Multi-cellular organisms have solved a special problem that single celled organisms lack: how to make cells cooperate together and restrain themselves from reproduction. In single cell organisms, there is no, or little, cost to replication. Every division and replication results in higher fitness. Not so for multi cell organisms. Multi-cell organisms benefit because cells can differentiate and perform different jobs. This division of labor allows increased flexibility and potential for adaptation. But, flexibility comes with a cost: specialized cells must cease or slow their own cell division. This reduction in cell division is altruistic but is also potentially evolutionarily unstable. How? Rogue cells that prioritize replication are favored by short term selection. These traits benefit the cell, but not the organism as a whole. This conflict is inherent in multicellularity. When cooperation breaks down, cancer happens.
In cancer, clonal cells evolve ways to escape restraints on growth and motility. These evolved traits favor the fitness of the clones (in the short term anyway) usually to the detriment of the organism that gave rise to the cancer. However, cancer lineages are usually dead ends, so that adaptations that allow cancer are not passed on from generation to generation. New cancers have to start from scratch, evolving de novo mechanisms to evade controls on growth and reproduction in each lineage. At the same time, anti-cancer adaptations have evolved in multicellular organisms that anticipate cheating cells. Those adaptive mechanisms control and remove proto-cancerous cells. Multi-generational selection thus permits ongoing evolution of adaptations against outlaw cells. This keeps cancer at bay, at least most of the time. Restraints on cellular cheating create conditions that allow somatic cells to achieve specialized functions, even though they have no chance of leaving direct cellular descendants into the next generation. Specialized germ line cells in the ova and testes alone ensure that copies of the body’s genes make it into the next generation. Cells in specialized organs – including the brain, liver, heart, lungs, gut, and kidneys – cooperate with each other and support of the survival and success of the cell lines in the gonads. The idea that somatic cells are disposable and exist to support germ cells underlies the disposable soma hypothesis of aging. It is also a scheme that only works if copies of genes in somatic cells are shared in germ line cells. 100% relatedness, thus, is a prerequisite for specialized cooperation.
In addition to familiar organs in the body, recent work has illuminated the complex actions of the microbiome that appear to function in combination with other cells in the body. In fact, many observers cite the microbiota as an organ, akin to the liver, lungs, and heart of its host. The microbial organ is unlike any other, however, because it is not made up of the same genes as the rest of the host. The problem of cooperating with the other cells in the body pales in comparison with the problem of cooperating with the multiplicity of microbes – the trillions of bacteria, fungi, protozoans, and viruses that make up the microbiome. These microbes’ genes outnumber the human genome by a factor of 100. Cells in the human body have the benefit of being closely related (most cells being 100% related and identical except for copyediting errors of DNA that occur at a low rate; there are exceptions to this rule, of course). Host cells share no genetic material with the microbiome. How is it possible that all these cells get along?
Other examples exist in biology of vital functions being achieved by foreign DNA. In a remarkable and disgusting example, the tongue eating louse consumes and replaces the tongue of its fish host. The parasite then takes the place and function of the previous organ. Most of us would not outsource the function of our tongue, or any other part of our body, to a parasite. We’d be right to assume that there is a catch, even if the foreign agent can perform the function of an organ. The same is true for the microbiome. Alliances between host and microbe can exists, but these are fragile alliances. The mutually beneficial relationship is transactional and often conditional on a continuous transfer of resources from one partner to the other. In addition to resource transfers that we described in this NYAS paper, an entire arm of the immune system may have evolved to keep the microbiome in check, rewarding fitness enhancing activities of the microbiome while discouraging fitness reducing microbes. This innovation occurred approximately 500 million years ago, appearing first in jawed fishes with the first adaptive immune system.
The next step towards a cooperative microbiome occurred with the appearance of mammals 160 million years ago. With mammals came milk, and the interkingdom provisioning of milk resources. Although we commonly think of milk as a resource transfer between mother and offspring, it involves transfer of maternal resources to the newly established infant microbiota – metabolically costly human milk oligosaccharides are indigestible by infant mammals, but readily support the growth of protective Bifidobacteria.
There is evolutionary precedent to a cooperative relationship forming between unrelated single cell organisms. After all, this is what is presumed to have led to the ancestor to modern eukaryotes to on-board the first mitochondrion. The first mitochondrion may have resulted from a failed attempt at predation, or phagocytosis. A partnership could have started when both partners gained a benefit from the interaction, in much the same way the modern mitochondria are provided resources, safe haven, and guaranteed passage of mitochondrial genes into the next generation (at least in female hosts that reproduce!), and the host obtains an energetic return that provides a fitness benefit. This mutualism is evolutionarily stable for another reason. There are no free-living mitochondria. Shared fate, ensured by obligate vertical transmission, tends to favor mutualism. This is as opposed to parasitism, which is more likely when the host and symbiont can do just fine without each other.
Most members of the microbiota are perfectly happy to adopt a free lifestyle independent of their hosts. They can, and often do, jump ship at a moment’s notice, making mutualism and cooperation more unstable as compared to the mitochondrial example. This is why the microbiome is a reservoir of potential pathogens that can emerge from within to cause infection. Microbiomes harboring pathogens that can wreak havoc on the host is the basis for the so-called Trojan horse hypothesis. Because of these risks, the host immune system must remain forever vigilant of threats coming from the microbiome, and might be willing to partner with less dangerous microbial allies to ward off even worse interactions with even more harmful specialized pathogens.
More recent innovations have helped human hosts extract even more benefit from the microbiota. The advent of fermented foods – occurring at least 10k years ago – helps combat the colonization of food-borne pathogens into the microbiome. Thus intentional food fermentation can be considered a strategic partnership between domesticated microbes and humans. This partnership permits food preservation for a longer duration of time and prevents the loss of food resources to spoilage microbes.
I would argue that the elimination of specialized pathogens with vaccination, pioneered by Edward Jenner in the late 1700s, also promotes cooperation. Vaccines against Diphtheria and Haemophilus influenzae, among others, have extirpated harmful bacteria from the microbiome of children, with a positive effect on childhood mortality and public health. The ability to combat invasive bacterial disease with antibiotics has also had an undeniably positive effect, by reducing the chance that an invasive pathogen arising from the microbiome can harm or kill. Of course, antibiotic use and overuse have well-documented negative impacts on the human microbiome, which I laid out in the entry: Ten reasons to avoid an antibiotic prescription. But on balance, and when used appropriately, antibiotics help us manage some of the consequences of cooperation breakdown coming from the microbiota. Who among us would forego them completely, I wonder?
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Evolution of human diet and microbiome-driven disease
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Joe Alcock
Emergency Physician, Educator, Researcher, interested in the microbiome, evolution, and medicine
EvolutionMedicine 
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