Biol Philos (2010) 25:215–228

DOI 10.1007/s10539-009-9190-x

Mechanisms, malfunctions and explanation in medicine

Mauro Nervi

Received: 13 August 2007 / Accepted: 13 December 2009 / Published online: 24 December 2009

Springer Science+Business Media B.V. 2009

Abstract Mechanisms are a way of explaining how biological phenomena work

rather than why single elements of biological systems are there. However, mech-
anisms are usually described as physiological entities, and little or no attention is
paid to malfunction as an independent theoretical concept. On the other hand,
malfunction is the main focus of interest of applied sciences such as medicine. In
this paper I argue that malfunctions are parts of pathological mechanisms, which
should be considered separate theoretical entities, conceptually having a priority
over physiological sequences. While pathological mechanisms can be described in
terms of a Cummins-like mechanistic explanation, they show some unnoticed
peculiarities when compared to physiological ones. Some features of pathological
mechanisms are considered, such as outcome variability, ambivalence and depen-
dence on a range.

Keywords Mechanisms
Malfunction
Philosophy of medicine

Scientific explanation

Introduction

In recent years, many attempts have been made to define a ‘‘mechanism’’ as a

theoretical model able to explain both how a biological system behaves and how it
performs its task (Glennan 1996; Machamer et al. 2000; Craver 2001; Darden
2002). Usually attention has been paid mainly to physiological mechanisms, in
order to explain their attitude to preserve or increase fitness to the environment.
Very little is said, however, about those systems which have lost their functionality
as a consequence of a congenital defect, disease or direct damage. While this is a side

M. Nervi (&)
University of Pisa, Pisa, Italy
e-mail: mauronervi@gmail.com

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topic in biology, in applied sciences—and primarily in medicine—malfunction is

focused on as the main object of inquiry, and the operation of biologically undamaged
mechanisms is assumed as background knowledge. In other terms, there is a deep
pragmatic difference between biology and medicine, since the former deals with pure
scientific knowledge and the latter takes advantage of theoretical knowledge as a basis
for practical treatment of medical diseases. As a consequence, mechanisms in their
normal conditions (which we shall hereafter call ‘‘physiological mechanisms’’) are a
subject of scientific explanation in their own right in biology, but only a means to
understanding malfunctions in medicine.
In spite of all this, very little has been written about malfunction in itself.1 There
is a tendency to understand malfunction as the mirror image of function: once the
real nature of mechanisms is established, malfunction is defined as the impairment
of the corresponding mechanism, so that a philosophical definition of malfunction
becomes pleonastic. Every malfunction depends on an identifiable defect in the
mechanism, and pathology has a conceptual dependence on physiology.2
Such a simplistic view fails to describe the current practice of medical research.
When trying to understand diseases, the researcher’s attention is directed towards
the pathological sequence in the natural history of the disease, in order to find a
point in the sequence where therapy might successfully be applied. Although such a
sequence of events is grounded in physiological mechanisms, the pragmatically
different view of medical research argues for an independent description of the
pathological series, which is articulated as a mechanism of a separate type.
The aim of this paper is to inquire into the nature of the pathological mechanism
as an independent theoretical entity and to define its peculiarities, in contrast with
the received definitions of biological mechanisms. In the first section (‘‘Mechanism
malfunction versus pathological mechanism’’) physiological and pathological
mechanisms are compared, and prominent conceptual differences are described;
in the second section (‘‘Pathological mechanisms in medical practice’’) some
examples will be given to test the usefulness of this theoretical framework for
biological and medical research.

Mechanism malfunction versus pathological mechanism

The biologist’s concept of disease as background of normal mechanisms

The aim of Cummins (1975) paper was to rule out historical explanations of system
functions, by fencing the functioning system within its actual causal relationships.

