The danger of "Danger"

Alan J. Robinson robin073 at tc.umn.edu
Thu Jun 10 10:04:33 EST 1999


Paradigms lost...

>Subject:   The danger of "Danger"

>Date:      1999/06/01
>Author:    forsdyke <forsdyke at post.queensu.ca>

>Of late, the word "Danger" has repeatedly surfaced in the immunology
>literature as some entity that will allow us to do without self/not-self
>discrimination. What is really meant is that the
>conventionally accepted form of self/not-self discrimination has not
>sufficed to explain immunological phenomena.
>...           

>"Danger" is pure intellectual laziness. It explains nothing, but
>allows plausible handwaving which suffices, it seems, to satisfy reviewers    
>and (more importantly) the immunologists who review the grant applications    
>of other immunologists. While this situation prevails, it is,... well,...
>dangerous for an immunologist to become "not-self" (non-immunologist) and
>venture to contemplate how "Danger" might be detected in our bodies
>(professional suicide in the present peer-review environment).
>...

>Sincerely, Donald Forsdyke. Discussion Leader. Bionet.immunology
>http://post.queensu.ca/~forsdyke/theorimm.htm

Far from being intellectual laziness, the concept of "danger",
representing a threat to an organism's existence, is one of the most
powerful forces in all of biology.  The name of the game is survival -
which includes eating and not being eaten.  Darwin didn't give enough
attention to survival as the driving force for evolution, which has led
to a lot of confused thinking about evolutionary "fitness".

Anyway, immunology is one of several areas of biology where we have a
paradigm failure (in Kuhn's sense) - many experimentally observed
phenomena cannot be be fit into a single consistent, coherent conceptual
framework.

It's not just a lack of knowledge of the details - there's something
fundamentally wrong with the models we are using, and we can't put our
finger on the problem.

Some other areas of biology where we have a paradigm failure are:
 
*** Homeostasis  - there has to be more to this than just the HPA axis
and the sympathetic and parasympathetic nervous systems - See William
Blessing's work.  In addition, there is the question of the brain's
regulation of the immune system.  Metal'nikov's observation at the
Pasteur Institute in the 1920s of a conditioned response of the immune
system has never been explained.

But it isn't just psychological.  It's got something to do with
homeostasis and the neuromodulatory pathways in the brain which are
part of homeostasis - dopamine, norepinephrine, serotonin,
acetylcholine, and histamine).  Actually it's an active process,
because brain and body state must change to reflect different states
such as awake-sleep, active-resting, healthy-diseased etc.
(multiple physiological axes.)

*** Detailed computational model of the brain, sufficient to explain
how the brain carries out its perceptual, cognitive, and motor control
functions.

*** At a more restricted level, the disease schizophrenia.

     -------

The situation in immunology has partly arisen because 20th century
medical research has focused on infectious disease, to the almost
complete exclusion of other areas of medicine.  The AIDS epidemic has
perpetuated this situation.  See Jan Klein's commentary in
PNAS Sept 29, 1998 on immunological parochialism.

But infectious disease - which is a result of overcrowding - is not the
primary threat that animals and humans face.  It's simple day to day
survival - to prevent us from being eaten alive by ubiquitous
micro-organisms, and to put up additional lines of defense when the
primary physical barriers are breached, as in the case of trauma.
Indeed, the immune system is just part of an integrated system for
handling combined infection and trauma, and includes tissue repair,
which gets into the growth process itself and the issue of cancer.

See Nancy J. Rothwell and Frank Berkenbosch (deceased), "Brain Control
of
Responses to Trauma", Cambridge U. Press, 1994, for a groundbreaking
discussion of some of these issues.

My own model has acute trauma resulting from an unsuccessful
predator-prey
interaction as being one of the most powerful evolutionary forces, and
encompassing many different survival mechanisms in the brain and the
body -
there is the intense sympathetic arousal with pain and immune system
suppression during the chase, followed by the wounded prey in a
parasympathetic state of physical depression resting and recuperating in
its burrow, with a limb almost torn off and extensive blood loss. 

Much disease results from these survival mechanisms becoming
dysregulated. e.g. the autoimmune diseases.  The dysregulation occurs
at least initially in the brain, rendering invalid the current sharp
distinction between psychiatric and medical disease.

See C. Robert Cloninger's biosocial model of the brain for the
beginnings
of an integrated framework for incorporating these varied phenomena (of 
especial interest to neuropsychiatrists. among others <g>.  The
references
are in Medline.)

Alan J. Robinson
robin073 at tc.umn.edu



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