Can Phages Save Us from Superbugs? (Transcript)

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 Can Phages Save Us From Superbugs?

Antibiotic resistance is terrifying —  bacteria are developing resistance to our current antibiotics faster than scientists  can create new ones. So over the last few years, scientists have wondered: what if  we infected bacteria with viruses? It’s called phage therapy — using little viruses called bacteriophages to infect  and destroy specific bacteria. These little guys were first discovered in  the early 20th century, showed promise as a tool against bacteria, and then kind  fell off mainstream scientific radar in

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the 40s when antibiotics got popular. But now  that antibiotic resistance is such a concern, scientists are revisiting phage  therapy as a tool against superbugs. So going into this video, I had  three questions — Number one, how did early bacteriophage therapy get started?  Number two, what happened to it after the introduction of antibiotics? And finally,  what’s the status of phage therapy today? Before we get into the story,  let’s get a quick rundown on the biology of bacteriophages. Bacteriophage literally translates

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to bacteria eater. That thing that  looks like its head is called a capsid, and contains the phage’s DNA. Then it uses that  tube made of proteins to inject its DNA into a bacteria. The cell lets it replicate, then new  phages burst through the cell and destroy the bacteria in the process. This is called a lytic  infection because the cell lyses, or breaks open . But phages can also cause lysogenic  infections which are different. The virus still injects its genetic material into  the bacterium, but its DNA hides dormant in

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the cell until something activates it, /then/  it makes copies and bursts out of the cell. Now, when you think of phages, you probably  think of this thing — what’s called the T4 E coli bacteriophage. He makes for a memorable poster  child for phages, but there’s a ton of variation out there. Some of them only infect a single  strain of bacteria, and some are more broad. And the diversity makes sense when you  understand just how many phages are out there. Like, for how many bacteria there are on earth,

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there’s probably an order of magnitude  more bacteriophages. I saw a figure saying there are 10 to the thirtieth  individual bacteriophages on earth. And they’ve been found in freshwater and  saltwater, the air inside living things, inside dead things — literally, every ecosystem  on earth. And it’s this omnipresent feature of phages that let a scientist observe then  at the turn of the nineteenth century. This is Ernest Hankin, an English scientist who  came to India in 1891 to study a weird phenomenon.

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Epidemiological records showed that cholera  epidemics in India typically started in the east, then went west. But that didn’t make sense,  because cholera is a waterborne disease, and the biggest rivers in India, including the  Ganges River, flow west to east, which meant the cholera was going upstream. And even when there  was a cholera outbreak upstream, it didn’t cause outbreaks downstream. It was counterintuitive  to what they thought should happen. So Hankin came to the city of Allahabad,

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at the meeting of the Ganges and Yamuna  Rivers to see what was in the water. When he inspected water samples under  a microscope, he was surprised at how clean it was. He actually had a  hard time finding any bacteria. So he took water from the Ganges, put  it on his cultures of Vibrio cholerae, and noticed that it could kill them in just  a few hours while water from a well did not. And that was weird — it seemed like the Ganges  water had some kind of antibacterial effect. He decided to take another sample,  but this time he boiled it before

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putting it on the cholera germs.  And this boiled water had actually lost its ability to kill bacteria. This  made no sense, so he turned to a piece of new-ish lab tech that would let him  isolate something smaller than bacteria. It was called a Chamberland filter, which was  designed by one of Louis Pasteur’s students, Charles Chamberland. It’s a device  with a super fine porcelain filter that caught bacteria but let  anything smaller through. Like if you took a snot sample from someone  with influenza, mixed it with water,

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then passed it through the filter, any bacteria  would get caught in the filter while the viruses or small toxins would pass through. If that  new filtrate could make a test animal sick, an 1890s scientist might infer that  the disease was caused by a virus. Although at this point,t he field  of virology is just getting started. So Hankin passed a sample of Ganges  water through a Chamberland filter, and sure enough, the water was still  able to kill the bacteria. Meaning that whatever was killing the Vibrio  cholerae was smaller than bacteria.