1
Davies (2000) has the merit of describing malfunction as an independent question, but deals almost
exclusively with its evolutionary implications. Neander (1995) argues about malfunction from a purely
logical point of view, which is not very relevant to my point.
2
Neander (1995) clearly expresses this point of view: ‘‘The primary physiological analysis necessarily
abstracts away from maladaptive environments […] Descriptions of what happens when things are
maladaptive or malfunctioning are given against this background. That is medical descriptions of disease
processes tend to assume normal functioning of the body, except where abnormalities are explicitly
described or are inferable from those explicitly described’’ (p. 118).

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This approach has been recently endorsed by Salmon with his causal-mechanical
approach (Salmon 1984) and by the new concept of mechanism as it is identified in
recent papers (Glennan 1996; Machamer et al. 2000; Glennan 2002; Woodward
2002). Craver (2001) is particularly explicit in denying the relevance of
adaptiveness for a valid account of mechanistic role functions: ‘‘my account of
mechanistic role functions does not appeal to any sense of adaptiveness in an
environment; instead, it appeals only to roles in contextual systems. These
contextual systems may be adaptive or destructive, and they need not even be the
kinds of systems for which talk of adaptation is appropriate. Heart disease, high
blood pressure, cardiac arrythmia, and arterial hardening all have mechanisms that
span multiple levels, and this three-tiered perspective is as useful in those contexts
as in those that are adaptive’’ (Craver 2001, 67). The assignment of a role is enough
of a criterion to define the mechanism, independently of whether the mechanism be
overall adaptive or maladaptive.
However, there is an implicit agreement about the fact that a mechanism must be
valuable for the organism; this is a way of bypassing the difficulty of defining
malfunctioning mechanisms. According to this view, malfunction is conceptualized
as a failure in one or more steps in the physiological sequence of events. In the case
of the circulatory system, this sequence can be summarized as follows:
1. Spontaneous electric variation in specific myocardium
2. Co-ordinated contraction of the cardiac muscle
3. Ejection of blood from the ventricles into the aorta and the arterial system
4. Blood is transported to peripheral tissues through undamaged vessels
5. Water, oxygen and metabolites are exchanged with peripheral tissues within a
definite range.
Any description of mechanisms is purely conventional and guided by the
researcher’s explanatory interest, since every step in the above sequence could be
expanded to a lower-level mechanism with a corresponding causal sub-sequence.
By defining the steps of the mechanism, the researcher follows a schema that fits the
disease he has in mind. In other words, there is no objective description of any
mechanism, rather biological sequences are depicted by the biologist according to
the pragmatic need of explaining malfunctions.
This is enlightening when trying to explain disease as an impairment of the
normal mechanism. Any step in the sequence can be targeted by a pathogenic agent,
and the corresponding disease is then explained with reference to the interruption in
the sequence. One can explain many diseases in this way, e.g.:
1. Arrhythmias from interruption of the atrioventricular junction or the His-
Purkinje system which results in impaired conduction from the atria to the
ventricles: AV blocks, ventricular fibrillation, asystole;
2. Impairing of cardiac diastole by constrictive pericarditis, or insufficient
contraction in dilated cardiomiopathy;
3. Severe aortic stenosis, rupture of thoracic aortic aneurysm, compression of
thoracic aorta by a large mediastinic mass;

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4. Traumatic lesions of major vessels, thrombosis or embolia of peripheral

vessels;
5. Tissue oedema or microangiopathy.
There is no inconsistency in this approach, and sometimes it can be usefully
adopted for basic pathophysiological explanation. A model of mechanism is built
according to the researcher’s pragmatic purpose, and the disease is explained as
background of the central normal situation, which dominates the theoretical
scenario. When explaining basic pathological phenomena, one needs to stress the
similarity of structure between the normal mechanism and the pathological
phenomena being studied. In such a case the researcher with this explanatory
purpose postulates a mechanism to explain the disease: in other words, a
malfunction or defect in each step of the mechanism can explain a particular form
of disease.

