Several months into the coronavirus pandemic, I had a video medical appointment with a patient who was looking forward to getting infected by a virus. She had an aggressive bacterial infection in her hip that antibiotics could not cure. Having run out of conventional options, her medical team was preparing to give her an experimental treatment with bacteriophage (or “phage” for short), a virus capable of destroying the offending bacteria.
Covid-19 has us thinking of viruses as the enemy and yet here was someone excited about getting one. Her story was a reminder that most of the viruses in our midst are actually benign, and some are even lifesaving.
But which viruses help us and how do we promote them while dodging those, like the one causing covid-19, that cause disease?
“Phage is definitely an example of a good virus.” said Saima Aslam, an infectious- disease expert in organ transplantation at the University of California at San Diego.
Aslam considered using viruses therapeutically once she began running out of antibiotic options for her most challenging patients. One of those patients was in the hospital for eight months with a recurring Pseudomonas aeruginosa bacterial infection in his transplanted lungs. “Every few weeks he was on the ventilator, and every few weeks [the infection] was more antibiotic resistant,” she said. “We thought: He is not going to make it.” Desperate to help him, Aslam decided to treat him with a bacteriophage similar to the one that my patient was about to receive.
Aslam recalled how she sent a sample of her patient’s pseudomonas-laden sputum to researchers who matched it with a virus capable of infecting and then destroying it. Because phage therapy is not approved by the Food and Drug Administration, Aslam applied for special permission to administer the virus under the agency’s investigational new drug (IND) application, which makes exceptions for life-threatening situations. Days after the patient received his first dose of virus in an inhaled solution, his infection was treated. Although this patient did go on to have other health challenges, his response to the phage therapy was so dramatic that it inspired Aslam to use a similar approach with other patients.
While bacteriophage therapy is considered cutting-edge, scientists have known about bacteria-fighting viruses for over a century. In fact, phages were discovered at least a decade before penicillin, the first antibiotic to be identified. The scientists who found them had no way of seeing these submicroscopic infectious parasites — the technology for that didn’t yet exist — but they inferred that phages existed within a transparent substance that prevented bacteria from growing on a plate of agar. In 1917, Félix d’Hérelle, a French Canadian microbiologist and one of the first to make such an observation, called this substance “eater of bacteria” or bacteriophage. He developed a method to filter out the phage and then use it to treat salmonella infection in chickens, and shigella and cholera in humans.
But working with these helpful viruses proved tricky from the start. Bacteriophages are probably the most abundant and diverse entity on the planet and identifying which were most effective against a particular bacterial infection was difficult. Dosing was also challenging since phages continue to replicate, so their quantity is not constant. Given these hurdles, it’s understandable that doctors in most places abandoned phage therapy when penicillin and other chemical antibiotics became widely available. Antibiotics were shelf-stable, dependably dosed, mass produced and one formulation could kill a wide range of invaders.
But now, with widespread (and increasing) antibiotic resistance and few new antibiotics in the pipeline, doctors like Aslam are drawn to bacteriophages for precisely the qualities that made them seem inferior to antibiotics a century ago: their dynamic nature, complexity, specificity and diversity. While antibiotics offer fewer than two dozen mechanisms for killing bacteria, phages have vastly more. There are thousands of types of phages that can infect each bacterial species, making it nearly impossible to resist all of them. And even when the phage treatment does not kill the bacteria, it can force an “evolutionary trade-off” that often makes it more vulnerable to antibiotics.
“I like to figure out how to take these viruses and tame them and use them for applied purposes,” explained Paul Turner, Rachel Carson Professor of Evolutionary Biology and Ecology at Yale University and a self-described “bacteriophage hunter.”
Turner, who studies the therapeutic applications of phages, is exploring whether administering these viruses in a cocktail or in sequence can fight bacterial infections more effectively than simply prescribing one phage type. He has traveled to many parts of the globe to hunt for bacteria-eating viruses that could be useful to humans.
According to Ken Cadwell, a virologist in the Skirball Institute at New York University Langone Health who studies our virome, the virus that lives in and on us, we probably don’t need to go very far to find helpful phages: Scientists “are definitely examining phages in the gut for useful or interesting properties. This is cutting-edge stuff,” Cadwell said. He attended the first scientific meeting dedicated to the virome in March 2020, just days before the first stay-at-home orders to fight the coronavirus went into effect in many places.
