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Imagine the last time you were sick and needed antibiotics…now imagine that you took the antibiotic, but the infection didn’t go away. The antibiotic didn’t work. And then the next one didn’t. And then the next one, all the way until none of them worked.
It happens. And although I’ve never personally experienced this, I’d think it would be terrifying.
What would you do? Recently, some doctors have started using viruses called bacteriophages (or phages for short) that can kill bacteria. It’s called phage therapy, and it’s saving people’s lives.
In the US, phage therapy is something doctors can access only through special authorization by the FDA. But it’s gaining popularity. And in some countries, phage therapy is actually the preferred treatment of choice, but we’ll get to that later.
So, on this podcast episode, I talk to Dr. Jessica Sacher, who is the co-founder of Phage Directory, an organization that connects doctors and patients to scientists that work with phages. Phage Directory simplifies the process of finding the treatment patients desperately need for bacterial infections that have stopped responding to antibiotics.
When the antibiotics stop working, phages can cure superbug infections.
In this episode, you will learn about…
- An introduction to viruses
- Phages: viruses that infect bacteria
- How to see viruses
- Most viruses do not make us sick
- Could phages ever make us sick?
- What makes phages so specific to the bacteria they infect?
- What is phage therapy?
- Phage Directory: connecting doctors and patients to scientists with phages
- At-home microbiology activity: Fishing with phages
Listen to my episode with Dr. Jessica Sacher.
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An introduction to viruses
In this podcast interview, we discuss phages, but let’s begin with viruses since phages fall into this category of microbe.
Viruses are super small microbes, much smaller than bacteria. And, by many microbiologists, they are considered not living — they’re just a piece of genetic code encased in a shell. To become “alive,” a virus has to infect a cell. So, they are different from other microbes that are more self-sufficient (but some non-viral microbes are very simple too). So, a virus is basically a piece of genetic code that can infect a cell.
Some of the viruses we encounter in our daily lives are, of course, the obvious SARS-CoV-2 causing the COVID-19 pandemic and other viruses people are vaccinated against, like measles virus, hepatitis A virus, hepatitis B virus. A virus also causes HIV.
Most viruses we hear about are the bad ones. They receive more attention because they make us sick and therefore require action on our parts. But, as I’ve said before, I’m making a point to emphasize that most microbes are harmless, and many are beneficial.
Viruses that cause pandemics are, of course, scary, so I never want to downplay the seriousness of those issues. Since there is a bias towards the scary microbes, I want to show the other side of the story. So, in this blog post and podcast episode, we focus on some really cool and beneficial viruses, the phages.
Phages: viruses that infect bacteria
Viruses are characterized and classified based on what they infect. Phages are a virus that infects bacteria, so their full name is bacteriophage. Other viruses infect animal, people, and even archaeal cells. (In the episode, we discuss that researchers are still figuring out exactly what to call viruses that infect archaea since phage is reserved for bacteria — check out the full episode to hear about it.)
The size and shapes of viruses range, even within phages. There are smaller ones and bigger ones of different shapes. One of the main attributes that Jessica says varies among phages is the length of the tail. Having a tail is more common in phages compared to most human viruses. Some phages can look like spiders or space shuttles. So, you can picture them as a head, long neck or tail, and then feet at the bottom of the tail (see Giant Microbe below).
How to see viruses
Because viruses are so small, we cannot view them under a light microscope like those we might see in a science classroom or sometimes have at home. Special microscopes called electron microscopes are necessary. Instead of using light, they send electrons through the specimen, allowing you to see smaller stuff. These microscopes are very expensive, large, and complicated to use. Usually, at universities, there may be one in a department that is shared among many labs.
Because it can be difficult to become skilled at finding viruses under electron microscopes, and they are not readily available in any lab on any given day, virologists look at and count viruses using a plaque assay. It is the easiest way of “seeing” them. A plaque assay, Jessica explains, is when you grow bacteria on a Petri dish, add phage (or a sample you think might have phage in it) on top, grow the bacteria overnight, and the next day, you see plaques form if there was phage present that could infect and kill the bacteria. These plaques appear as see-through zones because of the dead bacteria. Without phages, the bacteria grow on the Petri dish and create a layer of cells, making it murky. But when phage is there, they kill the bacteria, which leaves “holes” where they do not grow.
