Edited by Sally Davies
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Cicadas might be a pest, but they’re special in a few respects. For one, these droning insects have a habit of emerging after a prime number of years (7, 13, or 17). They also feed exclusively on plant sap, which is strikingly low in nutrients. To make up for this deficiency, cicadas depend on two different strains of bacteria that they keep cloistered within special cells, and that provide them with additional amino acids. All three partners – the cicadas and the two types of microbes – have evolved in concert, and none could survive on its own.
These organisms together make up what’s known as a holobiont: a combination of a host, plus all of the resident microbes that live in it and on it. The concept has taken off within biology in the past 10 years, as we’ve discovered more and more plants and animals that are accompanied by a jostling menagerie of internal and external fellow-travellers. Some of the microorganisms kill each other with toxins, while others leak or release enzymes and nutrients to the benefit of their neighbours. As they compete for space and food, cohabiting microbes have been found to affect the nutrition, development, immune system and behaviour of their hosts. The hosts, for their part, can often manipulate their resident microbiota in many ways, usually via the immune system.
You yourself are swarming with bacteria, archaea, protists and viruses, and might even be carrying larger organisms such as worms and fungi as well. So are you a holobiont, or are you just part of one? Are you a multispecies entity, made up of some human bits and some microbial bits – or are you just the human bits, with an admittedly fuzzy boundary between yourself and your tiny companions? The future direction of medical science could very well hinge on the answer.
The American evolutionary theorist Lynn Margulis, who popularised the theory of symbiosis, first coined the term ‘holobiont’ in 1991. She was interested in long-term, tightly integrated associations such as those evident in lichens – the crusty-looking growths found on rocks and trees, made up of fungus conjoined with algae. Margulis thought that there was a tight analogy between an egg and a sperm coming together to form a new organism, and the coming together of two species to form a new symbiotic consortium, which she called a holobiont.
Margulis argued that the interactions within a holobiont aren’t too different from the life cycle of sexually reproducing organisms. The partners are integrated wholes that die and reproduce as one. But instead of sending out tiny cells to reproduce, holobionts send out individual organisms of different species.
With this framing in mind, when biologists began to use the term in the 1990s, they applied it to a few (usually two) organisms. But the word took on a very different cast in the hands of the American coral reef biologist Forest Rohwer and his colleagues, who defined a holobiont as a host and all of its associated microorganisms.
Two protagonists just aren’t enough when it comes to explaining the evolutionary success of corals. They are made up of clusters of polyps, tiny wiggling things that get by with just a few tentacles and a toothless maw. Coral polyps reproduce by cloning themselves, and then sticking together to form large colonies, supported by a jointly fashioned skeleton. The most spectacular corals work hand-in-hand with photosynthetic algae that they host within their own cells. The algae provide nutrients via photosynthesis, while the coral gives the algae both food and protection. And those simple little polyps don’t end their symbiotic relationships there. Corals don’t possess a complicated immune system to fend off pathogens; instead, they seem to selectively cultivate helpful or benign bacteria, which crowd out the harmful microbes. Corals also produce mucus that appears to be able to trap phages, viruses that infect and kill only bacteria. An enemy of an enemy is a friend, after all.
Rohwer and colleagues, unaware of Margulis’s idea, introduced the term holobiont to capture the dynamics of coral physiology. As a result, by the early 2000s, the scientific literature contained two contrasting definitions. One picked out an organism-like symbiotic pair that reproduced, while the other identified an ecological community of microbes indexed to a host.
For a time, the ecological account prevailed. But Margulis’s physiological conception of holobionts was revitalised in the late 2000s as part of a new theory: what’s known as the hologenome theory of evolution. Advocates merged both versions of holobiont into something a bit more conceptually loaded. On this view, the ecological notion of holobiont (the host and all its resident microbes) is given additional properties. It’s an entity that’s coherent enough to have its own hologenome, made up of the host genome plus all the microbial genomes. A major implication of this theory is that natural selection doesn’t just act on the genome of individual organisms: it acts on the hologenome of holobionts, which are seen as single units that can evolve at the level of the holobiont.
Today, researchers engage in fierce debate over which forces shape holobionts and host-microbiome systems. They can be roughly split into two factions, the ecological and the evolutionary. On the ecological side, holobionts are seen as complex and dynamic ecosystems, in constant flux shaped by individual interactions from the bottom up. So you are part of a holobiont. But this stands in opposition to the evolutionary account, which casts holobionts as higher-level entities akin to organisms or units of selection, and believes that they are shaped as a whole from the top down. On this view, you are a holobiont.
The ecological and evolutionary views make for very different predictions about how a holobiont will change over time. Evolutionary theory predicts that the parts of a unit of selection will tend to cooperate: to sacrifice their own interests for the good of the whole. Ecological theory, by contrast, predicts competition and exploitation: parts will cooperate only insofar as it benefits them. Think of the differences between an ant colony and a motley assortment of insects fighting over scarce resources.
A dominant view in medicine treats the body as a battleground where any invaders are bad and must be exterminated. But in an ecosystem, there are no bad guys, just species playing different roles. If the ecological account of holobionts is true, a human host is more like a habitat to be managed, with the right balance and competition between different kinds of microbes being an important consideration. What counts as healthy can depend on what kinds of services we want out of our attendant ecosystem. If the microbes in a holobiont are more like ants in a colony, or genes in a genome, they are parts of a larger integrated whole. So we might expect stable co-adapted partners living in concert across holobiont generations.
However, the evolutionary version of holobionts gives us reason to stick to an expanded version of the ‘us versus them’ picture of medicine. It’s just that now we have a few more allies on our side that we need to take care of. The evolutionary framework might also provide some justification for the calls for a return to a palaeomicrobiome that existed before the modern diet – for that would literally help to return a missing part of ourselves.
As things stand, the evidence leans heavily towards a more ecological interpretation of holobionts. Most of the partners come together anew each generation, and don’t interact in the ways that are necessary for higher-level integration into organismic wholes. The theoretical bar for making that transition is high, and getting over it is going to be rare. But it potentially varies from holobiont to holobiont. There is still a long and exciting scientific road ahead, as researchers begin to unravel the secret lives and complex effects of microbes on the development, behaviour and evolution of their hosts.