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Next, he decided to go further upstream  where, as part of funeral traditions, partially cremated corpses were sent down  the river. Hankin took samples of water from around the corpses, tested /that/ on the cholera  bacteria, and saw the same antibacterial effects. Sidenote, at this point in his research paper, he  made sure to tell a story about how he fought off a family of turtles to get to the bodies.  It has no impact on the paper whatsoever, but Hankin needed everyone in the scientific  community to know what a badass he was.

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So Hankin finished his observations,  and wrote a paper about them that was published in the Annals of the Pasteur  Institute in 1896. He concluded that there must have been something in the  Ganges that was smaller than bacteria that had antibacterial properties and maybe this  explained the weird pattern of cholera epidemics. Most of my sources pointed to this paper as the  first written account of bacteriophages in action. After Hankin’s report, a handful of other  scientists noticed similar antibacterial

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waters elsewhere, but for about 20 years,  nobody took it much further than observation. And that brings us to Fredrick Twort, a English microbiologist who  mostly worked on animal diseases. In the 1910s, Twort was trying to figure  out a way to grow viruses on Petri dishes similar to how scientists grew bacteria.  He tried growing viruses in all kinds of chemical and nutrient mixtures but nothing worked. Until one day, he was working  with smallpox virus and saw that his dishes had started growing bacteria.  But he noticed that within an otherwise

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totally smooth surface of bacteria,  there were little holes, or plaques, where the bacteria seemed to disappear. When he  looked a sample of the plaque under a microscope, he found little chunky bits that he thought  were dissolved carcasses of dead bacteria. This was way more interesting that  learning how to culture smallpox, so he switched gears and started  studying those little holes. He starts by taking more samples from the plaques, passed them through a filter to remove all the  big chunks, then put the resulting filtrate on

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a plate of live bacteria. And he saw the  same thing — that little glassy holes of dead bacteria would formn. Whatever was in the  filtrate was destroying bacteria in the dish. He repeated this process a couple  more times, and got the same results, even when he diluted it and passed  it through the filter a bunch. Which is kind of funny, because Twort had figured out a way to culture viruses,  but not the ones he wanted to. Unfortunately, his studies were cut short  by a lack of funding and… by world war one,

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or as he put it, “the circumstances  of the present year”. So he published his results in 1915 in The Lancet  and that was it for a few years. Until, that is, we get the superstar of  phage therapy history — Felix D’Herelle. D’Herelle grew up in the late 19th century and  was a bit…unconventional as a scientist. He had no scientific training, but decided to move to Canada  and call himself a microbiologist when he was 24. And all his early career was wild but  my absolute favorite story was how he

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was hired by the Quebecois government  to turn maple syrup into whiskey. Which, fun fact, is the Canadian version of alchemy. D’Herelle’s story starts in 1910,  when D’Herelle was working in Mexico. D’Herelle had heard about these swarms of  locusts that were destroying crops on the Yucatan Peninsula. Did he try to use  a pesticide to stop the locusts? Big nets or introduce a predator? No.  He basically created a bioweapon. He collected a bunch of dead locusts, and  isolated a bacteria from their carcasses that

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caused a deadly locust diarrhea. And after  safety testing the bacterium on himself, he cultured the bacteria, put it on the crops, and that caused a epidemic of locust  diarrhea. And you think your job’s crappy… This strategy seemed to work, so he used the bacterium again on  similar plagues around the world. But while he was culturing his bug bioweapon, he noticed the same thing that Twort had. Holes  would develop in the bacteria on the petri dish, then if he took some of the stuff from the  holes and put it on fresh bacteria, it would

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cause more holes. He didn’t publish anything  at the time, but it did pique his interest. A few years later, D’Herelle’s unconventional  career landed him an unpaid internship at the Pasteur Institute in Paris — one of the coolest  places to study infectious diseases at the time. But when world war one started, they sent  him to treat troops stationed outside of Paris. And while he was there, he got  a lot of experience treating dysentery. Now historically, dysentery had been a catch all  term for intestinal inflammation. But in 1898,

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a Japanese scientist named Kyoshi Shiga identified the cause of dysentery — a bacillus  that he named Shigella dysenteriae. Since both of these diseases were  gastrointestinal related D’Herelle wondered if he could create holes in the Shigella  cultures like he’d seen in the locust bacteria. So he started collecting stool  samples from his dysenteric soldiers, passed the stool through a filter to  remove the big microbes, then added the filtrate to live Shigella bacteria  — both in a flask and on petri dishes.

