>
<p>D'Hérelle’s actions weren’t an accident. In fact, he is credited with <a href="https://doi.org/10.1155/2007/976850">co-discovering phages</a>, and he pioneered the idea of using bacteria’s natural enemies in medicine. He would go on to <a href="https://doi.org/10.3389/fmicb.2012.00238">stop cholera outbreaks in India and plague in Egypt</a>.</p>
<p>Phage therapy is not a standard treatment you can find in your local hospital today. But <a href="https://doi.org/10.1038/s41564-019-0666-4">excitement about phages</a> has grown over the past few years. In particular, scientists are using new knowledge about the complex relationship between phages and bacteria to improve phage therapy. By engineering phages to better target and destroy bacteria, scientists hope to overcome antibiotic resistance.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/385370/original/file-20210219-17-10em1jg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/385370/original/file-20210219-17-10em1jg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/385370/original/file-20210219-17-10em1jg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=303&fit=crop&dpr=1 600w, https://images.theconversation.com/files/385370/original/file-20210219-17-10em1jg.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=303&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/385370/original/file-20210219-17-10em1jg.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=303&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/385370/original/file-20210219-17-10em1jg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=381&fit=crop&dpr=1 754w, https://images.theconversation.com/files/385370/original/file-20210219-17-10em1jg.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=381&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/385370/original/file-20210219-17-10em1jg.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=381&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">CRISPR allows biologists to edit genetic material and engineer organisms.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/structure-editing-medicine-concept-low-poly-royalty-free-illustration/1126485534?adppopup=true&uiloc=thumbnail_same_series_adp">LuckyStep48/iStock/Getty Images Plus</a></span>
</figcaption>
</figure>
<h2>Engineering phages</h2>
<p>Even if you are not a biologist, you may have heard of one type of bacterial immune system: CRISPR, which stands for <a href="https://doi.org/10.1146/annurev-biochem-072911-172315">Clustered Regularly Interspaced Short Palindromic Repeats</a>. This immune system helps bacteria store genetic information from viral infections. The bacteria then use that information to fight off future invaders, much as our own immune system can recognize a particular pathogen to fight off infection.</p>
<p>CRISPR proteins in bacteria <a href="https://doi.org/10.1146/annurev-biophys-062215-010822">locate and cut</a> specific sequences of DNA or RNA found in viruses. Such precise cutting also makes CRISPR proteins efficient tools for editing the genomes of various organisms. This is why the development of CRISPR genome-editing technology won the <a href="https://doi.org/10.1038/d41586-020-02765-9">Chemistry Nobel prize in 2020</a>.</p>
<p>Now scientists are hoping to use the knowledge about CRISPR systems to engineer phages to destroy dangerous bacteria.</p>
<p>When the engineered phage locates specific bacteria, the phage injects CRISPR proteins inside the bacteria, cutting and destroying the microbes’ DNA. Scientists have found a way to turn <a href="https://doi.org/10.1016/j.tibtech.2017.10.021">defense into offense</a>. The proteins normally involved in protecting against viruses are repurposed to target and destroy the bacteria’s own DNA. The scientists can specifically target the DNA that makes the bacteria resistant to antibiotics, making this type of phage therapy extremely effective.</p>
<p>The bacteria <em>Clostridioides difficile</em> is an antibiotic-resistant strain of bacteria that kills 29,000 people in the U.S. every year. In one demonstration of this CRISPR-based technique, researchers <a href="https://doi.org/10.1128/mBio.00019-20">engineered phages</a> to inject a molecule that directs the bacteria’s own CRISPR proteins to chew up the bacteria’s DNA like a paper shredder.</p>
<p>CRISPR isn’t the only bacterial immune system. Scientists are discovering more using creative microbiology experiments and advanced computational tools. They have already found <a href="https://doi.org/10.1038/s41587-020-0718-6">tens of thousands of new microbes</a> and <a href="https://doi.org/10.1126/science.aar4120">dozens of new immune systems</a>. Scientists hope to find more tools that could help them engineer phages to target a wider range of bacteria.</p>
<p>[<em>Get the best of The Conversation, every weekend.</em> <a href="https://theconversation.com/us/newsletters/weekly-highlights-61?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=weeklybest">Sign up for our weekly newsletter</a>.]</p>
<h2>Beyond the science</h2>
<p>Science is only half of the solution when it comes to fighting these microbes. Commercialization and regulation are important to ensure that this technology is in society’s toolkit for fending off a worldwide spread of antibiotic-resistant bacteria.</p>
<p>Multiple companies are engineering phages or identifying naturally occurring phages to destroy specific harmful bacteria. Companies like <a href="https://www.felixbt.com/">Felix Biotechnology</a> and <a href="https://cytophage.com/">Cytophage</a> are producing specialized bacteria-killing phages to replace antibiotics in human health and agriculture. <a href="https://www.biomx.com/">BiomX</a> aims to treat infections common in chronic diseases like cystic fibrosis and inflammatory bowel disease using both natural and engineered phage cocktails. Thinking globally, the company <a href="https://www.phageproinc.com/projects">PhagePro</a> is using phages to treat cholera. These deadly bacteria affect people primarily in Africa and Asia.</p>
<p>Alongside the commercialization of phage therapy, policies that facilitate safe testing and regulation of the technology are vital. To avoid replicating America’s poor COVID-19 response, I believe the world must invest in, engineer, and then test phage therapies. Proactive planning will help us combat whatever antibiotic-resistant bacteria might spread.</p><img src="https://counter.theconversation.com/content/154337/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Kevin Doxzen is affiliated with Arizona State University and the World Economic Forum</span></em></p>As the world has focused on the COVID-19 pandemic, other microbial foes are waging war on humans. Antibiotic-resistant bacteria pose a growing threat. But viruses may defeat them.Kevin Doxzen, Hoffmann Postdoctoral Fellow, Arizona State UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1505362021-01-11T19:08:25Z2021-01-11T19:08:25ZSuperbugs have an arsenal of defences — but we’ve found a new way around them<figure><img src="https://images.theconversation.com/files/370978/original/file-20201124-17-jykufq.jpg?ixlib=rb-1.1.0&rect=0%2C322%2C2835%2C1599&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Superbug _Acinetobacter baumannii_ captured by an electron microscope.</span> <span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Acinetobacter_baumannii.JPG">Janice Carr/Centers for Disease Control and Prevention</a></span></figcaption></figure><p>Researchers have not discovered any new antibiotics in decades. But our new research, published <a href="https://www.nature.com/articles/s41564-020-00830-7">today in Nature Microbiology</a>, has found a way to give a second wind to the antibiotics we do have.</p>
<p>It involves the use of viruses that kill bacteria.</p>
<h2>The problem</h2>
<p>Hospitals are scary, and the longer you remain in them, the greater your risk. Among these risks, hospital-acquired infections are probably the biggest. Each year in Australia, <a href="https://www.safetyandquality.gov.au/sites/default/files/migrated/1.2-Healthcare-Associated-Infection.pdf">180,000 patients suffer infections</a> that prolong their hospital stays, increase costs, and sadly, increase the risk of death.</p>
<p>It sounds absurd — hospitals are supposed to be the cleanest of places. But bacteria are everywhere and can adapt to the harshest of environments. In hospitals, our increased use of disinfectants and antibiotics has forced these bacteria to evolve to survive. These survivors are called “superbugs”, with an arsenal of tools to resist antibiotics. Superbugs prey on the most vulnerable patients, such as those in intensive care units.</p>
<p><em><a href="https://cmr.asm.org/content/21/3/538">Acinetobacter baumannii</a></em> is a superbug responsible for up to 20% of <a href="https://jamanetwork.com/journals/jama/fullarticle/184963">infections in intensive care units</a>. It attaches to medical devices such as ventilator tubes and urinary and intravenous catheters. It causes devastating infections in the lungs, urinary tract, wounds and bloodstream.</p>
<p>Treatment is difficult because <em>A. baumannii</em> can produce enzymes that destroy entire families of antibiotics. Other antibiotics never make it past its outer layer, or <a href="https://www.frontiersin.org/articles/10.3389/fmicb.2018.03301/full">capsule</a>. This outer layer — thick, sticky, viscous and made of sugars — also protects the superbug from the body’s immune system. In some cases, not even the strongest — and most toxic — antibiotics can kill <em>A. baumannii</em>. As a result, the World Health Organisation <a href="https://www.who.int/medicines/publications/WHO-PPL-Short_Summary_25Feb-ET_NM_WHO.pdf">named it a critical priority</a> for the discovery of new treatments.</p>
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<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/rising-antibiotic-resistance-in-utis-could-cost-australia-1-6-billion-a-year-by-2030-heres-how-to-curb-it-149543">Rising antibiotic resistance in UTIs could cost Australia $1.6 billion a year by 2030. Here's how to curb it</a>
</strong>
</em>
</p>
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<h2>A (somewhat) new solution</h2>
<p>It’s said that the enemy of your enemy is your friend. Do bacteria have enemies?</p>
<p>Bacteriophages (or phages, for short) are the natural predators of bacteria. Their name literally means “bacteria eater”. You can find phages wherever you can find bacteria.</p>
<p>Phages are viruses. But don’t let that scare you. Unlike famous viruses — such as HIV, smallpox or SARS-CoV-2, the coronavirus that causes COVID — phages cannot harm humans. They only infect and kill bacteria. In fact, phages are quite picky. A single phage normally infects only one type of bacteria.</p>
<figure class="align-center ">
<img alt="Electron micrograph image of multiple bacteriophages attached to a bacterial cell wall" src="https://images.theconversation.com/files/370980/original/file-20201124-23-1p6osov.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/370980/original/file-20201124-23-1p6osov.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=703&fit=crop&dpr=1 600w, https://images.theconversation.com/files/370980/original/file-20201124-23-1p6osov.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=703&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/370980/original/file-20201124-23-1p6osov.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=703&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/370980/original/file-20201124-23-1p6osov.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=883&fit=crop&dpr=1 754w, https://images.theconversation.com/files/370980/original/file-20201124-23-1p6osov.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=883&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/370980/original/file-20201124-23-1p6osov.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=883&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Phages attach to the outside of bacteria, initiating the killing process.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Phage.jpg">Dr Graham Beards/Wikimedia Commons</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<p>Since their discovery in the early 1900s, doctors thought of an obvious use for phages: treating bacterial infections. But this practice, known as phage therapy, was largely dismissed after the discovery of antibiotics in the 1940s.</p>
<p>Now, with the alarming rise of antibiotic-resistant superbugs, and a lack of new antibiotics, <a href="https://cmr.asm.org/content/32/2/e00066-18">researchers are revisiting phage therapy</a>. In Australia, for example, a team lead by Professor Jon Iredell at Sydney’s Westmead Hospital reported in February the safe use of <a href="https://www.nature.com/articles/s41564-019-0634-z">phage therapy in 13 patients</a> suffering from infections by another superbug, <em>Staphylococcus aureus</em>.</p>
<p>We began our study by “hunting” for phages against <em>A. baumannii</em>. From waste water samples sourced from all over Australia, we successfully isolated a range of phages capable of killing the superbug. That was the easy part.</p>
<h2>Erasing antibiotic-resistance</h2>
<p>When mixing our phages with <em>A. baumannii</em> in the laboratory, they were able to wipe out almost the entire bacterial population. But “almost” was not good enough. Within a few hours, the superbug showed how wickedly smart it is. It had found a way to become resistant to the phages and was happily growing in their presence.</p>
<p>We decided to take a closer look at these phage-resistant <em>A. baumannii</em>. Understanding how it outsmarted the phages might help us choose our next attack.</p>
<p>We discovered that phage-resistant <em>A. baumannii</em> was missing its outer layer. The genes responsible for producing the capsule had mutated. Under the microscope, the superbug looked naked, with no sign of its characteristic thick, sticky and viscous surface.</p>
<p>To kill their bacterial prey, phages first need to attach to it. They do this by recognising a receptor <a href="https://www.sciencedirect.com/science/article/pii/S0958166920301518?dgcid=coauthor">on the surface of the bacteria</a>. Think of it as a lock-and-key mechanism. Each phage has a unique key, that will only open the specific lock displayed by certain bacteria.</p>
<p>Our phages needed <em>A. baumannii</em>‘s capsule for attachment. It was their prospective port of entry into the superbug. When attacked by our phages, <em>A. baumannii</em> escaped by letting go of its capsule. As expected, this helped us decide our next attack: antibiotics.</p>
