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Background

An Ecological Perspective on Pathology

Are diseases simply phenotypic expressions of inter-organismal interactions that are happening at a scale too small for our eyes to see?


A common belief today is that most chronic diseases are modern phenomenons caused by present conditions miss-matching our ancient genetics. Exposure to stimuli that are incompatible with the recipient (analogous to spilling coffee on your laptop causing short-circuits and system malfunction). While this type of miss-match may very well explain increased disease-prevalence in modern society, the idea that the diseases themselves and the mechanisms that drive them have a modern origin is a very difficult idea to entertain when studying the scientific literature.

Conflicts with viral, bacterial, and fungal pathogens were known even by our unicellular ancestors. Dinosaurs occationally got gout and osteoarthritis and the first documented case of cancer is 240 million years old.1)https://www.nature.com/articles/387357a02)https://onlinelibrary.wiley.com/doi/full/10.1111/j.1475-4983.2012.01151.x3)https://jamanetwork.com/journals/jamaoncology/fullarticle/2723578?guestAccessKey=36a3caee-1474-4c66-88e0-e38dc4e8304d Evidence of cardiovascular disease has shown to be a common finding in ancient humans dating back at least 6000 years, including both pre- and post-agricultural populations, paradoxically even those who lived an active life while consuming a heart-healthy diet containing lots of fatty fish.4)https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)60598-X/fulltext5)https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2757994

Ancient Mechanisms to Cope With Ancient Problems

Cells, tissues and organism respond to noxious stimuli in almost the same way today as they have for millions of years. For example, the capacity for nociception and a reflexive aversive response to environmental irritants is more than 500 million years old and is shared with our last common ancestor of flatworms.6)https://www.nature.com/articles/s41593-017-0005-0 Pro-inflammatory cytokines produced by corals are seen to work on humans, producing the same cellular response in both organisms.7)https://www.pnas.org/content/111/26/9567 The ability to mount an auto-immune response is found in plants, pushing back the potential origin of something resembling rheumatic disease to maybe more than 1.3 billion years ago.8)That is if the mechanism that complex organisms uses to differentiate self from non-self or dysfunctional-self is assumed to originate from a common ...continue9)https://link.springer.com/article/10.1007/s00425-018-2956-010)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172062/11)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1689654/ Some of the signal-pathways mediating the mechanism of insulin resistance may be evolutionary conserved between humans and fruit-flies, which would mean that they are more than 780 million years old.12)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444297/13)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536057/ Fruit-flies are also seen to develop features of the metabolic syndrome when consuming a diet with the glycemic equivalence to a banana, leading some researchers to hypothesise that they may be “naturally diabetic” in the wild.14)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444297/

The prevalence of disease and associated mechanisms can be traced throughout the history of life and since disease does not seem to occur as spontaneous phenomenons (maybe not even cancer15)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197845/) but as responses and reactions, an interaction of some kind is an obvious prerequisite. Therefore it is my belief that to understand disease, we must stop considering them as defects and instead look deeper into the fundamental mechanics of life, which is biology and specifically at the fundamental nature of interactions between life-forms, and between life-forms and the environment which is the study of ecology, to figure out what is going on and why.

The Link Between Ecology and Pathology

Interactions between organisms is a foundation for continued existence of all forms of planetary life and can be either competitive or cooperative in nature, meaning that when one organism or a group has, produces or can acquire something that the other one needs, they can either directly compete over this “resource”, or they can try to negotiate an agreement. How these interactions plays out depends largely on the biological fitness of the organisms. If the difference between them is large, the stronger one will simply outpace, defeat or enslave the other, gaining all or most of the resource, but if both parties are of near equal fitness this instead sets the stage for a potential mutualistic exchange. These scenarios play out very similarly both at the macroscopic and microscopic level with interactions between multicellular and unicellular organisms respectively, and also in interactions between the two. From this perspective, the negotiation of international trade-agreements and the acting out of large-scale human conflicts looks a lot like what goes on between bacteria and fungi that tries to co-inhabit the root-system of the same plant.16)https://www.biorxiv.org/content/10.1101/130740v1.full

