Frederick Twort was the first to document a potential bacterial virus. However, these bacteriophages were rediscovered by Felix’ d’ Herelle in 1917, at the crux of World War I when he was assigned to look into an outbreak of Shigella bacteria that were causing dysentery. d’Hérelle first successfully treated several children at the Hospital des Enfants Malades in Paris, proving that bacteriophages could be used to treat bacterial infections. Thus, phage therapy was born.

This discovery led to increased excitement surrounding phage therapy to combat human bacterial diseases. In 1923, d’Herelle set up a research institute for bacteriophage therapy in Tbilisi, present day Georgia. Phages only target bacterial cells and ignore human cells, providing a safe and targeted approach to fighting bacterial infections. Before the advent of antibiotics, this institute had over a thousand employees producing phages for clinical use. In fact, 20% of bacterial infections in Georgia today are still treated by bacteriophages. The discovery of antibiotics, however, made this rising field lose momentum in the West. 

Phage therapy was overtaken by antibiotics in the 1940s and 1950s because they were easier to use and cheaper to manufacture than bacteriophage. A doctor didn’t need to know the exact pathogen that was infecting the patient to prescribe a broad-spectrum antibiotic, whereas phage therapy requires a clear understanding of the pathogen, thus making it more cumbersome. Antibiotics could also be mass produced in large scale based on chemical processes, which made them much cheaper.  And so the era of antibiotics was born. 

Antibiotics revolutionized modern medicine. Life expectancy skyrocketed, complex surgical procedures were developed, and life-saving drugs were discovered. But antibiotic resistance, the ability for some bacteria to survive a course of antibiotics, soon emerged. For a while, the pharmaceutical industry continued to invest and thereby found better and stronger antibiotics. Antibiotics built the pharmaceutical industry through multiple booms and busts as resistance would occur and subsequently be ‘solved’ with a new class of antibiotic. Today there are ten different classes of antibiotics with well over 100 FDA-approved drugs. 

Yet, with all these antibiotics, resistance continues to climb. The issue is a complex one, but simply put there are three compounding factors driving this issue: 

  1. Bacteria are constantly evolving, and antibiotics put evolutionary pressure on both the target bacteria and any others that may encounter the antibiotic in the patient’s body or in the environment. This evolutionary pressure leads to bacteria developing capabilities to resist being killed by the antibiotics and is made worse by over prescription of antibiotics and their use in agriculture.
  2. Antibiotic drug development is hard. It takes an average of 10-15 years and hundreds of millions of dollars to develop a new antibiotic. Decades ago, companies could expect that they would have many years to recoup these investments before bacteria evolved resistance to the drugs, but in recent years resistance has been emerging as fast as new drugs could be developed. Second, third, and fourth-generation antibiotics that seek to fight resistant bacteria have been developed, but these tend to be more toxic to patients than earlier-generation products. 
  3. Pharmaceutical development incentives are broken. With the rise of antibiotic resistance, doctors and hospitals have become very attuned to the importance of ‘antibiotic stewardship,’ which tries to delay emergence of resistance to important new antibiotics by using them only on patients who have no other options. This gives antibiotic drug development a much lower return on investment than drug development in other areas such as oncology. Multiple companies have gone bankrupt after developing and commercializing new antibiotics. This has led to both large pharmaceutical companies and traditional venture investors exiting the space. 

These factors have led to the formation of ‘super bugs’ or infections that are resistant to most or all classes of antibiotics in parallel with massive under-investment in development of new antibacterial products. Patients are now facing infections for which there are no known antibiotics that can treat their infections. 

With antibiotic resistance on the rise, scientists and entrepreneurs turned back to an old technology rather than trying to find a new small molecule. As the cost of genomic characterization was decreasing and automation technologies increase throughput, it became easier to sequence and characterize bacteriophage. In parallel, advances in biomanufacturing techniques made bacteriophage manufacturing less expensive. Thus, phage therapy became accessible.