morphostasis.org.uk

Restating The implications for micro-organisms

(The "shells" I refer to below are described in "Morphostasis: an evolving perspective" and in "Flushing out the phlogiston".)

(This page is still being worked on; the ideas here are not final and should be regarded as conjectures rather than firm beliefs.)

A consequence of the foregoing points is that micro-organisms, like for example bacteria, need cellular or tissue debris (alternatively "mess" - like, for example, unhealthy cells, apoptotic cells and disrupted tissue debris) as a substrate for their growth and survival within the tissues.  They are far too small to "eat" animal cells. Now, if the prime goal (purpose, aim, etc) of the immune (morphostatic system) is to tidy up tissue debris then a major "purpose" of those genes that code for pathogenesis in a micro-organism will be to disrupt the normal physiology of debris clearance (eg, viruses can fool the system so that it doesn't recognise the unhealthy status of infected cells). Pathogenic micro-organismss will both generate debris and impede its clearance; the injection of toxins to macerate a cell's contents, using a molecular syringe, is a common technique. Genetic disorders (eg, immune deficiencies) or acquired disorders (eg, diabetes, trauma) that impair the "scorched earth" efforts of the morphostatic system will all lead to an increased susceptibility to infection.

It’s a good idea to get firm definitions before we get too far. So, here goes:

Pathogen ~ an agent (living or inanimate) that has caused tissue damage.
Potential pathogen ~ an agent that has previously been known to damage tissues.
Pathogenic micro-organism (M-O) ~ a m-o that has caused tissue damage.
Potentially pathogenic M-O ~ a M-O that is capable of causing tissue damage.
Pathogen ~ is not synonymous with pathogenic M-O
Adaptive, cognate, anamnestic immunity ~ are alternative terms to describe immune mechanisms that learn to deal quickly with any challenge should it be encountered again.

Extant (conventional) explanations regard micro-organisms (M-Os) as elements that must be eradicated from the body's tissues: "microbes present" is deemed bad, "microbes absent" is deemed good. However, a morphostatic system may well be more tolerant and lenient to their simple presence. Nevertheless, if innate immune cells do come across them, they are likely to remember them as potential fuel and ingest them (an ability probably acquired from our free living amoebocyte ancestors from well over 700 my ago). Should microbes develop the capacity to delay the clearance of - or create further - debris, then antigen presenting cells that pick up representative debris will prime the anamnestic immune system to treat similar debris in a much more aggressive way when it is re-encountered and, in consequence, excite phagocytes to go into aggressive overdrive.

The anamnestic immune system is primed to respond in proportion to the level of the triggering pathogenic stimulus (including tissue debris processed without inflammation - like tidy apoptosis: this leads to tolerance). The outcome is to augment or dampen inflammation on any re-encounter of a similar stimulus. The evolutionary advent of anamnestic immune systems seems to have altered the capacity for regeneration. Sometime during the evolution from invertebrates to mammals, this increasing reliance on lymphocytes has been accompanied by the acceptance of a less than perfect but quick repair mechanism (fibrotic scarring) particularly when the damage has been intense (eg, burns) and in mature animals.

Invertebrates species are in good balance with their pathogenic M-Os (not individuals: some of these will succumb to infection). Look at sponges in an aquarium to illustrate this. Consider whether the sponges are unusually susceptible to infections because they don't have "sophisticated anamnestic immune systems". That implies that the increasing complexity of the immune (morphostatic) system carries with it an expanding number of potential Achilles heels to attack (see Footnote 1). The pathogenic M-Os get back in balance with their chosen host. But they also become more specialised and, therefore, more dependent on their host (they can't afford to annihilate this species). Don't forget the point that saprophytes pose the morphostatic (immune) system little significant challenge whilst pathogenic M-Os have evolved devious and sophisticated mechanisms to disrupt the clearance of debris.