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It was just like Hankin’s experiment  with the Ganges water and cholera. The next day, he checked on his samples, and  instead of a cloudy flask full of Shigella bacteria, the flask was transparent, meaning that  the filtrate had killed the bacteria. Sometimes it took hours, sometimes it took days, but whatever  this substance was dissolved away the bacteria. Since the antibacterial substance  was filter-passable, he knows the antibacterial substance is smaller than  a bacterium, so he’s thinking it’s either

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a tiny chemical or a virus. And how he  figured out what it was is kind of clever. D’Herelle noticed that if he inoculated new  batches of live Shigella with samples from an old filtrate, the killing power of the  old filtrate didn’t get any worse. He also noticed that when he diluted the filtrate,  and spread it over a petri dish of Shigella, he’d still see those little holes, or plaques.  D’Herelle reasoned that if the substance were strictly chemical, the effect would be spread out  evenly throughout the dish — so it was more likely

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that each of those plaques represented  a colony of self-replicating microbe. He also noticed that the substance wouldn’t replicate if the Shigella  had been killed with heat. And when he tried using this anti-Shigella  virus on the bacteria that cause typhoid or Staph infections, he couldn’t get it  to work. So Whatever this thing was, it was specific to the dysentery bacteria. Finally, he injected it into lab rabbits  and successfully prevented lab-induced dysentery infections without any safety concerns.

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He asked his wife to help him name  it, and they settled on bacteriophage, for bacteria eater. And he debuted his research  in 1917 at the French Academy of Sciences. Unfortunately, his papers weren’t  well received. His training was non traditional and the field of viruses  was still new. People wondered if maybe the phage was an enzyme? Or maybe  a gene? Nobody was that confident. Now, One of those scientists who questioned  D’Herelle’s results was Jules Bordet, a Nobel Prize winning immunologist and  founder of the Pasteur Institute in

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Brussels. If Bordet put your work under his  microscope, people were gonna hear about it. He thought that d’Herelle had found some kind of  self-replicating enzyme that lyzed the Shigella; he didn’t think it was a virus. And a few  years later, Bordet did an experiment that lent some evidence to his hypothesis. It  wasn’t until scientists could actually see viruses with electron microscopes  that the enzyme hypothesis went away. D’Herelle didn’t let the fact that a  Nobel Laureate was picking apart his

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research deter him. He was thinking about how  to use this stuff in medicine. And just like we saw with Louis Pasteur in the rabies  video, since he wasn’t a medical doctor, D’Herelle wouldn’t be able to give phages to  patients himself. So he got the word out to local clinics in Paris and said “let me know if you’ve  got any dysentery cases, I might be able to help”. And one day in August of 1919, a local  pediatrician referred an 11 year old boy to the Pasteur Institute for treatment of severe  dysentery. This would be D’Herelle’s first case.

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But before they could use phages, they’d  have to show it was safe in humans. So D’Herelle and a couple other doctors from the  PI took the phage preparation, which again, had been prepared from literal human  feces, drank it, and waited overnight. The next day they felt fine, so D’Herelle gave  the patient 2 milliliters of phage solution, and waited. Within a few days, the boy was  pooping normally, and a few days after that, doctors couldn’t find any Shigella  bacteria in his stool anymore. Whether

