Pathophysiology 11 (2004) 135–138
Review
Some categories of general pathology and biology: health, disease,
homeostasis, sanogenesis, adaptation, immunity
New approaches and notions
G.N. Kryzhanovsky
Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Baltijskaya 8, Moscow 125315, Russia
Received 25 June 2004; accepted 2 August 2004
Despite all significance of the problem, satisfactory defini-
tions of some very important categories of general pathology
and biology, particularly health and disease, have not been
found for a long time. Some formulations concerned only
biological mechanisms while others, in contrast, emphasized
the social aspect of the problem implying humans. Few defini-
tions consist of a number of mutually supplementing phrases,
which makes obscure the essence of formulation.
According to the well-known WHO definition, “Health is
a dynamic state of complete physical, mental, spiritual and
social well-being and not merely the absence of disease or
infirmity”. The WHO did not provide a definition of disease,
probably due to the difficulty of formulation.
This definition of health, which is correct in essence and
intuitively clear, has a humanitarian focus; in consistency
with the spirit and goals of WHO, it implies primarily hu-
mans. However it should be determined, what the “complete”
well-being is. A well-accepted everyday notion of “well-
being” needs explanation. It is not fully clear, what “social
well-being” is because this term also applies to humans only.
Obviously, the definition should be brief in its form but suffi-
ciently capacious in its content reflecting both biological and
social aspects. Also, the definition should bear a universal
meaning for at least animals and humans if not for all living
systems.
All organisms are inseparably linked with the environ-
ment. There is no life without the environment. The envi-
ronment predetermines behavior of the organism; human en-
vironment includes both biological and social and spiritual
spheres. Each organism has its own habitat to perform its
vital activity therein. Passive relations with the environment
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doi:10.1016/j.pathophys.2004.08.003
are mediated by behavior-independent biological processes
(for example, biological adaptation), whereas active perfor-
mance represents productive relations with the environment.
Searching for a shelter, digging a burrow, building of a nest
or house and creation of a space station are all apparent ex-
pressions of the productive activity of animals and humans,
respectively. Therefore, the productive activity is an adequate
criterion for the organism state. Such relation with the envi-
ronment underlies the definition of health and disease.
For comprehensive consideration of the problem and defi-
nition of the notions “health” and “disease”, it is necessary to
dwell on two additional general biological categories, home-
ostasis and sanogenesis.
Homeostasis: Homeostasis is the constancy of internal en-
vironment of the organism. The idea of homeostasis was put
forward long ago by Claude Bernard in the form of a state-
ment that the constancy of internal body environment is a
necessary prerequisite of its independent life. Cannon has
developed this idea and created a doctrine of homeostasis.
Homeostasis is provided by regulatory mechanisms at all
levels of the organism, starting from the molecular level and
up to higher systemic connections. The more complex and
higher the biological organization, the more it needs home-
ostasis and the more sophisticated are the mechanisms for
achieving homeostasis.
As it has been already mentioned above, however, the
organism cannot live without the environment; there is no
life independent on the environment. Effects of the environ-
ment, one way or another, influence homeostasis. Therefore,
homeostatic parameters are not absolutely stable values; they
change to a necessary degree under diverse impacts of the
environment and organism response to the impacts. Homeo-
static parameters change also during endogenous processes
136 G.N. Kryzhanovsky / Pathophysiology 11 (2004) 135–138
in the organism. The changes are not only acceptable but also
necessary because they provide optimum response of the or-
ganism to effects of the environment and realization of en-
dogenous processes. This is why it is reasonable to consider
dynamic, functional homeostasis rather than a strictly rigid
one. The extent of homeostatic fluctuations is determined
and regulated in accordance with needs and potentialities of
the organism. Homeostatic disturbances are both a result and
expression of dysregulatory pathology and an endogenous
reason for subsequent development of the given or another
form of pathology.
The environment of each cell and organ is heterogeneous;
it consists of many components with specific, variable pa-
rameters depending on activity of the cell or organ. In other
words, the environment of each structure occurs in the state
of dynamic functional homeostasis.
Brain homeostasis is provided by local homeostasis of its
media and structures and, on the whole, by the blood–brain
barrier, which is able to pass selectively and to conduct ac-
tively through transporters necessary substances in appro-
priate amounts. The blood–brain barrier protects the brain
against pathogenic agents and biologically active substances,
which may change cerebral activity in an improper way. For
instance, the barrier does not pass substances operating as
neurotransmitters; it passes only transmitter precursors. After
that the brain itself uses them to produce transmitters in re-
quired amounts and in appropriate regions. Each neuron and
each junction have their own microenvironment owing to spe-
cial membranes and barrier mechanisms of glial cells. Con-
tent of biologically active substances (glutamate, Na+ , Ca2+ ,
Cl− , K+ , etc.) in the intercellular space is strictly regulated
in dependence on neuronal activity and demands. Controlled
changes in interneuronal medium content of these substances
represent functional dynamic homeostasis. These changes
may be considerable; however, degree of the changes corre-
sponds to demands and functional load of neurons and glio-
cytes. Uncontrolled changes in content of these substances
result from and underlie further development of dysregula-
tory pathology.
