Phages are viruses that colonize bacteria, including those that cause infection and disease. A new book traces phage science’s fascinating and unlikely evolution. Phages are, at last, being recognized for their life saving potential. But challenges remain.
Viruses have a fearsome reputation. These infinitesimally tiny particles typically inspire thoughts of illness and disease in addition to their social and political havoc causing potential. It was a virus – SARS-CoV-2 – that led to the disease Covid-19 and the subsequent pandemic from which the world has only recently emerged. The Human Immunodeficiency Virus (HIV) causes the Acquired Immune Deficiency Syndrome (AIDS) and gave rise to the pandemic that shares the same name. A virus was the culprit behind the great influenza pandemic of 1918-1919, which killed tens of millions of people across the globe. On and on it goes deep down into the furthest annals of human history. No wonder we attempt to avoid viruses, well, like the plague.
It’s only relatively recently that the scientific community developed a more nuanced understanding of viruses, their exact structure, their staggering numbers and variety and the nature of their interactions with other microbial life forms, including bacteria. To begin with, that viruses are nucleic acid molecules wrapped in a protein was only learned in the early 1930s. Their strangeness stems from the liminal space in which they exist. Viruses are inert, seemingly lifeless, until they take over a host cell for the singular purpose of reproduction, which they do in numbers that confound the imagination. Viruses are quite literally everywhere and in numbers that make the world’s human population of however many billion seem like a rounding error. Staying completely clear of them is thus impossible. Besides the vast majority of viruses, like most fungi and bacteria, cause humans no harm and indeed assume vital roles in the maintenance of good health. Our microbiome, for example, is that still only dimly understood region in and on the human body that is comprised of the near full spectrum of microorganisms – fungi, bacteria and, yes, viruses.
Some viruses, moreover, have symbiotic relationships with bacteria. That is to say, this sort of virus needs bacteria to reproduce and the bacteria evolve in response to the viruses that seek them out. These types of viruses have a name: bacteriophages or, phages for short. Their unique relationship with their microbial counterpart can be discerned through a relatively simple experiment. Fill a beaker with water. Put so much live bacteria in the water that it is rendered opaque. Then drop a small number of phages into the same beaker of water. If it is a good match between the bacteria and the phage, the water will become gradually clearer. The reason for the water’s transformation: the phages inserted genetic instructions into the bacteria designed to allow it to assume control of the bacteria’s cellular machinery. The instruction is for the virus to reproduce itself in numbers so great that eventually they will burst through and destroy the bacteria. The virus then seeks other bacteria so that the same process can be renewed. And so the majority of bacteria gradually or, in some cases, quickly disappear.
The process by which phages colonize bacteria has far reaching implications for human health. When applied properly, phages can be used with sometimes breathtaking effectiveness to treat bacteria based infections and disease. Indeed a largely forgotten chapter in the history of medicine involves the use of phages to successfully cure individuals, many on the brink of death, from bacterial diseases such as bubonic plague, dysentery and cholera. Yet, in the west at least, phages rarely are used in this therapeutically promising sort of way. Sir Alexander Fleming’s discovery of penicillin in 1928 and the subsequent effectiveness of antibiotics is one obvious reason why. Yet as Tom Ireland makes clear in his recent book The Good Virus: The Amazing Story and Forgotten Promise of the Phage, the reasons so little is known about the phage in the west and phage therapy so uncommonly deployed is more fascinating than this one dimensional answer would suggest. The fascination is to do with the ways in which the phage intersects with and is shaped by the turbulent period in which its healing powers were first discovered and then, in the west at least, subsequently ignored.
Who is responsible for discovering the phage? It’s another interesting question posed by Ireland and one without a definitive answer. It’s beyond doubt that the French Canadian scientist Felix d’Herelle is the first to understand the nature of the phage and how they interact with their bacterial hosts. Similarly, d’Herelle is most responsible for initially developing and promoting phage therapy’s promise in treating bacterial infections and diseases. All of this is not to say, however, that he was the first to discover the phage.
