{"id":84163,"date":"2016-09-13T09:31:38","date_gmt":"2016-09-13T06:31:38","guid":{"rendered":"https:\/\/www.technion.ac.il\/blog\/a-cinematic-approach-to-drug-resistance\/"},"modified":"2016-09-13T09:31:38","modified_gmt":"2016-09-13T06:31:38","slug":"a-cinematic-approach-to-drug-resistance","status":"publish","type":"post","link":"https:\/\/www.technion.ac.il\/en\/blog\/a-cinematic-approach-to-drug-resistance\/","title":{"rendered":"A Cinematic Approach to Drug Resistance"},"content":{"rendered":"<p dir=\"ltr\"><span style=\"font-size: 14pt;\"><b>A Cinematic Approach to Drug Resistance <\/b><b><br \/>\n<\/b><\/span><b><i>Scientists film bacteria\u2019s maneuvers as they become impervious to drugs <\/i><\/b><\/p>\n<p dir=\"ltr\"><strong>At a glance:<\/strong><\/p>\n<ul dir=\"ltr\">\n<li style=\"font-weight: 400;\"><strong>Scientists at Harvard Medical School and Technion-Israel Institute of Technology have built a giant Petri dish to help visualize how bacteria move as they become immune to drugs.<\/strong><\/li>\n<li style=\"font-weight: 400;\"><strong>The device represents a new, more realistic, platform to study bacterial behavior and evolution than traditional lab dishes.<\/strong><\/li>\n<li style=\"font-weight: 400;\"><strong>The Hollywood-inspired approach is a powerful teaching tool that visually captures otherwise-abstract concepts, such as mutation and evolution.<\/strong><\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n<p><center><br \/>\n<iframe loading=\"lazy\" src=\"https:\/\/www.youtube.com\/embed\/4Flrxgm-p74\" width=\"560\" height=\"315\" frameborder=\"0\" allowfullscreen=\"allowfullscreen\"><\/iframe><\/center>&nbsp;<\/p>\n<figure id=\"attachment_20575\" aria-describedby=\"caption-attachment-20575\" style=\"width: 300px\" class=\"wp-caption alignright\"><a href=\"\/wp-content\/uploads\/2016\/09\/kishony3.jpg\"><img decoding=\"async\" class=\"size-full wp-image-20575\" src=\"\/wp-content\/uploads\/2016\/09\/kishony3.jpg\" alt=\"\" width=\"300\" height=\"148\" \/><\/a><figcaption id=\"caption-attachment-20575\" class=\"wp-caption-text\">Bacteria in action<\/figcaption><\/figure>\n<p dir=\"ltr\"><span style=\"font-weight: 400;\">In a creative stroke inspired by Hollywood wizardry, scientists from <\/span><a href=\"http:\/\/hms.harvard.edu\/\"><span style=\"font-weight: 400;\">Harvard Medical School<\/span><\/a><span style=\"font-weight: 400;\"> and <\/span><a href=\"\/en\/\"><span style=\"font-weight: 400;\">Technion-Israel Institute of Technology<\/span><\/a><span style=\"font-weight: 400;\"> have designed a simple way to observe how bacteria move as they become impervious to drugs.<\/span><\/p>\n<p dir=\"ltr\"><span style=\"font-weight: 400;\">The experiments, described in the Sept. 9 issue of <\/span><a href=\"http:\/\/www.sciencemag.org\/\"><i><span style=\"font-weight: 400;\">Science<\/span><\/i><\/a><i><span style=\"font-weight: 400;\">, <\/span><\/i><span style=\"font-weight: 400;\">are thought to provide the first large-scale glimpse at the maneuvers of bacteria as they encounter increasingly higher doses of antibiotics and adapt to survive\u2014and thrive\u2014in them.<\/span><\/p>\n<p dir=\"ltr\"><span style=\"font-weight: 400;\">To do so, the team constructed a two-by-four-foot petri dish and filled it with 14 liters of agar, a seaweed-derived jelly-like substance commonly used in labs to nourish organisms as they grow. <\/span><\/p>\n<p dir=\"ltr\"><span style=\"font-weight: 400;\">To observe how the bacterium<\/span><i><span style=\"font-weight: 400;\"> Escherichia coli<\/span><\/i><span style=\"font-weight: 400;\"> adapts to increasingly higher doses of antibiotic, researchers divided the dish into sections saturated with increasingly higher doses of antibiotic. The outermost rims of the dish were free of any drug. \u00a0The next section contained a small amount of antibiotic\u2014just