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Marc Guillonneau is only 17 years old, but since he was born he has been grappling with Netherton Syndrome, a rare genetic disorder that causes all of his skin to constantly peel. Aside from the physical discomfort, the disease also makes Guillonneau incredibly prone to bacterial infection since he doesn't have a layer of skin protecting him from the outside world. Guillonneau's immune system is then liable to kick into high gear to ward off these bacterial infections, but this can lead to sepsis, a condition that arises when the body's immune response damages its own tissues and organs.
Sepsis can quickly become life threatening and antibiotics are usually used to treat it. But for Guillonneau, antibiotics are rarely effective for more than a couple of weeks at a time. This puts him in a dangerous position: If Guillonneau develops sepsis and his body doesn't respond to new antibiotics, he will die.
"We tried many different antibiotics," Guillonneau told Motherboard. "I've lost track of how many I've taken. They'd work for a month, and then my body would become resistant and it'd stop working."
When Motherboard met Guillonneau earlier this year, he had traveled from France to the Eliava Institute in Tbilisi, Georgia to try an alternative to antibiotic drugs called phage therapy. This form of treatment uses a special kind of virus called a bacteriophage to destroy bacteria and treat infections. This method of treating bacterial infections has been known for about a century, but it has only been approved for therapeutic use in Russia, Georgia, and, recently, Poland due to concerns about using a replicating biological agent to treat infections.
Guillonneau's genetic disorder is exceedingly rare, but phage therapy is his last hope for treatment. Yet even for people who don't suffer from Netherton Syndrome, phage therapy may be one of the few technologies preventing deaths from antibiotic-resistant bacterial infections.
Since antibiotics were developed in the 1940s, several types of bacteria have naturally developed antibiotic resistance and some are already resistant to every known antibiotic in the world. If someone becomes infected with one of these so-called superbugs, they basically have to hope their body is able to fight off the infection on its own. If not, a previously treatable type of infection will kill them; indeed, 23,000 lives are already claimed each year in the United States due to antibiotic resistant bacterial infections. According to the United Nations, by 2050 more people will die from antibiotic-resistant infections than currently die from cancer around the world.
Earlier this year, the World Health Organization highlighted the urgent threat posed by these superbugs by releasing a list of the 12 most dangerous bacteria in terms of antibiotic resistance.
"Antibiotic resistance is growing and we are running out of treatment options," Marie-Paule Kieny, the assistant director-general for health systems and innovation at WHO, said in a statement released with the list. "If we leave it to market forces alone, the new antibiotics we most urgently need are not going to be developed in time. The pipeline is practically dry."
Although bacteriophages have proven to be an effective alternative to antibiotics for treating infections caused by these superbugs, their adoption in the United States and Western Europe has been incredibly slow. This partly has to do with the fact that some regulators view injecting people with a replicating biological agent as too risky, and partly to do with the fact that there is little to no market incentive for pharmaceutical companies to pursue bacteriophages since there is little use in patenting them (a similar bacteriophage cocktail wouldn't be covered by a patent.)
With the increasing awareness of the threat posed by antibiotic resistant superbugs -- the proliferation of which the Obama administration called a "crisis" back in 2014 -- phage research has come back into vogue in recent years. But this merely raises the question: Why has this alternative to antibiotics been shunned by most of the medical establishment for nearly a century?
Who killed the bacteriophage?
Although bacteriophages were first documented in the late 19th century, it wasn't until the 1940s that their mechanism of action was understood well enough to be wielded as a form of treatment. This is largely due to the pioneering work of Giorgi Eliava, a researcher in the Soviet Republic of Georgia who took phages from an experimental curiosity to an antibacterial therapy.
Like other viruses, bacteriophages are basically just a bit of DNA encased in a protein. Although they don't have onboard locomotion, when certain types of bacteriophages -- "phages" for short -- come into contact with specific types of bacteria, they bind to the outer membrane of the bacteria before releasing an enzyme called lysin that essentially drills a hole into a bacterial cell. At this point, the phage injects its DNA into the bacterium, halting its normal reproduction process. Instead, the bacterium is used as a breeding ground for more phages which continue multiplying in the bacterial cell until it explodes. Then the phages disperse and if they come into contact with other bacteria they repeat the replication process.
Bacteriophages are an advantageous antibacterial solution for a number of reasons. In the first place, they are the most common and diverse biological organism on the planet. One estimate puts their total number on Earth at estimated 10^31 -- 10 million trillion trillion -- more than the total number of other every other living specimen combined. Their populations are most dense in seawater, which can contain some 200 million phages in a milliliter of water, but phages are sure to be found wherever there is bacteria.
The other notable advantage of bacteriophages is the bacteria they target are usually pretty specific. Not every type of phage will bind to every type of bacteria, meaning that it's possible to create special "phage cocktails" consisting of a few different kinds of phage that can be administered to patients with bacterial infections. Not only do phage cocktails solve the problem of bacterial resistance (although a bacterium may have developed resistance to a certain kind of phage, it didn't develop a resistance for a human-made phage blend), they also don't pose a threat to the healthy bacteria that inhabit our bodies.
Phages seem like a pretty ideal solution to bacterial infections. They're freely supplied by nature in abundance and aren't as prone to developing bacterial resistance. (It is possible for bacteria to develop resistance to certain kinds of phages but since phages are also a biological organism, they can also evolve in ways that undercut emerging resistances.)
The reason phage therapies never really took off is that American researchers had simply found something better, or so it seemed. By the late 19th century it was well known that certain mold extracts had antibacterial properties, but it wasn't until the start of the World War II that these properties were leveraged on an industrial scale to make newly discovered antibiotics like penicillin widely available.
