Are humans a “clothed mass of microbes” engaged in a sort of panspermia?

humans-used-as-a-trojan-horse-by-microbes-aiming-panspermia-hj479

Beyond considering that humans are not just composed of eukaryotic cells but also of a huge number of microbes playing pivotal roles in the overall organism functioning, in this article it is additionally suggested to look at eukaryotic cells as a kind of evolved community of bacteria-derived individuals. Mitochondria are fundamental organelles for energy production, but also for driving cell fate. Although it is perfectly established that mitochondria are phylogenetically linked to bacteria, with theories suggesting they survived in a symbiotic parasitism within an ancestral eukaryotic cell, we alternatively encourage their consideration as the main orchestrators of eukaryogenesis. Bacteria gradually evolved into mitochondria, while the social interrelationship and architecture of a prokaryotic community transformed into eukaryotic cells. Last but not least, given the role of bacteria on Panspermia, and by converging mitochondrion and microbiome potential to respectively modulate cell and whole organism functioning, we wonder whether superior animals and in particular humans might be so far the most evolved product coming from two main bacterial socio-evolutive strategies engaged in an attempt to endure living matter expansion.


Introduction

The human being, superbly illustrated half a century ago as a “Naked Ape” (1), has proclaimed itself to be the most evolved expression of living matter on the planet and thus far, the known universe. Humans have been indeed incredibly able to interact and modify their inanimate and living surroundings to successfully conquer most environmental conditions throughout millennia. However, it is worth noticing that bacteria also did this for a long time before human beings appeared and in a much more efficient manner.

Bacteria are the oldest, structurally simplest and the most abundant form of life on Earth and have been recovered from ancient fossils dating back 3.5 billion years (2). In spite of their apparent simplicity, bacteria are increasingly being recognized as capable of performing most of the more complex functions observed in superior forms of life including communication (3-5), social behaviour (6-7) and even a sort of “thinking” (8). Many bacteria use cell-to-cell communication mediated by diffusible signal molecules to monitor their population density or confinement to niches and to modulate their behaviour in response to these factors (9). Moreover, it is reported that bacteria can sense signal molecules that they do not synthesize, thereby “eavesdropping” on signalling by other organisms in their immediate environment, indicating that interspecies communicative interaction can occur within polymicrobial communities in nature (9). Bacteria have developed intricate communication abilities to cooperatively self-organize into highly structured colonies with elevated environmental capabilities. It has been illustrated that this is in part due to their intracellular flexibility and their ability to collectively maintain linguistic communications through self and shared chemical cues and an exchange of messages and dialogues. Social identity, intentional behaviour, purposeful alteration of colony structure, decision making and recognition and identification of other colonies are some of the features that have suggested bacterial social intelligence (6). Indeed, it has been illustrated using bacteria, that environmental anticipation could be an adaptive trait repeatedly selected for during evolution (8). In agreement, in separate studies, from the point of view of one looking at the number of two-component systems used for signal transduction in bacteria, the existence of a kind of rudimentary intelligence in bacteria has already been suggested (10).

The strategies employed by bacteria to conquer nearly all environments to guarantee reproduction and persistence of the species under the most drastic adverse conditions are much more robust than those of superior animals and plants. Astonishingly, bacteria have even “conquered” the inner space of superior forms of life, including the human being (11). Though ignored for centuries, bacteria are an essential part of overall human homeostasis. While accounting for twice the weight of the brain, bacteria outnumber human eukaryotic cells in a proportion that may vary from 10:1 to 1:1 probably depending on individuals during different life stages among other factors. What is more striking is that bacteria are playing fundamental roles in the overall functioning and behaviours of human beings, leading many to consider them as an additional organ in the whole macro-organism performance (12,13).

As a matter of fact, the pool of genes coming from the microbiome is 100 times bigger and with a higher inter-individual diversity as compared to that found in the whole human eukaryome (14). Indeed, the microbiome variability seems to be more in line with the evident phenotypical differences among different subjects, and it has been already suggested that microbiome rather than eukaryome variability could have more impact on biodiversity (13).

