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Bacteriophages infecting a virus

The word phage means 'to eat'. That is a little confusing, because bacteriophages do not actually eat bacteria. In fact they are viruses that infect bacteria and it is a little known fact that they are the most numerous organisms in the Earth's biosphere.

What are Viruses?

Viruses are very odd life-forms. They are on the very edge of what we think of as life. A virus is just a protein capsule containing a strand of genetic material - DNA (Deoxyribonucleic Acid) or RNA (Ribonucleic Acid). So a virus is like a box containing a list of instructions to make more boxes containing lists of instructions to make even more. The list of instructions cannot be followed however, until the virus is able to find an organism with the equipment to follow those instructions.

That is the thing that makes viruses so odd and not perhaps quite as alive as other life-forms. Viruses are sometimes described as 'non-living particles'. They lack the internal machinery to replicate. They have a blueprint but are unable to do anything with it. All they can do is find a suitable host cell, inject their strand of DNA or RNA into it and let the host cell do the work of following the instructions. A virus is, in fact, dormant1 until the moment it is in close proximity to a suitable host.

There are many thousands of different viruses and they have evolved to infect the cells of different organisms which are, in turn, susceptible to particular viruses. We humans are susceptible to our fair share such as influenza, herpes, hepatitis, rabies and rubella. Viruses are able to mutate and evolve rather quickly so, for example, a form of pox that had been confined to birds can change its structure to allow it to infect humans. That's the bad news.

The good news is that thousands of viruses specialise in infecting bacteria - the sort of bacteria that can cause very unpleasant diseases in humans, like salmonella, cholera and e coli (Escherichia coli.) and the sort of bacteria that cause dysentery and which infect wounds. These viruses are called bacteriophages.

What are Bacteria?

Bacteria are single celled organisms that do not have a nucleus. Their DNA floats about freely inside the cell. There are many thousands of different types of bacteria, the vast majority of which are completely harmless to human beings. In fact, we oxygen-breathing animals would not have been able to evolve without bacteria. They started to make Earth habitable for us billions of years ago by putting oxygen into the atmosphere, and today they help to keep Earth's atmosphere just the way we need it for our continued existence.

They are beneficial in all sorts of ways to all sorts of organisms. There are bacteria living in our intestines that help us to digest our food and make vitamins. Nitrogen2 is a natural fertiliser and there are bacteria in soil, many of them living in little nodules on the roots of certain plants, like clover and alfalfa, that 'fix' atmospheric nitrogen, making it available as a nutrient for plants3. There are also bacteria that can make their hosts luminesce.

Without bacteria to break down and decompose organic materials, we would be wading through dead plants and animals. Bacteria are vital to life on Earth.

However, some bacteria are very harmful to us. Anthrax, botulism, bubonic plague, tetanus, typhoid and many other diseases are caused by bacteria. This is where the bacteriophages could come to the rescue.

An Infection on your Infection

Bacteriophages are the viruses that parasitise bacteria4. There are thousands of different bacteriophages, each of which may infect just one or several types of bacteria. Most bacteriophages look just like lunar landers (see for example Cellsalive). T4 (Type 4 bacteriophage5), a bacteriophage that infects e coli, for example, has a 20-sided head, a stout neck and pillar-like tail, ending in a sort of base-plate with six tail fibres extending out like a spider's legs around the bottom.

When a bacteriophage meets a suitable host bacterium, its response is triggered when the tip of one of its tail fibres comes into contact with the correct pattern and types of protein - the binding sites - on the surface of the bacterium. The tail fibres bind to the precise molecules that distinguish that particular bacterium as a suitable host and then it injects its strand of genetic material into the cell.

There are two main groups of bacteriophages and they have two different strategies for getting their host to replicate them. One group of phages simply instructs the machinery in the host cell to make more bacteriophages. The cell makes a mass of new phages - so many that the cell bursts and dies. The other group of phages attach their strands of genetic instructions to the DNA of the bacteria, thereby getting replicated along with the bacteria, generation by generation. This group of bacteriophages can also cut their piece of DNA free from the host's DNA at any time, instruct the host cell to replicate phages and, again, a mass of bacteriophages are produced which then burst and destroy the cell.

It seems that bacteriophages can be found just about anywhere their hosts can be found. For example, if scientists look for them where cholera is endemic they will find the phages that are parasitic on cholera bacteria. Where the bacteria are found, there also are found the bacteria's phages.

Medical Uses

Bacteriophages were discovered back in the early 20th Century, twice, in fact. First they were discovered in Britain in 1915 by Frederick Twort and then they were discovered again, in France in 1917 by Felix d'Herelle. Felix d'Herelle did a lot of work on bacteriophages, all over the world. It looked for a while as though they would be very useful in the fight against a wide range of diseases. Then, in the 1940s antibiotics came along and the West lost interest in phage therapy. However, work continued in Eastern Europe where great progress was made. Now, with the advent of the antibiotic resistant 'superbugs', Western scientists are again focusing on the therapeutic possibilities of bacteriophages.

