Author|Rachelle Wu
Editor|Hecate Ye
Typesetter|Dina Dong
Many people may have seen some popular science videos featuring microbes that resemble alien spacecraft, with icosahedral heads, spider-like legs, and a tail pin. These remarkably unique-looking microbes are called bacteriophages, which are a very special type of virus while its host is bacteria, not animal. Their appearance may not seem natural, but what's astonishing is that bacteriophages have been around for 3 billion years, almost appearing alongside bacteria on Earth. They are virtually omnipresent, outnumbering all organic life forms on Earth combined.
Although bacteriophages have been around for a long time, it wasn't until 1915 that bacteriophages were discovered by Frederick W. Twort, the Director of the Brown Institute in London. While studying a variant strain of the vaccinia virus used in the smallpox vaccine, Frederick W. Twort accidentally observed that certain bacterial colonies became watery in appearance and could no longer replicate (indicating that the bacteria were killed)
Based on this phenomenon, Frederick W. Twort wrote a short article, but due to the outbreak of the First World War and the extensive research and use of penicillin, he did not pursue further investigation. Meanwhile, Canadian medical bacteriologist Felix d'Herelle also discovered this virus capable of halting bacterial growth and named it bacteriophage[2]. Subsequently, he conducted some related research, proving that infecting a normal bacterial colony with the transparent transformation principle kills the bacteria. The transparent entity passes easily through a ceramic filter, can be diluted a million times, and restores its strength, or titer when placed on fresh bacteria. laying the groundwork for further exploration in the future.
It is not an exaggeration to say that phages are responsible for a significant portion of deaths on Earth. However, it is important to note that they only kill bacteria, not humans or other organisms. Each day, phages eliminate approximately 40 percent of the bacteria in the ocean [3]. Despite their effectiveness, phages have a crucial limitation: they rely on host bacteria to survive, making mass production and utilization by humans challenging. Phages come in various types, each primarily targeting specific cell types and their variants. When a phage encounters its target bacteria, it punctures the bacterial shell using spines on its tail and injects genetic material, RNA, into the bacterial cell. The phages then undergo rapid multiplication within the host cells. To further aid in bacterial destruction, phages produce a potent enzyme called endolysin, which creates holes in the bacteria's surface. As a result, excessive internal pressure causes the bacteria to rupture, leading to its demise. The phages seize this opportunity to exit and repeat the previous steps.
Currently, there is growing interest in phages as a potential avenue for disease treatment. In the past, antibiotics were widely used to combat bacterial infections. However, antibiotics have fixed chemical formulas, and bacteria can develop mechanisms to resist their effects by making mistakes during DNA replication. This resistance has given rise to superbugs, which are highly resistant to antibiotics and pose significant challenges in treatment. It is projected that by 2050, superbugs may surpass cancer as the leading cause of global mortality [3]. Continued research and clinical application of phages in humans offer hope in combating this alarming situation.
We are currently engaged in the development of targeted phage therapy for treating infections in humans. While the idea of injecting a large amount of virus into the body may sound risky, humans surprisingly possess immunity against phages. Phages cannot affect humans, as they exclusively target specific bacteria rather than indiscriminately attacking all bacteria like antibiotics. This selective nature allows phages to choose and eliminate specific harmful bacteria while preserving beneficial ones. Now, can bacteria develop immunity against phages? In reality, bacteriophages are viruses that continuously evolve and have been engaged in an evolutionary battle with bacteria for millions of years. They adapt and evolve themselves to combat bacteria effectively. Even if some superbugs have developed resistance against certain phages, they must have simultaneously lost their immunity to antibiotics. In such cases, a combination therapy involving antibiotics and phages can be employed to treat diseases. Consequently, phage therapy represents a long-term strategy in the fight against bacteria, offering benefits beyond the limited scope of antibiotics.
There have already been cases where phages have successfully treated diseases that were previously considered incurable by conventional methods. One notable example is the successful treatment of a mycobacterium lung infection, which had become resistant to antibiotics, using bacteriophages. John, a 26-year-old cystic fibrosis patient, had been experiencing recurrent lung infections since childhood, requiring hospitalization several times a year. By the time he reached adulthood, his lung function had deteriorated to 30 percent due to a persistent abscess infection caused by mycobacterium abscessus, despite multiple unsuccessful treatment attempts. Doctors predicted that he would not survive more than a few years without a lung transplant. However, due to the challenging nature of treating mycobacterium infections, which can spread beyond the lungs, no transplant hospital was willing to accept him. In a fortunate turn of events, John was exposed to bacteriophages, and researchers employed genetic engineering techniques to identify several phages capable of targeting the bacteria in his body. In September 2020, John began receiving infusions of phages. After a year, doctors observed a complete recovery in John's condition and arranged for a lung transplant. Currently, John has ceased all treatments for mycobacterium abscesses and has resumed a normal life [4].
While phage therapy is still in the experimental stage and cannot be applied on a large scale, there is hope on the horizon. Pharmaceutical companies have been hesitant to invest billions of dollars in a treatment that has not yet received official approval. However, significant progress has been made, and since 2016, the largest clinical trials involving phages have commenced.[3] This indicates that we may be approaching an era where antibiotics are no longer the primary means of combating bacteria. Phage research is an exceptionally promising field that, when utilized appropriately, has the potential to save numerous lives.
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