Wounded British soldiers, 10 April 1918. Photo courtesy of Wikimedia Commons.
Felix d’Herelle was a Canadian scientist who co-discovered bacteriophages. Bacteriophages are viruses that thrive on and kill disease and infection causing bacteria. Why was phage therapy’s promise never realized in the West? The answers are varied, but intimately connected. D’Herelle conducted research in highly volatile political and social environments. The science of phages was highly contested, particularly around the time d’Herelle was conducting his most important research. Eventually antibiotics displaced phage therapy completely. But antibiotic resistant bacteria points to the limits of antibiotics in the treatment of communicable disease. Scientists are thus reconsidering d’Herelle’s legacy and phage therapy’s promise.
By Don MacLean and Alberto Martin
France 1917. Allied soldiers are sitting uncomfortably in a mile long trench designed to protect them from enemy fire. The sky assumes great importance for men who must otherwise stare at walls of mud. When they look up from their crouched position they see an expansive sky brightened by the sun or the evening stars. It acts as a reminder of the world of beauty, promise and mobility that war forced them to leave behind. For now they must struggle to survive in nightmare conditions for which they could not possibly be prepared. They do not raise their head above ground level for fear of being shot. Beyond the trench is a formerly verdant field transformed by war into a muddy wasteland lined with barbed wire and littered with dead soldiers. The once lush field, the soldiers understand, is now a death trap. As for the trench, soldiers are aware that it too can be a death trap, albeit of a different sort. Lice are a fact of life from which is no real escape. Rats too numerous to count infest the trench and feed on the dead.
An even more insidious threat is posed by the Shigella Bacillus, the pathogen that causes dysentery and thrives in precisely these sorts of settings. The bacteria typically enter the body orally through the ingestion of contaminated food and water. If the soldier is lucky, he will be stricken with a relatively mild case. He will have severe stomach pains and the persistent passage of stool. Within days the infection might pass and he will return to normal health. The more severe cases, by contrast, will produce sustained abdominal pain, delirium, fever and the vomiting of blood. Some soldiers will die of the disease.
Indeed for soldiers fighting in the Great War, the spread of communicable disease was a constant threat against which there was often little defence. The greatest communicable disease episode came towards the end of the war. Between 1918-1920 twenty to fifty million people died from the Spanish influenza pandemic. It’s staggering toll and relentless spread was the twentieth century’s first example of a disease’s global potential. But the virus responsible was hardly the only pathogen causing havoc on human beings. Other types of disease-causing microorganisms – bacteria, parasites and other viruses – were also distressingly prevalent. Scarlet fever, tuberculosis, diphtheria, small pox: all were common communicable diseases. As for dysentery, by 1917 it had also exacted a heavy toll on Allied soldiers. As was true of other bacterial diseases, the gap was large between our understanding of the nature of dysentery and our ability to treat it. Scientists and doctors understood that the source of dysentery among soldiers was the Shigella Bacillus. Knowing this, however, did not translate into commensurate therapies. Treatment for dysentery involved a combination of administering castor oil, followed by repeated doses of saline. The diets of those suffering from the disease were reduced to a combination of gruels, rice water and barley water.[1] Such a change in diet would have had little therapeutic effect.
At the time, a Canadian scientist named Felix d’Herelle was working at the Pasteur Institute in France. Bridging the extraordinary gulf between our knowledge of disease causing pathogens and their effective treatment was among the Institute’s most important objectives. D’Herelle was conducting research on dysentery in the hope of alleviating the suffering of Allied soldiers. When studying the stools of those infected he observed the presence of “invisible microbe antagonistic to the dysentery bacillus.”[2] The microbe in question would kill the bacteria causing the infection. If enough of the bacteria were killed, d’Herelle reasoned, the patient would return to good health. By 1919 he used the ‘invisible microbe’ to cure many children suffering from dysentery.[3] As the scientist and writer William Summers remarks, “This invisible microbe he named the bacteriophage.”[4] There were not, moreover, seemingly any deleterious side effects. The writer Carl Zimmer tells the story of how D’Herelle would consume phages to demonstrate how harmless they were to a healthy human being.[5] His therapeutic breakthrough came too late to help Allied soldiers suffering in the trenches. Nevertheless D’Herelle, it seemed, had made an important discovery in the struggle to understand and better treat bacteria based communicable disease and infections.