<p>We tested the action of nine different antibiotics on the phage-resistant <em>A. baumannii</em>. Without the protective capsule, the superbug completely lost its resistance to three antibiotics, reducing the dosage needed to kill the superbug. Phages had pushed the superbug into a corner.</p>
<p>We established a way to revert antibiotic-resistance in one of the most dangerous superbugs.</p>
<h2>Looking forward</h2>
<p>Phage therapy has already been used in patients with life-threatening <em>A. baumannii</em> infections, <a href="https://aac.asm.org/content/61/10/e00954-17">with successful results</a>. This study highlights the possibility of using phages to rescue antibiotics, and to use them in combination. After all, two is better than one.</p><img src="https://counter.theconversation.com/content/150536/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jeremy J. Barr receives funding from NHMRC, ARC, and Ramaciotti Foundation. He is affiliated with ASM, AusBiotech, and the Centre to Impact AMR. </span></em></p><p class="fine-print"><em><span>Fernando Gordillo-Altamirano does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>We found a new way to revert antibiotic resistance. It involves using phage therapy to resensitise a type of bacteria to antibiotics.Fernando Gordillo-Altamirano, Medical Doctor, PhD Student, School of Biological Sciences, Monash UniversityJeremy J. Barr, Senior Lecturer in School of Biological Sciences, Microbiology, Monash UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1367322020-04-22T14:26:06Z2020-04-22T14:26:06ZIn defence of viruses<figure><img src="https://images.theconversation.com/files/329644/original/file-20200422-13243-gaw9ou.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/3d-illustration-bacteriophage-infecting-bacterium-1126283549">Design Cells/Shutterstock</a></span></figcaption></figure><p>Every day, in countries all over the world, people are dying because of <a href="https://theconversation.com/coronavirus-where-do-new-viruses-come-from-136105">a new virus</a>. This time they are dying from a new strain of coronavirus called SARS-CoV-2 that causes the acute respiratory disease known as COVID-19. And this is just the latest. Viruses are responsible for the deaths of millions of people throughout history, from smallpox to flu.</p>
<p>In this time of worry and self-isolation, it is easy to think that viruses are our enemies. And of course, it’s true that some of them are. Sars, Mers, Ebola, HIV, swine flu, bird flu and Zika are among those that have caused deadly outbreaks in recent years – but the list is very long. </p>
<p>However, it’s also true that the vast majority of viruses do not infect human beings at all, or even mammals. And many of these viruses could actually be good for us, either by promoting our health or saving us from other diseases.</p>
<p>It’s easy to forget that most life is microscopic. And, just like viruses specific to mammals infect mammalian cells, a multitude of viruses have evolved to be experts at infecting the cells of bacteria. These viruses are called bacteriophages (or phages, for short).</p>
<p>Whereas bacteria are living organisms made from a single cell, a virus is a <a href="https://theconversation.com/are-viruses-alive-giant-discovery-suggests-theyre-more-like-zombies-75661">biological entity</a> comprising a bundle of genetic material wrapped in a protein coat. It lacks the means to ensure its own independent existence so it infects a host cell to hijack its cellular machinery, enabling the virus to make copies of itself. To do this, it attaches itself to the cell’s surface and injects its genetic material into the cell where it can take control.</p>
<p>The principle is the same for viruses of humans and viruses of bacteria. Scientists have studied bacteriophages for decades, observing how <a href="https://www.technologynetworks.com/immunology/articles/lytic-vs-lysogenic-understanding-bacteriophage-life-cycles-308094">phages can spread</a> through a population of bacteria, first infecting and then bursting open cells as they rapidly multiply.</p>
<p>Or alternatively, how they can <a href="https://www.frontiersin.org/articles/10.3389/fendo.2019.00784/full">co-exist with remarkable stability</a>, often sustaining a diverse community of bacterial species in environments such as the open oceans or the human gastro-intestinal tract. They do this by preventing any single bacterium from growing to become too dominant, a lot like the way animal predators keep prey populations under control.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/329653/original/file-20200422-39205-1xvvjlo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/329653/original/file-20200422-39205-1xvvjlo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=483&fit=crop&dpr=1 600w, https://images.theconversation.com/files/329653/original/file-20200422-39205-1xvvjlo.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=483&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/329653/original/file-20200422-39205-1xvvjlo.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=483&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/329653/original/file-20200422-39205-1xvvjlo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=606&fit=crop&dpr=1 754w, https://images.theconversation.com/files/329653/original/file-20200422-39205-1xvvjlo.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=606&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/329653/original/file-20200422-39205-1xvvjlo.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=606&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Viruses are increasingly seen as essential to the microbe communities inside our body.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/gut-bacteria-flora-microbiome-inside-small-641605609">Anatomy Insider/Shutterstock</a></span>
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</figure>
<p>The more we understand phages, the more we are starting to view them as an essential component of microbial ecosystems, maintaining diversity and functionality rather than acting as agents of disease. For example, it is now known that a diverse microbiota – the community of micro-organisms living in our guts – is associated with <a href="https://theconversation.com/you-are-what-you-eat-why-the-future-of-nutrition-is-personal-119477">health in humans</a>. </p>
<p>This includes the proper functioning of the <a href="https://neurohacker.com/how-the-gut-microbiota-influences-our-immune-system">immune system</a>, the <a href="https://www.bmj.com/content/361/bmj.k2179">absorption of nutrients</a> in the intestine and even our changing <a href="https://www.ncbi.nlm.nih.gov/pubmed/30838027">moods and behaviour</a>. Phages play a key role in maintaining this diversity and are therefore, at the level of the microbial ecosystem within us, contributors to overall human wellbeing.</p>
<p>Another fascinating area of virus research is phage therapy. A virus specific to a harmful bacterium can in principle eradicate this infection from the human body, leaving human cells untouched. In this era of antibiotic resistance, when more and more harmful bacteria are developing resistance to our commonly used antibiotics, fighting bacteria with phages is a <a href="https://theconversation.com/antibiotic-resistance-scientists-are-reengineering-viruses-to-cure-bacterial-infections-127283">promising strategy</a>. </p>
<p>Antibiotics usually kill a broad range of bacteria, often including the ones that benefit us as well as the disease-causing organism we want to kill. But a phage can be used with precision, like a programmed bullet that only seeks out the invading bacterium.</p>
<h2>Inter-viral warfare</h2>
<p>Viruses can also be used to fight other viruses. In a <a href="https://stm.sciencemag.org/content/11/501/eaaw2607">recent study</a> of rhesus monkeys and the simian immunodeficiency virus (SIV), researchers found that another virus, rhesus cytomegalovirus, could be coerced to produce the same proteins as SIV. This meant it could be used as a vaccine to effectively teach the monkey’s immune system how to fight off SIV without exposing it to the harmful virus, a response that is maintained over time.</p>
<p>This is particularly important because immunodeficiency viruses have become experts at hiding from their host’s immune system by mutating, making it very hard for the body to develop a defence on its own. This work has huge implications for HIV treatment in the future.</p>
<p>It is easy to take a viral infection personally, attributing malice and cruelty to an unwelcome biological phenomenon. But the actions of a virus are, in many respects, as indifferent as the weather. And just like accurate weather forecasting can save lives, understanding the multifaceted nature of viruses in our world can also save lives.</p>
<p>It is the effective development and use of vaccines, after all, that has nullified the catastrophic effects of some of the world’s deadliest infections. Knowing how a virus spreads and how it operates can also inform government policy and allow us to behave in ways that keep us safe.</p>
<p>So, when dealing with those viruses that are, in a very real sense, our enemies, it is better to meet them with understanding rather than with fear. For those of us who feel that particular viruses are evil, even metaphorically, we should remember the words of Carl Jung: “Understanding does not cure evil, but it is a definite help, inasmuch as one can cope with a comprehensible darkness.”</p><img src="https://counter.theconversation.com/content/136732/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Hugh Harris works as a postdoctoral researcher at APC Microbiome Ireland, University College Cork where he is funded by Science Foundation Ireland under the Microbes to Molecules research theme.</span></em></p>While a few are killers, viruses are actually important to human health and incredibly useful in medicine.Hugh Harris, Postdoctoral researcher in Microbiology and Bioinformatics, University College CorkLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1272832020-01-20T12:25:27Z2020-01-20T12:25:27ZAntibiotic resistance: scientists are reengineering viruses to cure bacterial infections<figure><img src="https://images.theconversation.com/files/310650/original/file-20200117-118311-626g4a.jpg?ixlib=rb-1.1.0&rect=21%2C0%2C7167%2C4041&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Bacteriophages infecting a bacterial cell.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/3d-illustration-bacteriophage-infecting-bacterium-1126283543">Design_Cells/ Shutterstock</a></span></figcaption></figure><p>The world is in the midst of a <a href="https://theconversation.com/an-ambitious-plan-to-stop-the-rise-of-superbugs-119693">global “superbug” crisis</a>. Antibiotic resistance has been found in numerous common bacterial infections, including tuberculosis, gonorrhoea and salmonellosis, making them difficult – if not impossible – to treat. We’re on the cusp of a <a href="https://www.who.int/news-room/fact-sheets/detail/antibiotic-resistance">“post-antibiotic era”</a>, where there are fewer treatment options for such antibiotic-resistant strains. Given estimates that antibiotic resistance will cause <a href="https://www.nature.com/articles/nmicrobiol2016187">10 million deaths a year by 2050</a>, finding new methods for treating harmful infections is essential.</p>
<p>Strange as it might sound, viruses might be one <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5547374/">possible alternative to antibiotics</a> for treating bacterial infections. Bacteriophages (also known as phages) are viruses that infect bacteria. </p>
<p>They’re estimated to be the most abundant organisms on Earth, with probably more than 10<sup>31</sup> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2706577/">bacteriophages on the planet</a>. They can survive in many environments, including deep sea trenches and the human gut. While phages are efficient killers of bacteria, they don’t infect human cells and are harmless to humans. </p>
<p>Although phage therapy was <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3442826/">used in the 1930s</a>, it has since become a forgotten cure in the west. Although the treatment became commonplace in the former Soviet Union, it wasn’t adopted by western countries largely because of the discovery of antibiotics, which became widespread after World War II.</p>
<p>Bacteriophages are effective against bacteria because they’re able to attach themselves to the cell if they recognise specific molecules called receptors. This is the first step in the “infection” process. After attaching to the bacterial cell, the phage then injects its DNA inside the bacteria. </p>
<p>This causes one of two things to happen. After being injected with the phage’s DNA, the virus will take over the bacterial cell’s replication mechanism and start producing more phages. This process is known as a “<a href="https://www.newworldencyclopedia.org/entry/Lytic_cycle">lytic infection</a>”. This disintegrates the cell, allowing the newly produced viruses to leave the host cell to infect other bacterial cells.</p>
<p>But sometimes, the phage DNA gets incorporated into the bacterial host’s chromosome instead, <a href="https://www.sciencedirect.com/topics/immunology-and-microbiology/prophage">becoming a “prophage”</a>. It usually remains dormant but environmental factors, such as UV radiation or the presence of certain chemicals such as <a href="https://www.ncbi.nlm.nih.gov/pubmed/12545312">those found in sunscreen</a>, can cause the phage to “wake up”, start a lytic infection, take over the host cell and destroy it.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/310651/original/file-20200117-118331-7dxul9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/310651/original/file-20200117-118331-7dxul9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/310651/original/file-20200117-118331-7dxul9.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/310651/original/file-20200117-118331-7dxul9.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/310651/original/file-20200117-118331-7dxul9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/310651/original/file-20200117-118331-7dxul9.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/310651/original/file-20200117-118331-7dxul9.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">A cell in lysis.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/cell-lysis-destruction-can-be-used-343092215">Kateryna Kon/ Shutterstock</a></span>
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</figure>