In natural ecosystems, interactions between organisms eventually reach a state of equilibrium in relationship to the current environment. A stable hierarchy and flow of resources is established. However, this is not a static state and if the level of fitness in one organism starts decreasing, or if the fitness of another interlinked organism rises, the former will be in an inferior position to negotiate or compete for the resources needed to survive leading to a state of starvation and subsequent functional decline. Should the level of relative fitness of an organism drop too low they are killed and consumed wholly as a resource, becoming energy and biomass for other members of the ecosystem, which means that to prevent this from happening, a decline in the level of biological fitness increasingly has to be met by a reciprocal increase in the relative allocation of energy towards defensive strategies to respond to an increasing threat-level.17)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3601794/ This further exacerbates the problem of functional decline, mirroring the old biblical saying that for those who have, more shall be given and from those who have not, more shall be taken.

A Universal Definition of Disease

Functional decline is something that every disease have in common, even diseases that are characterised by hyper-function such as certain endocrine-disorders because they are preceded by failure of reciprocal regulatory systems. Symptoms then starts to show when the level of function in certain systems or sub-systems can’t keep up with the functional demands of specific tasks, like for load-handling systems in neuro-muscolo-skeletal disease, or nutrient-handling systems in metabolic disease.

Viewing the problem form an ecological perspective, I propose that disease, both communicable and non-communicable can be defined and specified as a state where an organism succumbs to competition from other organisms or to stressors of environmental origin which then leads to a transient or persistent decline of physiologic functions. In contrast, succeeding to to sustain equilibrium across time under the constant pressures of life equals health. These are very broad definitions, but they are applicable to pathological states in all forms of organisms, unicellular and multicellular, plants and animals, answering the question of how diseases fit into biology and ecology. Not as faults or defects but on the contrary as essential mechanisms that are as much involved with preservation of life as they are with death and demise.

Today, we are mostly protected from competition for our place in the food chain and from environmental stressors such as heat and cold. Also, industrial civilisation has a firm parasitic grip on the organisms that constitutes the human food-supply. So in theory, we should be thriving. But despite our near total dominance of natural ecosystems and centuries of scientific advancements, chronic disease is still very prevalent, even more so today than ever before.18)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351821/ The cited reasons for this found in the literature are numerous. Besides the “evolutionary miss-match hypothesis” mentioned briefly in the beginning and many other related theories, another common perspective is that the increased prevalence of chronic disease is just an inevitable consequence of an increasing part of the population now reaching post-reproductive age, and that health is not a primary force for natural selection. Age also cause a gradual functional decline, and indeed this contributes to the overall picture, but studies has shown that ageing of the population only explains about one third of the increased chronic disease prevalence seen now in modern society.19)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970764/ However, none of these common perspectives can help us answer the question as to why chronic disease occurs in the first place, apart from them just being avoidable or unavoidable defects.

The Original Classification of Disease might be Based on a Faulty Dichotomisation

I believe that the reason why this remains an unsolved mystery in modern medicine is that we have the wrong perspective on what disease truly represents, and therefore we are failing to properly recognise that there are ecological workings behind expressions of pathological phenotypes in organisms. Still, common theories for the origin of chronic non-communicable disease such as rheumatoid arthritis instead pits the body up against itself, and blames random genetic defects for what on the surface looks like friendly-fire from the immune-system (read the section on inflammation for an in-depth explanation of the “why” in autoimmune disease). The origin of this kind of reasoning goes back historically to a faulty dichotomisation of disease into infectious and non-infections categories that came because of an overestimation of the specificity of in-vitro microbial cultures, producing false-negative results that still constitutes the foundation for our understanding of non-communicable disease. The labeling of non-communicable disease might also be inappropriate because of the communicability of environmental factors, and also when considering that studies on gut-microbial transplants has shown many of them to be transferable (at least in experimental settings), hence contagious by definition.20)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711186/21)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767494/22)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4348024/ The believed absence of a rival biological will might be a reason why most pathophysiological explanations resort to reductionistic terminology like “aberrant responses”, implying faulty reactions to relatively harmless environmental stimuli. Like the body is just getting in its own way, and playing the devils advocate one could argue that it is the only sensible way to look at pathology if we were indeed the only organism involved. If we instead consider that that the expression of common pathological phenotypes is the result of an interaction with rival organisms, the pieces of the puzzle starts to come together, and things starts to make more sense.