It is really shocking to quote the relatively small size of the human genome (about 26,000 functioning units) (15) as compared to other organisms such as rice (Oryza genus) for example that has about 46,000 functioning genes (16). One thousand different strains of bacteria might be expected to contribute up to 4×106 potential mRNAs to the human transcriptome, thus making the human host-plus-microbiome genetic complexity closer to 4,026,600 mRNA transcripts, and hence possibly explaining the higher human genetic complexity over rice and other species (15, 17-19). Moreover, recent observations of microbiome-derived small non-coding RNA (sncRNA) and micro RNA (miRNA) translocation and signalling across endothelium and between cells and tissues, further support the concept that human homeostasis may be significantly impacted by microbiome-mediated sncRNA and miRNA trafficking (20-23). The hundred trillion bacteria in the body of an adult contain about 4 million distinct bacterial genes, with more than 95% of them located in the large intestine (24). Most of these genes encode enzymes and structural proteins that influence the functioning of mammalian cells, thus, the gut microbiome can be envisioned as an anaerobic bioreactor programmed to synthesize molecules that direct the mammalian immune system (25), modify mammalian epigenome (26) and regulate host metabolism (27) and behaivour (12,13). Considering the quantitative and qualitative relevance of microbiome on human homeostasis, it warrants one to examine humans as a “clothed” mass of microbes. Focusing on the macrobiotic “clothing”, we propose a novel concept of the eukaryotic cell, that might further support such alternative interpretation of humans as a mass of microbes, namely that eukaryotic cells are a sort of community of bacteria-like organisms; the mitochondria. Mitochondria are one of the most important and fascinating organelles of the eukaryotic cell. Though most studies have focused on its primary role in energy production, many recent works are unveiling novel fundamental roles for mitochondria in the orchestration of a large number of eukaryotic cell functions (28).

The parallel between mitochondria and bacteria is quite evident and fairly stated in most review studies (28). In addition to their similarity in size and shape, mitochondria have their own double-membrane, just like a prokaryotic cell does. Moreover, each mitochondria has its own circular DNA genome (like the bacterial genome, albeit much smaller), that lacks introns and is independent of nuclear DNA in which transcription is coupled to translation, a typical characteristic of bacterial DNA. Furthermore, among many other similarities, in mitochondria the codon UGA specifies the amino acid tryptophan (29-31) whereas in the conventional code it serves as a stop codon. Furthermore, mitochondria divide and replicate independently of host cell division in a manner akin to binary fission, by using homologues to the bacterial division protein FtsZ (32).

At this point, if redefining superior animals including humans as a mass of microbes (microbiome) “clothed” with a complex community of evolved societies of bacterial-derived individuals (mitochondria), it might be worth further wondering if such a product might be ultimately aimed, even if unintended, at pursuing living matter expansion on the planet and in the neighbouring outer space. Though limited, there are indeed some findings already accounting for the presence of alien bacteria in Earth’s outer stratosphere (33-36), meteorites (37) and even on some far inter-stellar dust clouds (38). Failed attempts to experimentally demonstrate the feasibility of abiogenesis have revived theories suggesting that the origin of life might not be on Earth but a much earlier and remote place in the universe. It has been postulated that primary and most robust elements might have traveled in search of places with optimal conditions to colonize and evolve, to be then further spread through spontaneous panspermia (39-43) or, as suggested by Crick in 1973, by a sort of Directed Panspermia (44).

Hypothesis

As previously mentioned, the fact that mitochondria are phylogenetically closely related to bacteria has been already suggested and supported by numerous studies (45,46). Regarding their origin, two main hypotheses have been suggested: the autogenous and the more accredited endosymbiotic (47).