That honour remains in dispute. Ireland writes of various microbiologists dating back to the nineteenth century who observed bacteria seemingly disappearing in the face of some other microbial agent or agents. There was the scientist Ernest Hanbury Hankin who, upon traveling to India in 1892, noticed that something in the Ganges River seemed to destroy the bacteria that causes cholera. Other scientists from various backgrounds made similar observations, including Indian scientists as late as 1916. But what those observed agents were always remained unknown. As Ireland suggests, scientists at that time had neither the tools or the vocabulary to understand that the mysterious agents in question were viruses.
These sort of details are important. They exemplify one of the themes that runs through The Good Virus. The strange and fascinating trajectory of phage science over the course of the twentieth century was inordinately shaped by the wider social and political contexts in which science unfolded. In myriad ways, d’Herelle’s work especially was shaped by the two world wars and the simultaneous rise of both fascist and communist, totalitarian regimes. But within the context of these tectonic changes and forces, phage science has also been shaped by chance or contingency. If someone other than Felix d’Herelle, for example, had been the first to identify the phage’s therapeutic potential western medicine’s approach to bacteria based diseases might have followed a different trajectory.
To illustrate his point, Ireland considers the competing fates of the two people most associated with the initial work on phages, the English scientist Frederick Twort and the aforementioned French Canadian scientist d’Herelle. Twort was born in 1877. Frederick was raised to follow in his father’s footsteps, who was also a doctor. He was apparently happy his life followed the trajectory it did and that by a young age he was part of the scientific and medical establishment. By the turn of the twentieth century he was doing formal experiments when he noticed that bacteria were being colonized and thus destroyed. Like others before him, he was unsure of what this meant, although he likely suspected it was significant. Alas he had too little time to draw even tentative conclusions. As Ireland relates, in 1915 the British government shut down the lab he was running in order to maximize resources going into the war effort.
Circumstances beyond his control thus dictated that Twort close the sort of formal space – the scientific lab – in which he might have developed and further refined his understanding of whatever it was he observed colonizing bacteria. He might have appreciated its science and medicine altering potential. For in 1915, bacterial based infections ravaged not only soldiers fighting and dying in the trenches but much of humanity as well. Cholera, typhus and dysentery: all were common diseases and causes of illness and death. Yes it was understood by that point that such scourges were bacteria based, but that is as far as it went. Treatments were mostly a hodgepodge of ineffective remedies, with predictably poor success rates. Here was something, what exactly Twort did not yet fully appreciate, that seem to destroy bacteria. Could the ability of this mysterious agent be somehow harnessed to destroy disease causing bacteria? It was a question Twort might have asked but didn’t get to formally pursue. A promising avenue of research was suddenly cut off.
D’Herelle was in many key respects the polar opposite of Twort. He was born in Montreal in April 1873, less than a year after Twort. In sharp contrast to his English counterpart, d’Herelle was at once formally unqualified, an outsider to the scientific establishment, but nevertheless a determined, risk seeking and capable scientist with a knack for making intuitive sense of observable or, in the case of phages, unobservable phenomena. His interest in science stemmed, in part at least, from chance developments experienced on his adventures exploring the world as a young man. There was his cycling tour down the Rhine at the tender age of sixteen and the cruise along the shores of South America, on which an outbreak of yellow fever left many dead and many more seriously ill. Likewise his lack of formal qualifications contributed to his mistrust of accepted theories or prevailing wisdoms that ran counter to his own observations and ideas. He had a certain disdain for what might be referred to as ivory tower scientists; science, he thought, should be conducted as much in the wider world as it is in the laboratory.
This explains his ambivalent relationship to the Pasteur Institute, where he was employed in the course of the Great War. Louis Pasteur, according to Ireland, was his inspiration. Working for the organization that carried Pasteur’s name was an honour. Yet he still rankled at the prospect of working at an institution too wedded to orthodox ways of doing science. He had corrosive relationships with his colleagues at the institute, most of whom were dismissive of his claims about phages and their therapeutic promise. Nevertheless it was while working at the institute in 1917 that he noticed the same mysterious agent that Twort observed years earlier. D’Herelle was studying the stools of Allied soldiers suffering from dysentery. The phages he observed were colonizing the bacteria that were making the soldiers ill. Unlike Twort, he was able to channel that insight into the first phage therapies. By 1919 he was using phages to cure children suffering from dysentery.
