The history of the concept
The likely sequence of events.
It is hard to be sure that this is fully correct after this length of time: I have not kept careful records. One of the problems (and distinct advantages) that I have had is being isolated from other people in the field. This has been largely a personal interest, at best being only loosely connected with paid employment.
I have written it with the assumption that the conclusions will prove dominantly right so it may have an arrogant air.
"You've got to get your name in print to get a Senior Registrar job".
A patient suffering from neuro–Behçet's Syndrome (BS) was admitted to Middlebrough General Hospital Neurological Unit and my interest began. I surveyed the medical literature for all the case reports I could find describing neuro–BS and also the general literature on BS
"What are the differences between neuro–BS and MS? Both are possibly auto–immune disorders. It's obvious I'm going to have to learn some immunology."
Mycobacterial adjuvants appear important in the pathogenesis of adjuvant arthritis and this has similarities to BS and the sero–negative arthritides. "There's obviously some sort of connection here. So lets look at TB." I also read a bit about the immunology of tumours and the idea of immunological surveillance. "Perhaps I should look at diseases like BS and the sero–negative arthritides and compare these to cancer and TB." I soon decided that TB appears to be acting in cancer mode at the age extremes and sero-negative arthritis mode in the middle years. It occurred to me that TB seems to mimic the sero-negative arthritides in the middle years of life. It struck me that syphilis does a similar thing. I deduced that these infections provoke immune auto-aggression to establish a suitable milieu ("culture medium") to enhance their growth and survival. Embarrassingly immature hypotheses followed. However, I established this principle of mimicry by TB and the changing incidence of various diseases with aging. It was about this time that I came across Burwell's article on morphostasis. Much that he wrote was clearly too imprecise to equate to current knowledge. However, it indelibly fixed in my mind the need for morphostasis and the likelihood that the immune system was closely involved with it. I also established the idea that auto-aggression was a normal process and, since it was allowed as a mechanism of morphostasis, it had to have controls (a shut off – eg, anergy). These points have remained central in the concept.
Meanwhile, – Neuro-BS and MS. "Well, it's clear that the encephalitis of BS ought to have an auto-aggressive element in it if the analogy with adjuvant arthritis is right. So lets find out more about the auto-immune nature of MS."
It is soon occurred to me that the phrase auto-immune seemed to be a misnomer (obscuring what is happening – an etymological blunder) and that diseases dominated by antibody activity are, anyway, different to those dominated by cell mediated auto-aggression. Tissue rejection is largely dominated by cell mediated immune responses.
In 1977 it had become apparent to me that many diseases probably had a dominant auto-aggressive basis. One paper had a large impact on my thinking. This outlined the dominant part played by cell mediated immunity in these disorders.
What about the structure of the sero-negative arthritides and what implication is there in the high prevalence of the overlapping component features that characterise these disorders? I was lucky in that Behçet's syndrome was probably the very best springboard for this. It became apparent that there is an inverse relationship between the population incidence of the components and the severer multiple component syndromes. "So why is MS not the component equivalent of the encephalitis of BS? Let's look at that and see if a case can be made for it. After all, although the CNS lesions of encephalitic BS are very different to those of MS, the transitional scleroses occupy a half way house towards the encephalitis of BS." I submitted a review of neuro-BS to the ***** pointing out many of these features. It was not accepted.
My spell as a neurological registrar ended and I decided to move into General Practice (July 1977). It was clear that I was not getting unanimous support that would help me move up to senior registrar status – very likely justified. I had to make a rapid career decision either to cut my losses or battle on looking for a senior registrar post. Without papers to my name, this seemed a forlorn hope. I moved to my current location as a GP.
Early in my GP career I managed to arrange 3 months of study leave supported by the (then) Dept Health & Soc Security to finish off the Neuro-BS paper. I spent 3 months wandering around the two main Wessex Medical Library divisions. However, although the Neuro-BS paper improved greatly and the rationale for my earlier presumptions grew stronger in my mind, in time it largely gave way to wondering about the wider implications. Until I was satisfied I understood this thing, immunology, I would not be able to understand what was causing the encephalitis in BS. I constantly felt that there was something not right or empty about conventional explanations. It didn't really make a functional entity – current explanations seemed inadequate and incomplete. "There's something missing." It was "Heath Robinson or Rube Goldberg".