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it was because of the phage or the boy’s  own immune system, he was healthy again. Pretty soon afterwards,d’Herelle  treated 4 more kids with phage therapy and got the same results.  Everyone recovered within a few days. Now, dysentery can resolve on its  own, so as exciting as this was, it didn’t immediately launch phage  therapy onto the world stage. In fact, D’Herelle sat on the  research and didn’t publish right away. Instead, in 1919, he went out  to the French countryside to study a Salmonella outbreak in chickens. He  thought that this would be a great

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opportunity to see if phage therapy was useful  in animals before he tried it on more humans. He’d start by taking a sample of the bacteria, just like he had with the germ that causes  dysentery, and he’d culture it in a petri dish. Then he’d check for those glassy holes,  or plaques, since that’s where the phage was. Then he’d take a sample of phage, and culture that  in the target bacterium. They’d purify the phages, then administer to the patient. Usually orally,  but topical preparations worked pretty well too.

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If you want to read about the modern process, check out this article that  I’ll link in the description. The chicken trial went well  — phages seemed to curb the Salmonella outbreak — but from  other scientists’ perspective, it wasn’t the strongest experiment. D’herelle  wasn’t big on using blinding or control groups. After his time in the countryside, he left  for Vietnam where he could develop phage therapy further. Unfortunately he started  to become dead set on this erroneous idea that phages were actually part of the immune  system. And probably due to some personal beef

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with vaccine pioneers at the Pasteur Institute,  he started rejecting the idea of vaccination. And maybe not coincidentally,  when he got back to the PI, his research had been defunded and lab taken away. And while D’herelle hadn’t actually published on  phage /therapy/ yet, two of his colleagues had. But while things were changing at the Institute,  the tide was starting to shift in d’Herelle’s favor too. Later in 1921, he published a book  called Bacteriophage and its role in immunity. And it was becoming clear that he wasn’t the only one  interested in pursuing phages in medicine anymore.

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By 1925, there were over a hundred research papers  investigating therapeutic use of bacteriophage. Throughout the rest of the 1920s, d’Herelle traveled the world trying phage  therapy against infectious diseases, and even successfully used it against the  plague bacillus. It’s around this time that he, as well as other drug manufacturers in France and  Brazil, started selling phage-based medicines too. All of this early success earned  D’Herelle an invitation to something called the Bacteriophage Inquiry in  the late 1920s, the biggest test of

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phage therapy to date. The British Indian  government invited D’Herelle and a bunch of Western scientists to study phage therapy on  local cholera outbreaks. For those curious, no, I couldn’t find evidence that the  Indian people gave informed consent. But from d’Herelle’s perspective,  it was a big success. In one case, they were able to reduce mortality from  63% in the control groups to 8% in the phage group. And phages in the drinking  water seemed to prevent future infections. Unfortunately, there were a /ton/ of confounders.  Like some of the villages were improving their

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hygiene and getting vaccinated, and  some were buying their own phages, so it was hard to pull meaningful data  from the trial. One committee concluded that phage therapy didn’t work any better  than the improved hygiene and vaccination. And this wasn’t great for fans of the  phage. But that wasn’t the only bad news. Phage therapy’s specificity was becoming  a major drawback — like even if you had a phage against say, typhoid fever, it might  not work against a different strain of typhoid. Also, the way that companies manufactured these  phage medicines was risky. It involved sampling

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from plaques of dead bacteria, which made  it easy to contaminate the final medicine. They were also starting to get some data showing  that bacteria could develop resistance to phages, and that the immune system could clear  phages from the body pretty quickly. And while that was a hit to the field of  phage therapy, it was about to get worse for d’Herelle personally. Because French  and Belgian scientists learned about Twort’s original paper from 1915, which  made d’Herelle seem like a plagiarist.