The Great War thus impacted the work of these two scientists in diametrically opposed ways. Twort’s ambitions to study these mysterious agents colonizing bacteria was stymied by the English government’s larger war priorities. For d’Herelle the Great War was the great catalyst: the fate of Allied soldiers suffering from dysentery especially inspired the research that led to his initial discovery of phages.
Armed with a crucial insight, he was ready to boldly step forth into the world to build on what he had discovered. D”Herelle, from that point forward, is the most scientist most definitively associated with phage therapy.
Ireland thus traces d’Herelle’s unlikely path, first as a scientist working in Guatemala in the late 1800s and then Mexico City shortly after the turn of the century, in 1907. After working in Paris at the Pasteur Institute during the Great War, d’Herelle set off to what for him were far flung places – Egypt and India – where he achieved great success using phage therapy. While working in Egypt in the 1920s he used phages to cure individuals suffering from bubonic plague, among other horrific diseases. In India his most successful trials were in the treatment of cholera. Later, after his star started to rise, he was persuaded to go first to the United States, where he taught at Yale before leaving after five years, disgruntled with not only his colleagues but with America generally. His departure was also prompted by an invitation from the Georgian scientist George Elivia to carry on his work in Georgia. Their partnership gave rise to the Elivia Institute in Tbilisi, Georgia’s capital city. Their collaboration unfolded under the dark shadow of Stalinism, characterized by, among other darkly sinister developments, paranoia and the ruthless and arbitrary targeting of political enemies. Elivia was among Stalin’s targets; perhaps, according to Ireland, because he liked to throw big parties and be the centre of attention. The KGB arrested him at one of their parties and, days later, his wife and murdered both shortly thereafter.
D’Herelle, understandably, feared the same fate and so fled Georgia and returned to France in 1937. Alas conditions in France had changed drastically since his initial departure both politically and scientifically. Europe was soon girding for war. The Nazis would eventually occupy France. Just as importantly, antibiotics had revolutionized the treatment of bacterial infections and disease. Their promise seemed unlimited. Whatever the apparent merits of phage therapy, antibiotics seemingly made them an afterthought in the Western scientific and medical community. D’Herelle, never well liked by his contemporaries and his ideas constantly contested, was already yesterday’s man.
D’Herelle died in 1949 from pancreatic cancer. As his health deteriorated he became at once more disillusioned and seemingly indifferent to phage science. Ireland refers to him as dogmatic. Yet by the start of World War Two the combination of his perpetual restlessness and his seminal work on phages had helped to establish what Ireland refers to as ‘parallel universes’ with respect to the treatment of bacterial based infections and disease. The West was fixated on antibiotics. Meanwhile, phage research and therapy, although started in France during the Great War, was now firmly entrenched in the Soviet Union, mostly thanks to d’Herelle’s years collaborating with Elivia in Tbilisi. Alas Stalin’s Soviet Union was increasingly a closed world to those countries outside of its orbit. Much of what was going on inside remained a mystery. Accordingly, however effective phage therapy might have been in the Soviet Union, this approach to treating bacterial based disease remained largely unknown in the west.
Ireland abruptly moves on from d’Herelle and Twort. This is understandable. D’Herelle especially understood far more about the therapeutic potential of phages than his contemporaries but relatively little about phages themselves, especially by today’s standards. Other scientists thus take centre stage in the story Ireland tells. Here too, the wider political and social context assumed an outsized role in shaping the place of phages in western science. In the late 1930s the same menacing winds that drew d’Herelle back to France were blowing countless others hither and thither but ultimately out of Europe. In Nazi Germany it wasn’t only Jews who were driven to flee; so too were other minorities and those who could not tolerate the ominous direction the country was being driven. Scientists, some Jewish but many not, were among those who fled. The same sort of dark turn was unfolding in Mussolini’s Italy, engendering the same sort of response. Max Delbruck was a German scientist who fled Nazi Germany. Salvador Luria was a Jewish Italian scientist who fled his country after a law was passed in 1938 stripping Jews of citizenship and disallowing them from holding positions of authority in universities and other such institutions. The US was a haven for displaced scientists and intellectuals. So, via circuitous and fraught paths, both found their way to the shores of New York. They would eventually meet in Philadelphia and begin an unlikely collaboration with the American scientist Alfred Hershey. Together they constituted ‘The Phage Group’, or, as Hershey referred to his two foreign colleagues and himself, “Two Enemy Aliens and a Misfit.”