Similarly, to study a virus that infects us, plaque assays are done with human or animal cells instead of bacterial cells. An example of a type of human cell that could be used is HeLa cells. These cells were named after Henrietta Lacks. Tumor cells were taken (in an unethical way) from her. And for the first time, researchers could continuously grow human cells in the lab. If you’d like to learn more about her story, you can read the book The Immortal Life of Henrietta Lacks, which explains the importance of her cells and all of the issues surrounding their use because of her lack of consent.
Most viruses do not make us sick
One important point about viruses that must be made is that most viruses are not pathogens, those that make us sick. Only a small minority of viruses make us sick. However, “there’s a huge bias in what we know about viruses,” says Jessica. “Usually, people only get research funding if they’re studying something that’s a pathogen (something that harms us or harms a plant). So we really don’t have a lot of information about the good viruses out there.” Despite only a small fraction being pathogenic, anything in the literature is probably on a pathogen. So it’s the opposite of what you would expect.
Could phages ever make us sick?
To use phages to treat infections, an important question to answer is whether or not they could actually cause an infection in a human. And so, Jessica shares that a lot of research has gone into understanding this question. “It’s pretty hard to get a phage to infect a different species of bacteria, let alone a different completely kingdom of cell.” But there are limits to our imaginations, so we need to do experiments to answer this question.
Though it does not seem that phages can infect us, Jessica tells us that there is a new body of work showing that phages seem to drift into human cells in the body and through them. The cells that line many parts of the body, like the gut, are called epithelial cells. And it seems that phages end up inside these cells. They are not infecting like they would their own host (not injecting DNA and causing replication of themselves bursting out of the cell). But they are coming in as entire particles, potentially used as a food source (protein).
So, it appears that there is more to the story than that phage could never do anything to a human cell. “We certainly don’t think they’re going to infect in the same way,” Jessica says, “but they’re still going in there. So we have to figure out what’s going on.”
What makes phages so specific to the bacteria they infect?
Phages are super specific to the host bacteria that they infect — they are specific down to the strain level. And this specificity is due to the receptor binding proteins of a phage. Going back to the phage body, it has a head, tail, and feet at the end of the tail. If you picture a spider’s legs, there are receptor binding proteins at the tip of its little feet, which are the host specificity proteins.
They stick to their host like Velcro, with one side on the feet and the other all around the cell. They use their proteins to physically stick to a specific type of cell. So, the phage and bacteria fit together like puzzle pieces. If they don’t fit, the phage floats away and won’t stick to the cell long enough to inject its DNA.
What is phage therapy?
Because phages are specific to their host bacteria, they can treat infections through phage therapy. It’s a means of using a phage as a medicine, like an antibiotic, only very targeted.
The problem with antibiotics
The normal way of treating a bacterial infection, at least in the US, is to prescribe antibiotics. We’ve done it this way for decades because antibiotics are great at killing bacteria. However, many kill bacteria indiscriminately because they are broad-spectrum, killing many different species. With most antibiotics used clinically, we can’t control which bacteria are killed with the ones causing the infection.
Killing or harming a large portion of the bacteria in our bodies has become an unsustainable strategy. First of all, a major problem with antibiotics now is that they have stopped working for certain strains of bacteria that cause some infections due to the rise of antibiotic resistance. Second, many antibiotics harm the bacteria that are important for our health, those in our microbiome. A better strategy is to be more targeted, killing only those causing the infection, which phage therapy can achieve.
On the other hand, antibiotics are not all bad. They are extremely important for infection treatment if used properly. The ability of antibiotics to kill lots of different bacteria can be a good thing. Some cases require treatment immediately, and there is no time to determine the exact strain of bacteria causing the infection. So, doctors can use antibiotics for time-sensitive scenarios when patients cannot wait for weeks, which right now is the time frame for phage therapy.
Phage therapy history
Phages were discovered before antibiotics, Jessica says, and have been used for more than 100 years. If someone had an infection, they could use phage. Phages were even commercially produced by Eli Lilly Company in the 1940s. The advantage of phage over antibiotics is that they are very specific to certain bacteria, which Jessica calls “a sniper version of an antibiotic.” They are like a super targeted narrow-spectrum antibiotic.
But antibiotics began to be widely used around the 1940s when penicillin was mass-produced. They worked really well, were easier and simpler to use. And their broad-spectrum activity allowed them to treat multiple different types of infections. So, eventually, in the US, phages were used much less frequently.
