The transformation of precision medicine in infectious disease

Before Alexander Fleming discovered penicillin, another more selective antibacterial agent rose to popularity in the early 1900s: bacteriophage.

In 1917, microbiologist Felix d’Herelle was tasked with identifying the cause of a dysentery outbreak impacting French troops. From his research, he noticed that Shigella bacteria was the primary culprit of this affliction. He then discovered an invisible microorganism that targeted and eliminated the dysentery bacillus, or rod-shaped bacteria, which he eventually named ‘bacteriophage’ (also known by the shorthand ‘phage’) for its supposed bacteria-eating capabilities. D’Herelle would later apply this knowledge to successfully treat children suffering from severe dysentery at the Hospital des Enfants Malades in Paris and create cures for other pathogens like cholera and typhoid. Encouraged by d’Herelle’s contributions and similar studies, there was soon overwhelming excitement surrounding phage therapy and its success in curing infectious diseases. In fact, this precision approach garnered so much attention that d’Herelle and George Eliava co-founded an institute in Tbilisi, Georgia, in 1923 that was dedicated to studying bacteriophages and clinical use of phage therapies. However, this movement’s momentum quickly fizzled out after the discovery of the first antibiotic, penicillin, in 1928.

Phage therapy fell out of favor with scientists, physicians and the public in the 1930s and 1940s primarily due to the uncertain biology behind bacterial viruses – which wouldn’t be studied in detail until the invention of the electron microscope – and the widespread availability and convenience of antibiotics in the early post-World War era. These miracle drugs could be prescribed broadly by physicians to cure a plethora of ailments without identifying the specific pathogenic strain. In stark contrast, phage therapies required isolation of specific phages to treat each bacterial pathogen, specific diagnosis of the pathogen afflicting each patient, and a much more complex manufacturing process than that required to produce antibiotics on an industrial scale. Together, these factors undermined the potential of targeted medicine and phage therapy research. Hence, the beginning of the golden age of antibiotic discovery.

The need for precision medicine

The emergence of antibiotics created modern medicine, yielding a massive epidemiologic transition: developed countries transitioned from populations with high mortality rates attributed to communicable diseases to skyrocketing life expectancies. Ironically, this shift in life expectancy increased the prevalence of chronic illnesses. Yet, this ‘one-size-fits-all’ approach to treating bacterial pathogens set us on an inevitable path to the evolution of even deadlier pathogens. While broad-spectrum antibiotics are excellent at obliterating harmful bacteria, they also indiscriminately eliminate beneficial bacteria in the body. Furthermore, the use of these medicines creates selective pressures on bacteria that favors the emergence of bacterial strains that are resistant to antibiotics, a phenomenon known as antimicrobial resistance (AMR). Naturally, the biopharmaceutical industry continued to develop natural and synthetic antibiotics that were stronger and better than their predecessors. However, as these medicines progressively became more potent at killing bacteria – both bad and good – they often also became increasingly toxic. Unfortunately, bacteria have intrinsic resistance mechanisms that are effective against weaker antibiotics and can rapidly evolve to evade the strongest antibiotics – creating more problematic bugs down the line.