In telling their story Ireland helps to correct a misimpression about the place of phages in the more recent history of western science. It is striking how many scientists have either not heard of phages or paid scant attention to them. To the extent that phages were talked about, it was in the context of they being assigned to the margins of western science by the start of World War Two and in the immediate post was period. But this sort of characterization belies a more subtle role for the phage. If a distinction can be drawn between science and medicine, it’s more accurate to claim that phages were driven to the margins of western medicine but not science. Scientists were not driven to study phages in the hope of finding a cure to, say, cholera, dysentery or plague or any of the other bacterial scourges that drove d’Herelle’s interest. Rather, phages were soon discovered to be an elementary form of life that could inform some of the fundamental questions with which biologists and physicists were grappling.
What, for example, was the nature of reproduction at the cellular level? This was the question, according to Ireland, that most intrigued Delbruck. He realized that in phages he had discovered a means by which to study and hopefully answer it. Indeed, when phages could be directly observed with ever more powerful microscopes, vital insights could be derived. To begin with, the phage was not, as so many had assumed, either an enzyme or protein or something inherent to bacteria. Rather it was understood phages were a virus that used bacteria to replicate by virtue of commandeering the bacteria’s cellular machinery. D’Herelle was, at last, vindicated. More astonishing was that the phages didn’t appear to enter the cell, but rather attached themselves to it. Eventually, it was observed, phages would then burst open the bacteria from the inside. This observation constituted a mystery: how did something that attached itself to the outside of the bacterial wall suddenly and in much greater numbers explode that same bacteria from its inside? The phage appeared to be injecting something into the bacteria, a type of blueprint.
The three men had different areas of expertise and interest. Hershey suggested it could be DNA that was inserted into the bacteria. Delbruck was dismissive of the idea that DNA was central to the process under investigation. The uncertainty derived from the limits in the understanding of DNA at the time. Luria, whose area of interest was the nature of the gene, understood Hershey was onto something. Such was the galloping pace of discovery, however, Luria didn’t believe he was equipped to understand the biochemistry involved. So he resolved to send a promising undergraduate student of his by the name of James Watson to Cambridge. As Ireland makes clear, in addition to being a brilliant scientist, Watson was also racist and misogynist. (He would be stripped of many honorary titles in his later years for racist views.) In any case, Watson and Francis Crick and Maurice Williams would go on to discover the structure of DNA in 1952 and would win the Nobel Prize in Medicine in 1962 their efforts.
The humble phage, for so long mischaracterized or dismissed as unimportant, had assumed a crucial role in one of the greatest achievements in the history of science.
Time marches on and so too does science. One of Ireland’s surprising insights is that phage science is no longer confined to ‘the good virus’s’ therapeutic potential to effectively treat bacterial infections and disease. On the contrary, phages are increasingly being incorporated into emerging disciplines such as nanotechnology, genetic engineering and synthetic biology. The idea motivating such convergences revolves around the potential to harness the different attributes of phages: their various shapes and sizes, the different modes of interaction with bacterial cell hosts and their ability to withstand high temperatures, to identify but a few. Phages might in the near future be used to address notoriously challenging illnesses.
Ireland writes, for example, of the blood brain barrier. This thin membrane is, of course, designed to protect the brain, to keep out that which should not interact with the source of our ability to think and feel. Alas, that which protects also makes diseases and illnesses of the brain infamously difficult to treat. Phages, as it turns out, can bypass the blood brain barrier, making it thus conceivable these tiny viruses could be used – taking one example – “to help diagnose or treat disorders of the mid brain.” Likewise, phages could potentially be used to deliver painkillers – ziconotide, for example – to the brain. Such innovations in the ways in which phages are used in scientific research are further and further removed from the era in which d’Herelle and Twort worked.
