Two years later, Félix d’Hérelle performed similar experiments but took these observations a step further. He was convinced that these bacteria-killing agents were some kind of new life form, which he proposed was a virus. He and his wife named them “bacteriophages.” There was fierce debate at the time about whether Twort or d’Hérelle had discovered phages first, and whether they were viruses or enzymes, because no one at the time knew what phages looked like, just that they seemed to reliably destroy bacteria.
The more I learned about Félix from the writings of his biographer, medical historian Dr. William Summers from Yale, the more he felt like a kindred spirit. He grew up in Montreal, so he considered himself Canadian, like me. He had been ostracized by his peers and was a bit of an oddball. A Google search turned up another coincidence: the University of Toronto, my alma mater, had published one of his monographs on phages in 1922. With a click of a button, I ordered a copy of the English translation from Amazon. It quickly became my bedtime companion.
Although Félix was ridiculed as a “vagabond scholar” with no formal education in science, as one of the earliest applied microbiologists, his “microbe-centered worldview” had been noted for its prescience. Attempting to model his career after Louis Pasteur, who pioneered our understanding of the role of microbes in alcoholic fermentation, Félix tried unsuccessfully to develop maple syrup into whiskey.
He’d even traveled to some of the same regions in his scientific explorations as Tom and I had. In 1907, he was hired by the Mexican government to continue work on fermentation. By 1909, he had succeeded in turning a species of agave into schnapps—which probably tasted similar to the age-old pulque “agave wine” that Tom and I had sampled in our travels there.
Félix also had a natural-born curiosity. In 1910, when a plague of locusts swarmed the Yucatán, the local natives showed him a place where the locusts were dying from an unknown disease. Félix noticed that these dead locusts were surrounded by copious amounts of black diarrhea. Culturing the locust poop, he concluded that they had died of the insect version of blood poisoning related to a coccobacilli bacterial infection. He seized on this finding, showing that by dusting coccobacillus cultures on the crops locusts devoured, without apparent harm to humans, he could wipe out the locust infestation. After using this approach to combat locust plagues elsewhere in South America and North Africa, he became famous as the “father of biological pest control,” but his scientific contributions didn’t stop there.
Félix astutely observed that some locusts seemed impervious to the coccobacillus infection, and when he streaked the coccobacilli onto agar with the poop from the locusts that recovered, he observed that clear spots formed around some of the bacterial colonies. Something was killing the bacteria, but what could it be?
It wouldn’t be until he moved to Paris years later that he would solve the mystery, and it was better than any Forensic Files episode. During the heart of World War I, Félix was working at the Pasteur Institute when an outbreak of dysentery occurred. Asked to assist with the outbreak investigation, he inoculated stool samples from the patients who survived into culture medium and let them incubate for eighteen hours, then filtered them. He then added the filtrate to test tubes that contained a culture of the Shigella bacteria causing the dysentery. The test tubes were initially cloudy, a virtual bacterial soup, but the next day, they were completely clear! He looked at the solution under a light microscope—no bacteria. That’s when he had his eureka moment. When he discovered that the bacteria-killing agent was able to pass through the Pasteur filter, he concluded that the agents responsible were smaller than bacteria and must be a virus that preyed upon them.
How could you not admire Félix, who in 1917 would write about that moment in the lab this way:
… on opening the incubator I experienced one of those rare moments of intense emotion which reward the research worker for all his pains: at first glance I saw that the broth culture, which the night before had been very turbid, was perfectly clear: all the bacteria had vanished… as for my agar spread it was devoid of all growth and what caused my emotion was that in a flash I understood: what causes my spots was in fact an invisible microbe, a filterable virus, but a virus parasitic on bacteria. Another thought came to me also. If this is true, the same thing will have probably occurred in the sick man. In his intestine, as in my test-tube, the dysentery bacilli will have dissolved away under the action of their parasite. He should now be cured.
“Rare moments of intense emotion” at the sight of the spotty Petri dish? His detached description of emotions made me laugh out loud. If Tom were here, he would say that Félix was speaking my language, and we would have laughed over it together. We will someday, I told myself, but that would have to wait. Tom might find a kindred spirit in Félix, too, in that they both were inclined to self-experimentation to try out new ideas in treatments. Tom had once made a disastrous attempt to desensitize himself to poison oak by ingesting it over the course of several days. (He got the worst case ever. Don’t try this at home.) Félix, determined to help sick children in an outbreak of dysentery, had pushed ahead on his own. Since phage therapy had not yet been used to treat a human bacterial infection, he first tried his phage prep on himself. Sounds crazy, but self-experimentation was actually pretty common a century ago.
He then gave a weakened version to a twelve-year-old boy who had severe dysentery, and his symptoms disappeared after a single dose. Three additional children were treated, and they started to recover within twenty-four hours, too.