It struck me early on that, in a zygote derived system, the natural way to set up a morphostatic system would be identity based. Cells should be able to communicate their identity (rather like war zone aeroplanes avoiding friendly fire) to establish themselves as "friends". It was logical to add a suicide mechanism onto this so that cells could work out, for themselves, that they are sick and so tell other cells about it. This lead onto an interest in identity. The library had a series of books on Receptors and Recognition. These set me off exploring this. Somewhere in this mêlée of ideas it struck me that it was important to work out how the immune system evolved. The stark, Minerva-like appearance of the anamnestic (cognate) immune system in the vertebrates seemed an anachronistic enigma to me. Clearly, I thought, people were missing something critical here. Only divine intervention could put that there without a long, understandable prelude.
In 1984 Prof **** saw what I had written and he arranged for me to come and present my ideas to the immunology group at ****. In preparing to get the best possible presentation I went into temporary overdrive. The idea of Tc-cell inversion came to me quite suddenly and seemed, to me, a clear vindication of the approach so far. There were long, bored, important faces at this presentation. It had been a waste of valuable professional time. I retain an impression of it as a dramatic display of "parent –> child" destruction. I felt that I had been subjected to an emotionally charged (humiliating) dismissal. I concur with the statement that "stale paradigms are held like religious beliefs". Threatening them demands that an upstart is belittled. Major players in the field enjoy the animal experience of authority and power and, I think, they play this sort of game to exercise it. Minds are, in consequence, pre-emptively closed and the querulousness of the intellect is subdued. Even in the most naive and outlandish hypothesis a positive side should be sought. Dismantling it needs to be intellectual and non-emotional. Dismantling can be as instructive as a well founded hypothesis.
I subsequently wrote around to a number of people trying to interest them in this approach to the concept. At that time it was largely based on the "clinical consequences" part of the paper. I submitted a speculative hypothesis to the J of Theoretical Biology (1984). This was not accepted. The criticisms they made were valid. As always, I was mixing wild speculation with a gradually condensing authority in other areas. It was undisciplined and wild.
It was about this time that it occurred to me that, since beta-2-microglobulin was an ancient molecule and it reacted with complement C1 in much the same way as antibody constant region genes, there had to be a function similar to the classical pathway that long predated the Minerva-like appearance of antibodies in vertebrates. So let's find out about complement (groan!) and see if some "Technicolor" can come to this tedious list of interactions. Well, it spawns multiple holes from one simple interaction at the cell surface. A fascinatingly complex multiplier mechanism that seemed to me to have a deeper origin than the task identified for it. Somewhere around this era it struck me that GJs seem to be formed in the same shape and possibly in a similar amplified manner. "Are they a similar size and could the complement system be related to the GJ system?" (This is a contentious and speculative part of the present hypothesis). From this time I scanned the literature for as much information as possible on gap junctions. One paper in particular (by Loewenstein) had a few sentences about GJ disconnection during cell ill health. This made a lasting impression on the way I thought.
In all this time, I would go through periods of prolonged disinterest followed by frenetic enthusiasm. I wrote to several key immunologists around 1983-1990 but did not get significant response.
One of these enthusiastic spells occurred in late 1991 and I wrote to Edwin Cooper asking if he thought there were ideas of interest worth sharing in the concept. He showed what I thought was fair interest in the idea and asked me to condense it. As a point of interest, in forming a hypothesis of this sort, the speculation shows through in the writing. When I was less secure, the style with its "maybes" and "ifs" was wordy, discursive and off-putting. Edwin Cooper was more interested in the molecular morphostasis part. At this point, I was fairly convinced that a phagocyte had to be the cell that specifically recognised self Mhc antigens because it had to work out what was healthy-self when the lymphocytes had called them to the scene of potential crime.
It was in January that it suddenly struck me that, of course, it was probably the natural killer cell that did this. I wasn't at the time aware of work that supported this concept (it did exist – Karre K.). The concept went through a frenzy of evolution and this is reflected in Edwin Cooper's letter to me about various versions. Anyway, the submitted article was eventually dismissed by the reviewers, receiving an emotive raspberry from one. It contained much of what was later submitted to the ****** (June 1992). I replied to this dismissal pointing out that I seemed to have been misunderstood. Edwin Cooper clearly felt it was worth risking pushing this forward again but the final reply was that it was not acceptable. He has been one of the most polite and interested parties that I have written to. Indeed, a comment in his recent book could, possibly, have been pointed at this paper (Phylogeny of the Immune System).
