In the War on Bacteria, It's Time to Call in the Phages
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science
Apr 2023
Ella Balasa was 26 when she realized the routine medical treatments that sustained her were no longer working. The slender lab assistant had lived since childhood with the side effects of cystic fibrosis, an inherited disease that turns mucus in the lungs and other organs into a thick, sticky goo that gives pathogens a place to grow. To keep infections under control, she followed a regimen of swallowing and inhaling antibiotics--but by the beginning of 2019, an antibiotic-resistant bacterium lodged in her lungs was making her sicker than she had ever been.
Balasa's lung function was down to 18 percent. She was feverish and too feeble to lift her arms over her head. Even weeks of intravenous colistin, a brutal last-resort antibiotic, made no dent. With nothing to lose, she asked a lab at Yale University whether she could volunteer to receive the organisms they were researching: viruses that attack bacteria, known as bacteriophages.
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That January, Balasa trundled to New Haven from her home in Virginia, burdened with both an oxygen concentrator and doubts over whether the treatment might work. Every day for a week, she breathed in a mist of viruses that biologist Benjamin Chan, scientific director at Yale's Center for Phage Biology and Therapy, had isolated for their ability to attack Pseudomonas aeruginosa, the multi-drug-resistant bug clogging Balasa's lungs.
And it worked. The viruses penetrated the goo, attacked the bacteria, and killed a portion of them; the rest of the bacteria weakened enough that antibiotics could knock them out. Balasa's body cleared the life-threatening infection faster than ever before.
Today, Balasa is 30; she continues to suffer from cystic fibrosis, but two more rounds of phages plus a change in medications have kept her from reliving the crisis that phage treatment quashed. Now she consults with companies developing cystic fibrosis drugs and works to bring visibility to new treatments, including phages. "I view them very much as a novel way of treating infections," she says. "If I had not been able to access phages, who knows what my life would be at this point?"
There's an asterisk to her success: Phages are unapproved drugs, not just in the United States, but in the United Kingdom and Western Europe, too. No company makes them for commercial sale in those countries, and hospitals and pharmacies don't stock them. To administer them, physicians must seek a compassionate-use authorization from a government regulator--in Balasa's case, the US Food and Drug Administration--showing their patients have no other options.
That process is inefficient and inherently unfair, since it limits availability to people who are lucky and persistent and whose doctors have strong professional networks. Still, journal articles and accounts by investigators suggest that well over 100 patients in the US have received emergency phage treatments, mostly unpublicized. Researchers are confident that if phages were legally available, more lives could be saved.
And, at last, that could be the case. In 2021, the National Institutes of Health gave 12 US institutions $2.5 million to research phage therapies. Last year, the NIH launched its first federally funded clinical trial of the beneficial viruses, backing 16 centers to test safety and possible dosing levels against Pseudomonas, the pathogen that sickened Balasa. Other academic centers and private companies have launched roughly 20 trials in the US and about 30 in the UK and Europe. And in January, a committee of the UK Parliament launched an inquiry into whether phages could be brought to market there.
A little more than a century after they were first used to cure an infection, it might finally be phages' time.
"I am hopeful that we have reached the stage where we can actually prosecute the case," says Joe Campbell, a program officer at the National Institute of Allergy and Infectious Diseases who runs an internal interest group on phages. "We can move beyond the wonderful, but scientifically unsatisfying, patient stories into something that regulators can say is efficacious."
To be fair, there are places where this would be old news. Phages pervade the natural world: There are possibly trillions of them distributed through every niche of the environment, each tuned by evolution to kill just one type of bacteria. And there are countries where doctors have been using them for decades. After World War I and a decade before the first recognition of antibiotics, a self-taught microbiologist named Felix d'Herelle harnessed phages' natural killing ability to cure dysentery in several children in Paris. By the 1930s, he had found a research home in what's now the Republic of Georgia. After Stalinism closed the USSR off from Western Europe and the US, phage research quietly flourished there.
It wasn't until the USSR collapsed in 1991 that phage treatments came to the attention of countries with big research budgets, via atmospheric news accounts of funding-starved researchers jury-rigging equipment in the dark. That was good timing, because it was simultaneously becoming clear that antibiotics were losing their power against rising drug resistance. Globally, it's estimated that 1.27 million people per year die from resistant infections. The World Health Organization calls drug resistance a "silent pandemic" that could kill 10 million people per year by 2050.
"As [resistance] concerns grow, there are not a lot of options out there," says Graham Hatfull, a professor of biotechnology at the University of Pittsburgh, who maintains one of the largest phage collections in the US and researches their utility against mycobacteria, which cause diseases such as tuberculosis. "That's really drawn focus to phages, because they seem to be one of the more promising aspects out there."