Phages have certain advantages over antibiotics.

  • If a suitable bacteriophage is introduced onto a suppurating6 wound, it will continue to increase in numbers as long as there are bacteria to infect and destroy. However, as soon as all the bacteria have been destroyed, the action of the phage will cease and the dormant phage particles will disperse harmlessly.

  • Because phages are so specific to the bacteria they infect, they will not harm beneficial bacteria such as those that help us to digest our food.

  • Some people are allergic to antibiotics so phage therapy could be a useful alternative for those patients who react badly to standard treatments.

  • Phage therapies can be administered to patients in just about every imaginable way - pills, potions, injections, enemas, nasal sprays, ointments and so on.

Again, because each phage infects a specific bacteria or range of bacteria, a person in hospital, where bacterial infections abound, can be treated with a range of phages targeted at several types of bacteria. They can be given a cocktail of phage types to attack one type of bacteria or they can be given a combination of phage and antibiotic treatment. In short, the small and dwindling arsenal of the doctors, diminished as it was by the overuse and misuse of the once very effective antibiotics, has now grown bigger.

Only the group of phages that cause their host to burst and die are used to treat patients. However, both kinds - this group, and also those that join their DNA to the DNA of the bacteria host - are useful in the typing of bacteria. It is not always easy for doctors to be able to tell what type of bacteria they are dealing with and because bacteriophages are so specific to their host bacteria, they can be used to test bacteria for type. One way to do this is to grow the unknown bacteria on some agar in a petri-dish. Then, phages can be introduced to the bacterial growth one at a time, until one shows signs of killing the bacteria. When this happens, a 'plaque' forms. This is a circular formation that indicates an area of dead bacteria. Bacteriophages cannot move independently, so if just one phage is placed on a dish of its favourite bacteria, that phage will infect the bacterium it lands on, the phages that burst out of that cell will infect the bacteria in close proximity to the cell of their birth and so on. The pattern formed is always the same as the phages burst out of the bacteria in concentric circles.

Another related use currently being researched is the testing of bacteria for drug resistance. In recent years tuberculosis or 'TB' has become resistant to a range of antibiotics that had previously worked so well against the disease; people had the mistaken impression that it was no longer a problem and it seemed to have been practically eliminated in the developed world. It used to be a major killer before the development of antibiotic treatments and the signs are that it will be again. However, some antibiotics still work against some strains of TB. Tests have to be carried out to discover which drugs will work in particular cases and this can be time consuming. Several phages that infect Mycobacterium tuberculosis, called mycobacteriophages have been modified to carry the firefly genes that code for the enzyme 'luciferase' - the stuff that makes a glow-worm glow. When these phages infect TB mycobacteria, their genetic material, including the firefly genes, integrate with the hosts' DNA and 'programme' the bacteria to make the enzyme. This causes the bacteria to glow ever so slightly when a substance called luciferin is added. The glow can be observed using special equipment such as a luminometer, or it can be photographed. In order to glow, the bacteria must be alive so the potency of an antibiotic drug can be gauged fairly quickly by observing the emission of 'bioluminescence' from infected bacteria.

Potential Dangers of Bacteriophage Therapy

A struggle is taking place to find new medications to replace those antibiotics to which disease-causing bacteria have become resistant. Bacteriophages could potentially be very useful indeed. With further careful research they are likely to become our friends and allies in the war against disease. However, caution is required. It must be remembered that bacteriophages are viruses and, in general, viruses tend to swap genes with each other and other organisms with which they come into contact. Scientists make use of this promiscuity, using viruses to transport genes into organisms they wish to modify genetically. Most of the genetic modification that happens in nature does not have disastrous consequences. Nevertheless, a good doctor would not indiscriminately introduce a soup of various bacteriophages into an ill patient. The important first step is to find out exactly what bacteria and viruses are present and then choose the remedial treatment with care and precision. It would be highly regrettable if a virulent bacteriophage swapped some genes with an infectious agent already present in a patient and these genes turned out to be key to increasing the potency of the infection.

1A dormant virus is referred to as a 'virion'.278% of our atmosphere is made up of nitrogen gas, N2.3Plants transform the fixed nitrogen into amino acids which are then converted into proteins.4Viruses are very much smaller than bacteria and whereas bacteria can be seen easily under an ordinary light microscope, an electron microscope is needed to study a virus.5When bacteriophages were first studied they were given type designations: Type 1 to Type 7.6Forming and secreting pus.

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