<p><a href="https://www.ncbi.nlm.nih.gov/pubmed/30651225">Lytic bacteriophages</a> are preferred for treatment because they don’t integrate into the bacterial host’s chromosome. But it’s not always possible to develop lytic bacteriophages that can be used against all types of bacteria. As each type of phage is only able to infect specific types of bacteria, they can’t infect a bacterial cell unless the bacteriophage can find specific receptors on the bacterial cell surface.</p>
<p>However, engineering techniques can remove the bacteriophage’s ability to integrate into the host’s genome, making them useful for treatment. Engineered phages have even successfully treated a drug-resistant <a href="https://www.nature.com/articles/s41591-019-0437-z"><em>Mycobacterium abscessus</em> infection</a> in a 15-year-old girl. </p>
<h2>Targeted treatment</h2>
<p>The reason bacteriophages are so effective against bacteria is because they’re only able to infect specific species. Antibiotics instead target a wide range of bacteria, including “friendly” bacteria not causing the infection. </p>
<p>But this also means that a single phage won’t kill all strains of a disease-causing bacteria. And because bacteria are <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3274958/">constantly evolving</a>, they can develop mechanisms that prevent phage infection. For example, if the bacterial cell has evolved and changed its surface receptors, the bacteriophage won’t be able to attach itself and kill the bacteria. </p>
<p>As part of this evolutionary process, bacteria can <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070868/#B1-viruses-10-00351">rapidly become resistant</a> to a single bacteriophage. But because there are <a href="https://www.ncbi.nlm.nih.gov/pubmed/23755967">many types of bacteriophages</a>, we can use a “phage cocktail” containing a combination of different bacteriophages to <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5971607/">target a broader range</a> of bacterial strains within a species. This decreases the chances a bacteria becomes resistant to all phages used in treatment. Bacteriophages can also be engineered to <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785837/">infect more strains</a> of bacteria.</p>
<p>However, the presence of what are known as <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3497052/">CRISPR systems</a> might complicate the possibility of using bacteriophages in treatment. CRISPR is a bacteria’s natural defence system that allows it to <a href="https://www.omicsonline.org/open-access/who-fights-whom--understanding-the-complex-dynamics-of-bacteria-phage-interaction-using-anderson-phage-typing-system-2332-0877-1000367-102463.html">become immune</a> to genetic material, such as phages, through infection, vaccination or the transfer of antibodies. Bacteria may be resistant to bacteriophages if they have previously encountered similar types and developed immunity. </p>
<p>But bacteriophages have also developed <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086933/">anti-CRISPR</a> proteins that can neutralise the host bacteria’s CRISPR systems. This means a phage can still be effective, despite the presence of the bacterial CRISPR system. Not all bacteriophages have genes that neutralise anti-CRISPR proteins. But with the ability to engineer phage genomes, these could be incorporated into phages that are to be used for treatment in the future. </p>
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Read more:
<a href="https://theconversation.com/soviet-era-treatment-could-be-the-new-weapon-in-the-war-against-antibiotic-resistance-57836">Soviet-era treatment could be the new weapon in the war against antibiotic resistance</a>
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<p>Although phage therapy isn’t routinely used in western medicine, phage cocktails are available treatments in Russia and Georgia. Phage therapy is also a <a href="http://www.ifrik.org/bacteriophages-alternative-antibiotics">common part of medical care</a> in Georgia, especially in paediatric, surgical care and burns hospital settings. Phages are used on their own or in combination with antibiotics and their use hasn’t been linked to any <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4690881/#B16-viruses-07-02958">adverse effects</a>.</p>
<p>With antibiotic-resistant infections becoming more common, bacteriophages offer the ability to treat such infections. But for <a href="https://www.ncbi.nlm.nih.gov/pubmed/29415431">bacteriophages to become commonplace</a> in treating bacterial infections, there needs to be <a href="https://www.intechopen.com/online-first/the-war-between-bacteria-and-bacteriophages">continued research</a> into phage biology to better understand how they interact with bacteria. Finding effective treatments for bacterial infections – other than antibiotics – is the first step in fighting further instances of antibiotic resistance.</p><img src="https://counter.theconversation.com/content/127283/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Andrew Millard receives funding from BBSRC, NERC</span></em></p><p class="fine-print"><em><span>Manal Mohammed does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Bacteriophages are viruses that infect bacteria. But could they be key in solving the antibiotic resistance epidemic?Manal Mohammed, Lecturer, Medical Microbiology, University of WestminsterAndrew Millard, Lecturer in Bacteriophage Bioinformatics, University of LeicesterLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1176782019-08-07T20:02:17Z2019-08-07T20:02:17ZViruses aren’t all nasty – some can actually protect our health<figure><img src="https://images.theconversation.com/files/287001/original/file-20190806-84230-1xovz4z.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Bacteriophages are viruses that attack and infect bacteria.</span> <span class="attribution"><span class="source">From shutterstock.com</span></span></figcaption></figure><p>Viruses are mostly known for their aggressive and infectious nature.</p>
<p>It’s true, most viruses have a pathogenic relationship with their hosts – meaning they cause diseases ranging from a mild cold to serious conditions like severe acute respiratory syndrome (SARS). They work by <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4788752/">invading the host cell</a>, taking over its cellular machinery and releasing new viral particles that go on to infect more cells and cause illness.</p>
<p>But they’re not all bad. Some viruses can actually kill bacteria, while others can fight against more dangerous viruses. So like protective bacteria (probiotics), we have several protective viruses in our body.</p>
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Read more:
<a href="https://theconversation.com/discovered-in-wwi-bacterial-viruses-may-be-our-allies-in-a-post-antibiotic-age-76503">Discovered in WWI, bacterial viruses may be our allies in a post-antibiotic age</a>
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<h2>Protective ‘phages’</h2>
<p>Bacteriophages (or “phages”) are viruses that infect and destroy specific bacteria. They’re found in the mucus membrane lining in the digestive, respiratory and reproductive tracts.</p>
<p>Mucus is a thick, jelly-like material that provides a physical barrier against invading bacteria and protects the underlying cells from being infected. Recent <a href="https://www.pnas.org/content/110/26/10771">research suggests</a> the phages present in the mucus are part of our natural immune system, protecting the human body from invading bacteria.</p>
<p>Phages have actually <a href="https://www.tandfonline.com/doi/full/10.4161/bact.1.2.15845">been used</a> to treat dysentery, sepsis caused by <em>Staphylococcus aureus</em>, salmonella infections and skin infections for nearly a century. Early sources of phages for therapy included local water bodies, dirt, air, sewage and even body fluids from infected patients. The viruses were isolated from these sources, purified, and then used for treatment. </p>
<p>Phages have attracted renewed interest as we continue to see the rise of drug resistant infections. Recently, a teenager in the United Kingdom was reportedly <a href="https://www.theguardian.com/science/2019/may/08/teenager-recovers-from-near-death-in-world-first-gm-virus-treatment">close to death</a> when phages were successfully used to treat a serious infection that had been resistant to antibiotics. </p>
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Read more:
<a href="https://theconversation.com/potential-treatment-for-eye-cancer-using-tumor-killing-virus-110558">Potential treatment for eye cancer using tumor-killing virus</a>
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<p>Nowadays, phages are genetically engineered. Individual strains of phages are tested against target bacteria, and the most effective strains are purified into a potent concentration. These are stored as either bacteriophage stocks (cocktails), which contain one or more strains of phages and can target a broad range of bacteria, or as Adapted bacteriophages, which target specific bacteria. </p>
<p>Before treatment, a swab is collected from the infected area of the patient, cultured in the lab to identify the bacterial strain, and tested against the therapeutic phage stocks. Treatment can be safely administered orally, applied directly onto wounds or bacterial lesions, or even spread onto infected surfaces. Clinical trials for intravenous administration of phages are ongoing.</p>
<h2>Beneficial viral infections</h2>
<p>Viral infections at a young age are important to ensure the proper development of our immune systems. In addition, the immune system is continuously stimulated by systemic viruses at low levels sufficient to develop resistance to other infections. </p>
<p>Some viruses we come across protect humans against infection by other pathogenic viruses. </p>
<p>For example, latent (non-symptomatic) herpes viruses can help human natural killer cells (a specific type of white blood cell) identify cancer cells and cells infected by other pathogenic viruses. They arm the natural killer cells with antigens (a foreign substance that can cause an immune response in the body) that will enable them to identify tumour cells. </p>
<p>This is both a survival tactic by the viruses to last longer within their host, and to <a href="http://www.bloodjournal.org/content/115/22/4377?sso-checked=true">get rid of competitive viruses</a> to prevent them from damaging the host. In the future, modified versions of viruses like these could potentially be used to target cancer cells.</p>
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<img alt="" src="https://images.theconversation.com/files/287008/original/file-20190806-84221-1qq8k9s.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/287008/original/file-20190806-84221-1qq8k9s.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=401&fit=crop&dpr=1 600w, https://images.theconversation.com/files/287008/original/file-20190806-84221-1qq8k9s.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=401&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/287008/original/file-20190806-84221-1qq8k9s.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=401&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/287008/original/file-20190806-84221-1qq8k9s.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/287008/original/file-20190806-84221-1qq8k9s.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/287008/original/file-20190806-84221-1qq8k9s.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Some viruses are bad news, but others might safeguard our health.</span>
<span class="attribution"><span class="source">From shutterstock.com</span></span>
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</figure>
<p>Pegivirus C or GBV-C is a virus that does not cause clinical symptoms. Multiple studies have shown HIV patients infected with GBV-C live longer in comparison to patients without it. The virus slows disease progression by <a href="https://www.ncbi.nlm.nih.gov/pubmed/22325031">blocking the host receptors</a> required for viral entry into the cell, and promotes the release of virus-detecting interferons and cytokines (proteins produced by white blood cells that activate inflammation and removal of infected cells or pathogens).</p>
<p>In another example, noroviruses were shown to <a href="https://www.ncbi.nlm.nih.gov/pubmed/25409145">protect the gut</a> of mice when they were given antibiotics. The protective gut bacteria that were killed by the antibiotics made the mice susceptible to gut infections. But in the absence of good bacteria, these noroviruses were able to protect their hosts.</p>
<h2>The future of therapeutic viruses</h2>
<p>Modern technology has enabled us to understand more about the complexities of the microbial communities that are part of the human body. In addition to good bacteria, we now know there are beneficial viruses present in the gut, skin and even blood. </p>
<p>Our understanding of this viral component is largely in its infancy. But it has huge potential in helping us understand viral infections, and importantly, how to fight the bad ones. It could also shed light on the evolution of the human genome, genetic diseases, and the development of gene therapies. </p>
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Read more:
<a href="https://theconversation.com/explainer-what-is-a-virus-22902">Explainer: what is a virus?</a>
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<img src="https://counter.theconversation.com/content/117678/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Cynthia Mathew does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>While some viruses make us sick, others can fight against bacteria, or protect us from more harmful viruses.Cynthia Mathew, Research Assistant, University of CanberraLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1196932019-08-02T12:22:54Z2019-08-02T12:22:54ZAn ambitious plan to stop the rise of superbugs<figure><img src="https://images.theconversation.com/files/285192/original/file-20190722-11329-1g91y42.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">These bacteria are resistant to antibiotics.</span> <span class="attribution"><a class="source" href="http://www.apimages.com/metadata/Index/UN-Antibiotic-Resistance/fa26edadda654372b9867ff34203505b/7/0">Melissa Brower/Centers for Disease Control and Prevention via AP</a></span></figcaption></figure><p>Antibiotic resistance is here to stay, but that doesn’t mean we can’t do anything to stop it.</p>