Pathological mechanism as an independent entity

Obviously, this is not the case in all medical explanations. Though one always has to
take for granted the knowledge of normal functioning in order to understand
pathology, the natural history of the disease is usually of primary importance for
therapeutic purposes.
The French surgeon Leriche made a point of this when he wrote in 1936: ‘‘it is
doubtful that by studying normal organisms, no matter if human or animal, we can
reach a satisfying view of the normal physiology of man. […] It is perhaps easier to
research the changes caused by disease or the effects of therapy during disease; thus
illness may become our main source of knowledge about the healthy man’’ (Cited
by Canguilhem 1966, 58). After an extensive review of prominent definitions of
health, Boorse 1977 also feels that ‘‘a direct attempt to analyze abnormal
functioning will better fit the medical notion of disease than the ideas of this
section’’ (550); and more explicitly: ‘‘The correct strategy is to deal first with
intrinsic health by examining what physicians call disease. An analysis of promoting
or conducing to health then automatically follows, but not conversely’’ (553).
In fact, when analysing the natural history of a disease we look for a point in the
sequence where a therapeutic intervention could be successful. Medicine is an
applied science which aims not only to observe and describe natural phenomena, but
also to find a therapy capable of modifying them: and some authors have based the
very idea of a philosophy of medicine on this pragmatical peculiarity (Engelhardt
1976, 95). When multiple accounts of the same biological (or pathological) process
are available, medical explanations tend to embrace the account which is most
likely to allow one to find or to explain a therapeutic approach.
The explanatory style is tuned to this teleology, and in a twofold manner: by
establishing malfunction as its central topic, with normality in the background, so
reversing the priority described above; and by describing causal chains of
pathological events which lead from the initial aetiology (if known) to the possible
outcomes of that particular disease. From this point of view, we observe a shift from
the malfunction of the mechanism to a real pathological mechanism, in which

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elements and activities are an independent part of the explanation of disease, and not
just the failure of normal biological activities. Pathology and natural history
converge to a new type of mechanism, which needs a formal definition of its
elementary components.
An example is diabetes insipidus. This disease occurs in two versions: either
damage to the hypothalamus may decrease the production of antidiuretic hormone,
or the kidneys may become insensitive to the normal blood concentration of the
hormone. In the first case we normally observe the following chain of pathological
events (in severe and untreated cases):
1. Extrinsic damage of the hypothalamus (from brain tumours or iatrogenic injury)
2. Decrease of production and incretion of antidiuretic hormone
3. Lack of permeability in the cells of the distal nephron, with no distal
reabsorption of water
4. Polyuria and polydipsia
5. Severe dehydration
6. Hypovolemic shock
7. Cardiac arrest and death
Each step is causally related to the previous one, and could be in turn subdivided
into lower level mechanisms, also causally subdivided into internal steps.
On the other hand, if diabetes insipidus is nephrogenic, most frequently no
apparent damage can be demonstrated, although there is a genetic impairment of the
production of membrane receptors in the distal nephron cells, with consequent
insensitivity to the hormone. The first two steps are then described differently:
1. Impaired synthesis of membrane receptors in the distal nephron
2. Cell insensitivity to antidiuretic hormone
…
after which the two chains converge. In this chain, as in any chain of events,
every step can be analysed into submechanisms.
One could object that each event in the chain is relational, being defined as the
negative counterpart of a normal biological mechanism. This is true, but the
objection misses the point. Medical explanation describes pathological phenomena
by stressing the causal relationship between a pathological event and its immediate
consequence; at the same time, it constructs a tree of causal relationships
constituting the natural history of the disease in a time interval. In fact, therapy
normally interrupts one or more of such causal relationships; when considering
pathology for therapeutic purposes it is therefore rational to describe pathological
mechanisms in their causal progression rather than with reference to the normal
mechanism. Heuristically, the pathological mechanism and the causal lineage in
which it becomes increasingly distant from normal behaviour and increasingly
global in its effects is the most relevant object of medical knowledge.
The difference between malfunction in the sense of impairment of a (normal)
mechanism and malfunction as pathological mechanism is one of pragmatic/therapeutic
relevance. In the Table 1 bold lines represent the relevant causal relationships.