In one part of the world, though, Eastern Europe and the former Soviet countries, phages were preferred and used instead of antibiotics (the opposite of the west, where antibiotics were used almost exclusively.) The country of Georgia (not the state) near Russia was a hotspot for phage therapy and has been for 90 years. There is a phage center, The Eliava Institute, still in operation. So, people around the world will fly to Georgia to get phage therapy.
The rise of phage therapy in the west
However, recently, western countries are beginning to use phages more and more. We’re seeing something of a phage therapy renaissance in the west because doctors and researchers are realizing the problems with antibiotics: 1) antibiotic resistant organisms are on the rise, so we need another means of treatment, and 2) the microbiome is extremely important — like an organ, it’s essential for health — and it’s unwise to indiscriminately kill microorganisms in and on our bodies.
So, the west is beginning to see how helpful phage therapy could be. Phages are very precise in what organisms they kill and are therefore more friendly to the microbiome by simply ridding out bodies of the pathogen, rather than any antibiotic susceptible organisms.
In the US, phage therapy can be used on an experimental basis through a pathway with FDA called compassionate use, emergency use, or investigational new drug. It can be used when a doctor has tried all standard of care for a patient and have no antibiotics left. The way this is done, Jessica says, is by literally picking up the phone and calling the FDA and telling them they tried everything for a patient, they need something new, and they have this solution. And it requires some paperwork to certify it will be as safe as possible.
Phage Directory: connecting doctors and patients to scientists with phages
Because of the specificity of phages, phage therapy can be challenging. You have to find the exact right phage to treat someone with. It’s not enough to treat an E. coli infection with an E. coli phage. You have to find out which strain of E. coli they are infected with and a corresponding phage for that strain.
Finding the right phage is done through testing the bacteria causing the infection against different phages through the plaque assay described above. This process of hunting for phages is a challenge.
Phage Directory, which started in 2017, helps streamline the phage hunting process by connecting doctors and patients to scientists that have phages that will “work” on the infecting strain of bacteria.
How Phage Directory started
Before Phage Directory, people were contacting scientists in any possible way to search for phages. Jessica, a PhD student at the time, noticed a means of contact was through Twitter when Dr. Steffanie Strathdee was tweeting about patients in need.
Dr. Strathdee is famous in the phage world because she saved her husband from a deadly infection by convincing the doctors to use phages to treat him. She researched phage therapy and found researchers willing to donate phages. And they used phage therapy for her husband on an emergency use basis in 2016 in the US. She and her husband documented their story in the incredible book The Perfect Predator.
Because Jessica had seen the story in the news and followed Dr. Strathdee on Twitter, she saw this tweet go out about a patient in Pittsburgh, Pennsylvania, who needed phages because she was dying from a cystic fibrosis lung infection that was no longer responding to antibiotics. The woman was Jessica’s age, so it felt very real to her. And she was surprised to discover more people were trying out phage therapy in the US. Jessica assumed it was a one-off situation. But researchers started responding to the call, even a lab next door to Jessica’s at the University of Alberta in Edmonton.
When Jessica saw the tweet, she was having coffee with her co-founder, Jan Zheng, a friend from swing dancing, and shared it with him. His background was in computer science, user experience design, building online communities and systems for people to help each other through crowdsourcing. When Jan discovered that Twitter was their “system,” he volunteered to create a website where researchers could sign up and list themselves as labs with phages. That way, when someone went looking for phages for a patient, they would have somewhere to find phages and researchers.
The website was up within a couple of days. And they took to Twitter to find phage researchers to sign up on the directory to help in the future. They would receive a phage alert when a patient was in need. And a researcher in a lab working with that type of bacteria could volunteer to screen for phages for that particular strain.
“People just started joining it. I never imagined that it would become an organization at that point. I really thought Jan was kidding when he said we were going to do this at all.”
In academia, we talk about big ideas all the time, says Jessica, but executing them takes years if they ever even happen. So, having something so significant happen within two days was unusual and exciting.
Doctors began using the system, and Phage Directory was featured in an article in STAT telling the story of Mallory, mentioned above, the woman dying from the cystic fibrosis lung infection. Sadly, she passed away before they were able to help her. But that solidified it for them. The reporter explained how Phage Directory would help prevent these sad cases from ending this way and connect more people to phage therapy. They have around 300 labs and counting who receive phage alerts and are prepared to help in the phage hunt. Getting phages to patients can take several weeks, but it’s worth the wait when there are no antibiotics left.