<p><a href="https://www.nytimes.com/2014/05/11/opinion/sunday/the-rise-of-antibiotic-resistance.html">A headline that always catches my attention</a> is that antibiotic resistance is on the rise. Underlying these headlines is that the disease-causing bacteria that make us sick are becoming less responsive to treatment by our most common antibiotics. If you read past the headline, you will see that the World Health Organization (WHO) predicts that by the year 2050, there will be <a href="https://www.bbc.com/news/health-30416844">10 million deaths annually from antibiotic resistant bacteria</a> (ARB). This would place ARB ahead of cancer as a leading cause of death worldwide. Those headlines assume that the world cannot do anything to intervene.</p>
<p><a href="http://www.thepridelaboratory.org/about-dr.-pride.html">I am a physician scientist</a> trained in infectious diseases who has had a front row seat as ARB has been on the rise. I am also a member of a group of researchers who are developing bacteriophages – viruses that kill bacteria – as alternatives to antibiotics as an additional means to limit ARB in the U.S. and worldwide. </p>
<p>To understand why ARB is approaching crisis levels, it is important to understand the limitations of the antibiotics and what trends are contributing to it.</p>
<h2>Antibiotic development has its limitations</h2>
<p>People have used antibiotics to treat infections <a href="https://doi.org/10.3389/fmicb.2010.00134">since the early 1940s</a>, but naturally produced <a href="http://doi.org/10.1016/j.cell.2017.04.027">antibiotics are millions of years old</a>. These medicines are derived from natural products that bacteria and fungi use to combat other bacteria. They use these products to eliminate their competition. </p>
<p>Most of the antibiotics produced by industry have one thing in common: they work the same way. They block the bacteria’s ability to make proteins, DNA, RNA or even its cell wall, the consequences of which are deadly to the bacteria. Thus most new antibiotics are not based on new ways to kill bacteria; <a href="https://www.bbc.com/news/health-41693229">they’re simply incremental improvements</a>.</p>
<p>The consequence is that when a bacterium develops immunity to one of these antibiotics, it often gains resistance to that entire antibiotic group. Simply put, a single resistance event can cause us to lose quite a few antibiotics that had previously been effective against that bacterium.</p>
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<a href="https://images.theconversation.com/files/285183/original/file-20190722-11314-1k7m22d.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/285183/original/file-20190722-11314-1k7m22d.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/285183/original/file-20190722-11314-1k7m22d.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=459&fit=crop&dpr=1 600w, https://images.theconversation.com/files/285183/original/file-20190722-11314-1k7m22d.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=459&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/285183/original/file-20190722-11314-1k7m22d.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=459&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/285183/original/file-20190722-11314-1k7m22d.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=576&fit=crop&dpr=1 754w, https://images.theconversation.com/files/285183/original/file-20190722-11314-1k7m22d.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=576&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/285183/original/file-20190722-11314-1k7m22d.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=576&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Here are five ways to kill bacteria.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/antibiotic-mechanisms-action-antimicrobials-342281939?src=e5Gb-FbQa_h3iFLWbEPxjA-1-87&studio=1">Designua/Shutterstock.com</a></span>
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<h2>Antibiotic resistance might be right under your nose</h2>
<p><a href="https://doi.org/10.1128/MMBR.00016-10">Much of the ARB problem is caused by humans</a>. Bacteria often become resistant to antibiotics after exposure to these drugs. The easiest way to think about this concept is, “What can grow, will grow!” You’ve got a body full of microorganisms - called your microbiome - that <a href="http://doi.org/10.1371/journal.pbio.1002533">includes an estimated 38 trillion bacteria</a>. While the antibiotic you take kills the bacterium making you sick, it also kills many of those other good bacteria that are harmless. That leaves you with a microbiome populated by many bacteria that are resistant to not just that single antibiotic, but often that entire group. Because only ARB can grow in this environment, your microbiome becomes populated largely with ARB. Thus, even healthy people who have taken antibiotics in the past may harbor ARB. </p>
<p>The problem gets even worse when you consider all the <a href="https://www.cdc.gov/media/releases/2016/p0503-unnecessary-prescriptions.html">unnecessary antibiotic use across the world</a>. <a href="https://www.mayoclinic.org/healthy-lifestyle/consumer-health/in-depth/antibiotics/art-20045720">Doctors use antibiotics in people with viral</a> infections even though they don’t work. Livestock producers feed them to animals to <a href="http://www.cidrap.umn.edu/news-perspective/2016/12/fda-antibiotic-use-food-animals-continues-rise">accelerate growth and provide health advantages</a>. More than 70% of all antibiotic use globally is in animals, and you can also be exposed to antibiotics just by handling and <a href="https://doi.org/10.3390/antibiotics6040034">consuming meats from animals raised on antibiotics</a>. All these exposures contribute to growing global antimicrobial resistance. </p>
<p>If we know the root causes of antimicrobial resistance, then why is it still occurring? It may seem like physicians and scientists have been sitting and watching this all happen. That’s not correct.</p>
<h2>We are not unified</h2>
<p>Hospitals in the U.S. are taking steps to limit ARB. For some patients, everyone who comes in contact with them must wear gown and gloves. This practice limits the spread of ARB throughout the hospital. Another control is preventing overuse of our most powerful antibiotics to curb the evolution of ARB. Usually, you have to call an infectious diseases physician like me to get access to these drugs. These two basic components of antibiotic stewardship have been quite effective in limiting ARB. </p>
<p>We still see ARB because not every hospital adheres strictly to these practices, and enforcement of <a href="https://www.uspharmacist.com/article/a-review-of-the-opportunities-and-shortcomings-of-antibiotic-stewardship">antimicrobial stewardship in hospitals</a> is not uniform. </p>
<p>Amplifying the problem is that some hospitals don’t routinely screen patients for antibiotic resistant microbes. There are <a href="https://doi.org/10.1128/AAC.00933-15">patients who carry ARB in their microbiomes</a> and it’s pretty difficult to block the spread if you don’t know who carries them. </p>
<p>These strategies together can limit ARB in a single hospital, a part of town, or even an entire city. But you may still be losing the battle across your state. So what can our leaders do to limit ARB? </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/285190/original/file-20190722-11329-xxxlr7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/285190/original/file-20190722-11329-xxxlr7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/285190/original/file-20190722-11329-xxxlr7.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/285190/original/file-20190722-11329-xxxlr7.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/285190/original/file-20190722-11329-xxxlr7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/285190/original/file-20190722-11329-xxxlr7.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/285190/original/file-20190722-11329-xxxlr7.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">In Norway, a decrease in the use of antibiotics and strict routines has led to fewer cases of MRSA (Methicillin-resistant <em>Staphylococcus aureus</em>), a virulent drug-resistant infection.</span>
<span class="attribution"><a class="source" href="http://www.apimages.com/metadata/Index/NORWAY-DRUG-RESISTANCE-MRSA/dc65fef4c76640a2b6aa01e7bd528659/17/0">AP Photo/Torbjorn Gronning</a></span>
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</figure>
<h2>How to reduce antibiotic resistance?</h2>
<p>The bottom line is that an alternative to antibiotics must be developed. A new industry has emerged that focuses on <a href="http://theconversation.com/are-viruses-the-best-weapon-for-fighting-superbugs-111908">using viruses to kill bacteria</a>, but these efforts have been inconsistent. </p>
<p>Bacteriophages have been used successfully in a few recent cases to treat ARB. A <a href="https://doi.org/10.1126/science.aax9709">patient with a severe skin, liver, and lung infection</a> and a man with a life-threatening ARB were both <a href="https://www.medpagetoday.com/meetingcoverage/idweek/75592">treated successfully with bacteriophages</a>, providing great hope for the future of phage therapy. </p>
<p>However, these cases provide only anecdotal evidence that such therapies can work. They are far from meeting the rigorous standards of efficacy the FDA applies to antibiotics. The government must encourage high quality, reproducible studies supporting the use of these antimicrobial agents to further our understanding of their potential in the treatment of ARB in the larger population.</p>
<p>The U.S. also needs to invest in the development of antibiotics that attack bacteria in novel ways. The government must have a policy of incentives to entice industry to attack this problem because <a href="https://doi.org/10.1016/j.socscimed.2016.01.005">market forces don’t favor huge investments in antibiotic development</a>. The reason is most patients use an antibiotic once every few years for a couple of weeks at a time to treat infections. Compare that to a heart medication that patients must use daily for the rest of their lives; the latter is clearly more lucrative. </p>
<p>Other strategies the U.S. could adopt include uniform screening and antibiotic stewardship practices across its hospitals. Physicians may not like a governing body intervening in their practices, but the U.S. must reduce unnecessary antibiotic prescriptions. And the U.S. must limit antibiotics in livestock. This could have a huge impact. </p>
<p>Finally, once the U.S. implements these efforts, it must export them to the rest of the world. Executing these changes in the U.S. alone won’t reverse this trend; but if we’re serious about altering the trajectory ARB and developing antibiotic alternatives, all options must be on the table.</p>
<p>[ <em>Deep knowledge, daily.</em> <a href="https://theconversation.com/us/newsletters?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=deepknowledge">Sign up for The Conversation’s newsletter</a>. ]</p><img src="https://counter.theconversation.com/content/119693/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>The authors do not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Many articles describe the rise of superbugs - bacteria that are resistant to antibiotic drugs - as inevitable. But society has the knowledge to stop the spread of these microbes.David Pride, Associate Director of Microbiology, University of California, San DiegoLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1170582019-05-17T10:45:43Z2019-05-17T10:45:43ZPhage therapy to prevent cholera infections – and possibly those caused by other deadly bacteria<figure><img src="https://images.theconversation.com/files/274702/original/file-20190515-60549-1s01gkj.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Viruses attack and infect a bacterium.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/3d-illustration-bacteriophage-infecting-bacterium-1126283546?src=S_9nerH_NRM2G4uylbOlTA-1-1">Design_Cells/Shutterstock.com</a></span></figcaption></figure><p>In the latest of a string of high-profile cases in the U.S., a cocktail of bacteria-killing viruses <a href="https://doi.org/10.1038/s41587-019-0133-z">successfully treated a cystic fibrosis patient</a> suffering from a deadly infection caused by a pathogen that was resistant to multiple forms of antibiotics. </p>
<p>Curing infections is great, of course. But what about using these bacteria-killing viruses – bacteriophages – to prevent infections in the first place? Could this work for some diseases? Although using viruses to prevent infections caused by bacterial infections might seem counterintuitive, in the case of bacteriophages: “The enemy of my enemy is my friend.” </p>
<p><a href="https://doi.org/10.1007/978-3-319-07758-1_4">Discovered a little more than 100 years ago</a>, bacteriophages, or phages, are generating renewed interest as potential weapons to fight bacteria that are resistant to multiple antibiotics – the so-called superbugs. Although the recent phage therapy has been focused on the treatment of sick patients, preventing infection stops a disease before it begins, keeping people healthy and preventing the spread of the germ to others.</p>
<p><a href="http://doi.org/10.2436/20.1501.01.292">We are </a><a href="https://www.nature.com/articles/ncomms14187">microbiologists</a> <a href="http://doi.org/10.1128/IAI.01139-08">who study</a> cholera because this ancient disease continues to thrive and can have a devastating impact on communities and <a href="https://en.wikipedia.org/wiki/2010s_Haiti_cholera_outbreak">entire countries</a>. The <a href="https://sackler.tufts.edu/facultyResearch/faculty/camilli-andrew/research">Camilli lab</a> has been focused on the disease for over two decades. We are interested in developing vaccines and phage products to prevent cholera from sickening people and triggering outbreaks. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/274703/original/file-20190515-60563-1ge9tfh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/274703/original/file-20190515-60563-1ge9tfh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=402&fit=crop&dpr=1 600w, https://images.theconversation.com/files/274703/original/file-20190515-60563-1ge9tfh.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=402&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/274703/original/file-20190515-60563-1ge9tfh.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=402&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/274703/original/file-20190515-60563-1ge9tfh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=505&fit=crop&dpr=1 754w, https://images.theconversation.com/files/274703/original/file-20190515-60563-1ge9tfh.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=505&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/274703/original/file-20190515-60563-1ge9tfh.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=505&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">This cholera patient is drinking oral rehydration solution in order to counteract his cholera-induced dehydration.</span>