To become pathogenic, micro-organisms will have evolved hand in glove with the “morphostatic system” (immune system if you like). It is a general assumption that the complexity of the immune system is driven to ever greater sophistication by its battle with micro-organisms. The problem with this view is that this is a war that can’t be won. Microbes evolve far too quickly. Although they have a small and limited number of genes, the evolution of this genome can be blisteringly fast in comparison with the germ line evolution of new animal-immune-system-genes (the somatic evolution of immune system processes is relatively fast - like, for example, learning the pattern of debris provoked by smallpox viruses so that a recurrence of full blown smallpox is soon prevented). These pathogenic M-Os are likely to find the Achilles heels of any new morphostatic (immune) system technique soon after it is “invented”. Hedrick’s article discusses this in detail.

Remember, the mechanistic shells of the immune (morphostatic) system become more specialised and more specific to each individual (ie, less generic) with each new enveloping shell. That means that the pathogenic M-O has to dedicate already sparse genetic resources to breaching each new Achilles heel. When that Achilles heel is located in the outer shells, the pathogenic M-O is forced to become more specialised, less generalised and therefore more dedicated and dependant upon its chosen host (eg, consider avian, bovine, human TB and, a topical example, avian flu). The survival and procreation of its chosen host species becomes the pathogenic M-O’s vested and critical interest; it is not wise to annihilate your host reservoir. With the breaching of each new Achilles heel, the pathogenic M-O commits more limited genetic resources to parasitizing a more and more specific and restricted host (order, species, race - even individuals).

Phagocytes have no problem whatsoever in recognising saprophytes as food/fuel and treating them accordingly. This is a no contest situation – "tiger and mouse" could be a more appropriate analogy than "cat and mouse". If the mouse wants a chance to use the tiger as food/fuel it will have to evolve some pretty devious approaches – or wait till the tiger dies. The latter is what most saprophytes do. Many of the virulent pathogenic M-Os aim to induce premature death in a small portion of their chosen host and then they set upon this feast with gusto. With increasing specialisation and commitment to their chosen host, they run the risk of becoming extinct if they don’t quickly reach a balanced compromise between killing their chosen species and self propagation. Simultaneously, they allocate a limited repertoire of DNA (or RNA) to pathogenesis and, in doing so, forfeit survivability in the saprophyte's chosen arena. (This might help to explain why influenza can be so lethal when it first jumps from one host species to another.)

I have a sneaking suspicion that the increasing complexity of the immune system, through the aeons, is related more to its role in morphogenesis, damage management and repair than to its role in defence against micro-organisms.

Why do I suspect this? First and foremost, invertebrates are in good balance with their pathogenic M-Os. So, is the increasing sophistication of the immune system a response to pressure from these new pathogenic M-Os ? Does each new barrage of debris clearing mechanisms require a new ring fencing barrage to sort out the new wave of debris generated by the culprits that learn to “breach” every new Achilles heel?

That led me to thinking; what are the primary differences between simple invertebrate species (that are in good balance with their pathogenic M-Os) and mammalian species like homo sapiens (that are in good balance with their pathogenic M-Os)? Well, complex nervous systems constitute one attribute that seems to coincide with the emergence of adaptive immune systems (there’s lots of evidence to indicate that nervous system complexity evolves in tandem with immune system complexity). Homeothermy is another but, then, much of the anamnestic immune system had already evolved in poikilotherms. Placentation became possible in mammals. However, it evolved late; so, while placentation may have been facilitated by an increasingly complex immune system, I don't think we can add this to the list of possible "purposes" that led to the evolution of complex adaptive immune systems. The notochord and segmented structure of vertebrates coincided with the emergence of cognate immune systems. Gills and jaws occurred around that time though gills were already used by some invertebrates. Highly structured and ordered cephalic structures, however, became commonplace, including complex front end nervous systems with the protrusions that constitute the receptors of the eyes (see Footnote 2). Perhaps the driving force that leads to the greater complexity of the immune system is the increasing complexity of morphogenesis, damage management and repair (particularly that related to the nervous system and eyes).  The sophistication of the mechanisms leading to tissue homeostasis may need to become more complex with the hand in glove emergence of (cephalic) neural tissues. So, more morphostatic shells develop and perhaps not, primarily, because of pressure from pathogenic M-Os. It seems that something about how higher cognitive functions are achieved and maintained may well require more complex immune systems.