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Those same Belgian researchers even got Twort  involved with the whole “is it an enzyme, or is it a microbe” question. And  when he came out on team enzyme, that didn’t exactly inspire  more confidence in D’Herelle. So that’s the state of things by the 1930s and  40s — a bunch of companies had come out with phage-based medicines, including American  companies like Eli Lilly, but there wasn’t a ton of evidence saying that phage therapy  worked. According to a 1934 review in JAMA, the available data was mostly ambiguous.  And with antibiotics starting to come out,

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getting a prescription for penicillin was the  easiest way to beat a bacterial infection. As far as D’Herelle, he got  a job at Yale for a bit, but managed to piss off his colleagues there  too. So when it came time for something new, he turned to the only other place that had  really embraced phage therapy — the Soviet Union. In 1917, Lenin took over a very sick  Russia. There was the Spanish flu, high infant mortality, and all kinds  of infectious disease. So in 1922, the Soviets did this massive overhaul of their  public health system, with infectious diseases

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getting priority. As part of this, they open  up research centers in major Soviet cities. Which means now I get to introduce you to a young scientist from the country of  Georgia named George Eliava. Eliava visited the Pasteur Institute in Paris a  couple times throughout the 1920s which is when he became friends with D’Herelle. And during his  visits, he started to believe in the future of phage therapy. Which must’ve seemed especially  bright since penicillin hadn’t come out yet. And since bacterial infections  were such a national priority,

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Eliava decided he’d take what he learned  about phage therapy at the Pasteur Institute and focus on it at his research center in  Tbilisi. He planned on inviting d’Herelle to live onsite and do research…but then Stalin  came to power and put a pause on those plans. Eliava kept busy at another research  institute and brought D’Herelle over a couple times from 1933 to 1935. Needless  to say, D’Herelle loved this. He never felt like he fit in at Yale, but he was  a scientific superstar in Georgia.

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By the end of 1935, Eliava had received  authorization for his phage center. Unfortunately, he had also pissed off a powerful government  official. So in 1937 he was arrested and killed by the secret police, they destroyed his life’s  work, and basically erased all memory of him. But they’d already spent a bunch of money  on the phage institute in Tbilisi. So they finished the building and renamed it the  Institute of Microbiology, Epidemiology, and Bacteriophage. This would become one of the  biggest phage research facilities in the world.

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Even without its founder, scientists at  the Institute and elsewhere in the USSR spent the next few years studying phages and  reporting the results in journals. But not in major American or European journals, so the  information didn’t spread throughout those areas. Then World War 2 happens, which  is where we see a big split in how the two regions approach infectious disease. If you haven’t watched my penicillin  video, quick summary: while Alexander Fleming found that penicillin had  antibacterial properties in 1928,

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but it wasn’t until the early 40s that it could  be used in medicine thanks to a research team led by Howard Florey. Then during World War 2, the  United States subsidized pharmacetuical companies to make billions of units of penicillin, which  helped penicillin get super popular in America. But during the war, the Allies actually sent  Howard Florey to Moscow to share penicillin with Russian scientists. Unfortunately, they struggled  to ramp up production like Florey had. So even with access to penicillin, the Soviets still  preferred using phage therapy throughout the war.

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For instance, Zinaida Yermolyeva figured out  a way to manufacture thousands of doses of anti-cholera phage, and used it on soldiers  during the Battle of Stalingrad. She later pioneered penicillin in Russia, but  she started out as a fan of phages. After the war, each medicine’s place was  firmly cemented in their respective cultures. Antibiotics were a culturally Western Europe, United States thing; phage therapy was  a Soviet thing. Scientists in the US and Europe did /use/ phages, but mostly as a  tool for studying biology, not for medicine.

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Like phages were super important in  demonstrating how DNA worked. And some of the first images taken by electron microscopy  were images of phages — and of course that settled that debate about whether phages were  enzymes or viruses. You had a picture of them. Meanwhile, the Soviets were producing phages  in all kinds of varieties — tablets, topicals, a Georgian research group even managed  to inject phages intravenously without causing an immune reaction. But they  were also using antibiotics. They

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were just another tool in the doctor’s  toolbelt instead of the end all be all. After the war, the phage research center  in Tbilisi continued to produce medicines, but also cranked up the research side. And  in 1952, a new phage research center was built in Wroclaw in 1952 — this  became the Hirszfeld Institute. Over the next few decades,  Soviet scientists conducted all kinds of phage therapy trials — phages  against multidrug resistant bacteria, prophylactic phages, phages for UTIs, and  surgical wounds, even for cystic fibrosis.

