Is an ancient therapy the answer to multi-drug resistance?

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BacteriophagesMore than a century since its debut on the fringes of medicine, phage therapy is moving onto centre stage. A couple of recent cases, in particular, have put the therapy under the spotlight.

According to a Leaps Magazine report, the deadly drug-resistant superbug Acinetobacter baumannii struck Tom Patterson during a holiday trip with his wife to the pyramids in Egypt and had sent his body into toxic shock. His health was deteriorating so rapidly that his insurance company paid to medevac him first to Germany, then home to San Diego.

Weeks passed as he lay in a coma, shedding more than a hundred pounds. Several major organs were on the precipice of collapse, and death seemed inevitable, perhaps hours away despite heroic efforts by a major research university hospital to keep Patterson alive.

Then, the report says, the doctors tried something boldly experimental – injecting him with a cocktail of bacteriophages, tiny viruses that might infect and kill the bacteria ravaging his body.

It worked. Days later Patterson’s eyes fluttered open for a few brief seconds, signalling that the corner had been turned. Recovery would take more weeks in the hospital and about a year of rehabilitation before life began to resemble anything near normal.

The report says in her new book The Perfect Predator, Patterson’s wife, Steffanie Strathdee, recounts the personal and scientific ordeal from twin perspectives as not only his spouse but also as a research epidemiologist who has travelled the world to track down diseases.

The report says part of the reason why Strathdee wrote the book is that both she and Tom suffered severe PTSD after his illness. She says they also felt it was “part of our mission, to ensure that phage therapy wasn’t going to be forgotten for another hundred years.”

The report says bacteriophages, or phages for short, evolved as part of the natural ecosystem. They are viruses that infect bacteria, hijacking their host’s cellular mechanisms to reproduce themselves, and in the process destroying the bacteria. The entire cycle plays out in about 20-60 minutes, explains Ben Chan, a phage research scientist at Yale University.

They were first used to treat bacterial infections a century ago. But the development of antibiotics soon eclipsed their use as medicine and a combination of scientific, economic, and political factors relegated them to a dusty corner of science. The emergence of multidrug-resistant bacteria has highlighted the limitations of antibiotics and prompted a search for new approaches, including a revived interest in phages.

The report says most phages are very picky, seeking out not just a specific type of bacteria, but often a specific strain within a family of bacteria. They also prefer to infect healthy replicating bacteria, not those that are at rest. That’s what makes them so intriguing to tap as potential therapy.

Phages and bacteria evolved measures and countermeasures to each other in an “arms race” that began near the dawn of life on the planet. It is not that one consciously tries to thwart the other, says Chan, it’s that countless variations of each exists in the world and when a phage gains the upper hand and kills off susceptible bacteria, it opens up a space in the ecosystem for similar bacteria that are not vulnerable to the phage to increase in numbers. Then a new phage variant comes along and the cycle repeats.

Robert “Chip” Schooley is head of infectious diseases at the University of California San Diego (UCSD) School of Medicine and a leading expert on treating HIV. He had no background with phages but when Strathdee, a friend and colleague, approached him in desperation about using them with Tom, he sprang into action to learn all he could, and to create a network of experts who might provide phages capable of killing Acinetobacter.

“There is very little evidence that phage(s) are dangerous,” Schooley concluded after first reviewing the literature and now after a few years of experience using them. He compares broad-spectrum antibiotics to using a bazooka, where every time you use them, less and less of the “good” bacteria in the body are left. “With a phage cocktail what you’re really doing is more of a laser.”

The report says collaborating labs were able to identify two sets of phage cocktails that were sensitive to Patterson’s particular bacterial infection. And the US Food and Drug Administration (FDA) acted with lightning speed to authorise the experimental treatment.

The report says this case was scientifically important because it was one of the first times that phages were successfully infused into the bloodstream of a human. Most prior use of phages involved swallowing them or placing them directly on the area of infection. The success has since sparked a renewed interest in phages and a re-examination of their possible role in medicine.

The report says over the two years since Patterson awoke from his coma, several other people around the world have been successfully treated with phages as part of their regimen, after antibiotics have failed.

The experience treating Patterson prompted UCSD to create the Centre for Innovative Phage Applications and Therapeutics (IPATH), with Schooley and Strathdee as co-directors. Previous labs have engaged in basic research on phages, but this is the first clinical centre in North America to focus on translating that knowledge into treating patients.

In January, IPATH announced the first phase 2 clinical trial approved by the FDA that will use phages intravenously. The viruses are being developed by AmpliPhi Biosciences, a San Diego-based company that supplied one of the phages used to treat Patterson. The new study takes on drug resistant Staph aureus bacteria. Experimental phage therapy treatment using the company’s product candidates was recently completed in 21 patients at seven hospitals who had been suffering from serious infections that did not respond to antibiotics. The reported success rate was 84%.