Apoptosis - as a defence mechanism - is not that desirable in the central nervous system where preservation of neurones is all important. It is now being noted that autophagy is the preferred way of coping with intracellular pathogens (pathogerms !) in the CNS. Autophagy leads to cross presentation (intracellular debris that would normally provoke a Tc response - CD8 presentation in the endoplasmic reticulum - is internally processed through the CD4 endosomal pathway and that leads to Th responses). So, Tc responses are down regulated in the CNS and substituted with Th1 and preferably Th2 responses. The appearance of autoreactive antibodies to CNS or eye antigens is associated with a GOOD prognostic outcome in EAE and EAO (experimental allergic encephalomyelitis and Exp' All' ophthalmitis) compared with Tc/Th1 responses.

Coincidentally, there may be a need to guard against the debris created by emerging pathogenic M-Os as they breach each new Achilles heel. But perhaps, and again this is no more than a suspicion, we have got that last point wrong too. Pressure from micro-organisms may prove to be nowhere near the potent driver for the increase in complexity of immune (morphostatic) systems that we have previously credited. This would be quite contrary to extant belief; and all because pathogenic M-Os are forced to become increasingly committed to and dependant on their host and because they are able to evolve into their new niche and achieve balance quickly.

The one thing that, I believe, can be stated with some confidence is that the detection and elimination of micro-organisms from the zygote derived colony (self) uses techniques inherited from the very early evolutionary origins of multicellulates. Once free living protozoans started to group together into colonies and then started to organise into distinctive internal divisions and structures (early organogenesis) they needed new morphogenetic techniques and exposed new Achilles heels that became available to be capitalised upon. In mammals the dominant contributors to micro-organism detection and elimination will rely dominantly upon the central shells used by the immune system (RNAi, NF-kappaB, p53, autophagy, apoptosis, prostaglandins, phagocytes, complement). The "higher"  (anamnestic) elements of the immune system are mainly targeted by (and - possibly, perhaps - reciprocally targeted at) pathogenic M-Os that have become progressively more specialised and dedicated to their host. The traditional idea of an immune system that is responsible for "bug hunting and elimination" will, if it exists in any sense other than being the consequence of "mindless" tissue homeostasis, most probably occupy the more central shells of the mammalian immune system.

So what creates the strong illusion that the micro-organism is remembered and destroyed? I guess it goes like this. Remember, the M-O needs to create a substrate of debris for its nurture. The anamnestic immune system remembers the signature of previously encountered tissue debris (this includes representative peptides from degenerating M-Os). With reinfection and infiltration of the M-O, there is initial growth that leads to debris that is reminiscent of the earlier encounter; this is quickly identified and targeted for accelerated clearance. The M-Os intended substrate is quickly and efficiently removed so that it is denied the nurture it needs. Now it becomes little different from a commensal or saprophytic organism and is treated as such by the more central shells of the immune system. Its survival tactic (debris generation) has been severely disrupted. Note that the deliberate generation of damage opens up the possibility that opportunists can cash in on the debris created by the specialised pathogenic M-Os. There is ample evidence that this does occur.

Now, so far I have talked about tissue debris but the really critical "structure" is the extracellular space (ECS) where the somatic cells live and construct their scaffold. As noted before, the system plays a "scorched earth" policy or, should I say, a scorched ECS policy. The critical process is to manage all potential resources in this space so that they do not become readily available to interlopers. Several techniques help: glucose is managed (with insulin) in such a way that it is only fleetingly available across the ECS (except in diabetes); oxygen is transferred rapidly from haemo- to myo-globin - it is "sucked" quickly from one to the other; haemoglobin helps to reduce the concentration of iron (essential for bacteria) by trapping it and amplifying its properties; and lastly gap junctions (GJs) are well set to act as conduits that allow cells to bypass the transfer of nutrient substrate across the ECS. When cells absorb apoptotic bodies and reprocess their molecules, the proceeds could, perhaps, be efficiently redistributed to adjacent cells without ever being exposed in the ECS. Perhaps this "scorched ECS" process might help us to guess some of the pressures that led to the evolution of GJs and plasmodesmata.