The most important role belongs to functional homeostasis
of neuronal internal medium. Content of intracellular mes-
sengers changes during intracellular processes providing per-
formance of neuronal function. In pathological processes,
the changed degree of metabolism and function realization
results in further development of these processes. A vivid ex-
ample of changes beyond the regulatory control is the above-
described disorder of calcium homeostasis resulting in neu-
ron death.
Along with humoral homeostasis, structural homeostasis
exists in organ and tissue cells. Structural homeostasis is the
continuous turnover of cells and intracellular structures; new
cells and new structures come to take place of worn and dy-
ing of apoptosis cells. Owing to this process, tissues and or-
gans retain their capacity for full-value functioning. Neurons
do not divide in the nervous system of an adult organism.
However, continuous regeneration of intraneuronal and ex-
traneuronal structures takes place. An illustrative example is
replacement of dendritic spines and even death and regener-
ation of dendritic terminals on cortical neurons of higher ani-
mals and humans induced by changes in stimuli. This change
provides optimum realization of the higher nervous activity
and behavior in the changing environment. At early stages of
development the nervous system actively gets rid of defec-
tive neurons by apoptosis to prevent neural diseases in the
adult organism. In senile age, not only defective but also idle
neurons die in the first place. This process is biologically jus-
tified because it economizes structural and metabolic material
necessary for functional neurons.
The dynamic functional homeostasis represents a complex
structural and functional process occurring at all structural
and functional levels of the organism and in various organs
and tissues to provide vital activity of the organism and per-
formance of multiple functions required for normal biological
and productive relations with the environment.
Norm: In the biological aspect, norm is the same health;
the definition of health applies to norm. In the diagnostic
aspect, norm is a quantitative expression of health parameters.
It is known from the practice, however, that all individuals
cannot have similar norm or similar state of health. Genuine
measure of health can only be individual as determined by
genotypic and phenotypic features of the organism at each
specific point of its vital activity but not in general. An average
value of some or other normal parameters is used in practice.
However, what is normal for the given organism may indicate
pathology in another one. It is well known, for example, that
athletes may display very high tachycardia during exercise.
Such heart rate is indicative of pathology in usual persons but
is necessary for performing exercise in athletes.
Sanogenesis: Sanogenesis is translated as recovery. In
Russia, S.M. Pavlenko actively promoted this notion. How-
ever, it was rejected for the reason that recovery cannot be
separated from disease because both processes are interre-
lated.
Indeed, pathogenesis and sanogenesis comprise a unit and
this unity is evident as a disease. However, the unity does not
imply identity, and mechanisms of disease and recovery are
not only different but directly opposite because they are re-
alized by antagonistic processes. Pathological systems and
sanogenetic anti-systems are related structurally and func-
tionally. Moreover, sanogenetic anti-systems are activated or
induced by pathological systems. However, these systems
have different biological significance and represent biologi-
cal antagonists.
Sanogenesis occurs at all levels of a complex organism,
from molecular and cell processes to higher systemic and
intersystemic interrelations. In their totality and interaction,
these mechanisms comprise a united sanogenetic system of
the organism, whose activity results in health.
Sanogenesis passes its own stages of development. Like
pathogenesis, sanogenesis involves unique processes for
eliminating various types of pathology. They represent typ-
ical sanogenetic processes. They include intracellular pro-
 G.N. Kryzhanovsky / Pathophysiology 11 (2004) 135–138
cesses, many of which are standard and lack nosologic char-
acteristics, and processes at other structural and functional
levels of the organism. These processes are incorporated to
different degrees and in different combinations into the sano-
genetic system of the organism, which is activated or formed
in each pathological process.
Health and disease: The above-said allows the following
definition of the categories “health” and “disease”.
Health is the state of an organism with undisturbed func-
tional dynamic homeostasis providing optimum performance
of organism functions to the extent necessary for productive
relations of the organism with the environment.
Disease is the state of an organism with disturbed func-
tional dynamic homeostasis and inability to perform to a
necessary extent the functions providing productive relations
with the environment.
These formulations reflect both biological and social as-
pects of definitions for health and disease.
It is reasonable to dwell in more detail on the “disease” cat-
egory. The organism is continuously exposed to pathogenic
influences regularly inducing pathological changes in tissues
and varying in their extent and form. However, the changes
are eliminated by protective sanogenetic mechanisms pre-
venting a local pathology from transformation into disease. A
similar situation takes place in endogenously induced patho-
logical processes. Malignant cells resulting from dysregu-
lation of the genetic apparatus are eradicated by immune
and tissue mechanisms preventing the development of tumor.