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At the same time, they also struggled to scale  phage therapy the same way that America scaled antibiotics. And yeah, part of that was economics  — the profit motive pushed pharmaceutical companies to scale and sell more antibiotics. But  the biology of bacteriophages made things harder. Phages were so specific. You couldn’t necessarily  mass-manufacture phage medicine for typhus and expect it to be effective everywhere — especially  in a country the size of Russia. On the other hand, antibiotics don’t discriminate —  they can kill multiple types of bacteria,

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which make more sense to mass manufacture.  Phage therapy requires more precision. Unfortunately, the popularity of antibiotics  led to their downfall. Scientists made all those great antibiotics, and bacteria developed  resistance to them. And the timing was terrible. Antimicrobial resistance became a hot  button issue in the 1980s and 90s, in a time when phage therapy  research almost fell off the map. The Soviet Union dissolved in 1991 and  Georgia became an independent nation, which meant that funding dried up  for their phage institute. Plus,

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civil war broke out, so the  institute fell into disrepair. And given that phages need to be refrigerated,  the constant electrical outages and chaos] outside threatened to ruin the library of  phages they’d been building for 80 years. Phage science needed to remind the world it was  there and valuable. It would need a spokesperson. And chief among them was doctor  Elizabeth Kutter — an engineer turned biologist after meeting  a bacteriophage researcher. Dr. Kutter spent her early career focusing  on the E Coli phage T4 — that lunar lander

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phage from earlier. At this point, she’s one  of those American researchers interested in phage for its biology. She sequenced  its genome and studied its mechanism for taking over a bacterium. She wasn’t really  interested in their therapeutic potential yet. But then, in the 1990s, she went on a work  trip to Russia. And while she was there; some of her colleagues recommended  that she visit Georgia, but like, as a tourist. Like, you should go  there for the food and scenery, and not the world-reknowned research institute  that lines up perfectly with your area of study.

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So she goes and has a great time, and  eventually meets the folks from the bacteriophage research Institute in Tibilisi,  which at this point had been renamed the Eliava Institute. After visiting, not only was she  excited by all the therapeutic potential, but she started arranging to send them research  supplies, and started a exchange program. A few years later, a man named Alfred  Gertler developed a drug resistant Staph infection after a compound ankle fracture.  And after years of antibiotics failing him,

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he had to make the decision to either amputate  his ankle so that he didn’t go septic and die, or try something else and save his ankle. After investigating experimental treatments,  he stumbled upon phage therapy. He showed up to a conference to meet Dr. Kutter, and they  decided they’d go to Tbisili to try phage therapy. After culturing the bacteria in his infection,  it turned out the Institute had a match for that particular strain of Staph. Gertler decided  to go through with treatment and within a

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few days of grueling procedures, his ankle  was totally free of Staphylococcus bacteria. There were a few other American researchers  picking up phage research too, like a group of researchers at the Univerity of Maryland who  wanted to study drug resistant bacteria. While they weren’t able to get funding or approval  for phage therapy against human infections, they decided to target the other side  of the antibiotic resistance puzzle: livestock. I dedicated half of the last  video to explaining how much agriculture

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contributed to antimicrobial resistance,  so these guys were addressing a real need. They founded a company called Intralytix,  and it would use phages to kill bacteria in food. And one of the hopes was to build  up some amount of trust in phages so that it could progress past food safety  and someday into a more expanded use. But as far as actual /human/ phage therapy, people were still limited to the  handful of clinics in Georgia, Russia, and Poland since it wasn’t approved almost  anywhere else, definitely not in the US.

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Demand was actually high enough that doctors  from the Eliava Institute opened up a second clinic in 2005 for international  patients and another clinic in 2012. The very small handful of clinicians  who did try phage therapy in the States weren’t doing it with approval. Although I  did read about a naturopath using phages, because, technically, phages are natural products. And that finally brings us to the 2020s.  We’ll do a big picture overview of some of the challenges facing phage therapy,  and end on why people are still hopeful.

