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0:00
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
0:25
a tool against bacteria, and then kind fell off mainstream scientific radar in 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?
0:53
Before we get into the story, let’s get a quick rundown on the biology of bacteriophages. Bacteriophage literally translates 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
1:15
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 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
1:40
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, there’s probably an order of magnitude more bacteriophages. I saw a figure saying there are 10 to the thirtieth individual bacteriophages on earth.
2:05
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. Epidemiological records showed that cholera epidemics in India typically started in the east,
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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, at the meeting of the Ganges and Yamuna Rivers to see what was in the water.
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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.
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Like if you took a snot sample from someone with influenza, mixed it with water, 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,
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and sure enough, the water was still able to kill the bacteria. Meaning that whatever was killing the Vibrio cholerae was smaller than bacteria. 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.
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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. 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
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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 waters elsewhere, but for about 20 years, nobody took it much further than observation. And that brings us to Fredrick Twort,
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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
5:44
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,
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passed them through a filter to remove all the big chunks, then put the resulting filtrate on 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
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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, 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
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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 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
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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 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,
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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 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
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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, a Japanese scientist named Kyoshi Shiga identified the cause of dysentery — a bacillus that he named Shigella dysenteriae.
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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. It was just like Hankin’s experiment with the Ganges water and cholera.
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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
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strictly chemical, the effect would be spread out evenly throughout the dish — so it was more likely 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.
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Finally, he injected it into lab rabbits and successfully prevented lab-induced dysentery infections without any safety concerns. 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
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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 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;
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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 research deter him. He was thinking about how to use this stuff in medicine. And just like
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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,
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doctors couldn’t find any Shigella bacteria in his stool anymore. Whether 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.
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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 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
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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. 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
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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
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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. 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,
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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 phage therapy to date. The British Indian government invited D’Herelle and a bunch of
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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.
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Unfortunately, there were a /ton/ of confounders. Like some of the villages were improving their 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.
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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 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,
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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. 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,
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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,
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the Soviets did this massive overhaul of their public health system, with infectious diseases 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
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phage therapy. Which must’ve seemed especially bright since penicillin hadn’t come out yet. And since bacterial infections were such a national priority, 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.
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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. 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
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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. Even without its founder, scientists at the Institute and elsewhere in the USSR
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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
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with access to penicillin, the Soviets still preferred using phage therapy throughout the war. 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,
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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. 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.
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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 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,
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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. At the same time, they also struggled to scale phage therapy the same way that America scaled
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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,
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which meant that funding dried up for their phage institute. Plus, 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
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turned biologist after meeting a bacteriophage researcher. Dr. Kutter spent her early career focusing on the E Coli phage T4 — that lunar lander 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;
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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. 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,
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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, 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
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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 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
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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 contributed to antimicrobial resistance, so these guys were addressing a real need.
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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
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of the challenges facing phage therapy, and end on why people are still hopeful. 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.
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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. 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
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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, 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.
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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. Like sometimes in animal experiments, their immune system will clear out the phage before
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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
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other hand, synthetic or genetically engineered phages could be patented, 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
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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. 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
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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 story of Tom Patterson. While he was on vacation in Egypt with his wife, Patterson contracted a multi-drug resistant form of Acinetobacter baumannii,
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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, she found phage therapy and decided to pursue it for her husband.
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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.
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And while awareness is good, the action over the last few years is even more encouraging. 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
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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”. 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
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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. 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.
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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 little caution here since scientists still don’t know a ton about phage therapy’s
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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
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could be super minimalist genes; just the barebones instructions for a functioning 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
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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, 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,
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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. 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,
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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. A little teaser for you, nobody knows exactly where Neosporin comes from If
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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.
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