Bacteriophages (phages), the viruses of bacteria.

Bacteriophages are the most numerous viruses on Earth, and viruses are more common than bacteria, the most numerous of cellular organisms. Specifically, bacteriophages are the viruses of bacteria, that is, they are sequences of genes (genomes) which move around from bacterium to bacterium while encased within protein shells called capsids, often killing bacteria in the process. Bacteriophages are hugely important to the ecology and evolution of bacteria, have enormous impacts on the global carbon cycle (which among other things controls whether climates globally warm), represent one promising means by which medicine's current antibiotic crisis – think MRSA – may be overcome. Phages also contributed greatly to biology's understanding of life in general and especially at the molecular level. They in addition were key to the development of genetic engineering. In short, phages are perhaps the biological world's least appreciated superstars.

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What are phages?     (return to top of article)

Bacteriophages were formally discovered in the mid to late teens of the 20th century, with the first publication coming out 1915 and then a second in 1917. They were early on speculated to be viral, but their dominant property was an ability to macroscopically "eat" bacterial cultures, specifically by reducing the cloudiness (turbidity) of those cultures. As a consequence of this property, rather than being described as "poisons" (the original meaning of the word "virus"), instead the term "phage" was attached to them, which means to eat or to devour, in Greek. Thus, a bacteriophage is an entity which eats bacteria, though today we know that this descriptor is not perfectly accurate. Nevertheless, phages are capable of macroscopically as well as microscopically destroying populations of bacteria.

Notwithstanding its name, a phage is a virus. A virus is a piece of nucleic acidRNA or DNA – which is surrounded by a coat that often predominantly consists of protein (called capsid proteins, or capsomeres). The protein capsid's job is protection of the nucleic acid, the genome of the virus, as it moves that genome from infected cell to newly acquired cell. Cell acquisition is the other job of the capsid, the attachment of the virus to the surface of the cell followed by the movement of the virus' genome into the cell. There virus genes are expressed, giving rise to a diversion of the cell's metabolism (chemical reactions) towards the production of new virus. A successful virus is both effective in finding cells to infect and capable of overcoming cellular or organism-level defenses (collectively, immunity) against virus infection.

A phage specifically is a virus which infects bacteria. In the past few decades microbiologist's have come to understand that "bacteria" actually represent a unique taxonomic category, domain Bacteria, which differs in fundamental ways from two other domain-level taxa, domain Archaea and domain Eukarya (domain Eukarya includes us). Unlike these two latter categories of cellular organisms, whose viruses are called simply viruses, because of the unique history of phage biology it is relatively rare to speak of the viruses of bacteria in those terms. That is, we typically refer to these viruses as bacteriophages, or phages for short. Phages, thus, are the viruses of domain Bacteria. Furthermore, phages are not able to infect members of either domain Archaea or domain Eukarya.

What are phages like?     (return to top of article)

Viruses are very diverse, in part because there are many ways that a cell can be hijacked to produce more viruses, and also because there are many ways that cells can block virus infections. Thus, viruses probably are subject to what is known as frequency-dependent selection for diversity. Phages are no exception. Like viruses in general, phages vary in terms of the basic structure of their genomes (their nucleic acid) as well as the structure of their protein capsid, and even can have lipids (fat-like molecules) in their coats (as do many animal viruses). In short, phages can have DNA or RNA genomes (unlike cellular organisms whose genomes uniformly consist of DNA), they can infect in ways that kill their hosts or in ways which do not (just like, for example, animal viruses), and they can take on a variety of morphologies, some relatively simple, and some quite complex.

It is these morphologies which are the most recognizable feature of phages. In particular, phages can be differentiated into those which possess appendages called tails and those which do not. The tail is invariably attached to a head – at least among functional phages – and together they form the "lunar lander"-looking structure that nearly universally says "virus", even to many who have little idea of what a virus in fact is. It is within the head, which takes on a geometrical shape called a polyhedron (more strictly, an icosahedron), that the DNA is found, and it is through the tail that the DNA is delivered to an unsuspecting bacterium. Alternatively, phages that possess unusual genomes, consisting in some cases of either RNA or only half of the DNA double helix, or which possess lipids in their capids, are both not and never tailed. To the extent we can describe viruses as organisms, the tailed phages in fact appear to be the most numerous category of organisms on Earth.

The primary phage task is the infection of bacteria, production of new phages, and the release of those phages from the infected bacterium. For tailed phages that release consists of lysis, which is the destruction of the outer portion of the bacterium so that the phage virions (virus particles) that form inside of the infected cell can reach the outside of new cells to infect. This lysis can be viewed as a form of decay, that is, lysis is one means of converting bacteria into soluble nutrients which are then available to other organisms, where these other organisms to a large extent consist of other bacteria. Alternatively, phages, in a process called transduction, can fail to lyse a bacterium, following infection, but instead carry new genes into that bacteria, in some cases converting otherwise benign bacteria into potential pathogens. Ongoingly, all around us, and even inside of us, phages affect bacteria in ways that can have profound effects on the world around us.

