This week we have something special: an excerpt from Tom Ireland’s excellent new book on phages, called The Good Virus. Tom Ireland is a freelance science journalist who “makes complex topics like microbes to mental health, biohacking and bioethics accessible and fun to read”, and has written science stories for places like BBC and New Scientist.
The Good Virus looks at phages’ role in medicine, molecular biology, and the planet’s ecosystems. In this extract, Ireland explores how marine phage ecology is helping to create new insights that can help phage therapy.
I’ve just begun to read the book, and I love how the tone strikes a good balance between casual and scientific, making it an easy recommendation to aunts, uncles, and grandparents who want to learn more about phages.
Outlets like New Scientist and the New York Times have been raving about it, and it’s also scoring high ratings across Good Reads and Amazon. If you’re curious to get your own copy, please pick up one up from your local bookstore — or buy online from your local bookstore with bookshop.org. You can also find more information from the US publisher’s website or the UK publisher’s website.
If you’ve started reading it, let us know what you think!
An excerpt from The Good Virus
Forest Rohwer looks more like a former Grateful Dead roadie than one of the world’s leading viral ecologists. With long grey hair and messy grey stubble, often kitted out in black T-shirt and black boots, he speaks in a surprisingly soft and slightly squeaky West Coast tone. Decades ago, Rohwer translated his love of nature and hunting – from big game tracking to spearﬁshing – into a career spent studying marine ecosystems – coral reefs particularly – and hunting viruses. When I ask him where he’s been to study phages, he answers with a smile and an eyeroll: ‘Like, the whole world.’
Despite his surfer dude demeanour, Rohwer has been instrumental in developing the complex molecular techniques that now allow virologists to ‘ﬁnd’ tens or even hundreds of thousands of different viruses at a time from samples of water, without the need to ever grow or see them. Known as ‘shotgun metagenomics’, the process involves chemically isolating all the viral DNA in a given sample and analysing it together, using computer analysis to estimate which of the DNA sequences in there represent unique viral species.
It was these genetic techniques that caused the number of known viruses in the world to spiral wildly from the early 2000s, from a few thousand to tens of thousands, and then to hundreds of thousands. As these results poured in, each one revealing more and more completely new viruses, it led some scientists to predict that there may be trillions of different species of phage in the world.
I ask Rohwer if he thinks it is even possible for researchers like him ever to get a handle on the full diversity of phages out there. In 2005, he published a paper called ‘Here a Virus, There a Virus, Everywhere the Same Virus’, in which he argued that perhaps all the different phages in the world have been so well mixed by ocean currents that the diversity isn’t quite as mind-boggling as we think. So while you might ﬁnd hundreds of thousands of different types of virus in a single litre on one side of the Atlantic, a litre on the other side of the world might contain roughly the same hundred thousand viruses; what matters in any given location is which of those phages are actually active, and which are present in large numbers. If this is the case, researchers should at some point be able to get a handle on all the different types of virus there are on the planet – although that may still be some years from now.
But that was 2005. Rohwer is now working on a theory that maybe there is not a quantifiable amount of phage species out there for scientists like him to catalogue and put a number on. Instead, he is starting to think the immense diversity found so far may be a result of new phages constantly ‘coming into being’ in a way that we don’t yet understand. Does he mean evolving into new species, but very quickly? I ask. No, he says, with a pause for added mystery. ‘Entirely new viruses may be emerging from the microbial ether more suddenly even than that’, he says. What could be driving that? I respond. ‘Probably magic,’ he says, laughing tiredly at the enormity of the question. ‘When you’re hunting for something new like that you can’t know what you’re looking for. You just have to design the way of hunting that helps you find it.’
If you’re beginning to think Rohwer’s work sounds esoteric and obscure, it isn’t. In fact, it is one of the rare ﬁelds where our understanding of marine systems is ahead of our understanding of human systems, rather than the other way round. Rohwer’s work has had a direct impact on helping us understand how the natural ecology of bacteria and viruses can affect human health.
Take his work on the phages living among the beautiful corals of the Paciﬁc and Indian oceans for example. His years studying reefs around the Caribbean and Sri Lanka have showed that bacterial colonisation of reefs is a primary factor in their decline around the world, and that environmental stresses caused by humans, such as overfishing, is likely the cause of these underwater bacterial infections. The bacteria that live on the coral are themselves infected by a variety of specially adapted phages – and so phages could have a major role to play in saving coral reefs around the world, or at least slowing their decline, by keeping harmful bacterial colonisation in check.
But here’s where it gets really interesting. In the early 2010s, Rohwer and his then-postdoctoral student Jeremy Barr observed that there were extremely high numbers of phages in the slimy mucous layer found on the surface of corals – up to four times as many as in the surrounding environment. These mucous surfaces form a kind of sticky protective physical barrier between the interior of the coral and the environment, but also provide ideal conditions for bacteria to stick to, feed on and colonise. They are surprisingly similar to the mucous surfaces found in the lungs and guts of many animals, including humans.
Rohwer and Barr discovered that phages living near these reefs had evolved the ability to adhere to and penetrate the corals’ mucous layer. The reward for the phages that could penetrate the mucous was access to lots of bacterial hosts immobilised in the mucous, and therefore greater reproductive success. Artiﬁcially removing the phages increased the chances of the coral beneath the mucous layer becoming infected with bacteria. So, in return for access to lots of potential hosts, the phages were helping reduce bacterial growth on the outer surface for the coral.