Principles of Parasitology and Predation Can Explain Pathological Phenotypes

There is a problem that comes with a life characterised by abundance such as ours, but it only becomes visible when we look at the situation through an ecological lens. When an organism manages to acquire valuable resources at a rate that exceeds its immediate need and capacity for safe and efficient storage, they become increasingly attractive targets for parasites. Wether it be large ones such as foxes and squirrels, or microscopic ones such as bacteria and fungi.

A parasite is any organism large or small that practices parasitism, which is defined as forcibly or by deception using another living organism as an intermediary in acquiring resources. It can be the main strategy that an organism uses to acquire resources, or it can be used intermittently and in selective interactions with organisms of both the same and different species. The practice of parasitism is very common in natural ecosystems, and even though it has a negative ring to it, it is nonetheless a working evolutionary strategy that has proven to withstand the test of time. In fact, one could argue that parasitism is a practice that is essential for the preservation of biology, partly because it is among the oldest drivers of evolution and also because it limits our innate tendencies as self-replicating organisms to move towards totalitarianism, which if left unchecked in ecosystems would otherwise undermine biodiversity in the long run.23)https://www.sciencedirect.com/science/article/pii/S1369848616300103

“succeeding to seize opportunities for growth and reproduction are the fundamental goals of all organisms, and inter-and intra-species competition for these goals are also what maintains all of biology (…) Hypothetically, in both small- and large-scale ecological scenarios if one or a few organism grew powerful enough to seize control of all others and then used them as nutrients to enable their own reproduction, biodiversity would disappear and life would fall apart. The reason why this scenario hasn’t occurred (yet..) is because of one simple fact: it’s easy to rob someone who holds more than he can carry. So luckily at the right time in evolution emerged the practice of parasitism, which balances out the ecological playing-field such as that if one organism accumulates too much, someone els could just come in and skim of the excess and hence get a competitive advantage. In this way, success is to some extent self-limiting where too much of it breeds parasites.”

Regulation of Nutrient Absorption

For a true parasitic relationship between two organisms to form, there are two prerequisites. The first is a continual accumulation of a resource surplus by the host, defined as the amount exceeding the minimum cost of the combined effort of sustaining vital functions and accumulating the resources in question. This then enables the parasite to steal these resources without killing the host, which is how parasitism differs from predation. The second prerequisite is a gap in relative fitness between the organisms that favours the parasite, which in this case manifests as the difference between the defensive capacity of the host (used to protect its accumulated resources) and the offensive capabilities of the parasite. A short-term resource-deficit can also lead to increased susceptibility to parasitic influence through lowered defensive-capabilities in the host, but to be sustained, a surplus is required and If the life of the host can’t be sustained this kind of interaction falls more under the definition of predation than parasitism.24)https://www.nature.com/scitable/knowledge/library/predation-herbivory-and-parasitism-13261134/ However, for the sake of the argument made in this section there is no need to differentiate between the two and they can be considered somewhat synonymous in terms of their physiological consequences.

So either way, an organism that gets on the loosing side of an ecological interaction (or just gradually succumbing to entropy as a consequence of age and/or for abiotic reasons related to the environment) universally express a phenotype that is characterised by gradual functional decline as a consequence of relative resource-deficiencies which initially affects functions, or processes that are unrelated to short-term survival. Like for example different maintenance-processes at the cellular level and endothermy, muscle-activity and higher brain-functions at the level of the organism. Vital functions can eventually be affected, which might cause the demise of the host. A similar degenerative phenotype can also be generated voluntarily by the host as a direct defensive strategy to limit resource-availability to the parasite/predator. Because organisms only have a certain amount of energy available, up-regulation of defensive functions necessitates a compromise with non-vital functions and it can be very difficult to differentiate host/prey defensive-responses from those that are a direct consequence of parasitic influence or predation. However, for our purpose it is enough to know that an organism that gets under parasitic or predatory influence expresses a phenotype that is characterised by a gradual functional decline, which can be visible both at the tissue-level (check the chapter on histopathology for more on this) as well as at the level of the whole organism (see the section on inflammation).