The new era of phage research is applying cutting-edge biologic and informatics tools to better understand and reshape the viruses to better attack bacteria, evade resistance, and perhaps broaden their reach a bit within a bacterial family. “As we learn more and more about which biological activities are critical and in which clinical settings, there are going to be ways to optimise these activities,” says Schooley.

The report says sometimes phages may be used alone, other times in combination with antibiotics. Genetic engineering using tools are being used to enhance the phages’ ability to infect targeted bacteria and better counter evolving forms of bacterial resistance in the ongoing “arms race” between the two. It isn’t just theory. A patient recently was successfully treated with a genetically modified phage as part of the regimen, and the paper is in press.

In reality, given the trillions of phages in the world and the endless encounters they have had with bacteria over the millennia, it is likely that the exact phages needed to kill off certain bacteria already exist in nature. Using CRISPR to modify a phage is simply a quick way to identify the right phage useful for a given patient and produce it in the necessary quantities, rather than go search for the proverbial phage needle in a sewage haystack, says Chan.

The report says one non-medical reason why using modified phages could be significant is that it creates an intellectual property stake, something that is patentable with a period of exclusive use. Major pharmaceutical companies and venture capitalists have been hesitant to invest in organisms found in nature; but a patentable modification may be enough to draw their interest to phage development and provide the funding for large-scale clinical trials necessary for FDA approval and broader use.

“There are 10 million trillion trillion phages on the planet, 10 to the power of 31. And the fact is that this ongoing evolutionary arms race between bacteria and phage, they’ve been at it for a millennia,” says Strathdee. “We just need to exploit it.”

 

The patient, a 15-year-old girl, had come to London‘s Great Ormond Street Hospital for a double lung transplant. It was the summer of 2017, and her lungs were struggling to reach even a third of their normal function. She had cystic fibrosis, a genetic disease that clogs lungs with mucus and plagues patients with persistent infections. For eight years, she had been taking antibiotics to control two stubborn bacterial strains.

Weeks after the transplant, doctors noticed redness at the site of her surgical wound and signs of infection in her liver. Then, they saw nodules – pockets of bacteria pushing up through the skin – on her arms, legs, and buttocks. The girl’s infection had spread, and traditional antibiotics were no longer working.

Now, a new personalised treatment is helping the girl heal. The treatment relies on genetically engineering bacteriophages, viruses that can infect and kill bacteria. Over the next six months, nearly all of the girl’s skin nodules disappeared, her surgical wound began closing, and her liver function improved, scientists report 8 May, 2019.

The work is the first to demonstrate the safe and effective use of engineered bacteriophages in a human patient, says Graham Hatfull, a Howard Hughes Medical Institute (HHMI) professor at the University of Pittsburgh. Such a treatment could offer a personalised approach to countering drug-resistant bacteria. It could even potentially be used more broadly for controlling diseases like tuberculosis. “The idea is to use bacteriophages as antibiotics – as something we could use to kill bacteria that cause infection,” Hatfull says.

In October 2017, Hatfull received the email that set his team on a months-long bacteriophage-finding quest. A colleague at the London hospital laid out the case: two patients, both teenagers. Both had cystic fibrosis and had received double lung transplants to help restore lung function. Both had been chronically infected with strains of Mycobacterium, relatives of the bacterium that causes tuberculosis.

The infections had settled in years ago and flared up after the transplant. “These bugs didn’t respond to antibiotics,” Hatfull says. “They’re highly drug-resistant strains of bacteria.”

But maybe something else could help. Hatfull, a molecular geneticist, had spent over three decades amassing a colossal collection of bacteriophages, or phages, from the environment. Hatfull’s colleague asked whether any of these phages could target the patients’ strains.

It was a fanciful idea, Hatfull says, and he was intrigued. His phage collection – the largest in the world – resided in roughly 15,000 vials and filled the shelves of two six-foot-tall freezers in his lab. They had been collected from thousands of different locations worldwide – and largely by students.

Hatfull leads an HHMI programme called SEA-PHAGES that offers college freshmen and sophomores the opportunity to hunt for phages. In 2018, nearly 120 universities and colleges and 4,500 students nationwide participated in the program, which has involved more than 20,000 students in the past decade.

There are more than a nonillion (that’s a quadrillion times a quadrillion) phages in the dirt, water, and air. After testing samples to find a phage, students study it. They’ll see what it looks like under an electron microscope, sequence its genome, test how well it infects and kills bacteria, and figure out where it fits on the phage family tree.