What are phages good for?     (return to top of article)

Phages play important roles in the ecology and evolution of bacteria. In fact, bacteria probably wouldn't be bacteria, at least as they exist today, without phages moving their DNA among themselves (phage-mediated DNA transduction) or phage-mediated diversification of their bacterial prey (frequency-dependent selection for more diverse bacteria-encoded anti-phage mechanisms along with the elimination of too successful bacteria, i.e., so-called "Killing the winner"). Much of what goes on between phages and bacteria, however, represents something of an ecological background, that is, it is simply what happens out there in the nature. Alternatively, the ability of phages to move DNA around, as noted, can give rise to bacterial pathogens, and indeed a number of phages actually encode toxins which can make us sick, including the toxins (actually "exotoxins") associated with the bacteria responsible for cholera, diphtheria, and even E. coli O157:H7, the so-called hamburger E. coli. The term "antitoxin" in its original popularization in fact was short for "anti-diphtheria toxin" where diphtheria toxin is the proximate cause of diphtheria – that is, the bacterium without this toxin will not cause diphtheria – but, in fact, diphtheria toxin is a expressed from a phage gene.

Given this apparent infamy, can we still speak of phages as, well, good? The answer seems to in fact be yes for at least four technologies. First, research on phages both underlies and continue to provide important tools for the molecular analysis of life, a key component of modern biomedical research (think biotech industry). Second, phages play important roles in the monitoring of environmental quality, especially by serving as surrogates for human viruses, both as indicators of fecal contamination and as models for virus dissemination especially in association with water. Third, phages have and continue to play important roles in the identification, classification, characterization, and detection of especially pathogenic bacteria. Lastly, phages are capable of killing both nuisance and pathogenic bacteria, in the guise of so-called phage therapy. I close this essay with a discussion focusing on the latter.

Phage therapy     (return to top of article)

Phage therapy is the application of phages that can kill bacteria to reduce in number or eliminate those bacteria. Phage therapy has four advantages over conventional antibiotic therapy. First, relatively rare encoding of exotoxins aside, phage virions are inherently safe, consisting of just benign proteins and DNA, and therefore display a larger therapeutic window, the difference between their toxic dose and their therapeutic dose. Vancomycin, typically described as an antibiotic of last resort, instead displays a very small therapeutic window, meaning that, unlike with phages, it is relatively difficult to avoid adverse effects. Second, phages are fairly narrow in their spectrum of activity, meaning that with phage treatment it is possible to kill bacterial pathogens while avoiding harming of normal flora bacteria, that is, our good bacteria. Because of this narrow spectrum of activity, with phage treatment superinfections are must less likely (contrast antibiotic-associated "C-Diff" or vaginal yeast superinfections), plus phages may be employed prophylactically with little fear of adversely affecting patients.

The third advantage of phages is that they often are capable of replicating to higher densities in situ, that is, within their target environment, such as our bodies. This may allow phages to penetrate further into bacterial infections, such as those which have formed biofilms. It also eases dosing concerns, as above, though in the other direction, that is, in addition to delivering too high phage doses beging less of a concern (in comparison to many antibiotics), in fact delivering too low phage doses, at least under certain circumstances, also can be less of a concern since phages reaching bacteria will tend to replicate. This replication produces locally high densities of phages which, in turn, can lead to bacterial demise. Fourth, and finally, phages are hugely numerous and hugely diverse. Therefore the "discovery" of novel phages with novel activities (especially novel spectra of activity) is very simple, often involving little more than a short trip down to a local sewage treatment plant for a sampling of untreated influent (don't worry, not only is this a standard procedure in microbiology, but the phages are fully separated from the rest of the components of sewage well before they are turned into a product). With modern sequencing technology along with bioinformatics (the analysis of the genes of organisms) even full phage characterization can be a relatively trivial endeavor.

Concluding remarks     (return to top of article)

Phages are natural, ubiquitous, in most circumstances harmless, and relatively easy to thoroughly characterize. They have the useful property of being able to kill bacteria that we don't like or want, plus have been used in this regard for going on one-hundred years. With the potential to become a technology of first resort in the humanity's ongoing battle against infectious disease, it is just a matter of time before the term "phage" becomes a household word.

I have additional writings that can be viewed as introductions to what phages are all about, including an Encyclopedia of Microbiology entry (Hyman and Abedon, 2009) and the introductory chapter to my 2008 book on Bacteriophage Ecology (see link, below), and both as listed in my CV. If you are interested in these or other publications on phages, please write to me.

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