It is my suspicion that this is whats going on at the core of chronic non-communicable disease and that the subtle progression of inflammatory and degenerative tissue phenotypes might be the result of local and systemic physiological processes succumbing to a persistent parasitic/predatory threat coming from the commensal microbiome.

Humans are Holobionts

Humans, as well as all other animals and plants are holobionts, which means that we do not exist as isolated organisms, but rather we form something analogous to an eco-system with the total number of organisms also living in direct relationship with us, like the billions of microbes such as bacteria, viruses, fungi and others inhabiting body-surfaces like the skin and the gastrointestinal tract.25)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482958/ Had we acknowledged this at an earlier point in the history of medicine, perhaps we would not have been so quick with labeling certain diseases as non-infectious (see my articles on gout and osteoarthritis for concrete examples of this).

From this perspective, it is also interesting to note the apparent similarities between the tissues and cell-types that constitute our body and more “primitive” multi- and uni-cellular organisms. Forest fungal-networks looks and functions a lot like the basic structures of our nervous-system, and stimulation of injured neurons with certain molecules that are produced by fungi when infecting plants have in fact been shown to stimulate axonal growth.26)https://link.springer.com/article/10.1007%2Fs00425-018-3051-227)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5558476/ Synaptic-signalling seems to work very much like viruses do when entering and leaving a cell, and the underlying machinery enabling this in us were already present in our last common ancestor with fungi28)https://jeb.biologists.org/content/218/4/501 Free-roaming amoeboid cells also bear striking resemblance to the macrophages patrolling our tissues as a part of our immune-system.29)https://www.cell.com/cell/fulltext/S0092-8674(17)31502-730)https://pubmed.ncbi.nlm.nih.gov/22143089/ Our cells most central metabolic machinery, the mitochondria is the result of a symbiotic union with bacteria and hence bacterial genomic sequences exists within our DNA, so it does not seem that far-fetched to assume that phylogenetically we might be the result of a genetic mash of many different unicellular organism and viruses, even on the inside, which is a notion that is gaining support by the gradual discovery of role of asexual inter-species horizontal gene-transfer in evolution.31)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4571569/32)https://royalsocietypublishing.org/doi/10.1098/rspb.2009.167933)https://www.nature.com/articles/nrg238634)https://www.frontiersin.org/articles/10.3389/fcell.2020.00229/full35)https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-018-0457-9 Of particular note (especially with regards to the current SARS-COVID-19 pandemic and our general “war on infectious disease”) is that about 40-80% of the human genome is estimated to have a viral origin, and since viruses are an important source of genetic mutations they are also important enablers of evolution.36)https://pubmed.ncbi.nlm.nih.gov/27128186/ All this taken together, it is interesting to think about where we would be today without “pathogens”.

I believe that when it comes down to it, the problems we face with pathology in modern society are fundamentally related to power. Specifically that we possess too much (or in some cases to little) of it and therefore have too much control over the ecosystem in which we make a living. As previously stated, when any organism gets too much power, by the very nature of life it tends to move towards totalitarianism by increasing the prevalence of its own genotype (both in terms of mass, size and numbers) and/or its extended phenotypes (which are the products of capitalism in our case, such as buildings, automobiles and corn-fields). This destabilises the ecosystem by favouring a select few species (which apart from us also includes the animals and plants produced in agriculture) while also making them all prime-targets for parasites (such as opportunistic microbes, rats or thieves of different kinds) which gravitate towards niches of resource-abundance. Hence within eco-systems, both at the level of forests and individual holobiotic organism too much power and influence of one organism over their existential conditions comes at the price of ecological instability and increased parasitic pressures. From this perspective the ecological consequences of agricultural mono-cropping is strikingly similar to what we now know about how our gut micro-ecology changes with diet and cause metabolic disease.

In summary, no matter how “separated from nature” we feel in western civilisation and whatever we do, we are not and will never be excepted from the rules of ecology, where success always comes at a price and with a risk. So, if we want to avoid getting “sick” we need to do what every other organism needs to do that have the same goal in mind, which is simply to become better players of the game, both in a competitive and cooperative sense.

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Per Bylund
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