<span class="attribution"><a class="source" href="https://upload.wikimedia.org/wikipedia/commons/a/ad/Cholera_rehydration_nurses.jpg">Centers for Disease Control and Prevention's Public Health Image Library</a></span>
</figcaption>
</figure>
<h2>Cholera outbreaks occur worldwide</h2>
<p>In the case of <a href="https://www.cdc.gov/cholera/index.html">cholera</a>, which is caused by the bacterium <em>Vibrio cholerae</em>, prevention is preferred because it spreads like wildfire once it strikes a community. When this bacterial pathogen is ingested, it inhabits the small intestine, where it releases a potent toxin that triggers vomiting and watery diarrhea, which cause severe dehydration. The vomiting and diarrhea encourage the spread of the pathogen within households and contaminate local water sources. Left untreated, cholera kills 40% of its victims, sometimes within hours of the onset of symptoms. Fortunately, death can be largely prevented by prompt rehydration of cholera victims. </p>
<p>In regions of the world lacking clean water and proper sanitation, <a href="https://www.cdc.gov/healthywater/global/wash_statistics.html">2.5 billion people are at risk</a>, and the CDC estimates that there are <a href="https://www.who.int/news-room/fact-sheets/detail/cholera">up to 4 million cholera cases per year</a>. New epidemics such as the recent massive epidemic in Yemen which has so far <a href="https://www.reuters.com/article/us-yemen-security-cholera/yemen-cholera-outbreak-accelerates-to-10000-cases-per-week-who-idUSKCN1MC23J">sickened over 1.2 million people</a> and the <a href="https://www.africanews.com/2019/05/07/mozambique-fights-cholera-outbreak-after-facing-cyclones//">outbreak in Mozambique</a> are often the consequence of humanitarian crises. War and natural disasters often cause shortages of clean water and impact the poorest and most vulnerable communities. </p>
<p>Cholera is highly transmissible in the community and within households. During outbreaks, an <a href="https://www.sciencedaily.com/releases/2018/06/180625122454.htm">estimated 80% of cases</a> are believed to result from rapid transmission within households, presumably occurring through contamination of household food, water or surfaces with diarrhea or vomit from the initial cholera victim. </p>
<p>Family members typically experience cholera symptoms themselves two to three days after the initial household member became sick. Thus, the people in the most danger are usually siblings and loved ones taking care of the sick person. There is currently no approved medical intervention to immediately protect household members from contracting cholera when it strikes a household. Vaccines for cholera require at least 10 days to take effect, and thus miss the mark in this emergency situation. </p>
<h2>Prevention of cholera using phages</h2>
<p>To address this need, we developed a cocktail of phages to be taken orally each day by household members prior to, or soon after, exposure to <em>Vibrio cholerae</em> to protect them from contracting the disease. We believe the phages should remain in the intestinal tract long enough to serve as a shield against the incoming cholera bacteria. Although this has only been <a href="https://doi.org/10.1038/ncomms14187">proven in animal models of cholera</a>, we hope that the phage cocktail will work similarly in humans. There are three advantages to using phages in this manner. </p>
<p>First, phages provide immediate protection. By acting fast, phages can eliminate the cholera bacteria from the gut in a targeted manner. That is important because cholera kills quickly.</p>
<p>Second, phages infect and kill multi-drug resistant strains of bacteria just as well as drug-sensitive ones. This is crucial since the cholera bacteria have become <a href="http://dx.doi.org/10.4102/ajlm.v7i2.778">multi-drug resistant</a> in many parts of the world due to <a href="https://doi.org/10.1016/S1473-3099(14)70780-7">widespread antibiotic use.</a> </p>
<p>Third, in contrast to antibiotics, which kill bacteria indiscriminately, phages are very specific and infect only their particular host species of bacteria. Thus, when using phages against a pathogen, they will not disrupt the good bacteria residing in and on our patients’ bodies which are part of the microbiome. In research in our lab <a href="http://doi.org/10.1038/ncomms14187">phages, called ICP1, ICP2 and ICP3,</a> which we are using, kill only <em>Vibrio cholerae</em> and should not disrupt the good bacteria in the intestinal tract. This is important because our good bacteria are essential for defending the body against other pathogens and vital for our general nutrition and health.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/274705/original/file-20190515-60567-qv0a58.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/274705/original/file-20190515-60567-qv0a58.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/274705/original/file-20190515-60567-qv0a58.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=401&fit=crop&dpr=1 600w, https://images.theconversation.com/files/274705/original/file-20190515-60567-qv0a58.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=401&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/274705/original/file-20190515-60567-qv0a58.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=401&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/274705/original/file-20190515-60567-qv0a58.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=504&fit=crop&dpr=1 754w, https://images.theconversation.com/files/274705/original/file-20190515-60567-qv0a58.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=504&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/274705/original/file-20190515-60567-qv0a58.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=504&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">People fill buckets with water from a well that is alleged to be contaminated water with the bacterium <em>Vibrio cholera</em>, on the outskirts of Yemen. Yemen’s raging two-year conflict has served as an incubator for lethal cholera.</span>
<span class="attribution"><a class="source" href="http://www.apimages.com/metadata/Index/Yemen-Times-of-Cholera/a1ac866ac46045b8b172c6b7e2e707ee/6/1">AP Photo/Hani Mohammed</a></span>
</figcaption>
</figure>
<h2>From test tube to product</h2>
<p>In collaboration <a href="https://en.wikipedia.org/wiki/Shah_M._Faruque">with</a> <a href="https://www.icddrb.org/index.php?option=com_content&view=article&id=4223&Itemid=2202&staffID=200">international</a> <a href="https://www.icddrb.org/index.php?option=com_content&view=article&id=4223&Itemid=2202&staffID=54">researchers</a>, we have been studying the cholera bacteria and its phages for over two decades at Tufts University, trying to uncover the details of how cholera spreads and how phages might affect its spread. The use of phages for prevention of cholera transmission was a natural outcome of this research, but by no means was it straightforward. </p>
<p>Development of our phage product required finding phages that <a href="https://doi.org/10.1038/ncomms14187">kill <em>Vibrio cholerae</em> in the intestinal tract</a>, having intimate knowledge of <a href="https://doi.org/10.1038/nature11927">how the phages infect</a> <a href="https://doi.org/10.1371/journal.ppat.1002917">the bacteria</a> and discovering how the bacteria become <a href="https://doi.org/10.7554/eLife.03497">resistant to the phages and how this affects their virulence</a>.</p>
<p>Our goal now is to test the phage cocktail in people during a cholera epidemic. Specifically, we need to determine if it is effective at preventing cholera transmission to family members in households where cholera strikes.</p>
<p>In this day and age, we need to change the paradigm of relying entirely on antibiotics to treat infections and develop other types of antimicrobial solutions. It’s time to bring phages in from the cold, and utilize them both for treating multi-drug resistant bacterial infections and in the prevention of infections.</p><img src="https://counter.theconversation.com/content/117058/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Andrew Camilli is a co-founder and scientific advisor of PhagePro, a company developing phage products to promote global health. He receives funding from the United States of America National Institutes of Health. </span></em></p><p class="fine-print"><em><span>Dr. Minmin Yen is the CEO of PhagePro, a phage startup that prioritizes global health. She receives funding from the National Institutes of Health. </span></em></p>Cholera kills fast, and outbreaks are common in war-torn regions and after natural disasters where clean water is scarce. A new strategy to prevent cholera infections is a ‘cocktail’ of live virus.Andrew Camilli, Professor of Molecular Biology & Microbiology, Tufts UniversityMinmin Yen, Research Associate of Molecular Microbiology, Tufts UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1119082019-03-06T11:40:41Z2019-03-06T11:40:41ZAre viruses the best weapon for fighting superbugs?<figure><img src="https://images.theconversation.com/files/261720/original/file-20190301-110134-1u7yr0g.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">These are viruses called bacteriophages that infect only bacterial cells. </span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/3d-render-bacteriophage-viruses-infecting-bacterial-479306521">Ewa Parylak/shutterstock.com</a></span></figcaption></figure><p>Antibiotics won the battle against resistant bacteria, but they may not win the war.</p>
<p>You probably know that antibiotic-resistant bacteria, also known as superbugs, have hampered physicians’ ability to treat infections. You may also be aware that there has been a steep <a href="https://www.cdc.gov/drugresistance/pdf/11-2013-508.pdf">decline in the number of new antibiotics</a> coming to market. Some headlines suggest humanity is doomed by antimicrobial resistance; <a href="https://www.cnn.com/2019/01/24/health/antibiotic-resistance-climate-change-gbr-scli-intl/index.html?no-st=1551070126">even politicians and governments have weighed in</a>, comparing rising antimicrobial resistance to other popular crises such as climate change. Although I believe these assertions are exaggerated, antimicrobial resistance is a serious problem. </p>
<p><a href="http://www.thepridelaboratory.org">I am a physician scientist</a> with a <a href="http://www.thepridelaboratory.org/publications.html">specialty in infectious diseases</a>. I have been fascinated by the role that bacteria play in human health, and the potential for using viruses to treat bacterial infections. </p>
<h2>What causes antimicrobial resistance?</h2>
<p>One significant factor contributing to antimicrobial resistance is the <a href="https://www.ncbi.nlm.nih.gov/pubmed/25859123">excessive use of antibiotics</a>. In the U.S., where antibiotics are widely available, some patients demand these drugs for many different illnesses. Many physicians appease their patients because they <a href="https://www.pewtrusts.org/en/research-and-analysis/articles/2017/06/30/why-doctors-prescribe-antibiotics-even-when-they-shouldnt">don’t understand when and when not</a> to use them and because there is <a href="https://www.cddep.org/wp-content/uploads/2017/06/antibiotic_legislation_timeline.pdf">no regulatory structure to limit their use</a>. Anyone with a prescription pad can prescribe any antibiotic to treat any condition and rarely, if ever, face any consequences. There are some <a href="https://www.cdc.gov/antibiotic-use/stewardship-report/outpatient.html">efforts to reduce antibiotic</a> use, but the scope of the problem in the U.S. remains large.</p>
<p>Some countries, <a href="https://www.who.int/bulletin/volumes/95/11/16-184374/en/">such as Sweden</a>, use incentives to encourage doctors to improve antibiotic uses. But there is no counterpart for this system in U.S. hospitals and clinics. </p>
<p>The problem goes beyond humans; 70 percent of all antibiotics <a href="http://www.cidrap.umn.edu/news-perspective/2016/12/fda-antibiotic-use-food-animals-continues-rise">are actually used on animals</a>. This means that humans can be exposed to antibiotics by <a href="http://doi.org/10.3390/antibiotics6040034">just handling animal products</a>. The drumstick you are preparing for dinner might also have <a href="https://doi.org/10.1093/jac/dkg483">antibiotic-resistant bacteria</a> <a href="http://doi.org/10.1177/003335491212700103">tagging along</a>. </p>
<p>Once antimicrobial resistance develops in a bacterium, it doesn’t always go away. For example, methicillin-resistant <em>Staphylococcus aureus</em> (MRSA) evolved resistance to multiple different antibiotics; yet, despite efforts to reduce its spread by <a href="https://doi.org/10.1086/500664">limiting the use of antibiotics</a> that led to its emergence, <a href="https://doi.org/10.1086/597296">MRSA still persists</a> in hospitals and the community.</p>
<h2>An alternative to antibiotics</h2>
<p>Another reason for finding alternatives to antibiotics is that <a href="http://doi.org/10.7554/eLife.00458">we share our microbes with the people and pets who live around us</a>; thus, others can acquire one of these superbugs without ever taking an antibiotic.</p>
<p>A not-so-obvious reason for developing new therapies is that our bodies are home to a large community of microorganisms, including bacteria, called our microbiome. These microorganisms are necessary to maintain our health. Those same antibiotics that kill harmful bacteria also kill the good ones. </p>
<p>There is an alternative to antibiotics, but it was dismissed by medicine years ago. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/261739/original/file-20190301-110143-1ch0sto.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/261739/original/file-20190301-110143-1ch0sto.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/261739/original/file-20190301-110143-1ch0sto.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=307&fit=crop&dpr=1 600w, https://images.theconversation.com/files/261739/original/file-20190301-110143-1ch0sto.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=307&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/261739/original/file-20190301-110143-1ch0sto.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=307&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/261739/original/file-20190301-110143-1ch0sto.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=386&fit=crop&dpr=1 754w, https://images.theconversation.com/files/261739/original/file-20190301-110143-1ch0sto.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=386&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/261739/original/file-20190301-110143-1ch0sto.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=386&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Antibiotics or wrong diet damage the good and bad bacteria flora living in the gut.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/antibiotics-wrong-diet-damage-good-bad-1225328413">Soleil Nordic/Shutterstockcom</a></span>