Felix d’Herelle was born in Montreal on April 25, 1873. His father was a free thinker, his mother Roman Catholic. Felix’s father died when he was just a young boy. As Summers relates in his fine biography Felix d’Herelle and the Origins of Molecular Biology, d’Herelle’s mother either inculcated or merely did nothing to quell her son’s desire to explore the world. His love of travel was only matched by his love of learning. These twin passions would shape d’Herelle’s life. When he was sixteen years old, Felix’s mother gave him a bike and enough money to travel through the Rhine. In the year 1890 she gave him enough money for a trip through South America. While leaving Rio de Janeiro on a boat there was an outbreak of yellow fever. As was true of dysentery, yellow fever produces a range of symptoms. Relatively mild cases ended in remission after bouts of muscle and joint pain, headaches and fever. Severe cases, however, were much direr. The infection would eventually produce organ failures. The heart, liver and kidney would all be subject to attack. There would be bleeding disorders, seizures and delirium. Many at this stage would then slip into a coma from which they would not emerge. Although the ship had a medical staff on board, there was little they could do to contain the spread and to save lives. In the end, 22 people perished. As Summers indicates, d’Herelle had a grim sort of fascination with the entire episode. “One morning seven bodies, one by one, slid into the sea,” the young d’Herelle writes in his diary. At the tender age of seventeen, d’Herelle also noticed that his reaction to the spread of disease was different from that of his fellow passengers. Most were understandably nervous and fearful, if not hysterical. D’Herelle, by contrast, remained cool, almost detached and stubbornly clung to the belief that he wouldn’t be infected with the disease that had stolen the lives of so many other passengers and crew members. It was one of many formative experiences for the young d’Herelle. It confirmed his love of travel and established both his fascination with disease and his readiness to immerse himself in various locales in order to understand and treat even the most dreaded infections.
Dysentery among French children was the first bacterial communicable disease d’Herelle successfully treated with phage therapy. Researching and refining his therapies, however, would take d’Herelle well beyond Europe’s borders and involve other types of bacterial infections. The afflictions he chose to treat suggest a fascination with diseases with the grimmest reputations. A case in point is d’Herelle’s treatment with bacteriophages of patients in Alexandria, Egypt diagnosed with bubonic plague, a bacterial infection caused by Yersinia Pestis. For centuries, plague was a recurring problem in Egypt, as elsewhere in the Middle East and Europe. Disease incidence in Egypt was facilitated by its proximity to Black sea ports. The ports acted as a bridge allowing for the transport of bacteria carrying agents both to and from Europe. The plague was feared because its course was often swift and devastating.
The therapeutic potential of phages was sometimes striking to behold. Individuals on the threshold of death were sometimes not beyond saving. D’Herelle himself documents how an 18 year old male suffering from bubonic plague was experiencing “fever, lassitude, vertigo and bilateral tonsillitis.” His symptoms grew more severe over the next couple of days, following which he was hospitalized. After one day in the hospital his temperature was soaring, his pulse was 130, “the face was congested, the eyes were injected and drooping and prostration was extreme.” D’Herelle proceeded to inject bacteriophage into the center of the two buboes. The condition appeared to worsen over the course of the rest of the day but by next morning had improved dramatically. The young man’s symptoms hadn’t yet subsided, but he was in less pain and was more alert, and the buboes started to shrink. Within a couple of days they had shrunk further and the patient’s appetite returned. Within 15 days of his initial diagnosis, the buboes were removed painlessly and altogether. Two weeks later, as d’Herelle relates, “healing was complete.”[6]
Cholera was another scourge that drew d’Herelle’s attention. By that time – the early 1920s – the disease had become global in scope. In his book Plagues and Peoples William McNeill describes how shipping routes originating in India served to spread cholera to, among other hitherto unaffected places, China, Japan and Indonesia. Russian military adventures in the 1830s facilitated its entry into as far west as Poland. From there it traveled to first England and then Ireland before finally traveling across the Atlantic to Canada and then eventually America. By the time of d’Herelle’s arrival in India it was also understood that the vibrio cholerae was the bacterial source of the disease. So too was the connection between unsanitary conditions and its spread. Water contaminated with feces was the most important source fuelling its proliferation. Accordingly, securing clean water was crucial in any effort to curb its spread. In most western cities the installation of clean water infrastructure eliminated the threat cholera had hitherto posed.