“This programme engages beginning students in real science,” says David Asai, HHMI’s senior director for science education and director of the SEA-PHAGES programme. “Whatever they discover is new information.” That basic biological info is valuable, he says. “Now the phage collection has actually contributed to helping a patient.”

That wasn’t the programme’s original intent, Asai and Hatfull say. “I had a sense that this collection was enormously powerful for addressing all sorts of questions in biology,” Hatfull says. “But we didn’t think we’d ever get to a point of using these phages therapeutically.”

The idea of phage therapy has been around for nearly a century. But until recently, there wasn’t much data about the treatment’s safety and efficacy. In 2017, doctors in San Diego, California, successfully used phages to treat a patient with a multidrug-resistant bacterium. That case, and the rise of antibiotic resistance, has fuelled interest in phages, Hatfull says.

Less than a month after he heard about the two infected patients in London, he received samples of their bacterial strains. His team searched their collection for phages that could potentially target the bacteria.

They tested individual phages known to infect bacterial relatives of the patients’ strains, and mixed thousands of other phages together and tested the lot. They were looking for something that could clear the whitish film of bacteria growing on plastic dishes in the lab. If a phage could do that, the team reasoned, it might able to fight the patients’ infections.

In late January, the team found a winner – a phage that could hit the strain that infected one of the teenagers. But they were too late, Hatfull says. The patient had died earlier that month. “These really are severe, life-threating infections,” he says.

His team had a few leads for the second patient, though: three phages, named Muddy, ZoeJ, and BPs. Muddy could infect and kill the girl’s bacteria, but ZoeJ and BPs weren’t quite so efficient. So Hatfull and his colleagues tweaked the two phages’ genomes to turn them into bacteria killers. They removed a gene that lets the phages reproduce harmlessly within a bacterial cell. Without the gene, the phages reproduce and burst from the cell, destroying it. Then they combined the trio into a phage cocktail, purified it, and tested it for safety.

In June 2018, doctors administered the cocktail to the patient via an IV twice daily with a billion phage particles in every dose. After six weeks, a liver scan revealed that the infection had essentially disappeared. Today, only one or two of the girl’s skin nodules remain.

Hatfull has high hopes: the bacteria haven’t shown any signs of developing resistance to the phages, and his team has prepped a fourth phage to add to the mix.

Finding the right phages for each patient is a big challenge, Hatfull says. One day, scientists may be able to concoct a phage cocktail that works more broadly to treat diseases, like the Pseudomonas infections that threaten burn patients.

“We’re sort of in uncharted territory,” he says. But the basics of the young woman’s case are pretty simple, he adds. “We purified the phages, we gave them to the patient, and the patient got better.”

Abstract
A 15-year-old patient with cystic fibrosis with a disseminated Mycobacterium abscessus infection was treated with a three-phage cocktail following bilateral lung transplantation. Effective lytic phage derivatives that efficiently kill the infectious M. abscessus strain were developed by genome engineering and forward genetics. Intravenous phage treatment was well tolerated and associated with objective clinical improvement, including sternal wound closure, improved liver function, and substantial resolution of infected skin nodules.

Authors
Rebekah M Dedrick, Carlos A Guerrero-Bustamante, Rebecca A Garlena, Daniel A Russell, Katrina Ford, Kathryn Harris, Kimberly C Gilmour, James Soothill, Deborah Jacobs-Sera, Robert T Schooley, Graham F Hatfull, Helen Spencer

 

Phage therapy’s biggest obstacle, Strathdee believes, was its poor fortune to be discovered before penicillin, in 1917, reports The Verge. (That phage therapies’ discoverer, Félix d’Herelle, was widely disliked did not help.) When the antibiotic first arrived, with its broad-spectrum, scorched-earth ability to eliminate vast swaths of different bacteria, the phage – which could only attack one specific bacteria at a time – the deemed less useful. The continued research and usage of phages in Eastern bloc countries like Poland and Georgia helped put the nail in the coffin; geopolitical bias made phage research for the Communists.

The report says the specificity which made phages once seem less desirable is now their greatest appeal. By overusing antibiotics, humanity unwittingly tipped the scales in an evolutionary arms race, leaving behind the strongest, most drug-resistant bacteria. The phage is now a potentially potent weapon against these so-called superbugs.

Hatfull says that phages have been locked in an invisible war with bacteria for potentially 3bn years, predating most forms of life we see today and predating bacteria just as long. The typical phage depicted in science books and as phage centres’ mascots are from the family Myoviridae. Looking something like the love child of a spider and a syringe, they feature a thin body topped with a “head” like a Dungeons & Dragons die, and end in a protrusion which injects their genetic material into the bacteria. The virus replicates inside the hijacked host, eventually destroying the bacteria as it escapes. This process is called the lytic cycle, and hunter-killer phages are called lytic to distinguish them from other phages which do not kill their prey.