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Table 1 Two explanatory

patterns of disease: a difference
in pragmatic relevance

Bold lines symbolize causal

relationships with greater
pragmatic relevance to the
overall explanation. Ph 1, 2, …
and Path 1, 2, etc., are the single
states or elements whose
sequence constitutes the
physiological or pathological
mechanism

The causal relationship is stressed at each step, thus making the pathological
mechanism (i.e., the causal sequence of pathological states pragmatically relevant to
therapy) an independent entity as a whole.
Moreover, it should be said that most pathological mechanisms are not linear and
quarantined in their effects, but can spread out into branches and interfere with other
systems, embedded as they are in a net of mutual biological influences. Example,
hyperglicemia following the onset of diabetes mellitus interferes with the
functioning of distant structures like kidney, retina and peripheral vessels, causing
the new onset of pathological chains. Thus, pathological mechanisms seem ramify
largely independently of the initial mechanisms from which they arose; indeed, they
are often different mechanisms entirely, in that they involve different components
and may cut across one another: for example, the set of all organs involved in
diabetes does not itself form a physiological system. This suggests that an
appropriate account of pathological mechanisms should also be independent of the
underlying physiological mechanisms.

Pathological mechanisms

Unlike normally functioning biological systems, pathological mechanisms often

have different outcomes. It is an important feature of pathological mechanisms that
their nature is not identified by specific outcomes; while a physiological mechanism
has always a favourable outcome in normal conditions, a pathological one may
result in outcomes ranging from death to complete recovery. Even when recovery is
the most frequent outcome, mechanisms continue to be pathological. For example,
infection from Rhinovirus—the etiologic agent of the common cold—induces a
causally related sequence of pathological events which results almost invariably in a
complete restoration of normal mechanisms, and consequently of health. However,
the infection mechanism is undoubtedly a pathological one.

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Variability in the outcome is the consequence of internal and external factors.

While normal mechanisms have to work within a defined range, and there is
selection for homeostatic activity that maintains that optimal range, pathological
mechanisms work with no predefined range. On the other hand, the mechanism as a
whole is influenced by external factors of the host organism. General regulating
factors may play a decisive role in the outcome of the pathological mechanism. Pre-
conditions such as age, sex, concomitant diseases, immune capacity, and familiarity
may decide the outcome in a single case ceteris paribus. Pathological mechanisms
are invariant for the type, but subject to the influence of regulating factors in a single
token.
I define a mechanism as ambivalent if it possesses the potential to work as
adaptive or maladaptive in the presence of different regulating factors. This is the
case in autoimmune diseases where, for obscure reasons, the homeostatic
mechanism of humoral and cell-mediated immunity may change into an almost
unstoppable pathological mechanism.
In other cases, ambivalence is inherent in the mechanism itself, which can be
physiological and pathological at the same time. In septic shock, the immune
defence against bacterial aggression may assume a pathological role when
hypercatabolism causes more damage than benefit to the organism. But the
mechanism of hypercatabolism, though with opposite effects, is one and the same.
Finally, in special environments pathological mechanisms may become fitness-
enhancing when compared to their physiological counterpart. Sickle cell anemia
decreases life expectancy by several decades, but plays a protective role against
malaria infection. No matter how paradoxical this may sound, the pathological
mechanism of anemia becomes a primary means of survival for the organism in
environments where malaria is highly endemic.
To conclude, we can summarize the differences between physiological and
pathological mechanisms as in Table 2.
A closer look at practical examples may help to put this concept into practice. In
the next section, each of the variants of pathological mechanism we have just been
considering is illustrated by a specific example.

