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Bacteriophage Therapy: Stalin's Forgotten Cure

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Bacteriophage Therapy: Stalin's Forgotten Cure N EWS F OCUS 65 64 63 Bacteriophage therapy, pioneered in Stalin-era Russia, is attracting renewed attention in the West as a 62 potential weapon against drug-resistant bugs and hard-to-treat infections 61 60 59 58 Stalin’s Forgotten Cure 57 56 TBILISI—Last December, three woodsmen in ten used as a last-ditch treatment. “The carpeted with them. “Mother nature gives 55 the mountains of Georgia stumbled upon a window of opportunity for new antibiotics you an endless source of phages,” says 54 pair of canisters that were, oddly, hot to the is rapidly closing,” asserts Janakiraman Sulakvelidze. And unlike most antibiotics, 53 touch. The men lugged the objects back to (“Ram”) Ramachandran, a former presi- they are very specific, Kutter says: “Phages 52 their campsite to warm themselves on a bit- dent of AstraZeneca India who 2 years ago can kill off a small fraction of the microbial 51 terly cold night. That turned out to be a ter- launched GangaGen Inc., a phage-therapy population and leave the rest intact.” 50 rible mistake: The canisters, Soviet relics start-up in Bangalore. Phages are like minuscule smart bombs 49 once used to power remote generators, were Although phages offer hope against drug- that home in on particular bacterial strains. 48 intensely radioactive and burned two of the resistant bacteria and could soon find a role Anecdotal evidence from decades of Soviet 47 men severely. The victims were rushed to as a treatment for burns, diabetic ulcers, and practice suggests that this results in far 46 the capital, Tbilisi, where doctors plied them other open wounds, experts concur that these fewer side effects than use of antibiotics. 45 with antibiotics but failed to prevent viral breeds are unlikely to knock antibiotics And whereas drugs lose effectiveness as 44 staphylococcus bacteria from invading the off their pedestal for most infections. “Phages they are metabolized, phages replicate in 43 deep wounds. Septic shock seemed just are certainly not going to replace chemicals,” their hosts, gaining strength in numbers and 42 around the corner. Then a kinder legacy of says Alexander Sulakvelidze of Intralytix, a thus increasing potency. 41 the Soviet Union came to the rescue. company in Baltimore, Maryland, that’s ex- EBI, the fastest company off the blocks, 40 Georgian doctors turned to a has completed safety testing in 39 therapy virtually unknown in the healthy volunteers of a phage 38 West: They unleashed the bacte- against vancomycin-resistant 37 ria’s natural predators. The doc- enterococci and plans to launch a 36 tors covered the open wounds clinical trial in patients with VRE 35 with novel biodegradable patch- in the middle of next year. “We 34 es impregnated with bacterio- really are living in a brave new 33 phages, viruses that infect bacte- world,” says Toney Ilenchuk, vice 32 ria. The business card–sized president of Biophage Pharma in 31 PhageBioDerm patches, recent- Montreal, Canada. He and others 30 ly licensed for sale in Georgia, are watching EBI closely, be- 29 eliminated the infection, and cause its experiences could deter- 28 within a few weeks the woods- mine how quickly the first phage 27 men were stable enough to go therapies against human diseases 26 abroad for treatment to replace reach the market—or whether the 25 the lost skin. approach slips back into obscu- 24 The episode shows that a rity in the Western world. 23 unique brand of medicine from Many are rooting for a 22 the Stalin era is alive and well in Irradiated. Georgian doctors covered this man’s radiation burns with patches comeback. “We need to do 21 this remote corner of the world. that released bacteriophages into the wound as they degraded. something, have some alterna- 20 More surprisingly, phage thera- tive to antibiotics,” says Diane 19 py might be about to stage a comeback in the ploring a potential market for PhageBioDerm Schaak of the Rowland Institute for Science 18 West. After a brief fling with phages before or similar products in the United States. Nor at Harvard University. “Phage therapy could 17 World War II, when the use of penicillin be- is it evident how the U.S. Food and Drug Ad- be a wonderful way to go.” 16 came widespread, Western physicians ignored ministration will regulate phage products, or 15 the therapy for more than half a century. if it will be permissible to alter phage strains A checkered past 14 “Phages were relegated to the dustbin of his- after FDA approval to counter bacterial resis- The first whiff of the microscopic predators 13 tory,” says Richard Carlton, president of Ex- tance. For these reasons, many experts expect came in 