The report says working together as a phage cocktail, lytic phages can target and destroy superbugs. When the bacteria begin to resist the phages, biologists can genetically modify the phages to better attack the bacteria. The phages can even work in concert with antibiotics, applying evolutionary pressure from both sides. The bacteria must “choose” what to become resistant to, leaving them vulnerable to the other treatment method.

“We don’t know enough about this kind of synergy,” Strathdee says. But further study can reveal which phages work best with which antibiotics, opening new methods of therapy. “Many of us don’t think that phage are ever going to replace antibiotics. We think they’re going to be an adjunct to antibiotics.”

The report says Mzia Kutateladze, director of the Eliava Institute in Tbilisi, Georgia, is excited to see phage therapy gaining traction and resources in the West. Whereas a few decades ago, Georgian scientists like Kutateladze were viewed askance for their use of phages, they are now finding new acceptance. “I really proudly can say, together with the Georgians, that we have many international patients who are coming to us,” Kutateladze says. “And we have very nice results with very, very desperate and chronic infections.”

The report says while promising, there are drawbacks to phage therapy. “The specificity is a double-edged sword,” Hatfull says. It’s advantageous for superbugs and for avoiding side effects. But that precision comes at a price: a phage that works for one strain of superbug in one patient may not work for another strain. Diagnosing the correct pathogen becomes absolutely critical, as phages not designed to attack the bacteria being treated are useless in said treatment.

Strathdee believes that a giant, open-source phage library is key to making phage therapy valuable. Scientists and physicians can use the library to match phages and bacteria, ensuring quicker treatment. With enough genomic information about bacteria and phages – and a large enough training set – Hatfull imagines a world where machine learning enhances therapies. One could sequence the pathogen, plug the genomics into the algorithm, and be told which phages to mix together in the most effective cocktail.

Jean-Paul Pirnay, a researcher at Queen Astrid Military Hospital in Brussels, takes this vision one step further. The report says Pirnay believes synthetic natural phages, which are being worked on at Queen Astrid, may help alleviate the specificity problem. A system for producing custom-made iterations of natural phages would mean quick tailoring to particular pathogens and would remove the expense of storing massive stocks of phage. Eventually, Pirnay imagines a world where phages that do not exist in nature – truly bespoke viruses – are designed with the help of artificial intelligence to be as effective as possible, an infinite tool box.

The report says adding fuel to the fire is new investment by pharmaceutical companies, since genetically modified phages can be patented. Johnson & Johnson is in a partnership worth hundreds of millions with Locus Biosciences, a North Carolina-based company which specialises in using boutique phages to inject CRISPR-Cas3 into bacteria. CRISPR-Cas3 is often compared to Pac-Man: once inside the bacteria, it shreds the bacteria’s DNA like so many blue ghosts, killing it.

Locus’ genetically modified phages help alleviate one of the challenges of phage therapy, which is that lytic phages do not always kill every bacteria. Locus can engineer the phages to have a more effective “depth of killing profile,” helping to ensure that everything the phage hunts is killed.

The report says there’s also potential in using phages as biological, targeted syringes. “In theory, you can deliver all different kinds of enzymes that do all different kinds of things,” Joseph Nixon, senior vice president of business development at Locus, says by phone. Nixon envisions phages being used to pinpoint cancer targets and – and he deems the “holy grail” – central nervous system targets.

Theoretically, phages could be used to target bacteria in other ways – potentially increasing their pathogenicity instead of killing them. Luckily, that’s unlikely, Pirnay writes. He says there are more practical methods available for weaponizing bacteria, including CRISPR-Cas tools.

The report says the phages, which target specific food-borne illness-causing bacteria, are not only effective at killing the pathogens, but are also certified kosher and halal, non-genetically modified, listed by the Organic Materials Review Institute, and are less abrasive than the chemical methods commonly used. The phages are sprayed onto the food, taking advantage of infrastructure which may already be in use, and cost slightly more than food safety chemicals, but are considerably cheaper than other non-chemical protections like irradiation and high-pressure pasteurization.

For similar health conscious and anti-superbug reasons, phages have veterinary applications as well; targeted phage therapies to treat sick livestock may remove the overuse of antibiotics from animals’ food supply.

Leaps Magazine report
Howard Hughes Medical Institute material
Nature Medicine abstract
The Verge report
Steffanie Strathdee interview


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