Pathological mechanisms in medical practice

Interpreting microbial infection

Cell infection by Poliovirus has a relative simple course. The etiologic agent is
inhaled and conveyed to the target cell. The virus adsorption occurs by interaction
of specific viral proteins with normal membrane constituents of the cell. After
binding to cell surface the virus releases its RNA genome into the cell; when
contacting the cell cytoplasm the viral particle loses its capsid and is interpreted as
an RNA-filament by the cell ribosomes. All cell activities are redirected now to the
replication and synthesis of new viral elements; the normal cytoplasmic components
and the nucleus begin to deliver material for building new viral RNA and protein
capsids for the mature virus. The proliferation of new virus particles leads to host

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Table 2 Differences between

Physiological mechanism Pathological mechanism
physiological and pathological
mechanisms
• Outcome invariability • Outcome variability
• Limited by a variational range • Influenced by regulating factors
with no range constraint
• Homogeneity • Ambivalence

cell lysis, thereby releasing newly formed viruses ready to infect other cells. The
main steps of the infection mechanism can be summarized as in Table 3.
Of course, every step in the mechanism can and should be analysed in its many
submechanisms, each with a role to play in the overall process of infection. From a
theoretical point of view, cell infection is interesting, since it is a simple
pathological mechanism with necrosis as the direct consequence of an individual,
well-defined pathogen noxa.
On the other hand, the pathological mechanism in this case seems more
teleological, as the infection mechanism is pathological for the host cell, but normal
for the viral biology and as such it is the result of a natural selection—on the virus
side, this time. Once again, we must appeal to pragmatics in order to justify our
approach. Each step in the mechanism may be considered from different points of
view. If one chooses the historical-etiologic view, it is clear that viral adsorption is
the consequence of the evolutionary emergence of receptors stereometrically apt to
bind to the target cell. This dispositional account will explain membrane crossing as
being triggered by the mutual disposition of membrane and viral receptor to interact
this way. On the other hand, the causal, mechanistic explanation will give a
sequence of interrelated steps in order to bring out the causal connections leading
from one step to the next. Clearly, the latter approach has more chances of being
advantageous to medical research.
Moreover, it should be stressed that not every infection mechanism has an
evident evolutionary advantage for the infecting agent. Clostridium botulinum, for
example, is an anaerobic spore-forming bacterium, widely distributed in nature.
Like similar bacteria, C. botulinum causes a local necrosis of the infected tissue, and
systemic damage by a potent neurotoxin with neuro-, entero-, and hemotoxic
properties.

Table 3 Main steps of viral

Mechanism of viral infection from Poliovirus
infection from Poliovirus
1. Adsorption
2. Crossing of the cell membrane
3. Capsid loss
4. Activation of host cell ribosome
5. Neosynthesis of viral particles
6. Host cell lysis
7. Release into the extracellular space
8. Adsorption to other cells

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The botulin neurotoxin does not seem to be a side product of the bacterium’s
metabolism, since its efficacy looks like a highly selected and purpose-built feature.
It is one of the most potent poisons known, the lethal dose for man being less than 1
microgram. When introduced into the circulatory system, it blocks release of
acetylcholine at cholinergic synapses of muscles, with consequent limp paralysis,
respiratory arrest and death. It is difficult to understand how the neurotoxin trait—
which causes the premature death of the host organism, with a lower probability of
propagating the bacterium—could be selected for; obviously, it should be a trait that
is selected against. Maybe there are unknown factors in the system explaining the
bacterium’s behavior: for example, a bacteriophage could have infected the toxin-
producing types of C. botulinum, and such viral infection is responsible for the
emergence of an unadaptive trait. Anyway, the case of C. botulinum is difficult to
explain from a historical point of view, while there is a general consent regarding
both the steps of its pathological mechanism and the therapy which can interrupt the
pathological sequence.

