In the fight against antimicrobial-resistant (AMR) superbugs, an important weapon may just be hiding in some polluted stream, in some remote village that lacks adequate sewage infrastructure, or in a wastewater treatment plant here in Connecticut.
For more than a decade, Yale’s Benjamin Chan has scoured these and other sites across the world, from villages in sub-Saharan Africa to a wastewater plant in New Haven, collecting what are known as bacteriophages, or phages. Phages, a class of viruses that infect bacteria, have long offered promise as an important tool against AMR, a global threat to public health fueled by the misuse and overuse of antibiotics.
Chan, the scientific director of Yale’s Center for Phage Biology & Therapy, is featured in a new documentary film, “The Good Virus,” which documents a network of scientists engaged in the fight against AMR, a public health crisis that is already causing millions of deaths annually. (The film will be screened on April 12 at the Yale Humanities Quadrangle, followed by a conversation featuring Chan, producer Vanessa Dylyn, and science writer Carl Zimmer. Learn more about the event and register.)
In an interview, Chan describes his own global hunt for novel phages that offer hope in the fight against baterial infections, how communities in some of the world’s under-resourced regions can independently create their own phage products, and how Yale’s phage therapy center is producing “bench-to-bedside” research in search of potentially life-changing solutions to a range of public health threats, including for patients here in New Haven.
The interview has been edited for length and clarity.
What are bacteriophages? And why are they considered an important weapon in the fight against antimicrobial-resistant bacteria?
Benjamin Chan: Bacteriophages are the viruses of bacteria, and they are the most numerous replicating entity on the planet: basically, they’re everywhere that bacteria are. They bounce around until they encounter a bacteria and then sort of feel around to see if it’s the right species or strain, because they’re super specific. If it is the right species, they begin the infection process by basically grabbing on to the bacteria and injecting their DNA, which shuts down the metabolism of the bacteria, creating copies of its genetic material which then explode out.
They’re potentially important in that fight for a couple of reasons. For one thing, development of new antibiotics has really slowed. And we have seen rising rates of antibiotic resistance across the world, which is a problem if we don’t have any tools to manage those infections. Phages offer one tool that acts in a mechanism completely different than traditional chemical antibiotics. Basically, they act as a whole new class of antibacterials. They outnumber bacteria by a ratio of about 10 to 1, so you can always find new phages that can infect bacteria. If it evolves resistance to one phage, you can always find a new one. I don’t want to curse the field and say it’s limitless, but it’s incredibly diverse — there’s a lot of potential.
Working with local partners, Chan has collected samples from wastewater sources in several nations in sub-Saharan Africa. In this photo he collects samples from a river in the city of Bukavu in the Democratic Republic of Congo.
Why has antimicrobial resistance become such a global threat? And what’s the potential scale of this threat in the coming decades?
Well, there are a lot of reasons it has become a problem. One is that many antibiotics are dispensed freely or inappropriately, and there’s the problem of people not using their complete course of antibiotics. These antibiotics also often end up in contaminated waterways. All this has led to the creation of these antibiotic-resistant bacteria, which all alone wouldn’t be much of a problem. But if these bacteria end up in a human or in a domestic animal and it causes an infection, then we don’t have tools to manage it. And it’s getting worse. There was a report which predicted that by 2050 antimicrobial resistance will cause 10 million excess deaths, which is more than has been caused by HIV AIDS.
It’s a bigger problem in lower- and middle-income countries for many reasons. Basically, if you have a high-density population with insufficient water treatment there’s a greater chance that there will be transmission of infectious bacteria from wastewater to people. And once it causes infections, the medical infrastructure is under resourced and may struggle to treat it; health systems are often using out-of-date or expired antimicrobials or ones that have been laundered through the medical system and are not meeting quality control. So it’s just creating a positive feedback loop where you’re going to get more antibiotic resistance.
But while these impacts for now are being felt the most in low- and middle-income countries, it’s just a matter of time before it reaches higher-income countries. As we enter what’s been called the post-antibiotic era, it’s going to be a problem everywhere.
How did you become involved in the search for bacteriophages? And what are the kinds of places you’ve targeted for this search?
In my research I focus on the isolation, discovery, and characterization of bacteriophages, with the hope of finding phages that can kill clinically relevant or medically relevant bacteria for the benefit of individuals or communities. I first got into this right after grad school, when I met a physician from the country of Georgia who’d worked with phage therapy. I just became obsessed with it and thought it was such a cool new way to consider treating infections.
As for where to find phages, well, if they are going to be a viable tool in the battle against AMR, then we should look in the regions that are already facing these threats, like sub-Saharan Africa, which offer great biological resources. Again, it is in these places where there are high population densities and where water infrastructure might not be as developed.