Five years after publishing his first paper in this regard (48), the first to articulate the theory of symbiogenesis was the botanist Konstantin Mereschowsky in 1910 (49). It is worth noting, however, that in 1883 another botanist, Andrea Schimper, was actually the first to observe that the division of chloroplast in green plants closely resembles free-living cyanobacteria, suggesting in one of his notes that green plants had arisen from a symbiotic union of two organisms (50). Several years later in 1918 Paul Portier published Les Symbiotes claiming that the mitochondria originated from a symbiotic process. This concept that was then further developed in 1920 by Ivan Wallin (51,52), whereas the botanist Boris Kozo-Polyansky was the first to explain the theory in terms of Darwinian evolution (53). Thereafter, though rather ignored for decades, thanks to detailed electron microscopic (54) and some molecular biology studies (55), in the 1960s there was a resurrection of the idea. Relevant advancement was further provided with microbiological evidence by Lynn Margulis (56). In her work “Symbiosis in Cell Evolution”, Margulis states that eukaryotic cells originated as a community of interacting entities (57). Another formidable concept coming from Margulis and Doirion Sagan is that “life did not take over the globe by combat, but by networking” (58). There are, however, several interpretations of the theory. In most cases, it is envisioned as the pre-existence of a kind of anaerobic amitochondriate eukaryotic cell that engulfed an aerobic bacterium establishing a symbiotic interrelationship that resulted in a relevant evolutionary advantage. The most relevant evidence in support of this theory was provided by reproducing in vitro the occurrence of a kind of symbiotic parasitism following infection of amoeba with bacteria (59).

Considering more recent theories arguing against the pre-existence of amitochondriate eukaryotes (60,62), though still in line with the concept of symbiosis and networking, we would like to consider a slightly different scenario, namely that eukaryotic cells were built up as a result of prokaryotic cell social evolution. In other words, as illustrated in (Fig 1), it is suggested that bacterial colonies evolved in their social structure and functioning, pressing on each individual component (the bacterium) to evolve into mitochondria and on the whole community to evolve into what we now know as an eukaryotic cell. There is general agreement on the fundamental role of society in the evolution of living matter including the conversion of apes into humans. However, much less relevance is given to how such inter-individual and social laws were perhaps also leading prokaryotic communities into eukaryogenesis. Furthermore, considering the increasing relevance attributed to the microbiome in the whole organism homeostasis and behaviour, we ponder whether humans, as a representative of superior animals, could be the most evolved instrument resulting from a symbiotic crosstalk among different bacterial socio-evolutive products, unintentionally aimed at better interacting with the environment, in a sort of directed Panspermia. Wherever the human being reaches when going into space, deliberately or not, he will be carrying bacteria, which presumably will be the first to adapt, colonize and ultimately modify the new environment. Indeed, in support of this reasoning, the presence of Earth microbes surrounding the MIR space station has been already reported (63,64).

hj479_fig1

Figure 1 | A proposed model of humans as an evolved product resulting from the convergence of two main bacterial socio-evolutive strategies unintendedly aimed at further improving social networking in order to take over not only the globe but also outer space.

 

Evaluation of the Hypothesis

There is much evidence indicating that bacterial colonies are not simply a mass of disconnected individuals, but rather a society that exhibits a structural organization with a corresponding distribution of functions (65,66). It is worth noticing that under certain circumstances, relatively heterogeneous bacterial populations are able to circumscribe their confinement by means of a pseudo membrane giving rise to an entity known as biofilm (67). In such context, considering the well-known propensity of bacteria to intercommunicate and to exchange DNA (68), it would not be surprising that a rudimentary intra-community structure to store shared DNA (primitive karyon) might have emerged. Taken together, though still rough and requiring millennia of evolutionary refinement, it would not be difficult to envision the emergence of a draft picture quite close to what is commonly known now as a eukaryotic cell.