With only a rudimentary knowledge of phage biology, I spent a few hours that morning scouring PubMed to brush up. A century after Félix discovered bacteriophages, scientists now understood a lot more about them. A single drop of water can harbor a trillion phages and they are found virtually everywhere—in soil, oceans, and our bodies. The way phage hijack bacteria and use them to replicate was straight out of science fiction—Invasion of the Body Snatchers—only it wasn’t fiction. No wonder phages are the most numerous creatures on earth. They are astoundingly efficient microscopic machines. Connect. Inject. Replicate and release, destroying the bacterium’s cell wall in the process.
Despite the phage’s impressive takedown of the host bacteria once inside them, phages do face a few challenges. First, they must evade the body’s immune system and defensive responses. Second, phages must outrace bacterial resistance, which can occur in a matter of minutes, as bacteria that are susceptible to a particular phage die, and mutant bacteria that are resistant to the same phage flourish, with new space to take over. In the same way bacteria have developed adaptive strategies to resist antibiotics, they use a host of tactics to fend off phages, including their own kind of immune systems, called CRISPRs. Bacteria may block, disable, or “change the locks” on the receptors the phages need to gain access. They may modify molecules to toughen their slimy protective shield, or create internal mechanisms that interrupt the phage’s replicating process or interfere with the virions’ ability to assemble for the final destruction of the host cell.
But two can play at that game, and do. Phages evolved to prey on bacteria, and although bacteria had gene-slicing CRISPR mechanisms to defend against at least some of them, phage have evolved anti-CRISPR defense mechanisms so they can continue the assault. Moreover, there are billions of different phages, many having evolved to target the same bacteria but through different receptors. The task for researchers is to find the ones that match up with a target bacterium, purify them so they’re safe to use, and then deliver them into the body—in this case, Tom’s.
The evidence was persuasive. On paper, phage therapy appeared to be ideal for treating multi-drug-resistant bacterial infections like Tom’s. I ticked off their advantages on my fingers. Phages are the natural predators of bacteria, and many of them can be found for targeting the harmful ones without hurting the “good” ones. Since phages are plentiful in nature, theoretically they should be relatively easy to find for targeting many bacter
ial pathogens. They dwindle in number when their host bacteria are sparse, and grow when and where that bacterial population is plentiful, as in an infection. When the host bacteria thin out, phages adrift are filtered out by the liver and spleen, where specialized cells in the immune system engulf them, then digest them, and they’re gone. This means that they largely disappear once their job is done. Antibiotics exert much longer-term effects, with known side effects that can damage human tissues and upset the natural balance of your microbiome. But would phages work in practice the way they work in theory? The jury was still out on that.
It wasn’t that nobody had tried to find out. Phages and penicillin were discovered in the same era—phages in 1917, penicillin in 1929. But why was a successful treatment discovered one hundred years ago not being used more widely? The surprising lag time was a factor that had echoed through the history of both phage therapy and penicillin. The miracle of penicillin had languished for a decade between its discovery and commercialization by pharmaceutical houses, because it took time to isolate, purify, and expand it for the masses. The growing casualties of World War II created an imperative that had finally prompted action.
But a hundred-year delay? After his discovery, Félix had gone on to apply phage therapy to thousands of cases of cholera and bubonic plague in India. His big ego and tendency to show off drew international attention. He attracted an ever-widening circle of followers and became Sinclair Lewis’s inspiration for his 1925 Pulitzer Prize–winning novel, Arrowsmith. All the hubbub increased the popularity of phage therapy for a while.
But there were critics and complications. Although Félix insisted on matching his phage preps to a patient’s individual infection, that wasn’t considered practical, so some companies just manufactured the phage preparations in the lab for general use. Eli Lilly, a division of Abbott and a company that was later acquired by L’Oréal, started selling phage preparations to treat wounds and upper respiratory tract infections. Some had trendy names like Staphylo-gel. Soon there were problems. A few were sold with exaggerated claims that they could cure viral infections—like herpes—which they couldn’t possibly do, because bacteriophages target bacteria, not other viruses. And until the late 1930s, phage cocktails were often sold without being purified, so some actually could have caused harm. Other manufacturers mistakenly sterilized their phages with agents that were supposed to “stabilize” them. All told, many phage preparations being sold were useless.
Within the scientific community, phage therapy faced major challenges from the get-go. For roughly thirty years after Félix identified them, scientists still didn’t have the technology to see them. Some scientists, including some Nobel laureates, pooh-poohed Félix’s claim that phages were microorganisms; they believed phages to be enzymes. It wasn’t until the first electron microscope was developed in 1940 that bacteriophages could finally be visualized, and Félix was vindicated. Today, new treatments undergo randomized clinical trials and bioethics reviews, but these standards and review processes weren’t established back then. Without proper controls and safety checks, phage therapy couldn’t be trusted.