Elsewhere, however, that sort of knowledge was not always acted upon. Indeed in India cholera remained common and a source of dread. Full of confidence, d’Herelle arrived there in the 1920s to help contain its spread. His case studies, however, took place within a context hardly conducive to well funded and orderly medical investigations. To be sure, in some respects the conditions were ideal: cholera was rampant, morbidity and mortality rates high. Politically, economically and socially, however, there were many obstacles with which d’Herelle had to contend. In the 1920s there was growing opposition to British rule. Communal tensions were on the rise and the British medical establishment was notoriously conservative. Suffering Indians were not their first priority. Clinical trials were challenging to say the least. Yet the case studies did proceed, sometimes with remarkable results. For example, there were 198 cases of cholera from selected villages investigated. Of those 198 cases, 124 were not given “the antivibrio phages.” The other 74 cases were given the phage treatment. The mortality rate among the first and larger group was 63%. The mortality rate among the other group was 8%. That constitutes a remarkable difference.
This sort of therapeutic success was hardly unique. Nor was it always d’Herelle who was conducting trials. Abedon et al highlight the findings published in a 1936 issue of La Medicine of a trial in which phages were used to treat typhoid fever. Twenty one patients suffering from the fever caused by the salmonella typhi were administered phages for 3-5 days. This was in contrast to another sixty four patients administered the conventional therapy. The results were noteworthy. Mortality rates among those given the conventional therapy were 15.6%, as compared to 4.8% for those administered phages.[7]
The French scientist Suave was astounded by the ability of phages to effectively and painlessly eliminate breast and dental abscesses stemming from bacterial infections. It was simply a matter of time, he believed, before phage therapy would eliminate the need for anesthesia and surgery in the treatment of similar type infections.[8]
Bacteriophage therapy was emerging as a focal point of scientific study. Its promise appeared to be great. D’Herelle was hardly the only scientist working with phages, but it was his name more than any other that was associated with phage therapy. His star was rising. He had thus seemingly made an important contribution in the struggle against communicable diseases, but what exactly had he discovered? What was the nature of the process that resulted in the elimination of pathogenic, disease and infection causing bacteria? Were bacteriophages autonomous, living organisms? If so, what was the nature of these organisms? Bacteriophages are viruses that thrive on bacteria. Bacteriophages destroy the bacteria by inserting themselves into the bacteria and assuming control of its machinery. In so doing, the bacteriophage reproduces and eventually bursts through the bacterial cell wall. More remarkably, the virus will then migrate to other areas of the body harbouring the infection and repeat the process.[9]
But little of this was known at the time of d’Herelle’s research and trials. Molecular biology was still in its infancy, the tools at the disposal of researchers relatively primitive by today’s standards. Something resembling the modern microscope, it’s worth recalling, was only invented in the 1800s. Not long before d’Herelle’s time, the prevailing orthodoxy was that cholera, plague and other scourges were caused by a noxious vapor emanating from things in the ground – dead bodies and decaying matter were the preferred culprits – that would target those who were ill or otherwise compromised. The miasma theory of disease transmission, as it was known, had been only recently been discarded for one more rooted in fact. That a world of microbes invisible to the naked eye was causing the spread of the most fearsome diseases was understood – but only dimly by today’s standards. Nothing of bacteria’s constituent parts was known. Science was decades away, for example, from the discovery of DNA and RNA. Similarly, bacteria’s dynamism – their ability to evolve in the face of threats – was not yet appreciated. Even less was known about viruses.
From the outset the nature of the bacteriophage was thus contested. Many of d’Herelle’s contemporaries were persuaded of the therapeutic promise of phages. Another scientist of the day, Tamezo Kabeshima, found “bacteriophages worked exactly as d’Herelle said they would in rabbits infected with shiga bacillus.” However, he went on to claim that phages were not “living beings….it is nothing but a sort of catalyzer.” This feeling was echoed by Bordet, another contemporary of d’Herelle. He countered d’Herelle with his theory of “transmissible bacterial lysis. “Lytic activity,” Bordet maintained, “was of bacterial origin….it’s production was provoked by an immune reaction in the infected animal.”[10]
D’Herelle was not persuaded by any argument that insisted bacteriophages were not autonomous from bacteria. His experiments demonstrated that enzymes would not act the way bacteriophages do. Yet his own understanding was incomplete. Thus, for example, d’Herelle initially conceived of bacteriophages as an ‘ultramicrobe’ and not specifically as a virus. But his sense of the process by which phages interacted with bacteria was essentially correct, albeit relatively unrefined. Referring to the ultramicrobes as ‘corpuscles’, d’Herelle recognized that their proliferation was at the expense of the bacteria. The ultramicrobe took over the bacterial cell’s machinery. The increase in their numbers, moreover, did not proceed in an incremental but rather exponential fashion.