We suggest some preliminary questions that, if addressed, like small pieces of a puzzle, might provide some support to continue pursuing the current proposal:

  • Are different kinds of mitochondria, exhibiting different types of functions inside the eukaryotic cell, reflecting an evolved form of what is observed in some prokaryotic communities? Inside some bacterial populations different members may exhibit different social functions (69). It is worth considering whether mitochondria might also exhibit some kind of functional distribution, such as energetic, apoptotic, proliferative, epigenomic control, etc.
  • How much have mitochondria evolved in their intercommunication mechanisms? Bacteria maintain a constant flux of intercommunication including genetic material (68). Could such bacterial intercommunication pathways have evolved in mitochondria as well? Electromagnetic signals are just an example of a poorly explored field by which mitochondria may intercommunicate and control nuclear transcriptional activity (70).
  • To what extent have mitochondria evolved a direct defensive role toward eukaryotic cells? Extensive studies have addressed many of the mechanisms implemented to ensure immunity in multicellular organisms (71). Similarly, it is well known that prokaryotic cells such as bacteria are able to recognize and protect themselves and the community against foreign invaders and menaces (72). The extent to which such roles are evolved in mitochondria in order to guarantee the intra-eukaryotic space “immunity” is worth further exploration.
  • How different are mitochondrial subpopulations originating from different eukaryotic cell types (tumors, stem cells, oocytes, neurons, muscle, etc.)? Though there is tremendous diversity among fully differentiated eukaryotic cells, the nuclear information is the same in all of them, making it possible, by nuclear transfer, to reprogram almost every differentiated cell, including tumors (73), into any other healthy and phenotypically distant cell type (74). Cell fusion with stem cells has been indeed postulated as a possible mechanism for correcting and/or reprogramming harmful mutations (75). In this sense, looking at mitochondria as main orchestrators of the eukaryotic cell fate, a further exploration of differences and consequences of mitochondrial exchange among different cells and tissues is warranted.
  • Not including the genomic level, how different are mitochondria and microbiome across different species? It is a well-known paradox that genomic differences among species do not correlate with obvious phenotypic diversity (76). Looking strictly at the entire eukaryotic genome, humans and mice are 98% identical (77). Is the remnant 2% enough, or might it be more appropriate to also include a microbiome and mitochondriome comparison, to explain the objective morphological, functional and intellectual differences?

Relevance

In addition to any potential phylogenetic and/or philosophical significance in terms of living matter evolution, the current proposal might also provide a novel approach to better understand, predict and/or therapeutically modulate eukaryotic cell functioning. Looking at the eukaryotic cell, not as a single individual but rather as a society of prokaryotic-like elements, might provide new insights into the overall function of the whole system. Noticeably, even if mitochondria could be simply a symbiotic parasite-like element in eukaryotic cells, it remains a fact that they regulate and control many cellular functions, closely resembling what the microbiome does in the human being.

As recently reviewed (28), there is much evidence illustrating a relevant role for mitochondria, not only in energy production, but also in controlling many aspects of cell life, stress and death (78,79). Mitonuclear communication pathways may include not only genetic crosstalk (80,81) but also reactive oxygen and/or nitrogen species (ROS/RNS) (82,83), lncRNA and miRNA (84-86) or even much more astonishing mechanisms such as the recently suggested electromagnetic field (70).

Though apparently distant, the microbiome has also recently gained much attention not only in gastrointestinal homeostasis, food metabolism and nutrient absorption but also as a bioreactor programmed to synthesize molecules which direct the mammalian immune system (25), modify the mammalian epigenome (26) and regulate host metabolism (27,87). Moreover, there is much evidence illustrating the relevant role of gut microbiota on stress control (13,88,89) and behaviour (13,90-92). Even though communication pathways are not fully unveiled, it is clear that alterations in gut microbiome may lead to relevant changes in circulating levels of several neuromodulators, such as serotonin (93,94) and endotoxins (95). Additionally, it would also be relevant to note that interspecies lncRNA and miRNA trafficking (85,86) as well as reported electromagnetic fields (70) might represent unexplored communication pathways.