After penicillin came to market, phage therapy was relegated to the back burner, at least in North America. But it was more than science that cooled commercial interest. There were political reasons, too. I was struck by the fact that one of the few centers offering it was in Tbilisi. The story of how that came to be was as surprising as the phages themselves. After World War I ended, Félix met a young Georgian bacteriologist named Giorgi Eliava at the Pasteur Institute in Paris. They hit it off, and Eliava worked with him on some phage projects. Eliava returned to Tbilisi in 1923 to resume his position as head of their modest microbiology institute. His dream was for it to become the first center in the Soviet Union to feature phage therapy. He pulled it off in 1926.
The new center was awesome, situated on the bank of the river that runs through Tbilisi, amid a cypress grove. It even had Stalin’s blessing, but that connection gets stranger. In 1934, Eliava invited Félix to visit and help make their center the world’s premier phage therapy institute. Félix spent six months in Tbilisi. After Félix planned to relocate there permanently, a home—“d’Hérelle’s cottage”—was erected and dedicated to him on the grounds of the institute.
But if there was a bromance between our phage pioneer and Stalin, it was not to last. Eliava was arrested and declared an “enemy of the people” by his nemesis, Lavrenti Beria, the chief of secret police, whom Stalin referred to as “our Himmler.” Beria saw to it that Eliava was executed in 1937; he was one of many scientists to suffer a similar fate around that time. Devastated by Eliava’s death, Félix never followed through on plans to return, so he never lived in the cottage constructed in his honor. In fact, it became occupied temporarily by what would eventually become the KGB, who later came under Beria’s command.
What later became known as the Eliava Phage Center struggled initially but became renowned throughout the region and internationally. At its peak, in the 1980s, it employed about eight hundred people, including more than one hundred phage researchers. They manufactured phage cocktails, sprays, salves, ointments, and tablets—up to several tons a day—about 80 percent of it going to the Soviet army, mainly to treat dysentery.
In 2016, the main phage therapy centers were the Eliava; a second one in Tbilisi, and another one in Wrocław, Poland. They had decades of experience with phage therapy, and despite the lack of endorsement by Western medicine for so long, people still flew there regularly from the West to get different kinds of infections treated.
Why didn’t phage therapy get replaced by antibiotics in Eastern Europe like it did here? Since the discovery of penicillin was considered a military secret in the early years of World War II, at first, they didn’t even know about it. And even after they did, penicillin wasn’t available there on a consistent basis. There, as in the United States, penicillin was so hard to manufacture in sufficient quantity that until production techniques were perfected, it was so precious that it was recovered from the urine of patients who received it. No such problem with phages. They turned out to be ideal for treating battle wounds. The Japanese military used phages, and so did the Germans; some were found in medical kits used by Rommel’s forces in North Africa. And the Russians used phages to treat wounds in their war against the Finns during World War II, and more recently in Chechnya.
Apart from the logistical issues, another reason why phage therapy didn’t get taken up in the West is because if you supported it, you would be labeled a pinko commie sympathizer. This “Russian taint,” wrote Dr. Summers, was enough to scare off most Western scientists, research funding, and commercial interests alike. People really started to jump off the bandwagon—especially in the US—when the American Medical Association published a series of damning reports in the 1930s and ’40s concluding that there was limited data to support the efficacy and reliability of phage therapy, except for its use in treating staph infections. The hardened position against further study to advance phage science reeked of political bias not only geopolitically, because of its popularity in Russia, but within the Western scientific community itself. Isolationism is no friend of true science.
One of the few researchers who kept popping up in the older phage literature was the now retired NIH biologist Carl Merril. Nearly eighty, he had worked to advance phage therapy in the US for fifty years—longer than I had been alive. But the politics of that era had shuttered interest in phage research here, and the limitations of technology and the incomplete data available from countries where it was used meant that Carl faced an uphill battle.
I would learn later that despite the obstacles Carl faced in his 1970s experiments at his NIH lab, he had found that when phages are systemically administered to lab animals, they are destroyed by the liver and spleen. In the mid-1990s, he and his protégé, Biswajit Biswas, learned to select phage strains in the lab that could evade the filtering action of these organs so they could remain in circula
tion longer and thus serve as more effective antibacterial agents. By 2002, they used phage therapy to successfully treat mice that were infected with the superbug Enterococcus faecium that were resistant to vancomycin—one of the big-gun antibiotics. Following these productive animal experiments, Carl tried to get the NIH to support clinical studies but had no success. Eventually, trends in funding and internal politics turned against him completely. Pressured to retire, he finally did, but he never abandoned his scientific conviction that phage therapy, further refined, could save lives.
I couldn’t get over the irony. Just as phage therapy was abandoned in the West, phage biology—the pure science of it—was taking off in other ways. If you look at the early Nobel Prize laureates in basic science at the time, about half of them were phage researchers. Much of the work had been done in the 1940s and ’50s, receiving recognition only much later. Phages had been used to show how genes turn on and off. Phage enzymes had launched the fields of molecular biology, genetic engineering, and cancer biology. More recently, phages were critical in seminal research by Drs. Jennifer Doudna and Emmanuelle Charpentier that identified the CRISPR-cas9 gene editing system that is revolutionizing synthetic biology.
The Perfect Predator Page 16