Imagine throwing back a bucket full of clear liquid the next time you catch a stomach bug and the antibiotics don’t work. It is full of solutions bacteriophagesviruses that look like little rocket ships. Only these benign microbes attack and destroy the bacteria, and your infection clears up in a matter of days. That future is within reach, writes journalist Lina Zeldovich in her new book Living Medicine: How a Life-Saving Cure Was Almost Missed—And Why It Will Save Us When Antibiotics Fail. The book chronicles the decades-long and sometimes grim history of an infection that has long been neglected by US science in favor of antibiotics.
As microbes develop smarter and smarter ways to avoid antibiotics, some scientists have turned to bacteriophages, pulling them out of wastewater and testing their pathogen-killing abilities in the lab and clinic. Experimental trials are underway to test bacteriophage therapies against, for example, superbugs Shigellaresistant to vancomycin Enterococcusand a tension Escherichia coli Involved in Crohn’s disease. And some food industry producers use Food and Drug Administration-approved “phage sprays” to decontaminate, say, lettuce or sausage. (The treatment has not yet been approved for medical use by the US public.)
American scientific He spoke with Zeldovich about the differences between bacteriophages and antibiotics, the history of bacteriophage experimentation, and the future regulation and use of the therapy in the US.
About supporting science journalism
If you like this article, please consider supporting our award-winning journalism subscribe. By purchasing a subscription, you’re helping to ensure a future of impactful stories about the discoveries and ideas that shape our world.
(Following is an edited transcript of the interview.)
How concerned should the average person be about antimicrobial resistance?
Many of the scientists I interviewed for the book told me that they are very worried that the next pandemic will be bacterial because we are losing our antibiotic armor. In 2019 I found a statistic that said that every 15 minutesSomeone in the US dies from an antibiotic-resistant infection. I just couldn’t wrap my head around it. And COVID made things worse because people were sicker and used more antibiotics. The United Nations has made grim predictions that if we continue business as usual and don’t find viable alternatives to extinct antibiotics by 2050, we will start losing millions of people to infection.
What drives this resistance? Overuse of antibiotics, or reliance on a single type of therapy?
Resistance is an inevitable side effect of evolution: the organisms we want to compete with will always develop their own defenses. But we certainly overuse antibiotics in medicine and in agriculture. The mainstream media highlights people who order unnecessary antibiotics. But Big Agriculture plays a much bigger role. When you feed antibiotics to cows, pigs or chickens, they then poop into the environment, where the drugs continue to cause damage. They kill some soil bacteria, but not all. So successful mutants appear in soil and water. And then they can end up on our plates, where we consume them and get sick and have no viable treatment left. Hospitals are also superbug breeders because they require sterile environments.
What possible solutions are scientists exploring, and where do bacteriophages fit into them?
Phages are viruses that only infect bacteria. Their biological machinery does not match that of our cells, but the machinery of bacteria is almost identical. The virus attaches itself to the bacteria, squeezes inside, multiplies and then bursts the cell. Bacteria can develop resistance to a phage that captures it, but due to evolution, the phage can also develop more mechanisms to attach to bugs. Phage and bacteria have evolved side by side for millions of years. There are billions of phages in nature. The scientists who work on them say that they are an inexhaustible resource.
Alternative approaches include finding new antibiotics, also in nature. (Penicillin, the first naturally derived antibiotic, came from mold.) But that takes longer than finding the right phages and is harder to do now. You can also use artificial intelligence to design antibiotics and synthesize in the laboratory.
Do you think bacteriophages are currently receiving enough attention or investment?
I think they are finally reaching the first scientific level. Phages were first discovered in 1917, before antibiotics. In the 1920s and 1930s (phages) it was a great time. In some cases, they were the only anti-infective drugs, and they were used quite successfully by doctors almost all over the world. But then companies started marketing phages for things they couldn’t do (such as curing viral diseases, fungal infections, or allergies), and two famous American doctors (Monroe Eaton and Stanhope Bayne-Jones) decided that phages were too unpredictable to use. Soon after, we took antibiotics, and almost completely forgot about the phages.
