Drinking this bowl of Ganges water can cure super-resistant bacteria?

Compared to other, more macroscopic species, writing about a virus seems to be a losing battle from the start.

Compared with the long history of biological evolution, the history of human civilization and natural history research is too short. As a special type of virus, bacteriophages are invisible to the naked eye or optical microscope. It was not until the advent of electron microscopes that humans could get a glimpse of their full picture.

Enterobacteriaceae phage T4 under a transmission electron microscope. Image: expasy.org

We can't find any literary works praising their delicate morphological structure or ingenious reproduction mechanism, nor any historical figures leaving anecdotes about them. So far, we still don't know when and where they originated. They just exist silently in every corner of the world as loyal partners of human research on molecular biology and medicine.
Countless mysterious "creatures"

Back in 1896, British bacteriologist Ernest Hanbury Hankin, who was studying cholera in India, accidentally discovered that there was a substance in the unboiled water of the Ganges River that could inhibit the growth of Vibrio cholerae, thereby limiting the spread of the cholera epidemic. Subsequent studies found that this substance was so small that it could pass through ceramic bacterial filters (with small holes that bacteria could not pass through).
The banks of the Ganges in Varanasi, Uttar Pradesh, India. Image: Wikimedia

More than 20 years later, British bacteriologist Frederick Twort and French microbiologist Félix d'Hérelle independently discovered a tiny substance that can kill bacteria. Twort speculated that this substance might come from a special bacterial growth cycle, an enzyme secreted by the bacteria themselves, or a virus that can infect bacteria. Unfortunately, the outbreak of World War I interrupted his research. On the other hand, d'Hérelle was convinced that the virus that ate his Shigella dysenteriae culture was a virus that can parasitize bacteria. Based on the Greek φαγεῖν (phagein, meaning to devour), he named this type of virus bacteriophage, or bacteriophage.

Twort (left) and d'Hérelle (right). Image: wikimedia

It is now known that bacteriophages are a type of virus that can infect bacteria and archaea. They are composed of proteins and nucleic acids and can be divided into 19 families based on their morphological structure and nucleic acid types. Unlike other types of organisms, viruses are not named according to binomial nomenclature. The naming of plant and animal viruses generally follows the form of "host + disease + virus", such as tobacco mosaic virus (TMV) and canine parvovirus (CPV), while bacteriophages are generally named in the form of "host bacteria name + bacteriophage + number", such as Enterobacteria phage T4.

Tobacco mosaic virus was the first virus identified by humans. Image: wikimedia

In the 1940s, American geneticist Milislav Demerec isolated a series of bacteriophages from sewage samples from sewers and named them bacteriophages T1 to T7 according to the host and plaque* size. Among them, Enterobacteriaceae phage T4 belongs to the Myoviridae family. As we know from its name, T4 can infect Escherichia coli of the Enterobacteriaceae family. *Plaques - empty spots produced on the culture medium due to bacterial death.

Plaques appearing on a bacterial culture after inoculation with bacteriophage. Image: Ninjatacoshell / wikimedia

In Buddhist terms, there is a phrase "the number of grains of sand in the Ganges River" to describe something that is difficult to count. This may be used to describe the bacteriophages first discovered in the Ganges River. Currently, bacteriophages are the most numerous species on Earth*. They exist almost everywhere there are bacteria on Earth, and 70% of the bacteria in seawater contain bacteriophages. *The essence of bacteriophages is viruses. Viruses are very special and are not "living things" in the strict sense. Like general life forms, they carry genetic material (DNA or RNA), can proliferate, and evolve through natural selection, but at the same time they lack cell structures, which is an important reason why they are excluded from "life". At present, viruses are described as "organisms at the edge of life" that are free from "life".

Biological or nanorobot?

Under an electron microscope, T4 is tadpole-shaped, about 90 nanometers wide and 200 nanometers long, with an ellipsoidal head and a cylindrical tail. Further analysis of its morphology and proliferation has given T4 a strong sense of science fiction.
The head of T4, also known as the capsid, is an elongated icosahedron composed of 152 protein capsid particles, which encapsulate a double-stranded linear DNA that can encode 289 proteins. The head and tail are connected by a neck ring. The tail is a hollow tubular structure, consisting of a tail tube and an outer tail sheath, a base plate at the bottom, 6 spikes connected to the base plate, and 6 tail filaments. The morphological structure and infection pattern of T4 bacteriophage. Image: Guido4 / wikimedia; Chinese translation: Species Calendar