In many ways, phages look like the solution to problems that beset antibiotics. They each kill only one type of bacteria, so they are less likely to disrupt microbiomes. They penetrate complex matrices that defeat antibiotics--not just the thick mucus caused by cystic fibrosis, but the thin films of organisms that develop on pacemakers and artificial joints. And they are unthinkably abundant, a refreshing change from an antibiotic pipeline that gets ever more narrow as companies search for novel ways to attack bacteria.
"This is one of the challenges of the phage space right now: There are all these tantalizing little indications that maybe something good can come from this technology," says Robert McBride, cofounder and CEO of Felix Biotechnology, which has been funded by the Cystic Fibrosis Foundation to develop a Pseudomonas phage that was identified at the Yale center. "And yet we still don't have a rigorous, large, controlled, blinded set of data to support the general case."
Assuming that phages can be put through trials the way antibiotics have poses questions the field can't yet answer. Regulatory structures in the US, UK, and Europe ensure antibiotics' safety and efficacy by evaluating them with well-established measures. Antibiotic chemistry has had more than 80 years, since the 1941 debut of penicillin, to answer basic questions about formulas, dosing, and timing: how fast a compound moves into particular tissues, for instance, or how slowly the body eliminates it. Phage research has barely begun to tackle them.
Even achieving one successful trial won't provide those answers. Because phages are so specific--narrow-spectrum, to use an antibiotic term--choosing the right one, and deciding how to administer it, will be different for sepsis, for a urinary tract infection, or for a heart valve cloaked in biofilm. And beyond determining formulas, there's the formidable challenge of scale.
"When you're dealing with an individual person's infection, doctors have intimate knowledge of the case, and you can take the time to figure out how to pair these things optimally with antibiotics, and do different artisanal things," says Paul Bollyky, an infectious disease physician and associate professor who leads a phage-research lab at Stanford University. "The boring, systematic, expensive work of figuring out how to optimally prepare and store and deliver these things hasn't been done."
The challenges of constructing trials to cover all these issues may mean that compassionate-use cases will dominate phage treatments for now. That doesn't mean the field is stalled. Trials gather data from participants horizontally, so to speak, by examining the experience of many patients at the same time. But Paul Turner, an evolutionary biologist who directs the Yale center and is a scientific cofounder at Felix, points out that it's also possible to learn by gathering data longitudinally from individuals, an approach used as far back at the HIV epidemic and deployed during Covid with the help of increasingly inexpensive sequencing. The Yale Center has treated roughly 50 patients under compassionate use so far, including Balasa, "and we are learning a lot from each of the individuals volunteering," he says.
Whether a patient can get help at an academic center depends on which phages that institution has characterized and how rapidly other scientists can be recruited to help. Since its founding in mid-2018, UC San Diego's Center for Innovative Phage Applications and Therapeutics has been contacted by 1,725 patients. The faculty there determined that 343 of them could benefit from phage therapy, but they were able to locate phages for only 140. (Due to clinical or bureaucratic barriers, only 56 were treated.)
"Phage hunts" require spreadsheet searches, emails, and pleas on Twitter, and sometimes going out in the field to scoop up environmental samples as well. "It's like having a million locks scattered around the world, and then having to match them to billions of keys," says Steffanie Strathdee, an epidemiologist and the center's codirector. Strathdee knows that search from the inside, because donated phages saved her husband, UCSD psychiatry professor Thomas Patterson, from a superbug infection in 2016.
When a key turns, though, it can open a door to wonders. In February, the Centers for Disease Control and Prevention reported that brands of artificial tears contaminated with extremely drug-resistant Pseudomonas had sickened 68 people, killing three and causing four others to lose an eye. The agency passed three bacterial samples to the UCSD center, which matched them to phages that could combat the infection. "Hopefully there won't be more cases," says Robert Schooley, a professor of medicine who is the center's codirector. "But if there are, we can ship these phages and explain to physicians how to use them."
That speaks to how important it will be to achieve unified, public phage libraries--a gap that currently is filled only by the volunteer nonprofit Phage.Directory, which lets clinicians send out international calls. A better solution would be philanthropic and federal funding resembling the kind of support that fueled the pandemic's Operation Warp Speed--and that, decades ago, built up the then-new field of antibiotics. That would be appropriate, because modern phage research is an equally new field, and the economics of combating infection are more difficult than they were in 1941.
The researchers who built Phage.Directory--Jan Zheng and Jessica Sacher, currently working in Australia--were inspired to start it by a Twitter plea for phages launched by Strathdee in 2017. The search was on behalf of a 25-year-old cystic fibrosis patient named Mallory Smith, whose newly transplanted lungs had been taken over by a multi-drug-resistant bacterium called Burkholderia that she had been battling since she was 12. She received the right phages, but the infection had progressed too far. Smith died in November 2017, but an autopsy showed the phages had begun to control the bacteria.
"They told us at the time that we were five years too early," says Diane Shader Smith, Mallory's mother, who guided her daughter's story into being developed for a book and movie, and who now speaks internationally about antibiotic resistance and phage research. "Well, here it is five years later. And maybe things are happening now."
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