The researchers quickly found this neat symbiotic relationship was happening not only in corals but also in the mucous of more complex marine organisms like sea anemones and in ﬁsh. In all these organisms, phages were acting like live-in security guards, packed into their mucous in high numbers and helping stop bacteria from colonising these important barriers between their insides and the outside worlds. As the organisms co-evolved, the marine animals had made their mucous more attractive to the phages. In return, the phages were providing them with a kind of external immune system.
Rohwer’s student, Barr, now head of the bacteriophage research unit at the University of Monash in Melbourne, began to wonder if the same phenomenon was occurring in the human body too. And, perhaps unsurprisingly at this point, it was: the same molecules that helped the phages stick to mucous in the sea could be found in the mucous surfaces throughout the human body.
Back in the 1920s, one of Felix d’Herelle’s more outrageous claims was that phages were an integral part of our immune system, a kind of live-in virus that our bodies had co-opted to counter bacterial infections on our behalf. He was widely derided for the idea and, until just a few years ago, it was still widely believed that phages did not interact with animal cells. But now, almost a century later, Barr’s lab in the suburbs of Melbourne is focusing speciﬁcally on what he now calls our ‘third immune system’: the ecosystem of phages that protects us from bacteria alongside our other, more well-studied innate and adaptive immune systems. Barr’s work has upended the idea that phages do not interact with mammalian cells, telling Science in 2017 that the notion was ‘BS’. He has even observed phages being engulfed by human cells and trafficked around the body. The exact way this is achieved is unclear, but the work tantalisingly suggests that our bodies actively co-opt and deploy phages where they are needed like working parts of the immune system. His work also suggests that through our guts, we absorb as well as host tens of billions of phages each day. Phages seem able to freely penetrate our bodies; ending up in areas of the body once classiﬁed as ‘sterile’ and lacking microbes, for example the blood, lungs, liver, kidney and even within the brain. It goes a long way to explaining why phages only sometimes illicit an immune response when administered therapeutically – our bodies have co-evolved with these viruses and rarely see them as foreign objects, unlike other viruses.
So, we know now that the delicate barriers that separate our bodies from the outside world appear to have evolved to be especially welcoming for phages, and that our bodies interact with phages in many ways once thought impossible – all thanks to phage ecologists studying seemingly obscure marine viruses at the bottom of the sea. Barr is now studying how phages modulate the delicate balance of bacteria in our intestines, known to be associated with many different types of poor health, in the hope that one day phages can be used to reverse or correct disorders of the gut.
Meanwhile, Rohwer is now using his understanding of the complex microbial diseases of coral to tackle cystic ﬁbrosis, a disease in which the primary problem is an excess of mucous, which then leads to extremely persistent infections. ‘Since we’re already working with a lot of mucus, it makes sense,’ says Rohwer nonchalantly. His knowledge of infections on coral reefs can be applied to the complex community of viruses and bacteria in the lungs of cystic ﬁbrosis patients, and their dynamics, helping us see the lungs of cystic ﬁbrosis patients as entire ecosystems, not just as unhealthy organs.
Further studies of the ecology of phages in complex ecosystems – captured in the messy real world, rather than in carefully controlled lab experiments – is providing important insights for those hoping to use viruses to treat infections. The warm, wet environs found in and on the human body are complex microbial ecosystems too, after all.
In ‘the wild’, phages rarely completely eradicate populations of their hosts: to do so would mean they have no cells in which to replicate. Instead, microbial communities exist in a state of permanent ﬂux, where dominant bacterial strains become subject to intense viral attack and less numerous strains are left in relative peace (or with phages lurking quietly inside them). When the dominant strain is killed to the point that its abundance declines below a certain point, the amount of phages available to kill them declines too. Another bacterial strain starts to dominate and the phages of that particular strain start to proliferate. This dynamic, known as ‘kill the winner strategy’, tells us that a single type of phage is unlikely to ever completely eradicate a bacterial pathogen from our bodies – but it could degrade the population to the point where our immune system, or antibiotics, or different phages, or a combination of all three, ﬁnish off the remaining bacteria and clear the infection. If all this has been gleaned from just over thirty years’ worth of work on phage ecology in a few marine and soil ecosystems, imagine what we could learn from the rest of the phages out there in the world.
For now, a surprisingly small but passionate community of viral ecologists are tasked with a near-impossible job: ﬁnding, analysing and classifying the most abundant and diverse life form on the planet. The vastness of their task is hard to comprehend: this super diverse and hyper-abundant group of viruses represents the largest reservoir of unexplored genetic information on the planet. With potentially trillions of different types of phages out there, many refer to them as the ‘dark matter of biology’.
US Edition: https://wwnorton.com/books/9781324050834
UK Edition: https://www.hachette.co.uk/titles/tom-ireland/the-good-virus/9781529365245/
Published with permission of Hodder & Stoughton. © Tom Ireland 2023. The Good Virus: The Untold Story of Phages by Tom Ireland (published in the UK by Hodder & Stoughton, £25.00 and in the United States by W. W. Norton, $30.00).