In these communities, there is an opportunity to develop new phages that could then be sold to higher-income countries. I like to think of it as a way to create an economic benefit for those who are most affected and potentially reduce and reverse the impact of AMR. This is what led me to really want to work with individuals in these areas, and with an NGO called Phages for Global Health. Together we’ve taught workshops in some of these countries, training scientists and physicians how to isolate their own phages.
A pig approaches Chan as he collects a sample from a polluted waterway in Cité Soleil, an impoverished commune in Port-au-Prince, Haiti.
Where has this work taken you specifically?
Well, we’re looking all over, particularly in wastewater sources in sub-Saharan Africa. We’ve done a lot of work in Kenya, Uganda, Tanzania, Congo, Ghana, but we also have some partnerships in South America. I really love the collaboration part because it involves a lot of what they call “citizen science,” which is basically work that involves everybody. And the concept is pretty simple: It’s as easy as collecting a water sample and sending it to a lab. The bigger the network we have, the more phages we’re able to collect.
How do you know when you’ve found a phage that holds promise?
We start by looking for bacteria associated with human disease, and human sewage is a great source for that. We basically take the sewage sample, or whatever phage source we have, and then filter it out — we get rid of the solids, the bacteria, and other materials. We take the filtrate — phages and small particles that pass through the filter — and spot it on a lawn of bacteria. And if there’s a clearing in the lawn of bacteria, then there’s possibly a phage there. At that point we’ll do some more sophisticated work, but really it’s just about narrowing down and cleaning up each step until we get a nice phage that we can grow on a certain strain of bacteria.
Once you’ve identified it, what are the next steps toward developing a possible treatment?
So once we’ve isolated a phage, then we start characterizing it; we do genetic sequencing and other basic steps to make sure there’s no toxin encoding or antimicrobial resistance genes, since we don’t want to contribute to the problem we’re trying to fix. Then we characterize the receptor: each phage attaches to only certain strains of bacteria via a certain protein or sugar or fat or something else on the surface. Our group tries to focus on finding phages that utilize virulence factors as receptor binding sites.
Our philosophy is that we will use a phage that kills bacteria that have these receptors and only those bacteria; If this virulence factor is on the surface of bacteria, then the phage we use will kill only those ones which will drive the evolution of that population. So if it evolves resistance to the phage, it can’t cause disease anymore or is antibiotic sensitive. Basically, we’re trying to exploit trade-offs with the understanding that the evolution of resistance is almost unavoidable. So we’re trying to correct the problem by using evolution to our advantage.
Your search also happens closer to home: Can you talk about your work here in New Haven?
So, yes, we do work with the Greater New Haven Water Pollution Control Authority, at a wastewater plant, and they’ve been great partners. I’ll sometimes write to my contact there, and ask, “Can we stop by to pick up sewage?” And we’ll show up, pick up sewage, bring it back to the lab, and then do our thing. Isolate phages.
Working with them we’ve found quite a few phages, but one that we found specifically targets [drug-resistant] Staphylococcus aureus. MRSA [methicillin-resistant Staphylococcus aureus] is a pretty big problem, especially for those with prosthetic joint infections. But we found that a really cool effect of this phage is that it either kills MRSA or, if the staph evolves resistance, it becomes sensitive to these penicillins again. So we basically reverse antibiotic resistance.
We’ve had really good success with treating prosthetic joint infections in clinical cases here at Yale-New Haven. And in other institutions, they were actually able to salvage limbs when there didn’t seem to be many options left other than amputation. We were able to go in with the phage and fix the infection.
Has this phage yielded any other promising results?
Well, it’s still an investigational treatment, so we’re trying to figure out in what situations it works most effectively and where it doesn’t work as well, but we’ve definitely seen some really positive outcomes. In addition to the prosthetic joint infections, we’ve had encouraging results in terms of improved lung function and in some pulmonary cases at the adult cystic fibrosis center. And we’ve had a couple of promising cases in the treatment of life-threatening infections for multi- or pan-resistant bacteria. We’ve managed to completely fix some pretty serious infections.
How is the Center for Phage Biology and Therapy at Yale’s contributing to this emerging field?
We’re isolating, characterizing, and discovering new phages. Some of those might not have clinical use necessarily, but they help us better understand the science of phage biology.
Some of these phages that we’re isolating were shared by people from all over the world. There will be someone who saw us on BBC and they’ll ask, “Can I send you a water sample?” If people can get us samples, we’ll happily screen them for phages. We’re also doing clinical research through compassionate use clinical trials. And we do translational work where once we take these phages from the environment, we test how well they work in, say, saline or in something like an injectable or in a nebulizer or in syringes.
So we are able to do bench-to-bedside work within the center, which is pretty satisfying. Especially when you receive a sample from the environment, it goes through all the steps, and then ends up making a difference in someone’s life. It’s super rewarding and makes all the crazy stress worth it.