Very little it is indeed fully established and further studies would be certainly required to better understand the precise molecular mechanisms by which mitochondria control the nucleus and cellular fate, as well as how the microbiome can regulate human brain and behaviour. In that sense, though seemingly unrelated, it might help to learn from several examples in nature that illustrate the opportunistic hijacking of the host by the hosted organisms pursuing their own benefit (96-99). It is indeed shocking to observe how an ectoparasitoid like the larvae from the Reclinervellus nielseni wasp can take control of the brain of the Cyclosa argenteoalba spider to reprogram its behavior, taking advantage of the spider web-building abilities, to instead build and care for the larvae cocoon (97). Similarly, it is also amazing to note how a microorganism such as a fungal parasite can manipulate the brain and behaviour of an ant in order to spread their space-conquering capabilities (99). What are the mechanisms and mediators used by such parasites to take control and reprogram the brain and behaviour of their victims in order to use the host’s special abilities for their own benefit? How distant or close from such mechanisms and purposes could the interrelationship between humans, their microbiome, and the cells with their mitochondria be?

In any case, far from any sensationalism, mystic or idealistic interpretations, it might be worth simply to consider the real nature of “naked apes” homeostasis more in depth. The human being should not be exclusively observed as a single entity, but as an heterogeneous “condominium” in which the last outcome depends on complex inter-individual and social interactions between all elements comprising it.

Presently, there is insufficient effort dedicated to exploring potential mitochondrial impairment responsible for many cell/tissue dysfunctions. Indeed, most in-vitro screening cascade studies on drug development are focused on biochemical, genetic, cellular and tissue effects, but little is done to investigate mitochondrial functioning, which increasingly extends beyond energy production (28). For instance, the impact of new chemical entities on mitochondrial dynamics (fusion and fission) as well as on mitochondrial control over the nucleus is largely disregarded during standard screening studies through in drug research and development.

Moreover, most current therapies pay little attention to the impact of pharmacological actions on microbiome and mitochondria regulatory functions. For instance, while it is well established that antibiotics have important effects on microbiome homeostasis leading to several gastrointestinal (GI) disorders, much less attention is given to the fact that GI dysbiosis may also lead to several systemic disturbances. Furthermore, given the strong similarities between bacteria and mitochondria, antibiotics may also affect some of the many mitochondrial regulatory functions on distant cells and tissues (100-103). Similarly, in addition to gastric disturbance, anti-inflammatory drugs (NSAIDS) may also impair intestinal permeability by a mechanism involving mitochondrial uncoupling (104-107). Little is known about how such mechanisms might also be affecting microbiome functionality as well as some of the mitochondria regulatory functions in other cells/tissues. Lastly, greater effort should be made to understand how increased intestinal permeability that leads to altered microbiome entrance into systemic circulation might be negatively affecting systemic inflammatory processes, (108-110) including CNS disorders (110-112).

Conclusion

In conclusion, independently of whether humans are simply a “clothing”, a subject hijacked by the host or the final refined product resulting from the convergence of two different microbial socio-evolutive strategies, it might be worth giving more consideration to the fact that the ultimate “aim” of bio-evolution is not humans but the perpetuation of living matter. Humans could be just a piece of the whole biosphere puzzle and might not be necessarily the most important nor the end result. We may simply be the most sophisticated living matter approach, intentional or not, engaged in an attempt to endure a goal of bioevolution that is panspermia (38-44,113-116).

Conflicts of Interest

Author declares no conflicts of interest.

About the Author

The author holds a Master Degree in Pharmaceutical Sciences, a PhD in Experimental Pharmacology, decades of experience in R&D in different international biopharmaceutical environments and has authored numerous research papers and patents. Some of his main endeavors include being an Intern Fellow at Glasgow University, a Visiting Scientist at Wellcome Research in London, a Senior Researcher at Merck in Rome and the Head of Pharmacology Department at NicOx Research Labs in Milan. At present, in addition to conducting basic research in a Private Studio of Clinical Pathology and Nutrition, he collaborates with a community pharmacy while offering consultancy on oxidative stress for drug research and development.

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