</figcaption>
</figure>
<h2>The original phage therapy story</h2>
<p>That alternative was something called phage therapy, which uses viruses that infect bacteria, called bacteriophages, to kill disease-causing bacteria. Bacteriophages, or phages, were used frequently in the <a href="http://doi.org/10.4161/viru.25991">early- and pre- antibiotic eras</a> between the 1920s and ‘40s to treat life-threatening infections. </p>
<p>But phage therapy had many disadvantages. The first was that phages were unpredictable. One type of phage might wipe out the bad bacteria in one individual but not another’s. So hospitals had to keep a broad collection of phages to kill disease-causing bacteria from all their patients. An antibiotic such as vancomycin, by comparison, predictably kills entire groups of bacteria. </p>
<p>Another downside is that phage collections require maintenance. So not only did hospitals have to keep a large variety of phages on hand, but they had to keep them in shape. So medicine chose antibiotics for convenience, and hadn’t looked back in any meaningful way, until recently.</p>
<h2>Making a comeback?</h2>
<p>So, why is phage therapy making a comeback? Antibiotic resistance is an obvious answer, but doesn’t explain the full story. </p>
<p>As a specialist in infectious diseases, I have been interested in phage therapy as long as I can remember, but only recently have I felt comfortable saying this out loud. Why? A physician might be considered a “quack” just for mentioning phage therapy because the early attempts were neither a rousing success or a colossal failure. Like any therapeutic, it had its strengths and weaknesses. </p>
<p>However, now scientific advances can guide us toward which phage is best for destroying a particular microbe. With the rising antimicrobial resistance crisis, physicians and scientists have a well-timed opportunity to work together to develop effective phage therapies. </p>
<p>The proof of this comes from recent landmark phage therapy cases. The successful treatment of a <a href="http://doi.org/10.1128/AAC.00954-17">physician with a life-threatening infection and a grave prognosis caused by a multi-drug resistant bacterium</a> at my institution serves as a great example. Another pivotal case <a href="https://www.buzzfeednews.com/article/azeenghorayshi/phage-therapy-follow-this">circulating in popular media</a> has kept this trend going. We physicians may be able to treat just about any disease-causing bacterium; it is just a matter of finding a suitable phage. </p>
<p>A big part of phage therapy research is devoted to “<a href="https://seaphages.org/">phage hunting</a>,” where we microbiologists scour the soil, the oceans and the human body to identify phages with the potential to kill the bacteria that ail us. While the pace of these studies has been slow, the new research is revealing the therapeutic potential of phages in medicine.</p>
<p>You might think that with all the phage hunting and landmark cases that we would start using phage therapy all the time, but we don’t. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/261740/original/file-20190301-110110-8ixh81.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/261740/original/file-20190301-110110-8ixh81.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/261740/original/file-20190301-110110-8ixh81.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=338&fit=crop&dpr=1 600w, https://images.theconversation.com/files/261740/original/file-20190301-110110-8ixh81.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=338&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/261740/original/file-20190301-110110-8ixh81.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=338&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/261740/original/file-20190301-110110-8ixh81.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=424&fit=crop&dpr=1 754w, https://images.theconversation.com/files/261740/original/file-20190301-110110-8ixh81.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=424&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/261740/original/file-20190301-110110-8ixh81.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=424&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Bacteriophages target only specific stains of bacteria.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/3d-illustration-bacteriophage-infecting-bacterium-1126283543">Design_Cells/Shutterstock.com</a></span>
</figcaption>
</figure>
<h2>The case for using phages</h2>
<p>One advantage of antibiotics is that since they have been used for decades, we know a lot about their safety. Physicians make simple calculations every day about the risk-benefit ratio of using antibiotics, but aren’t equipped to make the same calculations about phages. Does anyone really want a doctor injecting them with a virus to cure a bacterial infection? I doubt that would be anyone’s choice when the question is posed that way. </p>
<p>But, remember that phages are natural. They’re on every surface of your body. They are in the ocean and soil, and in your toilet and sink. They are literally everywhere. Thus, putting a phage into your body to kill a bacterium quite frankly is something that nature does to us every single day, and as far as we know, we are no worse for the wear. </p>
<p>Phages are estimated to <a href="https://daily.jstor.org/fighting-bacterial-infection-with-viruses/?utm_source=marketing&utm_medium=social&utm_campaign=twitter">kill half the world’s bacteria</a> every 48 hours and are probably the most potent antibacterial agents out there. Is there really a compelling reason to be concerned when a doctor gives us a phage instead of us acquiring that same phage from our sink at home? Only time will tell. Unfortunately, as antimicrobial resistance continues to rise, time may not be on our side.</p><img src="https://counter.theconversation.com/content/111908/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>The authors do not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Bacteria are becoming resistant to even the most powerful antibiotics. These expensive, hard-to-treat infections are prompting physicians to reassess using viruses to destroy bacteria.David Pride, Associate Director of Microbiology, University of California, San DiegoLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1041052018-10-09T10:44:53Z2018-10-09T10:44:53ZMeet the trillions of viruses that make up your virome<figure><img src="https://images.theconversation.com/files/238796/original/file-20181001-195278-zxp1fb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Every surface of our body -- inside and out -- is covered in microorganisms: bacteria, viruses, fungi and many other microscopic life forms.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/microbiome-microorganisms-bacteria-viruses-microbes-crawling-714045286?src=4HMvDP6bwGcrS9t-IJGgSA-1-6">vrx/Shutterstock.com</a></span></figcaption></figure><p><a href="https://theconversation.com/conozca-los-billones-de-virus-que-constituyen-su-viroma-104813"><em>Leer en español</em></a>.</p>
<p>If you think you don’t have viruses, think again.</p>
<p>It may be hard to fathom, but the human body is occupied by large collections of microorganisms, commonly referred to as our microbiome, that have evolved with us since the early days of man. Scientists have only recently begun to quantify the microbiome, and discovered it is inhabited by at least <a href="http://doi.org/10.1371/journal.pbio.1002533">38 trillion bacteria</a>. More intriguing, perhaps, is that bacteria are not the most abundant microbes that live in and on our bodies. That award goes to viruses.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/238779/original/file-20181001-195256-6s5ayh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/238779/original/file-20181001-195256-6s5ayh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/238779/original/file-20181001-195256-6s5ayh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=703&fit=crop&dpr=1 600w, https://images.theconversation.com/files/238779/original/file-20181001-195256-6s5ayh.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=703&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/238779/original/file-20181001-195256-6s5ayh.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=703&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/238779/original/file-20181001-195256-6s5ayh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=883&fit=crop&dpr=1 754w, https://images.theconversation.com/files/238779/original/file-20181001-195256-6s5ayh.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=883&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/238779/original/file-20181001-195256-6s5ayh.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=883&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Transmission electron micrograph of multiple bacteriophages attached to a bacterial cell wall.</span>
<span class="attribution"><a class="source" href="https://upload.wikimedia.org/wikipedia/commons/5/52/Phage.jpg">Dr. Graham Beards</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<p>It has been estimated that there are over <a href="http://doi.org/10.1016/j.coviro.2011.12.004">380 trillion viruses</a> inhabiting us, a community collectively known as the human virome. But these viruses are not the dangerous ones you commonly hear about, like those that cause the flu or the common cold, or more sinister infections like Ebola or dengue. Many of these viruses infect the bacteria that live inside you and are known as bacteriophages, or phages for short. The human body is a breeding ground for phages, and despite their abundance, we have very little insight into what all they or any of the other viruses in the body are doing. </p>
<p>I am a physician-scientist studying the human microbiome by focusing on viruses, because I believe that harnessing the power of bacteria’s ultimate natural predators will teach us how to prevent and combat bacterial infections. One might rightly assume that if viruses are the most abundant microbes in the body, they would be the target of the majority of human microbiome studies. But that assumption would be horribly wrong. The study of the human virome lags so far behind the study of bacteria that we are only just now uncovering some of their most basic features. This lag is due to it having taken scientists much longer to recognize the presence of a human virome, and a lack of standardized and sophisticated tools to decipher what’s actually in your virome.</p>
<h2>The 411 on the virome</h2>
<p>Here’s a few of the things we have learned thus far. Bacteria in the human body are not in love with their many phages that live in and around them. In fact they developed CRISPR-Cas systems – which <a href="http://doi.org/10.1016/j.cell.2014.05.010">humans have now co-opted for editing genes</a> – to rid themselves of phages or to <a href="http://doi.org/10.1126/science.1138140">prevent phage infections altogether</a>. Why? Because phages kill bacteria. They take over the bacteria’s machinery and force them to make more phages rather than make more bacteria. When they are done, they burst out of the bacterium, destroying it. Finally, phages sit on our body surfaces <a href="http://doi.org/10.1073/pnas.1305923110">just waiting to cross paths with vulnerable bacteria</a>. They are basically bacteria stalkers. </p>
<figure class="align-left zoomable">
<a href="https://images.theconversation.com/files/238782/original/file-20181001-195256-8oif9s.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/238782/original/file-20181001-195256-8oif9s.png?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/238782/original/file-20181001-195256-8oif9s.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=744&fit=crop&dpr=1 600w, https://images.theconversation.com/files/238782/original/file-20181001-195256-8oif9s.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=744&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/238782/original/file-20181001-195256-8oif9s.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=744&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/238782/original/file-20181001-195256-8oif9s.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=934&fit=crop&dpr=1 754w, https://images.theconversation.com/files/238782/original/file-20181001-195256-8oif9s.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=934&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/238782/original/file-20181001-195256-8oif9s.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=934&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">A virus called a bacteriophage infects bacteria and inserts its genetic material into the cell. The bacterium ‘reads’ the genetic instructions and manufactures more viruses which destroy the bacterium when they exit the cell.</span>
<span class="attribution"><a class="source" href="https://upload.wikimedia.org/wikipedia/commons/b/ba/11_Hegasy_Phage_T4_Wiki_E_CCBYSA.png">Guido4</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>It’s clear that there’s a war being fought on our body surfaces every minute of every day, and we haven’t a clue who’s winning or what the consequences of this war might be. </p>
<p>Viruses may inhabit all surfaces both inside and outside of the body. Everywhere researchers have looked in the human body, viruses have been found. Viruses in the blood? Check. Viruses on the skin? Check. Viruses in the lungs? Check. Viruses in the urine? Check. And so on. To put it simply, when it comes to where viruses live in the human body, figuring out where they don’t live is a far better question than <a href="http://doi.org/10.1016/j.jmb.2014.07.002">asking where they do</a>. </p>
<p>Viruses are contagious. But we often don’t think about bacterial viruses as being easily shared. Researchers have shown that <a href="http://doi.org/10.1186/s40168-016-0212-z">just living with someone will lead to rapid sharing of the viruses in your body</a>. If we don’t know what the consequences are of the constant battle between bacteria and viruses in our body, then it gets exponentially more complicated considering the battle between your bacteria and their viruses that are then shared with everyone including your spouse, your roommate, and even your dog. </p>