What then of the clear indication that microbes seem to influence things like Mhc pleomorphism? With a "horror autotoxicus system" that works on the specific recognition of a "combination lock" identity profile (of cell surface ligands/receptors), this exposes an Achilles heel susceptibility  where identity mimicry becomes a means of gaining a Trojan Horse style of entry. The Mhc apparatus makes this "combination lock" identity more complex and more individual. But, once again, this drive by micro-organisms might be overemphasised. The need for it may be related to debris recognition, removal and repair mechanisms rather than "bug hunting and killing". The immune system, I guess, does not add major shells to its armamentarium to help identify and destroy micro-organisms; my guess is that new shells are required for extra morphogenetic processes (including debris removal and repair). An analogy with Microsoft Windows (or any other operating system) may be helpful. Programme additions and revamps are made to improve its function (they are rebuilds); soon after the rebuild, the virus creators discover loopholes (Achilles heels) that they can exploit. In response Microsoft releases patches (tinkering) to close these loopholes. The mammalian immune system probably does much the same. The responses rely on both somatic and germ line evolution. Somatic solutions can be quick to evolve but cannot be passed on down the germ line. Advantageous germ line solutions evolve to patch up blind spots that are not routinely dealt with by the somatic evolution of appropriate immune responses (the least fit are either disadvantaged or die - so they have fewer descendants).  Nevertheless, the basic "purpose" could still be "debris disposal and tissue repair" and this is what may be made more robust - rather than any improvement in the recognition and killing of pathogenic M-Os.

The two perspectives do end up being very similar so you might question why we should bother with such a "sleight of hand" mental gymnastic. However, the advantage of shifting perspectives is that the simplistic "bug-hunting" view has allowed us to (largely) ignore the active role of the pathogenic M-O in tweaking out loopholes (pathogenesis) and the coercion of the immune system into damaging its own tissues to provide nurture for the invaders. It has also allowed us to regard bug-hunting and killing as the prime object - and that has left us wondering why transplant reactions, auto-immunity, atheroma, cancer and injury responses  also seem to have links with the immune system. And as for horror autotoxicus, it just does not function in the simplitic way so far anticipated. You may be able to think of more examples that are anomalies for the conventional view but resolve under a tissue homeostasis view (or under the broader principle of morphostasis).

The situation, when it comes to immunisation against infectious diseases, is different. Here, human intervention ensures that the purpose that emerges (potentially out of many failed attempts) is the provocation of a response that is dominantly focused on some epitope of the pathogenic M-O (other induced responses are abandoned as ineffective). We need to inflict minimal collateral damage and achieve early immobilisation (often by interfering with the pathogenic mechanism) and the effective - though not necessarily complete - clearance of the pathogenic M-O (usually by reducing the organism's pathogenic status to that of a commensal or saprophyte). And, this is not always easy to achieve. One of the common techniques is to deliver "mashed up" bits (mess/debris) of the pathogenic M-O together with adjuvant (mess/debris). This works well for the less dedicated and less sophisticated pathogenic mechanisms (eg, tetanus) but is much less effective for the more dedicated and more sophisticated pathogenic mechanisms (eg, HIV, malaria and TB). The human intervention that redirects the underlying purpose (morphostasis/tissue homeostasis) to our own goals inflates the impression that the purpose was, all along, bug hunting and killing.

Footnotes:

1. In simple systems, the component units tend to be more versatile, less specialised and less dependent on other units when there is a failure of part of the system (they are still versatile enough to "stand in"). In complex systems, it is the opposite. The component units tend to be less versatile, more specialised and more dependent on other units when there is a failure of part of the system (they are no longer versatile enough to "stand in").
2. The role of the morphostatic system in the vertebrate eye may ultimately provide a deeper understanding of this need for the system to become more complex. Another important point may be that, in non-vertebrates, the morphogenesis of their nervous systems is largely "hard-wired". On damage, the system "knows" how to regenerate back into a functional entity. In vertebrates, and in particular in mammals like apes, we know that the morphogenesis of their developing brains (particularly in children) have a great capacity for adaptation to experience rather than being fully hard wired (we humans have to learn to walk over many months unlike more "primitive" vertebrates where this ability is hard-wired). Thus we humans have "an adaptive nervous system": I have deliberately chosen this phrase to emphasise the analogy with our "adaptive immune system". Because our nervous systems are highly adaptive we cannot afford to allow inflammation and primitive regenerative processes to run amok - or we would forfeit survivability.