The discovery and mass production of penicillin turned out to be a watershed moment for immunology research and in the next few decades there was a boom in antibiotic research.
Although the treatments that resulted from this research saved countless lives, it had a number of unanticipated effects. For starters, the rise of antibiotics put a quick end to efforts to mass produce phage therapies, something that was being pursued by pharmaceutical giants like Eli Lily in the early 1940s. Another unforeseen consequence was how quickly bacteria would develop resistance to these antibiotic drugs as they became way overprescribed and their sale way under-regulated.
Now, only 70 years after their creation, antibiotics have brought the world to the brink of crisis, and researchers are turning to nature's antibacterial remedy as a solution.
Return of the phages
Although the rise of antibiotics led to a rapid and steep decline into bacteriophage research in the US and Western Europe, the former Soviet Union never stopped pumping money into these antibacterial technologies. As a result Russia and Georgia are two of the only countries in the world where phage therapies have been approved for human patients, and they are currently at the forefront of phage-related immunology research.
"Bacteriophage therapy has not improved anywhere except the former Soviet Union," Mzia Kutateladze, the director of the Eliava Institute in Georgia, told Motherboard during a visit. "We've been using phages since 1923, over 90 years already. I hope the Western countries are also ready to develop this forgotten cure for the future."
The Eliava Institute is home to one of the largest collections of collections of bacteriophages in the world. For this reason, the institute is sought out by patients like Guillonneau from around the globe who haven't found success treating their ailments with antibiotics. Yet despite the size of the institute's phage library, there's always the chance it will encounter an infection for which it doesn't yet have a phage cocktail to treat. Given the staggering number of bacteriophages on Earth, chances are there are some out there that will treat any type of bacterial infection, they just need to be discovered first.
"Every phage you pull from the environment is going to be new to science," Benjamin Chan, an associate research scientist at Yale University, told Motherboard. "We want to get different phages and add them to our library so if the need arises for this phage, we have it."
This is why Chan spends more time than most hanging out at the Greater New Haven Water Pollution Control Authority in Connecticut, where he can collect samples from the bacteria-infested water. Where there's bacteria, there's bound to be bacteriophages, and discovering new bacteriophages could very well save lives. Yet Chan isn't sure that the FDA will be approving phage therapies any time soon, despite their promise as a solution for antibiotic-resistant infections.
"They're hesitant to use bacteriophages because they're a virus," Chan said. "When we think 'virus' we're thinking of something that's going to cause a disease, rather than fix it. I think phages are only going to be incorporated more into therapeutic use in the US out of desperation. We're going to need something."
Instead, Chan said it's more realistic to petition the FDA to host bacteriophage libraries that catalog all the types of bacteriophages that have been discovered by researchers around the world and their effectiveness at treating certain diseases. This would aid physicians from places like Washington, Oregon and Texas, who can petition the FDA to allow them to use phage therapies for their patients after all other treatment options have been exhausted.
Vincent Fischetti, a professor of immunology at Rockefeller University, shares Chan's skepticism about the FDA ever giving the greenlight to phage therapies. But Fischetti doesn't necessarily think this is a bad thing. In fact, he thinks he's found an even better solution.
When phages attach themselves to a bacterium, they release an enzyme called lysin that penetrates the cell wall to allow the virus to insert its DNA into the cell. For over a decade, Fischetti and his colleagues at Rockefeller have been focusing on isolating this enzyme as a pure form of antibacterial treatment.
The process begins by collecting bacteria and phage from places like New York City's East River and filtering out all the bacteria, leaving only the phages in a water solution. Next, this solution is reduced to a sediment consisting only of phages, which are put into a soluble to create a concentrated viral solution. At this point, Fischetti and his colleagues remove the DNA from the virus, cut it up into pieces, and then insert the DNA into a bacterium that will be used to express the genes in that piece of DNA. This process is to effectively screen the DNA segments to find which pieces produce the bacteria-killing enzyme.
When the pure lysin is applied to bacterial infections, it effectively pops the bacterial cells open and instantly destroys them. In this sense, it is almost more effective than just using bacteriophages as is, since researchers don't have to worry about the enzyme self-replicating in the body and producing unintended harmful side effects. This, claims Fischetti, will be the main selling point for FDA approval.
"I think phage cocktails will have a use, but it will be a boutique treatment," Fischetti told me on the phone. "But phage cocktails are very complex and difficult to deal with, so I think lysins will be accepted before phages will only because it's a purified material and the FDA is more comfortable with that."
Moreover, lysin solutions have a monetary incentive backing their development. Fischetti and other researchers are able to patent the lysin solutions they develop, giving them a several-year monopoly over the manufacture of the particular enzymes once they are patented. Phage cocktails, on the other hand, can be manufactured as endless derivatives of a same basic recipe, all with more or less the same effectiveness, which makes patenting them essentially useless. Fischetti thinks that the ability to patent lysin solutions to antibiotic resistant infections will be a major boon to research in the area.
One can only hope Fischetti is right. Beginning in 2009, the FDA has run a few initial trials for various phage therapies, but none of these trials or therapies were for human subjects. According to Fischetti, the issue isn't being treated with an appropriate sense of urgency by the public and the powers that be.
"I think people haven't appreciated that these bugs are becoming, and are, resistant to antibiotics," Fischetti told me. "We are at a very critical time and it's getting to a panic point where people are getting infected with these organisms and dying. The longer we delay, the more serious this problem becomes."