The process of T4 infecting E. coli is similar to a micro-injection: after the protein on the tail fiber recognizes and binds to the lipopolysaccharide receptor on the host cell, the tail sheath shrinks, the tail tube pierces the outer layer of the bacterial cell wall, and degrades the inner layer of the cell wall under the action of lysozyme, so that the DNA in the head can be injected into the bacteria through the tail tube unimpeded. Then the DNA begins to transcribe RNA, translate into protein, and mass-produce the necessary components for self-replication for assembly: the empty capsid first wraps the DNA, combines with the assembled tail, and finally connects to the tail fiber. In this way, an originally healthy E. coli cell is hijacked and converted into a T4 "assembly factory". Under the action of lysozyme and lipase, the wall of the assembly factory eventually collapses, and the released phage will continue to look for the next victim. At present, we still cannot confirm when and where the phage evolved. Their exquisite structure and efficient infection and proliferation process make many people sigh that this is not like an earth creature, but a "nano robot" left behind by some alien civilization. Therefore, T4 has become a frequent guest in many works of art and science fiction. In the first season of the animation "Rick and Morty", there is a plot of E. coli outbreak, but the image of "E. coli" in the film is actually a distorted bacteriophage. "Rick and Morty".

T4 has a simple structure, is easy to culture in the laboratory, and is harmless to the human body. Therefore, it is often used as a model species in molecular biology and virology experiments. Many Nobel Prize winners in Physiology or Medicine have used T4 as a research model. For example, the 1969 winners Max Delbrück, Salvador Luria and Alfred Hershey won the prize for discovering the replication mechanism and genetic structure of viruses. The three Nobel Prize winners in Physiology or Medicine in 1969. Image: nobelprize.org

Phage therapy

If you follow science news, you may know that antibiotics are no longer effective against many drug-resistant "superbugs." Currently, researchers are beginning to try to use bacteriophages as a "new" therapy to control infections, and many bacteriophage products have entered the clinical trial stage.
In fact, phage therapy is nothing new. As early as 1919, Félix d'Hérelle, the discoverer of phages, used phages isolated from chicken feces to kill Salmonella, thereby curing typhoid fever in chickens. In August of the same year, he successfully cured two children with dysentery using phages isolated from the feces of recovered dysentery patients.
Under an electron microscope, a group of bacteriophages are infecting a bacterium, and their relative sizes are clearly visible. Image: Graham Beards / wikimedia

In the 1940s, antibiotics led by penicillin began to be mass-produced and commercialized, causing phage therapy to be gradually forgotten. Only a few countries, mainly the Soviet Union, still insisted on the research and application of phage therapy. During World War II, phages were used to treat dysentery, typhoid fever and gangrene in Soviet soldiers. Due to the lack of antibiotics, the newly established New China also developed phage preparations with the help of the Soviet Union and successfully cured cases of dysentery and Pseudomonas aeruginosa infection. The movie "Spring in the World", adapted from real events, tells the story of using phages to treat infections in burn patients. Since then, due to the abuse of antibiotics, "super bacteria" that can tolerate almost all antibiotics have emerged. Faced with the dilemma of no drugs available, phage therapy has returned to people's vision. Compared with antibiotics, the advantage of phage therapy is its strong specificity: as long as the right phage strain is found, it can only hit the target pathogenic bacteria, while antibiotics may kill both beneficial and harmful bacteria in the same environment. For example, T4 only kills E. coli. Studies have shown that T4 and T5 can be used together to control infection with hemorrhagic E. coli O157:H7 strains in sheep intestines. Hemorrhagic E. coli O157:H7 culture. Most E. coli are not pathogenic, and only a few strains, such as O157:H7, can cause intestinal infectious diseases. Image: foodsafetycertification.ca

However, phage therapy is not without flaws. The narrow host spectrum is both an advantage and a weakness. A phage strain can often only kill a specific strain of a certain bacteria, so finding a corresponding phage that can fight the target pathogen is also a major challenge. Faced with complex infection situations, researchers often adopt a "cocktail preparation" approach, mixing multiple phages to expand the host spectrum. In addition, as a substance introduced into the human body from the outside, phages may also stimulate the immune response of some people and cause side effects such as allergic reactions. There is also a reminder: Although phage therapy is promising and specializes in treating super-resistant bacteria, considering the serious pollution of the Ganges, it is better not to drain the Ganges water.