about the minimum amount needed to kill the bacteria\u2014and each subsequent section represented a 10-fold increase in dose, with the center of the dish containing 1,000 times as much antibiotic as the area with the lowest dose. <\/span><\/p>\n<figure id=\"attachment_20578\" aria-describedby=\"caption-attachment-20578\" style=\"width: 300px\" class=\"wp-caption alignright\"><a href=\"\/wp-content\/uploads\/2016\/09\/Roy-Kishony-300x2191.jpg\"><img decoding=\"async\" class=\"size-full wp-image-20578\" src=\"\/wp-content\/uploads\/2016\/09\/Roy-Kishony-300x2191.jpg\" alt=\"\" width=\"300\" height=\"219\" \/><\/a><figcaption id=\"caption-attachment-20578\" class=\"wp-caption-text\">Technion Prof. Roy Kishony<\/figcaption><\/figure>\n<p dir=\"ltr\"><span style=\"font-weight: 400;\">Over two weeks, a camera mounted on the ceiling above the dish took periodic snapshots that the researchers spliced into a time-lapsed montage. The result? A powerful, unvarnished <\/span><a href=\"https:\/\/vimeo.com\/180908160\/7a7d12ead6\"><span style=\"font-weight: 400;\">visualization<\/span><\/a><span style=\"font-weight: 400;\"> of bacterial movement, death and survival; evolution at work, visible to the naked eye.<\/span><\/p>\n<p dir=\"ltr\"><span style=\"font-weight: 400;\">The device, dubbed the Microbial Evolution and Growth Arena (MEGA) plate, represents a simple, and more realistic, platform to explore the interplay between space and evolutionary challenges that force organisms to change and adapt or die, the researchers said.<\/span><\/p>\n<p dir=\"ltr\"><span style=\"font-weight: 400;\">\u201cWe know quite a bit about the internal defense mechanisms bacteria use to evade antibiotics but we don\u2019t really know much about their physical movements across space as they adapt to survive in different environments,\u201d said study first author Michael Baym, a research fellow in systems biology at HMS.<\/span><\/p>\n<p dir=\"ltr\"><span style=\"font-weight: 400;\">The researchers caution their giant Petri dish is not intended to perfectly mirror how bacteria adapt and thrive in the real world and in hospital settings, but it does mimic more closely the real-world environments bacteria encounter than traditional lab cultures. This is because, the researchers say, in bacterial evolution, space, size and geography matter. Moving across environments with varying antibiotic strengths poses a different challenge for organisms than they face in traditional lab experiments that involve tiny plates with homogenously mixed doses of drugs.<\/span><\/p>\n<p dir=\"ltr\"><b>A Cinematic Inspiration<\/b><b><br \/>\n<\/b><\/p>\n<p dir=\"ltr\"><span style=\"font-weight: 400;\"><a href=\"\/wp-content\/uploads\/2016\/09\/kishony2.jpg\"><img decoding=\"async\" class=\"alignright size-full wp-image-20580\" src=\"\/wp-content\/uploads\/2016\/09\/kishony2.jpg\" alt=\"\" width=\"225\" height=\"300\" \/><\/a>The invention was borne out of pedagogical necessity\u2014to teach evolution in a visually captivating way to students in a graduate course at HMS. The researchers adapted an idea from &#8211; of all places &#8211; Hollywood. <\/span><span style=\"font-weight: 400;\">Senior study investigator Roy Kishony, who led the research while at HMS and is now at the Israel Institute of Technology, had seen a <\/span><a href=\"http:\/\/www.sciencemag.org\/news\/2011\/09\/dont-call-it-viral-marketing-story-behind-contagions-microbial-billboard\"><span style=\"font-weight: 400;\">digital billboard<\/span><\/a><span style=\"font-weight: 400;\"> advertising the 2011 film \u201cContagion,\u201d a grim narrative about a deadly viral pandemic. The marketing tool was built using a giant lab dish to show hordes of painted, glowing microbes crept slowly across dark backdrop to spell out the title of the movie. <\/span><span style=\"font-weight: 400;\">\u201cThis project was