Phages are for sea turtles too
Phage alerts usually go out for human infections, but Jessica shared a case where a veterinarian with a sea turtle in desperate need used the alert system. “She somehow found out about us and asked us if we have Citrobacter phages because they had a sea turtle with its whole shell infected with this bacteria. It had been infected for years and had gotten in the bone,” says Jessica. It was dying, and they could no longer treat it.
So, Phage Directory sent out an alert on New Year’s Eve, thinking no one would respond. But to their surprise, it was their most viewed tweet. People shared it everywhere. “I think that really helped get the word out about pages too.”
When they received responses, the labs were excited because they didn’t expect to find a use for Citrobacter phages. Citrobacter is usually not a human pathogen. People study it because it’s “the E. coli for mice,” says Jessica. It is typically a safe species of bacteria. So, undergraduate institutions can use it for teaching.
The first step in the phage hunt is to culture the bacteria and send it by mail. Some labs got hits for the right Citrobacter phages, and some labs didn’t. Eventually, the sea turtle received phage therapy.
Treating the turtle took a few months, in this case, because they had to treat and then re-treat with new phages because the bacteria evolved resistance to phages. Resistance is not something that just happens with antibiotics. It is a survival mechanism for bacteria. But you can take the new strain and find new phages. So phage therapy is a process that lends itself to much more rapid iteration. If you had to find a new antibiotic, it would take years.
Through Phage Directory, it is clear that researchers are dedicated to helping out with the phage therapy effort. The research community is incredibly dedicated to coming together to help out on a volunteer basis using research funds. In Stephanie Strathdee’s case, Jessica shares, researchers and grad students spent the night trying to find phages for her husband. Researchers are not used to getting to be a part of something that helps right away. (I can completely relate to this from my years in research.) It takes a long time, sometimes 50 years, to see anything come from the research you do. So, it is inspiring to have a part in something right now.
At-home microbiology activity
For the activity, Jessica asked folks on Twitter for suggestions. Dr. Mya Breitbart responded, sharing a wonderful activity she and her co-authors wrote about in a paper entitled Elementary Student Outreach Activity Demonstrating the Use of Phage Therapy Heroes to Combat Bacterial Infections.
This phage outreach activity is great for elementary school-aged children and can be done at school or home. It doesn’t even involve real phages, so there is no concern over growing live microbes.
What you do is create a phage therapy-like scenario using villains (bacteria causing the infection) and superheroes (phages). Inside a big hula hoop, which represents a petri dish, you place printed off paper bacteria cutouts of the villains causing infections. Then, kids use fishing rods with bait, the phage superheroes. The activity shows the specificity of the phages because each one has a certain attachment (magnet, pipe cleaner hook, and velcro) that corresponds to the bacteria. So, the phage superhero can fly in and fish for your specific corresponding microbe out of the petri dish. The magnet will attach magnet, the pipe cleaner will attach pipe cleaner, and the velcro to velcro. And when you pull the microbe out, you get a circle that remains as a plaque. It helps teach the concept of having a whole bunch of microbes in a mix and phages coming in to precisely take out certain bacteria.
Click here to read the article detailing the activity and providing the templates for cutting out.
This is a great activity that will allow kids to play around with phages without dealing with any live microbes.
Links & Resources
- Phage explainer video by Kurzgesagt (in collaboration with a phage scientist James Gurney)
- A news story about a 7-year-old girl whose leg was saved from amputation using phages
- The Perfect Predator: A Scientist’s Race to Save Her Husband from a Deadly Superbug: A Memoir by Steffanie Strathdee and Thomas Patterson (Book)
- Salt in My Soul: An Unfinished Life by Mallory Smith (Book)
- The Immortal Life of Henrietta Lacks by Rebecca Skloot (Book)
- What is the microbiome? (Blog post)
- Using microbes to treat infections (microbial therapeutics): Dr. Brian Klein (Blog post + Podcast episode)
Connect with Dr. Jessica Sacher
Dr. Jessica Sacher is a PhD microbiologist who helped start Phage Directory, an organization that helps doctors and scientists use phages — bacteria’s natural microbial predators — to treat bacterial infections when antibiotics don’t work. She is from a small town in the Canada prairies and stumbled upon a love for microbes when an enthusiastic professor told her how transplanting microbes from one mouse to another could make the second mouse look more like the first. She was hooked on the importance of microbes from then on!
Connect with Dr. Jessica Sacher: Phage Directory website, Jessica’s website, @JessicaSacher (Twitter), and @PhageDirectory (Twitter).
Using microbes to treat infections (microbial therapeutics): Dr. Brian Klein