Even accumulation of tumor cells in the form of a clinically
undetectable node is not yet a tumor disease though this node
must be eliminated to prevent the disease. The presence of
an epileptic focus is not yet epilepsy. It is known that indi-
viduals without apparent disease may display some limited
epileptic activity. The pathological process transforms into
disease only when mechanisms of sanogenesis become irre-
placeably disturbed, and the organism fails to function to a
necessary and optimum degree. An individual with limited
abilities does not fall ill if he is sufficiently adapted to the
environment due to compensatory and plastic processes, and
can function to a necessary extent. Whether the individual
would feel either as a disabled person or an active member
of the society depends largely on the care of him, which rep-
resents a productive attitude towards him of the society and
state. This is the social aspect of the problem of health and
disease.
The idea that a disease is a pathological category only
applies to a whole organism is not completely correct. A cell
is also an organism with its own environment, homeostasis
and functions and therefore the cell may be sick as well. A
disease may develop in not only animal but also in plant life;
a tree may also be sick. In animal and plant life, definitions
of a disease differ in accordance with their specificity having
in principle a single meaning.
Of importance is the issue of the nature and relations be-
tween pathogenesis, sanogenesis, immunity and adaptation.
An idea appeared in its time based on empiric experience and
137
practical data that immunity and adaptation to pathogenic im-
pacts result from a disease and develop after the disease had
been survived. Some pathologists, including such outstand-
ing pathologist as I.V. Davydovsky, have shared this idea.
However, the idea is wrong in principle.
Jenner and Pasteur using non-pathogenic for humans at-
tenuated infectious agents (e.g., infectious agent of cow-
pox or attenuated infectious agent of rabies) showed that
immunity may develop also without a disease. The use of
such non-pathogenic agents became the principle of vaccina-
tion. Further investigation of chemical and structural nature
of infectious agents demonstrated that they had two deter-
minants, one of which was pathogenic, pathology-inducing
while the other was immunogenic, stimulating immunogene-
sis. It became clear that the used for vaccination attenuated or
pathogenic agents were the infectious agents with eliminated
or attenuated pathogenic determinant. At present synthetic
vaccines exist, which represent polymer-bound immunogenic
domains. The immune response induced by such vaccines can
surpass many times the response to natural vaccines.
It clearly follows from the above-said that it is not nec-
essary for the organism to survive a disease or a pathologi-
cal process in order to develop immunity (resistance). This
generalization applies to effects of any pathogens. Pathogen
exposures do more than do not induce immunity, resistance
and adaptation in the broad sense of the word but they also
destroy both mechanisms of these processes and mechanisms
of natural resistance.
Adaptation to a stressor of any nature develops in physio-
logical stress induced by sub-pathogenic impacts. Such stress
activates adaptive processes but does not mediate pathology.
A severe, pathological stress induces dysadaptive and dys-
regulatory disorders of integrative systems in the organism
along with injuries of internal organs. This pathology may
acquire the form of disease. At the third (by Selye) stage of
such stress, physiological and protective mechanisms of the
organism become exhausted and the process terminates with
death.
Epileptic attacks are associated with appearance of anti-
epileptic substances in the liquor of patients and animals,
which provide reversal of the attack and prevent new ones.
These substances are both markers and products of the ac-
tivated anti-epileptic system. Our studies [1] have demon-
strated that anti-epileptic substances may appear in the liquor
of animals also without an epileptic attack, only under stim-
ulation of structures in the anti-epileptic system.
Pathological process, if not beyond cutoff, activates pro-
tective and sanogenetic mechanisms resulting in recovery and
possible development of immunity. This biologically benefi-
cial result has an excessive price; it is fraught with compli-
cations and is not always sufficient for establishing a stable
state of health.
It is important to emphasize that the fact that pathological
process stimulates protective mechanisms does not suggest
that the process itself is a sanogenetic mechanism. Allergic
inflammation enables eradication and elimination of the al-
138 G.N. Kryzhanovsky / Pathophysiology 11 (2004) 135–138

lergen but allergy itself is a pathology. The fact that allergy is
a destiny of vertebrates does not imply that allergy is an ac-
quired sanogenetic mechanism and a biologically beneficial
process. This fact only indicates peculiarities of evolutionary
development of responsiveness in the animal life.
As stated above, pathogenetic and sanogenetic mecha-
nisms are interrelated to comprise a unity in the form of
disease; however, they are principally different and antag-
onistic. One should distinguish them; it is necessary for both
pathogenetic therapy and creation of therapeutic means.
Reference
[1] G.N. Kryzhanovsky, A.A. Shandra, L.S. Godlevsky, Karganov,
Antiepileptic properties of cerebro-spinal fluid after activation of
antiepileptic system of brain, Epilepsia 30 (5) (1989) 631–635.