fun and joyful throughout,\u201d Kishony said. \u201cSeeing bacteria spread for the first time was a thrill. Our MEGA-plate takes complex and often obscure concepts in evolution, such as mutations-selection, lineages, parallel evolution and clonal interference, and provides a visual seeing-is-believing demonstration of these otherwise vague ideas,\u201d Kishony said. \u201cIt\u2019s also a powerful illustration of how easy it is for bacteria to become resistant to antibiotics. <\/span><span style=\"font-weight: 400;\">Co-investigator Tami Lieberman says the images spark the curiosity of lay and professional viewers alike.<\/span><\/p>\n<p dir=\"ltr\"><span style=\"font-weight: 400;\">\u201cThis is a stunning demonstration of how quickly microbes evolve,\u201d said Lieberman, who was a graduate student at the Kishony lab at the time and is now a postdoctoral research fellow at MIT. &#8220;When shown the video, evolutionary biologists immediately recognize concepts they\u2019ve thought about in the abstract, while non-specialists immediately begin to ask really good questions.\u201d<\/span><span style=\"font-weight: 400;\"><br \/>\n<\/span><b><br \/>\n<\/b><b>Bacteria On the Move <\/b><\/p>\n<p dir=\"ltr\"><span style=\"font-weight: 400;\">Beyond providing a telegenic way to show evolution, the device yielded some key insights about the behavior of bacteria exposed to increasing doses of a drug. Some of them are:<\/span><\/p>\n<ul dir=\"ltr\">\n<li style=\"font-weight: 400;\"><span style=\"font-weight: 400;\">Bacteria spread until they reached a concentration (antibiotic dose) in which they could no longer grow.<\/span><\/li>\n<li style=\"font-weight: 400;\"><span style=\"font-weight: 400;\">At each concentration level, a small group of bacteria adapted and survived. Such resistance occurred through the successive accumulation of genetic changes. As drug-resistant mutants arose, their descendants migrated to areas of higher antibiotic concentration. Multiple lineages of mutants competed for the same space. The winning strains progressed to the area with higher drug dose, until they reached a drug concentration at which they cannot survive. <\/span><span style=\"font-weight: 400;\"><br \/>\n<\/span><\/li>\n<li style=\"font-weight: 400;\"><span style=\"font-weight: 400;\">Progressing sequentially through increasingly higher doses of antibiotic, low-resistance mutants gave rise to moderately resistant mutants, which eventually spawned highly resistant strains able to fend off the highest doses of antibiotic.<\/span><span style=\"font-weight: 400;\"><br \/>\n<\/span><\/li>\n<li style=\"font-weight: 400;\"><span style=\"font-weight: 400;\">Ultimately, in a dramatic demonstration of acquired drug resistance, bacteria spread to the highest drug concentration. In the span of 10 days, bacteria produced mutant strains capable of surviving a dose of the antibiotic trimethoprim 1,000 times higher than the one that killed their progenitors. When researchers used another antibiotic\u2014ciprofloxacin\u2014bacteria developed 100,000-fold resistance to the initial dose.<\/span><\/li>\n<li style=\"font-weight: 400;\"><span style=\"font-weight: 400;\">Initial mutations led to slower growth\u2014a finding that suggests bacteria adapting to the antibiotic aren\u2019t able to grow at optimal speed while developing mutations. Once fully resistant, such bacteria regained normal growth rates. <\/span><span style=\"font-weight: 400;\"><br \/>\n<\/span><\/li>\n<li style=\"font-weight: 400;\"><span style=\"font-weight: 400;\">The fittest, most resistant mutants were not always the fastest. The fittest mutants stayed behind weaker strains that braved the frontlines of higher antibiotic doses.<\/span><\/li>\n<\/ul>\n<p dir=\"ltr\"><span style=\"font-weight: 400;\">The classic assumption has been that mutants that survive the highest concentration are the most resistant, but the team\u2019s observations suggest otherwise.