We are in the middle of a war that has been raging for several billion years, and its continuation is certain for as long as life exists on our planet. The number of bacteria on earth has been estimated at 4-6 x 1030 cells,equal to approximately 350 – 550 Pg of carbon (1Pg = 1015 grams). That’s a lot of carbon for a little thing. For a long time, bacteria were thought to be the most abundant and diverse organisms on the planet, but for every organism there is a parasite, and the bacteria’s mortal enemy is the phage (or the bacteriophage as it is also known). Phages are viruses of bacteria, and outnumber their hosts 10 to 1. Every day, these viruses kill half the bacteria living in the oceans, and they are infecting bacteria all over the world at a rate of 10 trillion times a second. But we didn’t even know they existed until the 20th century.
It was a French-Canadian microbiologist, Felix d’Herelle in 1917, who first coined the term “bacteriophage”, but cleverer than that – he also realised their potential. What can you do with a natural, rapidly reproducing, bacteria killing machine? Well, use it to kill bacteria of course! And so, he began to make phage concoctions hoping to create a treatment for dysentery. He later set up other commercial phage products which were marketed by the company which we know today as L’Oréal. I’m not sure the adverts for a remedy for dysentery would be quite as glamorous as the ads we see today (picture a voluptuous blonde bombshell, staring seductively into the camera – “Don’t let dysentery get in the way of your day. Because you’re worth it”).
However, with the introduction of antibiotics in the 1940s phages were forgotten in the Western world, with only small regions of the Soviet-Union continuing use. As such, much of the research which continued into its use as a therapy against bacterial infections was conducted and written in Soviet countries, and published in Russian journals which the Western world did not have access to. But still in Eastern Europe and some countries in the Middle East you can buy phage cocktails over the counter – either for skin or stomach infections, depending on your ailment – without prescription, and without diagnosis. But how safe are they?
Without specific and thorough pharmaceutical tests, it would be foolish to say it is impossible they carry a risk. There may be risks associated with how they interact with our own gut commensals, potentially changing microbial community dynamics, and impairing digestion (antibiotics also carry this risk). However, the truth is, at this moment you are made up of around 1013 human cells, 1014 bacterial cells, and about 1016 phage particles. So your body is already quite adapted to their presence.
Phages have a number of benefits which make them attractive for therapeutic use against harmful microbial agents. Firstly, they seem to be highly specific to prokaryotes, which means they pose no threat to our own eukaryotic cells. Secondly – and perhaps the crux of the argument – is that they are able to coevolve with their host. The reason we are now facing a new and demoralising fight against pathogens which are resistant to multiple antibiotics is that antibiotics are not living organisms, and therefore are unable to adapt to bacteria which become resistant. Phages, on the other hand, can evolve to re-infect a host type which might have initially evolved resistance. This is known as an arms race – it is the same process we see between the cheetah and the gazelle. The cheetah eats the gazelle, so the gazelles which are fastest will be able to escape, survive and have babies; as such, the species on the whole will gradually evolve to be faster. In response the cheetah must evolve to be faster too if he hopes to catch his dinner, and so the fastest cheetahs are the most likely to be able to catch the prey, and have and feed more babies; and so cheetah’s as a species evolve to be faster… over thousands of years the results are svelte, speedy creatures with features adapted to these predator-prey dynamics. So now picture a bacterial cell and a phage (or have a look at the picture associated with this post) – the phage attaches to the bacterial cell surface, usually targeting a surface structure such as a channel used to take up nutrients or a motility structure (like the flagella – a tail like appendage which helps the bacteria to swim) and then injects its DNA into the cell. This phage DNA then hijacks the replication system used by the bacteria to replicate its own genome, and multiplies within the cell. It then packages this DNA up into new protein coats, also made courtesy of the bacterial cell, and finally bursts out of the cell – killing the host in the process – releasing the new viral progeny to hunt for a new victim. In order to resist phage infection the bacteria can change shape and organisation of these surface structures so as to prevent binding; in response the phages find new ways to bind to these modified structures – and so on and so forth. And it is due to these “adapt or die” dynamics that arms races continue. However, whereas the race between the cheetah and the gazelle needs to play over thousands of years before we can observe a change, bacteria and viruses have much faster generation times (about one generation every 20 minutes), so these changes can be observed over a number of days.
So why, if phages have the potential to fight all kinds of bacterial diseases, are they not already available for use? Well, getting permission and patenting for a new drug takes time – and phages in particular come with their own set of problems. Firstly, it is a wide source of debate as to what phages should be classified as in terms of a therapeutic agent. Something which is alive (although whether viruses are living or not is a whole new debate, which I will save for another post) is a lot more difficult to patent than a small well-defined molecule made industrially – this will affect how the drug can be administered and indeed, what type of trials can be conducted in order to produce new therapies. Secondly, not enough is known about their biology in order to understand all the consequences which may develop through clinical use – for example, there are two types of phages, lytic and lysogenic. The lytic, which I previously described, is an obligate killer and will inevitably end in the death of its host – good for clinical treatment. The lysogenic phage however is a little trickier, this does not kill the host but inserts its DNA into the host’s genome and replicates via vertical transmission. The trouble here is that because they have the biological machinery to move around the genome, they also have the potential to carry dangerous genes between different bacteria – and if they carry a gene which makes a once harmless bacteria into an infectious pathogen, this will of course have negative implications for clinical treatment. So we must ensure we know the conditions under which a lytic phage could become a lysogen. Thirdly, we also must guarantee that we can keep an arms race running; otherwise we will find ourselves in a similar situation we now face with antibiotics, with multi-resistant strains of bacteria which are tolerant to all the phages we can throw at it. Early trials have suggested that a combined approach using antibiotics and phages might be the best option. When a bacteria mutates to become resistant to an antibiotic or a phage it usually changes the function of the cell in some way. It seems that a combined approach would need the bacteria to change in so many ways that it would be left weak in the environment and our immune system should then be able to clear the infection. It also reduces the risk that bacteria will become completely resistant to one or the other treatment. As an aside, there are other issues with re-classifying phages to enable them to be used as drugs. All the therapies which are still used in Eastern Europe would be removed from the shelves and the small cottage industries which have manufactured them for decades would go out of business – making room for the pharmaceutical giants who will have the money and power to ensure their products get the EU stamp of approval.
It’s clear phages are very good at infecting bacteria – they have had several billion years to perfect the art! But it is only relatively recently that their potential is being realised and possible applications being explored. At a time when multi-resistant “super bugs” are beginning to pose a real threat to modern medicine, it’s an exciting time for researchers to be involved. It seems to me, the best case scenario is an effective new phage therapy which evolves with the infection; reducing the incidences of life threating conditions caused by multi-resistant pathogens we are unable to fight using current antibiotics. And the worst case scenario? If we are unable to use phages in their natural form, then they surely hold secrets to effective attack on bacterial populations – and by understanding these processes we may be able to use and develop new therapies to target pathogens in different ways. Either way it seems that in fight against bacteria, we may be beginning to discover a new type of weapon with which we can fight back.