D’Herelle was prepared to engage in debate with his scientific colleagues and laboratory experiments were crucial in the development of his own understanding of phages. His approach to science, however, demanded that he immerse himself in those settings that were themselves a contributing factor in the spread of disease. He was less interested in the abstract and more interested in applying science to pressing problems of human health. It was as though he knew his discovery was in advance of the current scientific understanding of disease. The science would follow so long as his trials had such promising outcomes. This is no doubt one reason why d’Herelle chose to go to Egypt and India – among other places – rather than letting the debate about the nature of phages remain confined to European laboratories.
D’Herelle possessed a restlessness that was well suited to his peripatetic approach to science. He was wholly committed to his research and to the best approaches to science, but he also seemed impatient and always prepared to uproot himself and his family. Thus, although d’Herelle took a position at Yale, his connection to the university and to the United States was always tentative. Those responsible for recruiting d’Herelle were impatient with his tendency to leave for extended stretches of time. He felt a similar ambivalence to his new home. D’Herelle was dismayed by the state of scientific research in America. The Great Depression had compromised funding, among other things. In the 1930s he received an invitation to conduct his research in the Soviet Union. Stalin’s purges hadn’t yet begun, nor had the persecution of scientists and other intellectuals. For those outside, the Soviet Union at the time represented an untested but promising alternative to western capitalism. D’Herelle believed that ‘scientific’ socialism promised the opportunity to conduct scientific research free of superstition and ‘mysticism.’ There was also a professed commitment to resolving practical problems. He was soon stationed at the Tiflis Bacteriological Institute in Tiflis, Georgia.
Georgiy Eliava was the person responsible for persuading d’Herelle to move from Yale to the Bacteriological Institute. According to Summers, they became close friends. Eliava was a committed scientist who did his best to remain removed from the increasingly toxic political environment dominating the Soviet Union. He was also impressed by the promise of phage therapy. But despite his best efforts to lead a quiet life of scientific discovery he was a victim of Stalinism. He and his wife – a Polish opera singer – were arrested and executed on the same day. It is not known why they were so ruthlessly targeted.
The death of his good friend and his wife was a blow to d’Herelle. They were not the only ones to arbitrarily suffer at the hands of the totalitarian state that had come to dominate the Soviet Union. Darkness had descended and no one living under Stalin could live free of his iron rule. D’Herelle knew this and thus did not return to the Soviet Union after a summer spent in France in 1937, as he had initially planned. He instead remained in France, even as Germany made its ominous advances. The Nazis did eventually occupy France, but d’Herelle remained in the country’s southern region. His reputation seemed to afford him some protection. He thus continued to work on phages even as war swirled all around him.
Nevertheless by the end of the 1930s and early 1940s forces of change were conspiring to relegate phage therapy to the margins of Western scientific research. A report published by the American Medical Association in 1941 went to great lengths to undermine phage therapy’s credibility. The problem with the report, according to Abedon et al, was that it was error filled and hardly objective. Failed phage therapy trials were not properly contextualized. Proper dosage was essential if phage therapy was to be effective. Similarly, phages could be administered too late in an infection’s progression for them to do much good. The report was entirely unworthy of the impact it had on the scientific community.[11]
Western science, more importantly, was about to undergo a profound shift in direction with the introduction of antibiotics in the late 1930s and early 1940s. Although the development of antibiotics did not begin with Sir Alexander Fleming, it was his discovery of penicillin in 1928 that facilitated the eventual treatment with antibiotics of tuberculosis, gangrene and syphilis. The discovery of other antibiotics – streptomycin, chloramphenicol and tetracycline – fuelled the effective treatment of a long series of other bacterial based infections and diseases. Indeed antibiotics helped to initiate a profoundly steep decrease in the incidence of bacterial disease, particularly in the developed world.
D’Herelle, meanwhile, was getting older and his health would start to decline. He was diagnosed with pancreatic cancer in the early 1940s and would die of the disease in 1949. Phage therapy’s most important proponent was thus removed from the scientific scene.
If phage therapy was relegated to the margins of western science it escaped the dustbin of history. D’Herelle’s time in Georgia ended in tragedy and he was forced to flee. Nevertheless he worked there long enough that the seeds for phage therapy’s continued development were planted. The result has been a historical development that has curiously unexplored: divergent approaches to the treatment of bacteria based communicable diseases and infections when comparing the West and the former Soviet Union.
