www.morphostasis.org.uk

At its simplest

The simplest way of introducing you to this change in perspective is to have you realise the following:-

The general perception of how the immune system works has traditionally been rather like this. "Hey guys! (that is, immune cells and antibodies),  there are bugs out there. Let's go find and kill 'em. While we're about it, we'll remember what they looked like last time so that we can recognise and kill 'em faster next time around."

A morphostatic system works in a different way. "Ooopppss! Something's making a tissue mess. Better go tidy up the mess and fix any losses. While we're about it we'll take a snapshot of this mess. We'll remember the most unusual signature of it. Then, if we meet a similar mess in the future, we'll ramp up the accumulation of mess eaters and make these act more aggressively when they get there."

In the first view, the bugs are the primary target. In the second view, the bugs (and their debris) are only noticed when they can’t help make and become part of the tissue mess or they have properties that are characteristic of tissue mess (or, perhaps, more specifically, "potential fuel" - eg, primary fuel like bacteria or fuel for recycling in the form of degenerating self tissues). There is no focus (by the adaptive immune system) on targeting and killing micro-organisms per se.

Individual cells (and particularly phagocytes) have an ancient capacity to recognise potential microbial "food" and my guess is that this is where PAMPs and PRRs will eventually be shown to owe their origin. (Don't forget that to be a successful intracellular pathogenic organism your first task is to get yourself invited in. At least some PAMP signals will be directed here.)

Note: The complement system ensures that all biological material is tagged "suitable for degeneration" unless it is protected by complement inhibitors. Long straight molecules do not poke into the "basket" where the reactive part of the complement molecule is situated (ready to latch onto its targets). Thus, long straight molecules, like collagen, are spared but "ligandy" ("sticky outy") sort of material, that pokes in easily, is soon tagged. This is the closest the system comes to "attacking" foreign organisms but, even here, the attack (tagging really) is focused on biological material in general and not "foreign". Tagged self cells then ensure that they escape from this degeneration by using complement inhibitors to divert the downstream response away from aggression (even into co-operation). The overall process is not an immune cell attack on foreign - even though it does create the illusion that this is what is happening.

Fundamentally simple, hey?

A good analogy

- is that of a city which has mess  removal systems for garbage, sewerage dead bodies etc.. In particular, mess that might be used as potential fuel (fires) or food (vermin/infestations) needs to be controlled. If, say, the garbage part fails, certain diseases will become rife (particularly those associated with vermin) and if the sewerage fails, diseases like typhoid and cholera become rife. (Note that we have long since "realised" it is not sensible to leave dead flesh lying around.) No one in their right mind suggests that these collecting systems are primarily designed to kill the organisms responsible. That they have an effect in suppressing them is incontrovertible.

Another tautology

Then there is the tautology of a morphostatic system (tissue homeostatic system). Its existence is so obvious that it is essentially tautologous to have to emphasise it. But we need to. Where are the vast tomes and mountains of articles dedicated solely to this subject? They ought to be there in view of its importance.

It is worth asking yourself this set of questions:

And ..... talking about pathogens

This is one of the most bizarre points in common, extant perceptions of immunological function. The term pathogen has been generally used as a lazy abbreviation for a pathogenic organism. Consequently, the word pathogen has gradually become synonymous - and now legitimately interchangeable - with "an invading (foreign) organism". But, by etymological definition, a pathogen is nothing more than an agent (living, organic, inorganic or a physical condition - like, for example, heat or even - and this is a really potent pathogen - a lump hammer hitting your thumb) that provokes damage in the tissues it affects.  I agree, unreservedly, that the immune system (or, rather, the morphostatic system) is constantly on the alert for pathogenic stimuli -  these litter the extra-cellular fluid with the debris of damaged tissues. And, what is more, I agree that the immune system "memorises" these pathogenic stimuli so that it responds rapidly and in an amplified manner the next time that they are encountered. And it is probably also sensitive to the use of invasion tools by microbial agents.

An analogy might help; though some people (analogous to micro-organisms) decide to become burglars (analogous to pathogens) they do not conveniently oblige by proffering an outward appearance that marks them out as burglars except inasmuch as they might need to carry swag bags, wrenches, lock picks etc that are the necessary "tools" for the action intended. Naked, in the bath back home, they are just like ordinary people (micro-organisms). It is only their behaviour, their equipment and the consequences of their actions, that mark them out as a burglars (pathogens). 

I contend that this uncritical use of the term pathogen as a legitimate alternative for "an invading (foreign) organism" has led us to adopt one of the most remarkable conceptual blind spots in the history of science. Being a micro-organism is neither necessary nor sufficient for it also to be a pathogen. Pathogenicity is a discrete, distinct and additional property. But, in this world of "dog eats dog" it is a safe bet that, given the opportunity, many micro-organisms will have a go at it. However, it is worth thinking around the following point. It has recently been estimated that one gram of soil contains over a million microbial species. Only a very small proportion of these have the "skills" (dedicated genetic repertoire) to become pathogens.

It should be readily apparent, using simple logic, that this uncritical view helps to perpetuate the "self/nonself" view of lymphocyte activation. Further, it shows how the protagonists of "self/nonself discrimination by lymphocytes" may actually be scoring an own goal in favour of the "danger" protagonists.

