Imagine that the next time you catch a stomach bug and antibiotics fail to work, you knock back a vial of clear liquid. The solution teems with bacteriophages, viruses resembling tiny rocket ships. These benign microbes exclusively dock onto and destroy bacteria, and your infection clears in a matter of days. Such a future is within reach, journalist Lina Zeldovich writes in her new book The Living Medicine: How a Lifesaving Cure Was Nearly Lost―And Why It Will Rescue Us When Antibiotics Fail. The book chronicles the history of a decades-old, sometimes finicky approach to infection that U.S. science has long dismissed in favor of antibiotics.

As microbes develop cleverer and cleverer ways to evade antibiotics, some scientists have returned to bacteriophages, scooping them from wastewater and testing their pathogen-killing abilities in the laboratory and clinic. Experimental trials are now underway to test bacteriophage therapies against superbugs such as Shigella, vancomycin-resistant Enterococcus, and a strain of Escherichia coli implicated in Crohn’s disease. And some food industry producers already use Food and Drug Administration–approved “phage sprays” to decontaminate their supply of, say, lettuce or sausage. (No medical uses of the treatment have yet been approved for the U.S. public.)

Scientific American spoke with Zeldovich about the differences between bacteriophages and antibiotics, the history of bacteriophage experimentation, and the therapy’s potential future regulation and use in the U.S.

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[An edited transcript of the interview follows.]

How worried should the average person be about antimicrobial resistance?

Many scientists whom I interviewed for the book told me they are very worried that the next pandemic is going to be bacterial because we’re losing our antibiotic armor. In 2019 I found a statistic that said that every 15 minutes, someone in the U.S. dies from an antibiotic-resistant infection. I just couldn’t wrap my mind around that. And COVID only made things worse because people were sicker and used more antibiotics. The United Nations has made some dire predictions that if we continue business as usual and don’t find any viable alternatives to defunct antibiotics by 2050, we’ll start losing millions of people to infection.

What’s driving this resistance? Antibiotic overuse, or reliance on a single type of therapy?

Resistance is an inevitable side effect of evolution: the organisms we want to outcompete will always develop their own defenses. But we also certainly overuse antibiotics in medicine and in agriculture. In the mainstream media, there’s a lot of emphasis on people demanding antibiotics that aren’t necessary. But Big Agriculture plays a much bigger role. When you feed cows, pigs or chickens antibiotics, they then poop them out into the environment, where the medications continue causing damage. They kill certain soil bacteria but not all. So successful mutants appear in the soil and the water. And then they can arrive on our plates, where we consume them and get sick from them and have no viable treatments left. Hospitals are also superbug breeders because they require sterile environments.

What possible solutions are scientists exploring, and where do bacteriophages fit among them?

Phages are viruses that only infect bacteria. Their biological machinery does not match that of our cells, but it near perfectly matches bacterial machinery. The virus attaches itself to bacteria, squeezes inside, multiplies and then bursts the cell. Bacteria can develop resistance to a phage that preys on it, but because of evolution, the phage can also evolve more mechanisms to attach to the bugs. Phages and bacteria have evolved alongside each other for millions of years. There are trillions of phages in nature. Scientists who work on them say they’re an inexhaustible resource.

Alternative approaches include finding new antibiotics, also in nature. [Penicillin, the first naturally derived antibiotic, came from mold.] But this takes longer than finding suitable phages and is harder to do now. You can also use artificial intelligence to design antibiotics and synthesize them in the lab.

Do you think bacteriophages are currently receiving enough attention or investment?

I think they’re finally coming to the scientific forefront. Phages were first discovered in 1917––before antibiotics. In the 1920s and 1930s [phages] had a really great moment. They were in some cases the only lifesaving infection medicines, and doctors almost all over the world used them fairly successfully. But then companies started marketing phages for things they could not do (such as curing viral disease, fungal infection or allergies), and two prominent American physicians [Monroe Eaton and Stanhope Bayne-Jones] determined that phages were too unpredictable to use. Shortly after, we got antibiotics, and we almost completely forgot about phages.

Countries in Eastern Europe and in the former Soviet Union always used phages alongside antibiotics because antibiotics are difficult to manufacture. In the Soviet Union, for instance, there were often antibiotic shortages, 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 U.S., we embrace convenience and stability. Antibiotics had a longer shelf life than phages; they could be made into pills; and you didn’t need to run a bunch of tests to identify the pathogen to target.

Now that we have this pressing issue of antibiotic resistance, more money is coming into bacteriophage research. In the early 2000s pioneers told me it was impossible to get any money. That’s been changing, maybe in the past eight years or so.

Is it fair to say desperation forced the FDA to consider bacteriophage therapies?

That’s not a bad word for it. I think the real pivoting point was the Tom Patterson case. In 2015 Patterson [a researcher at the University of California, San Diego] contracted an antibiotic-resistant bacteria called Acinetobacter baumannii in Egypt, while traveling there on vacation with his wife, Steffanie [Strathdee]. Steffanie is herself a scientist, so she began looking for alternative treatments and stumbled upon phages. Tom’s doctor was somewhat familiar with the concept and said he’d try anything that might work. So Steffanie contacted a researcher at [Texas A&M University] and the Navy, and doctors eventually gave Tom a cocktail of an antibiotic and a phage [under a special exemption from the FDA] that killed the bug.

I later learned that the FDA actually wanted to see a case like Tom’s. Tom’s treatment worked well [as a proof of principle] because his disease was so serious and his treatment was well documented. After that, money started trickling in. When I was writing the book, there were 50 clinical trials. Now there are many more. They’re all in different stages.

How far along are some of these trials, and what kinds of hurdles do they face?

Everything starts in phase 1, where you just need to show safety in a small number of participants. The clinical trial process is slow—and for a reason: you don’t want to put something out there that could cause more harm than good, right? So bacteriophages are still in the fairly early stages. I am fairly optimistic that we are moving in the right direction in the U.S. I just don’t know how much time we have on our hands. Some European phage researchers told me they feel our regulatory bodies need a better way to approve these treatments, not necessarily on an individual basis. In Europe, and in Germany in particular, the rules are a bit less rigid.

Many of the bacteriophages currently being studied destroy stomach bugs. If you inject phages intravenously rather than swallow them, can you target a wider range of pathogens?

We don’t have solid knowledge of what happens in the body. With anything intestinal or urinary tract infections, bacteriophages can go very far. Intravenously? That’s a different story.

Does it feel like an eventual phage therapy approval is inevitable, or could the field be derailed by a horrible adverse effect?

I think people are committed enough because 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.

Generally speaking, adverse reactions are very unlikely if phages are prepared correctly: If you give phages intravenously, that phage solution has to be really, really purified, with no bacterial debris [that the immune system can vigorously reject]. Otherwise your system can go into toxic shock. A hundred years ago there weren’t any good technologies to adequately purify solutions, but that’s no longer a problem today.

There’s also a question about to what extent the immune system can go after phages themselves, [possibly limiting the efficacy of the treatment]. We don’t have enough information about this, though. For a phage to work, it needs to extinguish the infection before the immune system destroys it.

Could scientists ever engineer phages with desired traits such as, say, the ability to evade the immune system more easily?

They probably could. If you knew which genes to replace with what genes, you could design a stronger phage. You could 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 tweaked it or combined it with other ingredients, you could patent the product.

How might regulatory bodies speed up the process?

It’s complicated. I don’t write about policy much, 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 inside a person. And given that they multiply within the body, how do you establish the dose? We like to have things measured, but with phages you almost have to trust Mother Nature to do what she does.