I then tried the ***** again (the Morphostasis and Immunity 1992 paper). They kept it for 7 months before dismissing it out of hand. "Tant pis pour les fleurs" resounds in my mind! Again, an emotional (animal vs intellectual – humiliating) response I thought. Then I tried the other journals.
In about July I knew there was merit in a least some of the ideas. In particular, the concept was born that lymphocyte commitment (in the spectrum "tolerance <–> aggression") was dependant on the spectrum of "tidy apoptosis <–> messy necrosis". Two journals rejected versions that made this point. But how could I get people to listen? I circulated three prominent researchers who had an interest in related areas of research. None replied though I did make it clear that this would not offend me. In December 1993 I personally placed a copy of the paper "to date" into the hands of **** when at a conference. I believe he still has a copy.
Polly Matzinger's article on "Tolerance, danger, and the extended family" appeared in The Annual Rev Immunol. I wrote to to numerous people with a copy of the main (Morphostasis and Immunity) paper to date. None except ***** have responded, though again I made it clear that I wouldn't expect one. A recent symposium on self/non-self discrimination appeared to be missing the point and I wrote to four of these authors, to many others and two prominent journals in an attempt to "infect" them with the concept. I wrote to Polly Matzinger and have had sporadic correspondence with her since then.
Then various articles appeared that lent support to the ideas so far. These included articles about GJs and cell suicide, and cell death in plants. David Vaux (and others) wrote a leader in Cell on apoptosis.
Finally, I thought I had better try Medical Hypotheses. However, not even after submission was I aware of ever having seen this journal. It does not feature on the shelves of our library. It seems to me to be a clear indictment of the bio-medical fraternity that only one such journal exists and the only articles that the bio-medical press are interested in publishing seem to be empirical studies or reviews by mainstream experts (the promulgators of Kuhn's normal science). An editorial leader from Nature "The Hypothetical Way of Progress" emphasised how poorly hypothesis is regarded in the life sciences. This is particularly true of broad hypothesis.
This is largely covered by the articles in print and the phlogiston article (in the "Unpublished" folder). There have been many emails to and from (mostly "to" I think) during this time but all these are too much for these pages and the respondents probably too easily identifiable. I hope, however, you get a feel for how difficult it is for a non-entity with a novel idea to make any impact on "normal science".
Was it right?
Well, no – of course – it was not all right. But it was absolutely right in essence and absolutely right in as much as a complete shift in paradigm was both due and required to enable rapid progress. I am happy now that "the snowball is rolling" and is now unstoppable. I came across a Christmas cracker "wise crack" in Dec 2002,
"Even if you're on the right track, you'll get run over if you just sit there." (This quote has been attributed to Will Rogers.)
Well, that race to stay out in front (in the formulation of concept) has had its toll on me. And, it is no longer remotely possible to stay out in front now that so many people are adopting perspectives that I can, at last, agree with. So it's time to sit back and become an observer. But there may still be a few general philosophical/logical points I could yet contribute.
Costs and income
- Costs – about £1000 in publication fees. More than 20,000 miles, in car, travelling to library and back. Considerable costs in photocopying. More than 1000 weeks of 4-10 hrs a week dedicated to activity around it (time difficult to average out). WWW domain site and maintenance (about £600 so far). Internet access – essential for searches and literature awareness – £30/month (c £1000 total). [This is now a lot more as this was written a long time ago.]
- Income – one 3 month period of partially subsidised study leave (in which I was out of pocket of true costs) in about 1981. Otherwise nothing. The "terra firma" article was sponsored by Inspec (now absorbed into other companies – about £250 of the publication costs mentioned above).
- Grants – none. Chances of getting one – zero. It's not "normal" science.
- Interest in articles – this (apparently) seems to be remarkably thin. They get an occasional mention but citations, even recently, were very thin (I no longer have access to a citation search engine to check myself) (Note 2014/09/06: no longer valid now that Google Scholar can do this). Perhaps this is what they deserve – but I suspect this is not really the case and future historians of science may acknowledge this.