1896, when British chemist E. H. 12 ponential Biotherapies Inc. (EBI), a firm that phage concoctions for livestock and Hankin reported that water straight from the 11 based in Port Washington, New York, that is food-borne pathogens will find their way to sewage-ridden Ganges and Jumma rivers 10 one of more than two dozen racing to re- market first (see sidebar, p. 730). could kill the cholera pathogen. It wasn’t until 9 claim phages from that dustbin. Despite the uncertainties, proponents say 2 decades later that a pair of scientists, work- 8 Driving phage therapy’s potential rehabil- that as a medicine, bacteriophages have a lot ing independently, concluded that the bacteria 7 itation is the accelerating crisis of antibiotic going for them. “They are the most abun- slayers must be microbes themselves. In 6 resistance. Some cases are particularly chill- dant life forms on Earth,” notes phage biolo- 1915, British bacteriologist Frederick W. 5 ing: Last July, for example, U.S. health au- gist Elizabeth Kutter of Evergreen State Twort described an “ultramicroscopic virus” 4 thorities reported the first instance in which College in Olympia, Washington. A drop of that somehow killed bacteria in solution. But 3 a stalker of hospital wards, methicillin- seawater or sewage teems with millions of it was noted biologist Félix d’Herelle of the 2 resistant Staphylococcus aureus, had also phages; any exposed surface of our bodies, Pasteur Institute in Paris who made the critters 1 acquired full resistance to vancomycin, of- not to mention our digestive tracts, is famous: He and his wife coined the term bac- CREDIT: JIKIA DAVID 728 25 OCTOBER 2002 VOL 298 SCIENCE www.sciencemag.org N EWS F OCUS 65 teriophage in 1916 after d’Herelle isolated an by bacteria in the suspensions used to culti- tinued its pioneering work, including the de- 64 “anti-Shiga” microbe from the feces of pa- vate phages, and they were rarely tested be- velopment in the 1940s of phages against 63 tients with dysentery and grew it in the bac- fore use to see if the phages were viable. anaerobic infections such as gangrene. Soviet 62 terium that causes the disease. But whereas Western physicians abandoned authorities placed a high value on the Eliava 61 D’Herelle was also the first to compre- the fickle medicine, Soviet scientists kept Institute’s work. When it came to ordering 60 hend the promise that phages held as a dis- the faith. new equipment and supplies of enzymes, 59 ease treatment. In 1919, he and his col- says microbiologist Mzia Kutateladze, who 58 leagues made a phage preparation for a 12- Stalin’s antibiotic alternative joined the institute in the late 1980s, “we got 57 year-old boy with severe dysentery. After Sunlight streams through a picture window whatever we wanted.” 56 guzzling 100 times the intended dose to into an office suffused with the yeasty smell The Soviet military was perhaps the 55 check its safety—“the first clinical safety of agar as Amiran Meipariani removes a log- biggest consumer of phage preparations, 54 trial,” jokes Sulakvelidze—they gave the di- book from a desk drawer. The silver-haired many of which were produced in Russia— 53 luted preparation to the boy, who recovered and -moustached bacteriologist scrolls down and still are—according to Georgian tech- 52 fully within a few days. a record in cramped Cyrillic 51 Over the next several years, d’Herelle handwriting of the last batches 50 helped set up phage-therapy trials across the of medicinal bacteriophages 49 globe. “He would go to villages and observe shipped abroad by the Eliava 48 who was recovering on their own from an ill- Institute here in Tbilisi. On the 47 ness, isolate phages from these people, and wall behind him is a 1930s 46 grow them in the lab,” says Ramachandran. photograph of the man who 45 Phage therapy was off to a flying start, and it started it all in Georgia, a dash- 44 gained in popularity after the 1925 publication ing young scientist with oiled 43 of Arrowsmith, a novel by Sinclair Lewis in black hair and deep-set eyes. 42 which a doctor deploys phages against an out- Under Giorgi Eliava’s intense 41 break of bubonic plague in the West Indies. gaze, Meipariani, who has 40 Back then, “phages seemed like a miracle worked here for 45 years, puts 39 answer to many devastating infectious dis- a finger on the most recent en- 38 eases,” says Kutter. The drug giant Eli Lilly tries in his log: 88,600 phage 37 and a plethora of entrepreneurs piled into the tablets for intestinal illnesses 36 phage business, but their record was spotty. and 497,000 tablets for prophy- Heady days. Félix d’Herelle (seated) and Giorgi Eliava (right) 35 In some patients the concoctions worked laxis against Salmonella, both in Tbilisi shortly before Eliava was shot.
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