In Eastern Europe and the former Soviet Union, phages were always used together with antibiotics because antibiotics are difficult to manufacture. In the Soviet Union, for example, there was a shortage of antibiotics, so doctors would go to a river, find a bunch of phages, test them in the lab and use them. It was a different mentality. In the US, we stand for comfort and stability. Antibiotics had a longer shelf life than phages; they could become pills; and you didn’t have to run a bunch of tests to identify the target pathogen.
Now that we have this serious problem of antibiotic resistance, more money is being poured into bacteriophage research. In the early 2000s pioneers told me it was impossible to get any money. That is changing, maybe in the last eight years or so.
Is it fair to say that desperation forced the FDA to consider bacteriophage therapies?
That’s not a bad word. I think the real focal point was the Tom Patterson case. In 2015, Patterson (researcher at the University of California, San Diego) recruited a bacteria resistant to antibiotics. Acinetobacter baumannii In Egypt, he was traveling there on holiday with his wife, Steffanie (Strathdee). Steffanie is a scientist herself, so she started looking for alternative treatments and came across phages. Tom’s doctor was somewhat familiar with the concept and said he would try anything that might work. So he contacted Steffanie (Texas A&M University) and an Army researcher, and the doctors finally gave Tom a cocktail of an antibiotic and a phage (under a special FDA exemption) that killed the bug.
I later learned that the FDA wanted to see a case like Tom’s. Tom’s treatment worked well (as a proof of principle) because his disease was so severe and his treatment was well documented. After that, the money started rolling in. When I was writing the book, there were 50 clinical trials. Now there are many more. They are all in different stages.
How far along are some of these trials, and what kind of obstacles do they face?
It all starts in phase 1, where you have to demonstrate safety in a small number of participants. The clinical trial process is slow—and for one reason: You don’t want to put anything in there that could do more harm than good, right? So bacteriophages are still in their early stages. I am quite optimistic that we are moving in the right direction in the US. I don’t know how much time we have. Some European phage researchers told me that they think our regulatory bodies need a better way to approve these treatments, not necessarily individually. In Europe, and Germany in particular, the rules are a little more rigid.
Many bacteriophages currently being studied destroy stomach bugs. If you inject phages intravenously instead of swallowing them, can you target a wider range of pathogens?
We have no solid knowledge of what happens in the body. With intestinal or urinary tract infections, bacteriophages can go a long way. Wait inside? That’s another story.
Does the acceptance of phage therapy seem inevitable, or could the field be derailed by an enormous adverse effect?
I think people are committed enough that we don’t have an alternative. And people have adverse reactions to antibiotics all the time, and the drugs are still on the market. Without them things are worse.
Adverse reactions are generally very unlikely if phages are prepared properly: if you give phages intravenously, that phage solution must be really, really purified, free of bacterial debris (which the immune system can forcefully reject). Otherwise, your system can be hacked toxic shock. A hundred years ago there was no good technology to properly purify solutions, but this is not a problem today.
There is also the question of how far the immune system can go after the phages (potentially limiting the effectiveness of the treatment). We don’t have enough information about this, though. For a phage to work, it must kill the infection before the immune system destroys it.
Could scientists engineer phages with desired characteristics, such as the ability to more easily evade the immune system?
Probably possible. If you knew which genes to replace, you could design a stronger phage. You can also administer multiple phages in a sort of cocktail. Genetic engineering is often attractive to pharmaceutical companies because you can’t patent a phage alone—it’s a natural organism—but if you modify it or combine it with other components, you can patent the product.
How can regulatory bodies speed up the process?
It’s complicated. I don’t write much about politics, but I imagine the FDA could regulate bacteriophages like they do the flu vaccine. One problem with regulating phages is that they evolve over time and even within a person. And given that they multiply inside the body, how do you set the dose? We like to measure things, but with phages you almost have to trust Mother Nature to do what she does.
