It was the 3rd of December 1917 when Felix Hubert D’Herelle reported on an «invisible microbe antagonistic to the dysentery bacillus» [1]. Two years prior, bacteriologist Frederick Twort published the first report of viruses that infect and kill bacteria [2], uncovering their therapeutic potential as antimicrobial agents. Times were different back then, and the discovery of bacteriophages was met with great curiosity by the scientific community to treat infectious diseases. However, at the time, the field of virology was still in its infancy, and phage therapy became rapidly displaced by the discovery of antibiotics.
Since then, science has come a long way, and phage-based therapy has now re-emerged as a potent alternative for treating multi-drug resistant bacteria. As scientists continued to study them over the last century, phages have also contributed to other scientific breakthroughs – and they may continue to do so in the future.
A long way back
In 1952 Alfred Day Hershey and Martha Chase used the T2 bacteriophage to prove that DNA was the carrier of genetic information [3]. Less than a decade later, Francis Crick and Sydney Brenner took advantage of phage T4 to demonstrate that the genetic code was based on groups of three nucleotides called codons [4]. In following years, scientists discovered multiple DNA-manipulating enzymes encoded by phages, favouring the rise of molecular biology, and paving the way for the development of new gene-modifying tools [5].
Most recently, the study of phages played a central role in deciphering the function of CRISPR-Cas, a primitive ‘immune system’ that prokaryotes use against mobile genetic elements [6]. This finding helped create powerful gene-editing techniques which have been incredibly useful in the field of synthetic biology. Many phage-derived technologies have been adapted to program biological systems, and phage components are now being used to build genetic circuits – but what makes them so convenient in this area of science?
Versatile forms of… life?
Phages have several features that make them very useful for scientific research: they have relatively small genome sizes, fast growth rates and are easy to manipulate. Due to their ability to infect different bacterial strains, they can infect hosts with incredible specificity and efficacy, enabling rapid genetic manipulation. Phages are also the most numerous biological entities on Earth, and they are arguably the oldest group of microorganisms, with some estimates placing their ancestors before the divergence of Bacteria from Archaea and Eukarya [7].
One of the best advantages of bacteriophages is their great diversity. Throughout their ancient history, phages have developed multiple strategies to take over their host’s resources, making them a rich source of components for synthetic biology. What does the future hold for these microorganisms?
The value of hijacking biological systems
Nowadays, bacteriophages hold great potential for modifying non-model bacteria [8]. Certain species like Pseudomonas putida or Lactococcus lactis offer unique characteristics for metabolic engineering, but these microorganisms remain underutilised due to the scarcity of available tools to build synthetic genetic circuits [9]. Because of the long history of co-evolution between bacteriophages and bacteria, phage-based components are completely adapted to their non-model hosts, making them standout opportunities to solve this issue.
Bacteriophages can also be used to combat bacteria as an alternative to other therapies. Antibiotic overuse has caused the emergence of antimicrobial resistance, posing serious threats to public health. Lytic phages have demonstrated a high degree of success and safety in various in vivo and human models, and bacteriophage genome engineering could help to further improve phage host range or reduce phage resistance using synthetic biology approaches [10].
In short, despite their ancient history, the potential of phages continues to be exploited today. With some embellishments and improvements, their use could even be more helpful! Making it easier to use alternative bacterial hosts for every possible application. From the clinical setting to their industrial uses, their potential appears to be as high as their varied genetic components. Who knows what other exciting developments might take place in the future?
References
- D’Herelle F. (1917). Sur un microbe invisible antagoniste des bacillus dysentérique.
- Twort, F. W. (1915). An investigation on the nature of ultra-microscopic viruses. Lancet 186, 1241–1243.
- Hershey, A. D. & Chase, M. J. (1952). Independent functions of viral protein and nucleic acid in growth of bacteriophage. Gen. Physiol. 36, 39–56.
- Crick FH, Barnett L, Brenner S, Watts-Tobin RJ. (1961). General nature of the genetic code for proteins. Nature 192: 1227–32.
- Rohwer, F., Segall, A. (2015). A century of phage lessons. Nature 528, 46–47.
- Sebastien Lemire, Kevin M. Yehl and Timothy K. Lu. (2018). Phage-Based Applications in Synthetic Biology. Annual Review of Virology 5:453-476.
- Veesler, D., & Cambillau, C. (2011). A common evolutionary origin for tailed-bacteriophage functional modules and bacterial machineries. Microbiology and molecular biology reviews: MMBR, 75(3), 423–433.
- Eveline-Marie Lammens, Pablo Ivan Nikel & Rob Lavigne. (2020). Exploring the synthetic biology potential of bacteriophages for engineering non-model bacteria. Nat Commun 11, 5294.
- Michael J. Volk et al. (2023). Metabolic Engineering: Methodologies and Applications. Chemical Reviews 123 (9), 5521-5570. DOI: 10.1021/acs.chemrev.2c00403.
- Sani Sharif Usman, Abdullahi Ibrahim Uba & Evangeline Christina. (2023). Bacteriophage genome engineering for phage therapy to combat bacterial antimicrobial resistance as an alternative to antibiotics. Mol Biol Rep 50, 7055–7067.