You can probably see that I, too, have fallen under this "Emperor's new clothes" spell when you read my published articles. It was only during the proof reading of the "Terra firma to terra plana" article that it began to dawn on me that the term pathogen was being used both inappropriately and far too loosely.

Should you doubt the importance of this conceptual blind spot, then try this exercise.

I have now added a section in the Philosophy pages that explores the origin of this trend to use pathogen as a synonym for pathogenic (micro-)organism.

(Note that in his "Immunity in infectious diseases", Elie Metchnikoff frequently refers to "pathogenic [micro-] organisms". He never once abbreviates this phrase to the term "pathogen". Cambridge Univ Press 1905, reprinted 1907.)

Lastly (and this is like a city's mess disposal system):-

A critical function for the body's clearance systems is to rapidly remove debris that might serve as food (energy supplies and building materials) for micro-organisms and so starve them out of contention. (Go and take a look at a healthy sponge in an aquarium to realise that invertebrates manage this very well; then contrast this with the stinking - infected - mess of something like a beached dead fish.)  Further, this debris is an important source of the material needed for self regeneration.

Conversely, pathogenic organisms must acquire two important properties. First, they must ensure the generation of (intra- or extra-cellular) tissue debris (to serve as food) and, second, they need to (focally) disable the inflammatory clearance process. Either suppression or gross over-stimulation are sufficient to achieve this. Also, remember that, for each host species affected, the number of "all pathogenic micro-organism species" represents a very small fraction of "all micro-organism species" (even though we are painfully aware and constantly reminded of the pathogens).

Glucose homeostasis (minimising the persistence of extracellular glucose) and oxygen transfer (haemoglobin to myoglobin transfer) act in a similar way to minimise access, by invaders, to important metabolites.

It is almost a scorched earth (scorched extracellular space) policy that sequesters away nutrients and metabolites from potential invaders. Invaders must dedicate genetic resources to ensuring the generation of supplies and other metabolites - or, alternatively, get themselves invited into the host's cells where there are more accessible resources. These conditions are, naturally, proinflammatory for phagocytes and APCs so the invading organisms are obliged to be proinflammatory (pathogenic) themselves.

So, microbes have two distinct influences when encountered by phagocytes (including antigen presenting cells like dendritic cells). First they have features characteristic of microbes (in general) and the phagocyte remembers these, from its evolutionary roots, as potential food: an encounter with them up-regulates the phagocyte's activity (probably, in part, by TLRs). The vast majority of the world's microbes are opportunists - they either live on inorganic material and some free energy gradient (eg, a hydrothermal vent) or feed on the corpses of dead plants and animals. So far, the majority of micro-organisms have little or no ability to attack living cells but they can become rapid colonisers once tissues are dead. This is the general micro-biological norm. Second, a small proportion of microbes have evolved mechanisms to generate their own cellular debris within living tissues (and this equates to pathogenicity). They aim to create microcosms of disruption and death (to which they need to dedicate precious genetic resources) to furnish themselves with the conditions they have long since evolved to utilise. Little wonder, then, that a macerated wound (from a physical pathogen like, for example, excessive heat) is a breading haven for microbes.

So a plea. Please, please, please - will all immunologists cease using this imprecise  talk of "pathogens" when they mean "pathogenic organisms" (organisms with the capacity to damage living tissues) or, at least, make it plain that they understand the importance of the distinction rather than demonstrate that they have have been bamboozled, by the repetition of an imprecise catchword, into thinking that the two are synonymous.

And a final comment - tissue resident dendritic cells would be well advised to take note of all instances of "potential food" (microbes) in the extracellular spaces surrounding tissue cells and regard them as threats (potential dangers) to tissue homeostasis. So it is probably not pathogenic organisms alone but any and all extracellular microbes that stimulate dendritic cells. So, are PAMPs (pathogen associated molecular patterns) really MAMPS (microbe associated molecular patterns)? Comparison with a plant's host resistance genes suggests that it is not the general recognition of microbial patterns that is blocking the specific diseases caused through the pathogenic mechanisms deployed by certain micro-organisms but they are highly specific countermeasures that close the loopholes that these pathogenic processes are exploiting (very much like Microsoft's responses to closing the security weaknesses that are targeted by computer virus attacks).

So are PAMPs really non-existent? No, not at all. The real pathogen associated molecular patterns (to my way of thinking and remembering the lump hammer message from above) are the molecular signatures of spilt cells and general disorder lurking around in extracellular fluids (see this article).

Restating the implications for micro-organisms

This is an important section but, as it is growing and this "Start Here" page is supposed to be a short synopsis, I have moved the expanding text to this section (currently my favourite bit!).

The "take home" message

Stop thinking (restrictively) about pathogens and pathogen recognition. Instead, view the (overall) immune system as a process that is on alert to respond to and deal with pathogenic stimuli. And, view the adaptive immune system as a process "designed" to "remember"  the signature of previously encountered pathogenic stimuli and respond more vigorously to them when they are re-encountered.

Once you have digested this page:-

Go to Morphostasis: a revolution? This has the next most simple explanation.

This page was last updated on 07/01/08