Yet for all of the emerging research into the promise of phages, it is ’d’Herelle’s initial discovery that seems the most vital to further pursue, refine and render more mainstream. In d’Herelle’s time bacterial infections ravaged individuals and communities largely because there was yet no scientific and medical understanding of what could be used to kill the bacteria. This is no longer the case. The challenge of our time derives from the discovery of penicillin and the successful application of antibiotics in the subsequent decades. Antibiotics, for all of their dizzying power to stem bacterial infections, are static instead of dynamic. This is their achilles heel, their critical limitation. Through the process of natural selection, bacteria evolve to become resistant to antibiotics. The effect of this ongoing dynamic is predicable: antibiotics become less and less effective over time at treating the bacteria that make us sick. Indeed the threat of antibiotic resistant bacteria is not simply hypothetical or one looming on a not so distant horizon. On the contrary and as Ireland makes clear, the threat grows more acute by the day. Phages are not subject to this sometimes fatal limitation. Like bacteria, they too evolve. Surely this is among the phage’s most salient features when considering any future arsenal of treatments designed to counter antibiotic resistant bacteria.
Ireland is at his best when he highlights phages’ tantalizing promise to treat such infections. The Good Virus is dotted with stories of particular individuals whose lives were saved by phages. Each person’s experience is unique but the trajectories of unexpected illness, to near death, to phage led recovery follow a similar pattern. A life is upended by a freak accident or a strange but devastating bacterial infection, often acquired in some innocuous fashion. Ireland tells the story of one man who was infected after spending time in a cave while vacationing in Egypt with his wife. “The worst bacteria on the planet,” he writes, would turn their dream vacation into harrowing nightmare. As the infection spread, his array of symptoms grew ever more dire. There was severe vomiting, debilitating back pain and acute pancreatitis. He eventually went into shock and later psychosis. He fell into a coma from which he was not supposed to emerge. What followed was in keeping with a pattern that resembles something like the following.
Upon the discovery that antibiotics were useless in the face of such an infection, a sense of helplessness and resignation sets in. Doctors inform the patient there is nothing more they can do. A frantic, last ditch attempt to save the dying individual ensues. The dying patient’s advocates may have heard about these unique viruses that kill disease causing bacteria. Dig further and one learns that a therapy hiding in the shadows of western medicine was commonly deployed in the former Soviet Union going as far back as before World War Two. They might even learn about an eccentric French Canadian scientist named Felix d’Herelle who, in the 1920s and in places as far flung as India and Egypt, saved patients on the brink of certain death from such dreaded diseases as bubonic plague and cholera through their successful application. Go back a few more years, to the time of the Great War, and discover he used phages to cure children suffering from dysentery. They might ask: how is it phage therapy is not more widely used? A timely question but one for another day. For now, the patient advocates think, phage therapy is worth a try. We have nothing to lose.
But how does one access phage therapy in a timely fashion, especially in jurisdictions where it is not used? Where does one even begin? It takes an almost uniquely determined advocate, perhaps with connections in the scientific and medical community, to successfully undertake such an arduous journey. You have to find a scientist or a group of scientists with the capacity to discover a phage that will respond to the devastating bacteria in question. No small task but they do exist; they are part of a growing network of scientists and companies scattered across the globe – some in Canada – working to channel the power of phages. The burgeoning network seems to operate just beyond the bounds of hospital medicine. Thus you will require authorization from the formal medical authorities to attempt to use phages, even if the patient is at death’s door. Indeed the hurdles towards successfully accessing and then applying phage therapy seem too high and too numerous to even bother trying. Yet the patients whose illnesses Ireland meticulously documents are, against all odds, alive and well. Phage therapy managed to beat back the bacterial infections that could not be treated with antibiotics and that were driving them to an early death. Their stories serve to leave the reader with one lasting, hopeful impression: sooner or later phages will have their day.
The Good Virus: The Amazing Story and Forgotten Promise of the Phage
Author: Tom Ireland
Publisher: W. W. Norton & Company
Pages: 400
ISBN: 978-1-324-08643-7