To be sure, another aspect of d’Herelle’s legacy was the continued use of phages in parts of Europe for decades after his death. In France a phage research laboratory that d’Herelle himself opened was eventually run by his son- in-law. Their use was mostly confined to non-communicable bacterial infections. By the 1990s, however, phage production in France was phased out. Like everywhere else in the western world, antibiotics seemingly eliminated the need for alternative approaches to treating bacteria based infections and communicable diseases.
Conversely, the Soviet Union used phages to, among other things, treat soldiers. During the cold war access to any data detailing the efficacy of phages was non-existent. We do know, however, that in 1963 the Eliava Institute conducted a study involving 30,769 children designed to test the efficacy of phages in reducing the incidence of dysentery. Among those who did not receive phages, the incidence of dysentery was 6.7/1000. Among those who did receive phages, the incidence of dysentery was 1.8/1000.[12] To an unknown extent, phage therapy was used with some success in the former Soviet Union.
Phage therapy’s apparent promise but uneven application hints at an issue often ignored in the history of science. Science unfolds within wider social, political and economic contexts. Elements of those wider milieus can both facilitate and compromise the conditions necessary for rigorous scientific study and discovery. D’Herelle went to where disease was rampant. When used appropriately, phage therapy was promising. However, that promise must have been partially stymied by the wider political and social upheaval in which d’Herelle often found himself. Would his success in treating cholera in India with phages have been more definitive or embraced if the British medical establishment had been less indifferent to the plight of sick Indians? Similarly, would the results of his work at the Tiflis Institute in Georgia have been better if the Soviet Union under Stalin had remained open to scientific inquiry? Would the Soviet Union’s partial embrace of phage therapy have exerted any influence on western medicine if not for the Cold War? The answers to such questions are impossible to know but still worth considering. For given its early promise it is inconceivable phage therapy would not have been more widely and seriously explored if d’Herelle’s research had taken place in different, more stable environments.
The issue of context is also important when considering the fate of phage therapy in an era characterized by the overuse of antibiotics. Is the relegation of phage therapy to the margins of science indicative of its therapeutic limitations? Or did phage therapy’s promise become a moot point with the ascendance of antibiotics? These sorts of questions are no longer simply academic. For all of our enhanced medical understanding, the threat of communicable diseases to human populations has only waned, not disappeared. Since their discovery and development, antibiotics have been regarded as the great equalizer. For a long time this has been true. It is less so today. Antibiotics, despite their impressive record in treating bacterial infections and diseases, are subject to a single profound limitation. They are static. Bacteria, by contrast, are dynamic; they evolve in response to threats. This elementary truth is the underlying source of the growing emergence of antibiotic resistant bacteria. Phages, like their bacterial counterparts, are similarly dynamic and are thus not subject to the same limitation as antibiotics. Phage therapy, from this perspective, may yet prove to be crucial to stabilizing our relationship with disease causing organisms. If so, it will act as further proof that d’Herelle was a scientist well ahead of his time.
[1] A.A. Fletcher, “Notes on the Treatment of Bacillary Dysentery,” The Canadian Medical Association Journal, July 1917, p.1094
[2] Carl Zimmer, A Planet of Viruses, University of Chicago Press, p.36
[3] Abedon et al., “Phage Treatment of Human Infections,” p.67.
[4] William Summers, Felix d’Herelle and the Origins of Molecular Biology, p.48
[5] Carl Zimmer, op.cit, p.36
[6] William Summers, pp.125-126.
[7] Abedon et al, “Phage Treatment of Human Infections,” p.67.
[8] Abedon et al, “Phage Treatment of Human Infections,” p.69.
[9] Abedon et al, “Phage Treatment of Human Infections,” p.66.
[10] See also Carl Zimmer, A Planet of Viruses, chp 4 for an extended discussion on the disagreement between Bordet and d’Herelle.
[11] See Abedon et al, “Phage Treatment of Human Infections.” The report in question is the 1941 JAMA Review by Krueger and Scribner. The report, according to Abedon et al, “reflected a singular lack of care in researching the available data, if not outright personal bias in the conclusions.” p.71. It’s worth noting that the damaging effects of this report were most acute in the US.
[12] Carl Zimmer, A Planet of Viruses, p.37.