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Bear case In short, the biggest challenges are the specificity of  each treatment, the lack of high quality data, the lack of regulation to get that data,  and some other concerns about efficacy. I’ve talked enough about specificity —  some phages only attack specific strains of bacteria and some are broader, but  none of them are as broad as antibiotics. But we’re at the point where its /worth/  investigating the more specific option. And unfortunately, the US regulatory  system isn’t set up to evaluate them.

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Phage therapy doesn’t lend itself to  the typical randomized, control grouped, double blinded studies that scientists are  used to using to judge how well a drug works. Most of the studies on phages from the  Soviet era weren’t placebo-controlled, so they don’t meet the standard  for modern drug approval. And getting that kind of data isn’t  as straight forward as it seems. Because while antibiotics are static, predictable  molecules, phage therapy is often a mixture of many different phages to attack slight variations  of bacteria. And bacteriophages themselves change,

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which is actually one of their  advantages — they’re more dynamic. So from a regulatory perspective, phage therapy is a totally different product than  more predictable drug molecules. It’s also hard to predict how an actual  person will process different preparations of phages. With a normal drug, researchers  just need information about how the drug interacts with a human body. But for phage  therapy, they need to see how the human, the phage, /and/ the bacteria interact,  which makes trials even more complex.

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Like sometimes in animal experiments, their  immune system will clear out the phage before it can attack the bacteria or the liver  will inactivate the phages within a few minutes of administration or the subject  will develop antibodies against the phages. There are also concerns of phage resistance too,  but it’s less common than antibiotic resistance and it’s easier to find new phages when the first  ones don’t work. We’ll come back to this though, because when bacteria develop resistance to  phages, they tend to change in other ways too.

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And of course, one of the other  big challenges is money! Because, just like we saw with antibiotic research, when  a pharmaceutical company decides to invest in R&D for a new drug, they need to calculate a  potential profit before they start research. And phage therapy presents a weird business  dilemma — since phages are natural products, they can’t be patented, which reduces the amount  of money a company can make from it. On the other hand, synthetic or genetically  engineered phages could be patented,

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but those kinds of phages would be  so specific that the market would be super small. So there doesn’t seem to be  a good business model for phage therapy. Even for the few patients that do get  phages, these bespoke treatments are going to be expensive. A scientist at a company called  Adaptive Phage Therapeutics put it in perspective though — still gonna be cheaper and work better  than the alternative. Although I couldn’t find consistent information about whether  phage therapy is reimbursed by insurance.

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And finally, and this is my personal opinion,  there’s going to be a stigma about letting a virus into your body. Regardless of the  years of usage in Georgia and Russia, I think Americans especially are gonna be  skittish about the idea of a therapeutic virus. But then again, adenovirus vaccines  are a thing, so maybe I’ll be surprised. Alright, so those are some serious challenges, but clearly, people are still  really excited about phage therapy. The hype around phage therapy picked up  around 2016 thanks to the high profile

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story of Tom Patterson. While he was  on vacation in Egypt with his wife, Patterson contracted a multi-drug  resistant form of Acinetobacter baumannii, one of the most resistant pathogens  on the planet. And for months, his infection didn’t respond to antibiotics.  But luckily, his wife, Dr. Stefanie Strathdee, was a professor and director of a public health  institute, and she was able to read some research. She told this story in a popular TED  talk, so I won’t go in depth, but in summary Dr. Strathdee looked up alternative  treatments for A. Baumannii infection,

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she found phage therapy and decided  to pursue it for her husband. He wasn’t healthy enough to fly all  the way to the Eliava Institute, so Strathdee needed to figure out how  to use phage therapy on American soil. They decided to try it on a compassionate  use basis. This is a situation in which the patient has tried all the known  treatments, and they’re likely to die, so doctors can try experimental  treatments with patient consent. And luckily, it worked out. Through a  combination of phages from different sources,

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his doctors were ultimately able to save his life. Dr. Strathdee wrote the full story into  a book called The Perfect Predator, which I got for this video, and  obviously it goes into much more depth than I did. I’ll leave a  link to it in the description. Strathdee’s book and TED talk were an  inflection point — this was the moment that phage therapy entered the American mainstream  consciousness. Phage therapy was going viral. And while awareness is good, the action over  the last few years is even more encouraging.

