How Phage Work

An old poem says that “big fleas have little fleas upon their backs to bite ‘em,” and this line carries a grain of truth about the biological world. People commonly think of bacteria as parasites that cause all kinds of disease, and it may come as a surprise to learn that these tiny creatures can be infected by still tinier creatures.

First of all, it should be clear that the world is full of a great variety of bacteria, and that most are not pathogens—causes of disease. For instance, our lower intestines are full of bacteria that are essential to our intestinal health, including beneficial varieties of the Escherichia coli we so often hear about. Our skin is the natural habitat of many species of bacteria that do us no harm and are essential to our well-being, including Staphylococcus epidermidis, a relative of the notorious other species of staph that can cause terrible diseases. All in all, our bodies have 10 times as many bacterial cells as human cells.

All bacteria are so small that a good microscope is needed to see them well, on the order of a micrometer in length; a micrometer is a millionth of a meter (about a yard) or a thousandth of the little millimeter marks you see on a metric ruler. But these tiny organisms can be infected by still tinier viruses called bacteriophages, or simply phage. (The word rhymes with “page” but bacteriophage were discovered by a French-Canadian doctor, Felix d’Herelle, and physicians following his lead have generally rhymed the word with “garage.” You may still hear some people using that pronunciation.) There are many kinds of phage. Some look like tiny spheres, others like long rods. The rather classic type of phage, as shown in the photograph, have been likened to moon landers: they have a large hexagonal head attached to a narrow tail, and many types have some sort of thin fibers near the end of the tail. This visible covering, or coat, is made of several kinds of protein; this coat covers the phage’s genome (genetic material), a long piece of DNA carrying all of the phage’s genes. (Some other types of phage have no tails and have very small RNA genomes, as do many human viruses like HIV.)

Every type of phage is specific for one or a very few types of bacterium, which means that certain proteins of that phage’s coat –usually on tail fibers– can attach to molecules on the surface of those types of bacterium, and no other. A phage attacks a bacterium by attaching to it so that its DNA genome can slip through its tail into the cell. The phage genome immediately takes over the cell, disrupting its normal functions and converting it into a little factory for manufacturing more phage. The phage DNA starts to replicate, making many copies, and the cellular protein factories start to make enormous amounts of phage proteins. The cell begins to fill up with new phage, and in a typical infection it takes only about half an hour for perhaps a few hundred phage particles to accumulate. Then the cell suddenly bursts open, releasing the new phage, which can then attack other susceptible bacteria and repeat the process. In the laboratory we can take a rich culture of bacteria, so rich that the growth medium is cloudy with bacteria, and infect it with phage; the phage can kill the bacteria so quickly and effectively that the medium becomes clear within hours. Essentially the same thing can happen to bacteria infecting some part of a human or animal body.

Bacteriophage are very useful for curing bacterial infections because of their host specificity and ability to evolve with the host cell. The bacteria causing an infection may be a mixture of different types, and some of them might develop some resistance to any single phage, so phage are usually administered as a cocktail of several different species, in order to attack a range of bacteria and to greatly reduce the probability of resistance.