In the past decade there has been growing interest in understanding our microbiome — the trillions of microbes that we harbor in our gut and other organs. We have discovered that these foreign cells far outnumber our own and control everything from how we digest our food to how we feel.
Some of us were even mindful of protecting these microbes by not bathing too much or eating foods that could harm them. But one of the least explored parts of our microbiome is our virome — the viruses we harbor, including phages, that are the most plentiful type of virus and organism within us.
We know so little about these resident viruses, largely because they are hard to study; they hide within foreign cells and, unlike bacteria, lack reliable genetic markers that distinguish one species from another.
“But the tide is turning, and we are appreciating more and more the diversity of viruses out there and how they interact with the host,” Cadwell said. He credits recent advances in genomic sequencing for helping virologists better characterize viruses and associate their presence with specific diseases — or lack thereof.
What they are discovering is that bacteriophages within us might play a singular role in protecting our health.
For example, bacteriophages — not bacteria — might be the key ingredient in fecal transplants, a highly effective treatment for recurrent and debilitating diarrhea caused by the bacterium Clostridium difficile. This was discovered after researchers noted that sterilized stool from healthy donors worked just as well as bacteria-laden stool to treat the diarrhea. On closer inspection, the sterile stool was chock full of a diverse population of bacteriophage, suggesting that these were the active ingredient that made the difference. This same study reported that a range of intestinal phages, and especially ones belonging to the family CrAssphage (virologists have a sense of humor) reemerged in the gut after a successful transplant.
There is also evidence that our resident phages influence our health in ways that do not involve bacteria. When researchers followed a group of children at genetic risk for Type 1 diabetes, an autoimmune disorder, they discovered that those with a greater diversity of gut bacteriophage were less likely to develop diabetes. In this instance, their virome might be directly communicating with their own immune cells.
While virologists are just beginning to understand what constitutes a “healthy” virome, these studies suggest that our bacteriophage composition is key. So in this pandemic era of continuous hand-washing and wiping down every surface, how do we ensure that we host an array of these helpful virus?
Here’s what experts suggest:
●Don’t self-prescribe antibiotics from a leftover stash in your medicine cabinet, only take them when your health provider says they are necessary. Remember antibiotics kill off bacteria that are needed to sustain bacteriophages.
●Use basic soap to wash yourself and pass on the germicidal soaps as there is no evidence that antibacterial soaps are more effective at preventing covid-19, or other infections, than plain soap and water.
●Cut down on food preservatives (especially sodium benzoate, sodium nitrite and potassium sorbate), sugar and artificial sweeteners in your diet; studies have shown that these also reducebacterial diversity.
●Eat a rainbow color of plants to promote a diversity of gut bacteria. Researchsuggests that nutrient diversity promotes gut and bacteriophage diversity.
Yale’s Turner, an ecologist by training, sees bacteriophages as players within a complex community of organisms and offers a planetary perspective for how to preserve this viral resource.
When we protect our wilderness, Turner said, we are preserving a vast pharmacy of viruses that can ultimately protect us.
While he has found new phage types in sewage treatment plants and other parts of the built environment, he describes wilderness — places that host the greatest diversity of animals and plants — as the most reliable trove for a diversity of phages. One of his most stocked hunting grounds is Cuatro Ciénegas, a pristine area of wetlands and lakes in rural Mexico. He has also found useful phages in lakes, forests, and hot springs and from deep in the ocean.
Conveniently, protecting wild spaces may also help ward off the next pandemic since the spillover of potentially deadly viruses such as the coronavirus can occur when we encroach on nature through farming, urban development and other activities. These incursions allow viruses in animals to find their way into new hosts, including us, who are ill-prepared to deal with them.
“Covid-19 is among the most vivid wake-up calls in over a century,” infectious- disease expert Anthony S. Fauci and co-author David Morens wrote in the fall in the science journal Cell. “It should force us to begin to think in earnest and collectively about living in more thoughtful and creative harmony with nature.”
If rising sea levels, hurricanes, fires and fear of the next pandemic are not sufficient motivation to change our relationship with nature, then perhaps preserving phages for our individual health will be. As my patient on that call so clearly illustrated, good viruses might save our lives someday.
Daphne Miller is a clinical professor at the University of California at San Francisco and writes about the connections between our health and the natural world. @drdaphnemiller