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There are directories and libraries of  existing phages, which make it easier for people desperately seeking treatments to  find their potential match. There are phage therapy journals, conferences, and proper double  blinded phage therapy trials going on right now. And the Eliava Institute is still going strong  as a treatment and research center. According to The Good Virus by Tom Ireland “Between  2012 and 2019, clinics in Tbilisi treated over 10,000 patients over 1500 of them  foreign, from 71 different countries”.

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So big picture, why are people so excited  about phage therapy going forward? Of the things it’s got going for it is safety.  While the research hasn’t been the most elegant, there’ve been almost no reports of serious  complications as a result of phage therapy ever since its inception. Scientists  obviously want to keep testing phage medicines for safety before they roll out more  widely, but they’ve got a good track record. And even though bacteria can  develop phage-resistance, scientists often see those bacteria  become less virulent as a result.

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So yes these germs can evade the drugs, but  they also become less powerful as a result. Certain phages have even made drug-resistant  bacteria susceptible to antibiotics again. So some scientists have tried combinations of  antibiotics and bacteriophages in animal models, and they seem to be more effective than  either one used alone. The reviews I read only mentioned a handful of animal studies  and no human trials, so be patient there. Another advantage for phages is that  they’re auto-dosing. Again, we need a

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little caution here since scientists still  don’t know a ton about phage therapy’s pharmacokinetics — or how it actually  works in a human body. But in theory, you could drop a couple phages at the infection  site, and since they feed on bacteria, they’ll replicate on their own, which is  like automatically setting the right dosage. The next reason people are hopeful is because  scientists’ ability to pick the right phage is only getting better. They’ve got the ability  to do more accurate screening of the bacterial

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infection, and more built-up phage libraries.  So instead of guessing whether a selected phage will work against a bacteria, scientists can  put together cocktails of targeted phages. Purification techniques have gotten a lot  better too. Remember that those early phage scientists were picking samples from the  plaques within a live bacterial colony, which raises the risk of contamination. And scientists are attempting to create  a totally synthetic bacteriophage. These could be super minimalist genes; just the  barebones instructions for a functioning

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phage. They wouldn’t use bacteria to culture  synthetic phages at all, so there’s less risk of contamination. And the hope is that they’d  be easier to standardize and regulate too, which would get it closer to approval and market. And actually, there’s been  some progress there too! Broadly speaking, there are two  main models for the future phage marketing. There’s prêt-à-porter, which  would involve making pre-formulated, off the shelf phage cocktails. These would have  a long production time and cost a lot of money,

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but they more easily fit in with our existing  regulatory models. The other model is sur-mesure, which would involve making custom  drug cocktails for each phage patient. And those bespoke medicines might  be more likely than you think. In 2018, legislation in Belgium allowed  for phages to be used as customized, personally-tailored medicines. They  reclassified phage-based medicines as “magistral preparations”, what we in  the US call “compounding”. Basically, it lets the healthcare team make  one-off medicines for each patient.

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The hope is that pharmacists could pick  an existing phage from a phage bank, then put it into a carrier like a pill or gel. So to wrap things up, phage therapy is an interesting treatment. It has  advantages over antibiotics, but there are some series obstacles before  we’re all taking Influenza-phage or something. To reference the first episode of this  antibiotics series, it’s not a magic bullet. Speaking of which, this is my last official  video in the antibiotics series. But my supporters on Patreon get a bonus video all  about the mysterious history of Neosporin.

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A little teaser for you, nobody knows  exactly where Neosporin comes from If you want to check that video out and help me  to keep making videos like these, consider supporting me on Patreon. Either way, thanks for  watching, and I’ll see you in the next video.