<h2>Viruses keeping us healthy?</h2>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/238804/original/file-20181001-195260-1d8xn0z.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/238804/original/file-20181001-195260-1d8xn0z.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/238804/original/file-20181001-195260-1d8xn0z.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=399&fit=crop&dpr=1 600w, https://images.theconversation.com/files/238804/original/file-20181001-195260-1d8xn0z.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=399&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/238804/original/file-20181001-195260-1d8xn0z.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=399&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/238804/original/file-20181001-195260-1d8xn0z.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=502&fit=crop&dpr=1 754w, https://images.theconversation.com/files/238804/original/file-20181001-195260-1d8xn0z.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=502&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/238804/original/file-20181001-195260-1d8xn0z.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=502&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Viruses destroy the bacterium when they burst out of the cell. Here, the clear circles reveal where the bacteriophage have killed the bacteria.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/bacteriophage-activity-little-spots-on-right-175492538?src=ScqQu3941Q4d-DJ6NHxD6g-1-81">Guido4/Shutterstock.com</a></span>
</figcaption>
</figure>
<p>Ultimately, we need to know what all these viruses in the human body are doing, and figure out whether we can take advantage of our virome to promote our health. But it’s probably not clear at this point why anyone would believe that our virome may be helpful. </p>
<p>It may seem counterintuitive, <a href="http://doi.org/10.1136/bmj.j831">but harming our bacteria can be harmful to our health</a>. For example, when our healthy bacterial communities are disturbed by antibiotic use, other microbial bad guys, also called pathogens, take advantage of the opportunity to invade our body and make us sick. Thus, in a number of human conditions, our healthy bacteria play important roles in preventing pathogen intrusion. Here’s where viruses come in. They’ve already figured out how to kill bacteria. It’s all they live for. </p>
<p>So the race is on to find those viruses in our viromes that have already figured out how to protect us from the bad guys, while leaving the good bacteria intact. Indeed, there are recent anecdotal examples <a href="http://doi.org/10.1128/AAC.00954-17">utilizing phages successfully to treat life-threatening infections</a> from bacteria resistant to most if not all available antibiotics – a treatment known as phage therapy. Unfortunately, these treatments are and will continue to be hampered by inadequate information on how phages behave in the human body and the unforeseen consequences their introduction may have on the human host. Thus, phage therapy remains heavily regulated. At the current pace of research, it may be many years before phages are used routinely as anti-infective treatments. But make no mistake about it; the viruses that have evolved with us for so many years are not only part of our past, but will play a significant role in the future of human health.</p><img src="https://counter.theconversation.com/content/104105/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>The authors do not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Just because you don’t have the flu doesn’t mean that your aren’t teeming with viruses inside and out. But what are all these viruses doing, if they aren’t making you sick?David Pride, Associate Director of Microbiology, University of California, San DiegoChandrabali Ghose, Visiting Scientist, The Rockefeller UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1043512018-10-03T17:24:32Z2018-10-03T17:24:32ZHow the winners of the Nobel Prize in Chemistry have transformed research and saved lives<figure><img src="https://images.theconversation.com/files/239167/original/file-20181003-52663-1s36p01.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Frances Arnold, George Smith and Gregory Winter have won the 2018 Nobel Prize in Chemistry.</span> <span class="attribution"><span class="source">Ill. Niklas Elmehed/ Nobel Media</span></span></figcaption></figure><p>The Nobel Prize in Chemistry 2018 <a href="https://www.nobelprize.org/prizes/chemistry/2018/summary/">has been awarded</a> to three researchers for their work on “harnessing the power of evolution” to create compounds that are of benefit to humanity. One half of the nine million Swedish kronor (£770,686) prize will go to the American <a href="https://www.che.caltech.edu/faculty/arnold_f/">Frances Arnold</a> from the California Institute of Technology, US. The other half will go jointly to the American <a href="https://en.wikipedia.org/wiki/George_P._Smith_(chemist)">George Smith</a> from the University of Missouri, US, and the Brit <a href="https://www.cam.ac.uk/research/news/sir-greg-winter-wins-the-2018-nobel-prize-in-chemistry">Gregory Winter</a> from the <a href="https://www2.mrc-lmb.cam.ac.uk/">MRC lab in Cambridge</a>, UK.</p>
<p>Their work centres on techniques of “directed evolution” – a method which imitates natural selection. This can help to create new powerful proteins that achieve specific tasks.</p>
<p>The method is now widely used in the production of new synthetic drugs, such as <a href="https://en.wikipedia.org/wiki/Recombinant_antibodies">recombinant antibodies</a>, to process or produce biofuels and medical treatments. By engineering new molecules, the 2018 Nobel laureates have – according to the Royal Swedish Academy of Sciences – “taken control of evolution and used it for purposes that bring the greatest benefit to humankind”. </p>
<h2>Useful mutations</h2>
<p>One of the most crucial characteristics of evolving organisms – life as we know it – is the ability to replicate and mutate. All organisms can make copies of their genes and undergo changes that are passed to their progeny. In other words, we are totally dependent of evolving chemicals. </p>
<figure class="align-right ">
<img alt="" src="https://images.theconversation.com/files/239195/original/file-20181003-52666-1gh25or.png?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/239195/original/file-20181003-52666-1gh25or.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=717&fit=crop&dpr=1 600w, https://images.theconversation.com/files/239195/original/file-20181003-52666-1gh25or.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=717&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/239195/original/file-20181003-52666-1gh25or.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=717&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/239195/original/file-20181003-52666-1gh25or.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=901&fit=crop&dpr=1 754w, https://images.theconversation.com/files/239195/original/file-20181003-52666-1gh25or.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=901&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/239195/original/file-20181003-52666-1gh25or.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=901&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Frances Arnold.</span>
<span class="attribution"><span class="source">wikipedia</span>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<p>Arnold’s work focused on the directed evolution of enzymes – proteins that accelerate chemical reactions. Because they are so useful, scientists had long tried to create enzymes with desired properties artificially, but with little success. </p>
<p>Arnold – who is the fifth to join an important group of women to win the Nobel Prize in Chemistry – instead developed a method to produce mutations in the genes that produced certain enzymes in order to select the best ones. Different mutations will produce slightly different versions of the enzyme in each cell so, over time, one can select the one which works the best for a specific task. </p>
<p>Arnold’s discovery was hugely important – creating a completely new way to design and produce pharmaceuticals and renewable fuels for a greener transport sector. </p>
<h2>Phage revolution</h2>
<p>Smith and Winter also managed to use evolution to the advantage of humankind by developing a technique called <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3656071/">phage display</a>. </p>
<p>Smith first made the groundbreaking discovery of how “bacteriophages” – viruses that infect bacteria – work. Using standard DNA technology, Winter’s group then used the bacteriophages to evolve new proteins. Essentially, Winter used the phage technology in order to engineer new “antibodies” in the bacteria – large proteins that are used by the immune system to fight harmful bacteria and viruses. After many rounds of mutation and selection, artificial chemical evolution can select for the best antibody to fight a certain infection. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/239207/original/file-20181003-52660-1a79a65.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/239207/original/file-20181003-52660-1a79a65.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=703&fit=crop&dpr=1 600w, https://images.theconversation.com/files/239207/original/file-20181003-52660-1a79a65.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=703&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/239207/original/file-20181003-52660-1a79a65.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=703&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/239207/original/file-20181003-52660-1a79a65.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=883&fit=crop&dpr=1 754w, https://images.theconversation.com/files/239207/original/file-20181003-52660-1a79a65.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=883&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/239207/original/file-20181003-52660-1a79a65.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=883&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Electron micrograph image of bacteriophages attached to a bacterial cell.</span>
<span class="attribution"><span class="source">Dr Graham Beards/wikipedia</span>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<p>Winter was one of the first to produce functional mammalian antibodies or part of them in bacteria. Crucially, this moved the whole experimental area from being totally dependent on experimenting with animals to a complete new world of exact biology that could be performed in a simple Petri dish. It is therefore fair to say that one of the great contributions of their research was to reduce the number of animals used in the lab.</p>
<p>Winter has set up important commercial antibody producing facilities at Cambridge, producing drugs that can tackle devastating autoimmune diseases and metastatic cancer. Clearly his entrepreneurial vision, ability to surround himself by extremely competent people and openness to new techniques such as phage display makes him a worthy winner of this year’s Nobel Prize in Chemistry. </p>
<p>The work by all three recipients was largely carried out in the 1990s. Nowadays, scientists including myself base most of our research on synthetic libraries of proteins and enzymes, so it has truly transformed the entire field of protein engineering research as well as saving the lives of both animals and people. And this is only the start – we may see many more cures come from research involving these techniques in the future.</p><img src="https://counter.theconversation.com/content/104351/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Marcos Alcocer received funding from BBSRC.</span></em></p>The 2018 Nobel Prize in Chemistry goes to work on how to use the principles of evolution to create new medical treatments and renewable fuels.Marcos Alcocer, Associate Professor in Biochemistry, University of NottinghamLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/765032017-04-24T21:55:21Z2017-04-24T21:55:21ZDiscovered in WWI, bacterial viruses may be our allies in a post-antibiotic age<figure><img src="https://images.theconversation.com/files/166234/original/file-20170421-12655-1u4qoni.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Many in the Western Front contracted haemorrhagic dysentery.</span> <span class="attribution"><span class="source">Wellcome Library, London</span></span></figcaption></figure><p>As we again reflect on the sacrifices our Anzac soldiers, nurses and doctors made during the first world war, another centenary goes by unnoticed by most Australians.</p>
<p>It celebrates a scientific discovery made behind the Western Front, one that might soon affect the health and life of many Australians. Bacteriophages (viruses that attack bacteria) – described by Felix d'Herelle in 1917 – may now be the answer to a world where antibiotics are losing effectiveness.</p>
<h2>Dysentery in the trenches</h2>
<p>Historians record WWI as the first conflict in which more military deaths were attributable to <a href="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61790-6/abstract">hostile action than disease</a>. But the <a href="https://theconversation.com/flies-filth-and-bully-beef-life-at-gallipoli-in-1915-39321">filthy nature of trench warfare</a> on battlefronts like Gallipoli allowed infectious diseases like dysentery to spread widely among troops.</p>
<figure class="align-right ">
<img alt="" src="https://images.theconversation.com/files/166218/original/file-20170421-12633-1ipr8d1.png?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/166218/original/file-20170421-12633-1ipr8d1.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=764&fit=crop&dpr=1 600w, https://images.theconversation.com/files/166218/original/file-20170421-12633-1ipr8d1.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=764&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/166218/original/file-20170421-12633-1ipr8d1.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=764&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/166218/original/file-20170421-12633-1ipr8d1.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=960&fit=crop&dpr=1 754w, https://images.theconversation.com/files/166218/original/file-20170421-12633-1ipr8d1.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=960&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/166218/original/file-20170421-12633-1ipr8d1.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=960&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Felix d'Herelle led the investigation into the 1915 outbreak.</span>