<\/span><\/p>\n<p dir=\"ltr\"><span style=\"font-weight: 400;\">\u201cWhat we saw suggests that evolution is not always led by the most resistant mutants,\u201d Baym said. \u201cSometimes it favors the first to get there. The strongest mutants are, in fact, often moving behind more vulnerable strains. Who gets there first may be predicated on proximity rather than mutation strength.\u201d<\/span><span style=\"font-weight: 400;\"><br \/>\n<\/span><\/p>\n<p dir=\"ltr\"><span style=\"font-weight: 400;\">Co-investigators included Eric Kelsic, Remy Chait, Rotem Gross and Idan Yelin.<\/span><span style=\"font-weight: 400;\"><br \/>\n<\/span><\/p>\n<p dir=\"ltr\"><span style=\"font-weight: 400;\">The work was supported by the National Institutes of Health under grant R01-GM081617 and by the European Research Council FP7 ERC Grant 281891.<\/span><span style=\"font-weight: 400;\"><br \/>\n<\/span><\/p>\n<p dir=\"ltr\"><i><span style=\"font-weight: 400;\">Harvard Medical School (<\/span><\/i><a href=\"http:\/\/hms.harvard.edu\/\"><i><span style=\"font-weight: 400;\">http:\/\/hms.harvard.edu<\/span><\/i><\/a><i><span style=\"font-weight: 400;\">) has more than 9,500 full-time faculty working in 10 academic departments located at the School\u2019s Boston campus or in hospital-based clinical departments at 15 Harvard-affiliated teaching hospitals and research institutes: Beth Israel Deaconess Medical Center, Boston Children\u2019s Hospital, Brigham and Women\u2019s Hospital, Cambridge Health Alliance, Dana-Farber Cancer Institute, Harvard Pilgrim Health Care Institute, Hebrew SeniorLife, Joslin Diabetes Center, Judge Baker Children\u2019s Center, Massachusetts Eye and Ear\/Schepens Eye Research Institute, Massachusetts General Hospital, McLean Hospital, Mount Auburn Hospital, Spaulding Rehabilitation Network and VA Boston Healthcare System.<\/span><\/i><\/p>\n<p dir=\"ltr\">\n","protected":false},"excerpt":{"rendered":"<p>A Cinematic Approach to Drug Resistance Scientists film bacteria\u2019s maneuvers as they become impervious to drugs At a glance: Scientists at Harvard Medical School and Technion-Israel Institute of Technology have built a giant Petri dish to help visualize how bacteria move as they become immune to drugs. The device represents a new, more realistic, platform&hellip; <a class=\"continue\" href=\"https:\/\/www.technion.ac.il\/en\/blog\/a-cinematic-approach-to-drug-resistance\/\">Continue Reading<span> A Cinematic Approach to Drug Resistance<\/span><\/a><\/p>\n","protected":false},"author":3,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[24],"tags":[],"class_list":["post-84163","post","type-post","status-publish","format-standard","hentry","category-uncategorized"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v24.6 - https:\/\/yoast.com\/wordpress\/plugins\/seo\/ -->\n<title>A Cinematic Approach to Drug Resistance - \u05d4\u05d8\u05db\u05e0\u05d9\u05d5\u05df-\u05de\u05db\u05d5\u05df \u05d8\u05db\u05e0\u05d5\u05dc\u05d5\u05d2\u05d9 \u05dc\u05d9\u05e9\u05e8\u05d0\u05dc<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.technion.ac.il\/en\/blog\/a-cinematic-approach-to-drug-resistance\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"A Cinematic Approach to Drug Resistance - \u05d4\u05d8\u05db\u05e0\u05d9\u05d5\u05df-\u05de\u05db\u05d5\u05df \u05d8\u05db\u05e0\u05d5\u05dc\u05d5\u05d2\u05d9 \u05dc\u05d9\u05e9\u05e8\u05d0\u05dc\" \/>\n<meta property=\"og:description\" content=\"A Cinematic Approach to Drug Resistance Scientists film bacteria\u2019s maneuvers as they become impervious to drugs At a glance: Scientists at Harvard Medical School and Technion-Israel Institute of Technology have built a giant Petri dish to help visualize how bacteria move as they become immune to drugs. 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