<span class="attribution"><a class="source" href="https://upload.wikimedia.org/wikipedia/en/d/df/Felix_d%27Herelle.png">From the book Gesund durch Viren by Thomas Häusler, 1910. Wikipedia Media</a></span>
</figcaption>
</figure>
<p>Only twice during the <a href="http://www.gallipoli.gov.au/north-beach-commemorative-site/sick-wounded-interpretative-panel.php">Gallipoli campaign</a> did the proportion of Anzac troops being evacuated with wounds exceed those being taken off due to some form of illness.</p>
<p>The situation was scarcely better on the Western Front. In August 1915, ten infantrymen in the French army had contracted severe haemorrhagic dysentery – described as diarrhoea with heavy blood loss. </p>
<p>Investigation of this outbreak was assigned to a young French-Canadian scientist Felix d'Herelle. Working in Paris at the prestigious Institut Pasteur, he quickly isolated and identified the Shigella bacterium as the cause of the infantrymen’s dysentery.</p>
<p>At this critical time during the war, many researchers at the Institut Pasteur practically lived in the laboratory, often working through the night on important scientific pursuits. <a href="http://yalebooks.com/book/9780300071276/felix-dherelle-and-origins-molecular-biology">D’Herelle would sneak in</a> inquisitive side experiments during his rare moments of free time. And it was in these moments he made his great discovery.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/166238/original/file-20170421-12650-1uezl8z.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/166238/original/file-20170421-12650-1uezl8z.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/166238/original/file-20170421-12650-1uezl8z.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=197&fit=crop&dpr=1 600w, https://images.theconversation.com/files/166238/original/file-20170421-12650-1uezl8z.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=197&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/166238/original/file-20170421-12650-1uezl8z.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=197&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/166238/original/file-20170421-12650-1uezl8z.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=247&fit=crop&dpr=1 754w, https://images.theconversation.com/files/166238/original/file-20170421-12650-1uezl8z.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=247&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/166238/original/file-20170421-12650-1uezl8z.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=247&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">D'Herelle identified the Shigella bacterium as the cause of the infantrymen’s dysentery.</span>
<span class="attribution"><a class="source" href="https://www.cdc.gov/shigella/index.html">Centres for Disease Control and Prevention</a></span>
</figcaption>
</figure>
<h2>Invisible agents</h2>
<p>D’Herelle had a hunch. Previous research had suggested the possibility an invisible agent (possibly a virus) could kill bacteria. To investigate this, he decided to mix filtered (bacteria-free) faeces from dysentery-infected soldiers with a layer of Shigella bacteria he grew in a petri dish. </p>
<p>A day later, d’Herelle saw saw evidence his invisible virus appeared to be killing the bacteria. In 1917, d’Herelle <a href="http://www.tandfonline.com/doi/pdf/10.4161/bact.1.1.14941">published an article</a> in the proceedings of the French Academy of Sciences. Its title translated from French was “On an invisible microbe antagonistic to dysentery bacilli”.</p>
<p>Suspecting a virus but unable to prove these agents killed the bacteria, d’Herelle gave the antagonistic agents the name <a href="http://bio.classes.ucsc.edu/bio105l/EXERCISES/PHAGE/dH.pdf">bacteriophage</a> (from the Greek “phagein”, meaning to eat).</p>
<h2>The rise and fall of bacteriophage therapy</h2>
<p>Before antibiotics were developed in 1945, bacterial infections such as pneumonia and tuberculosis were among the <a href="https://www.cdc.gov/mmwr/preview/mmwrhtml/mm4829a1.htm">leading causes of death in industrialised societies</a>. </p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/166222/original/file-20170421-12665-y0m138.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/166222/original/file-20170421-12665-y0m138.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/166222/original/file-20170421-12665-y0m138.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/166222/original/file-20170421-12665-y0m138.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/166222/original/file-20170421-12665-y0m138.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/166222/original/file-20170421-12665-y0m138.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/166222/original/file-20170421-12665-y0m138.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/166222/original/file-20170421-12665-y0m138.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=754&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Scientific understanding of bacteriophages and biology at the time was limited.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/ajc1/6242867833/in/photolist-avEk7i-dBJ99c-wYT9Q-qJvuek-u12SG-drFewt-bwwd9B-Pmv7L-o39zRq-7PfoQs-geCCe8-9vELdj-GLSvz-J4E9R-GtA4Y-2aY77G-osrTSf-6eStNk-EShVp-qGyJ1h-9RPVKW-8i9cg7-cAkkA3-mtZJCx-q5q8P9-jBZuRe-9eaXqf-Qr2yx-4BHpGL-bVg578-9CN8DV-iPViKR-wRa3kn-a89MBq-agubN5-9Td3aU-nfNUXu-Fdvktk-ng4QDj-EC7Es-4eFiQN-BybXZr-nw2nuA-neNggw-nfaFH6-ntXeN7-F8eN6-nf6in2-nw2Eis-J4dpa">AJC1/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>D’Herelle pioneered bacteriophage (phage) therapy in the 1920s and 1930s to <a href="http://europepmc.org/articles/PMC2542891">successfully treat</a> a range of bacterial infections. These included skin and eye infections, septicaemia and intestinal diseases. The therapy was administered to patients orally, by injection or even through the general water supply.</p>
<p>But the use of phage therapy did not persist. Scientific understanding of bacteriophages and biology at the time was limited. Perhaps the most notable problem was that viruses remained invisible to human eyes until the electron microscope was <a href="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02250-9/abstract">developed in the late 1930s</a>. </p>
<p>It was also <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2542891">speculated</a> D’Herelle’s work on bacteriophages did not achieve greater prominence as he was regarded as a scientific outsider who allegedly had a tendency for hostility rather than persuasion.</p>
<p>Nevertheless, from the 1940s, d'Herelle’s bacteriophage techniques were used to unravel many molecular processes of genetics, leading to multiple Nobel prizes. But with the meteoric rise of antibiotics in treating bacterial diseases <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109405">from 1945 onwards</a>, use of bacteriophages to treat bacterial infections was largely forgotten.</p>
<h2>The post-antibiotic era</h2>
<p>We have now entered a new era in which the World Health Organisation <a href="http://www.who.int/mediacentre/news/statements/2011/whd_20110407/en/">has declared</a> antibiotic resistance a global health priority. Antibiotics can no longer be relied on to halt the spread of bacterial infections.</p>
<figure class="align-left zoomable">
<a href="https://images.theconversation.com/files/166225/original/file-20170421-12629-qs6mos.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/166225/original/file-20170421-12629-qs6mos.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/166225/original/file-20170421-12629-qs6mos.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/166225/original/file-20170421-12629-qs6mos.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/166225/original/file-20170421-12629-qs6mos.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/166225/original/file-20170421-12629-qs6mos.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/166225/original/file-20170421-12629-qs6mos.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/166225/original/file-20170421-12629-qs6mos.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">The World Health Organisation has declared antibiotic resistance a global health priority.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/us-mission/6946430257/in/photolist-bzQgGV-a7DyaQ-787EzG-9Ji7mk-a7Amwe-8FgYP6-7jTFUo-nmDuL2-cPJT3w-7jTisA-6zgUXA-d79ZWm-phbmfo-fPxGqz-6JEhr3-9M2DUT-8YRkJP-7jTFDu-9J42FX-8Fk8Vj-eapSfS-34Gqaf-34C8sg-Rcsrzw-cgbt1-pLJmYM-d79SjE-9NGKrb-6JEhr7-9NEtYQ-5Tk4VE-d1VENG-qZVqNi-nmdjBX-9NJybd-9NDrQR-9NGabs-9NEwpU-ejTVyX-nCqdTV-46uZse-7jPDre-ab95jd-nqBv1N-Sa23t1-nmdwsG-9NAsCc-9dBhot-nM2D4K-8MneV3">United States Mission Geneva /flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>The Australian government’s <a href="http://www.health.gov.au/internet/main/publishing.nsf/Content/ohp-amr.htm#tocstrategy">Antimicrobial Resistance Strategy</a> recognises “the single most powerful contributor to resistance is the global unrestrained use of antibiotics”.</p>
<p>As antibiotic resistance continues to spread, we are seeing the emergence of the century-old infections and diseases suffered by Anzac troops during WWI. </p>
<p>Bacterial infections routinely prescribed and treated with antibiotics are <a href="https://theconversation.com/explainer-what-are-superbugs-and-how-can-we-control-them-44364">transforming into superbugs</a> that threaten to send us back to a pre-antibiotic era. In recent years, strains of Shigella bacteria have re-emerged with broad-spectrum antibiotic resistance in industrialised societies such as <a href="https://www2.health.vic.gov.au/about/news-and-events/healthalerts/increased-antibiotic-resistance-for-shigellosis">Australia</a> and the <a href="https://www.cdc.gov/media/releases/2015/p0402-multidrug-resistant-shigellosis.html">United States</a>. </p>
<p>It’s worth noting that in the world’s poorest communities – where access to clean water and basic sanitation is lacking – dysentery was never defeated. <a href="https://wwwnc.cdc.gov/eid/article/16/11/09-0934_article">Shigella infects</a> hundreds of millions of people each year, and thousands die.</p>
<h2>Making a comeback</h2>
<p>But the future is not altogether bleak. Easy access to DNA sequencing technology is expanding our understanding of the microbial worlds that surround us. And there is a renewed interest in bacteria’s most ancient enemy, and d’Herelle’s important discovery, the bacteriophage. </p>
<p>Some of the original phage therapy techniques he developed have been <a href="https://theconversation.com/soviet-era-treatment-could-be-the-new-weapon-in-the-war-against-antibiotic-resistance-57836">maintained</a> in the former Soviet republic of Georgia, to treat recalcitrant infections such as Golden Staph caused by the bacterium <em>Staphylococcus aureus</em>. </p>
<p>These bacteriophage preparations <a href="https://www.phagetherapycenter.com/pii/PatientServlet?command=static_compassionate&secnavpos=6&language=0">can be imported</a> into Australia for personal use. Yet we previously had little use for them because antibiotics worked, and worked well.</p>
<p>This is changing as scientists, doctors and businesses are leveraging decades of bacteriophage research in a renewed attempt to combat antibiotic-resistant superbugs.</p>
<p>Australia is a growing hotspot for bacteriophage research, investment and <a href="http://www.ampliphibio.com">biotech companies</a>. Scientists at Flinders University are already <a href="http://news.flinders.edu.au/blog/2016/04/26/virus-therapy-to-attack-superbugs/">using bacteriophages</a> to combat bacterial diseases, including Golden Staph. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/166230/original/file-20170421-12650-fcg17q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/166230/original/file-20170421-12650-fcg17q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/166230/original/file-20170421-12650-fcg17q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/166230/original/file-20170421-12650-fcg17q.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/166230/original/file-20170421-12650-fcg17q.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/166230/original/file-20170421-12650-fcg17q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/166230/original/file-20170421-12650-fcg17q.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/166230/original/file-20170421-12650-fcg17q.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Australia is a growing hotspot for bacteriophage research.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/download/success">from www.shutterstock.com</a></span>
</figcaption>
</figure>
<p><a href="https://thebarrlab.org">My laboratory</a> is expanding on a <a href="http://www.pnas.org/content/110/26/10771">2013 discovery</a> which described the role bacteriophage viruses play in protecting our bodies from disease-causing bugs. </p>
<p>This unlikely symbiotic partnership is explained for a mainstream audience in a graphic novel (which I co-authored) called <a href="https://theinvisiblewar.com.au">The Invisible War</a>. It is set in the trenches of the first world war, featuring dysentery-ridden nurses, warring microbes and heroic viruses.</p>
<h2>Lest we forget</h2>
<p>Scientists from all over the world are gathering <a href="http://www.bacteriophage100.org/">this week</a> at Paris’s Institut Pasteur to commemorate the 100-year anniversary of the discovery of bacteriophages, made behind the Western Front. </p>
<p>So when remembering our troops, doctors and nurses this Anzac Day, consider also tipping your hat or your glass to the vital role bacteriophages play in our world. One day our health might just depend on them.</p>
<hr>
<p><em>This article was co-written with Dr Gregory Crocetti from <a href="http://scalefreenetwork.com.au/">Scale Free Network</a>.</em></p><img src="https://counter.theconversation.com/content/76503/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jeremy J. Barr receives funding from the Australia Research Council and is a member of the Australian Society for Microbiology.</span></em></p>When commemorating our troops, doctors and nurses this Anzac Day, consider also tipping your hat to the discovery of bacteriophages. In the post-antibiotic era, our health might just depend on them.Jeremy J. Barr, Lecturer in School of Biological Sciences, Microbiology, Monash UniversityLicensed as Creative Commons – attribution, no derivatives.