Abnormal physiological mechanisms: the case of autoimmune diseases

Mechanisms of immunity disorders may follow different patterns. In congenital

hypogammaglobulinemia, for example, there is a low antibody production by B-
cells, and this seems a consequence of a hyperactivity of suppressor-effector T-cells.
In such cases, the pathological sequence is triggered by a simple error in calibration
of cellular interaction.
More frequently, the pathogenic event consists in the immune system being
misinformed about its target. To defend itself from potentially destructive foreign
agents the organism is required to be able to recognize self from non-self: it has
therefore developed an immune tolerance to self tissues, while foreign elements
(most frequently microbes) are identified as such and destroyed by means of
antibodies or T-cells. It is noteworthy that the pathological mechanism may be more
complex, though fundamentally similar. In autoimmune haemolytic anemia,
autoantibodies are formed against normal red blood cell constituents. To diagnose
this disorder, an immunological test was developed (Coomb’s test) which can assess
the percentage of red blood cells coated with autoantibodies. Now, in a small
percentage of subjects undergoing the test for other reasons—say, healthy blood
donors—Coomb’s test may be positive with no evidence of haemolytic anemia,
which suggests that the autoimmune response in itself cannot be the only
mechanism of damage. We have here an example of the importance of regulating
factors for the outcome of pathological mechanisms. Though the autoimmune
mechanism proceeds as usual, the disease does not manifest itself unless unknown
factors are present to trigger its appearance.
There is no common biological trigger of autoimmunity, but probably many
different triggers may induce autoimmune diseases with different mechanisms. The
term ‘‘essential’’, with which autoimmune diseases are often labelled, is mostly a
sign of our ignorance about the initial cause of the mechanism.
In some artificial conditions like transplantation, we encounter pathological
conditions like transplant rejection where a clear aetiology and a well-established

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mechanism sequence are known. The recipient’s immune system attacks the
transplanted organ or tissue because it is recognized as a foreign element.3 The
mechanism is pathological only in view of the therapeutical advantages of
transplantation, as reaction to a non-self tissue is not a real abnormality. One could
say that in such cases the evolutionary pressure on the type overcomes the token’s
incidental advantage.
However, autoimmune response usually cannot be clearly explained, since the
initial cause is unknown. We simply observe a sudden breakdown in self-tolerance,
with consequent onset of immune aggression against self organs or tissues. In
Hashimoto’s thyroiditis, auto-antibodies develop against thyroid tissue, which leads
to tissue destruction and hypothyroidism (the latter being the common outcome of
several pathological, not necessarily autoimmune, mechanisms). In other cases, it is
not organ-specific tissue, but a tissue type in different organs, that is affected by the
autoimmune process, resulting in a multi-organ pathological process. Some
connective tissue disorders like systemic lupus erithematosus may have a complex
and multi-organ pathological mechanism, with many outcome possibilities.
In any case, a physiological mechanism like immunity turns out to be
pathological as a consequence of its quantitatively abnormal response4 and/or of
an error in recognising self tissues. In autoimmune diseases each step in the
physiological mechanism of immunity has reversed its meaning. We have no
impairment of individual steps of the mechanism, rather the sequence as a whole has
a pathological effect, though remaining ‘‘physiological’’. A major physiological
mechanism results in organism failure following the same steps that normally lead
to effective self-defense.

Ambiguity in septic shock mechanisms

In autoimmunity, a physiological mechanism is at work in which each single step

has changed its meaning though remaining the same. In some pathological
conditions, mechanisms preserve their physiological meaning at the same time as
they exert a disastrous effect on the healthy subsystems of the organism. I call this
an ambiguity of the mechanism (as a particular case of mechanism ambivalence), as
not only the mechanism itself, but also its physiological role is preserved, though
with a simultaneous—sometimes prevailing—pathological role.
One of such mechanisms is the innate immune system (IIS, Janaway 1989), a
non-specific immune defense which is readily mobilized when activated by
microbes and other non-self agents. In the presence of microbes and side products of
bacterial lysis, the innate immunity system immediately reacts by producing pro-
inflammatory mediators such as the cytokines tumour necrosis factor (TNL) and
interleukin 1 (IL-1). This highly functional response clearly benefits the organism’s

3
Note that blood transfusion reaction and the graft-versus-host reaction have conceptually the same
mechanism.
4
This is most clearly the case in anaphylaxis.

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defense. However, when bacterial infection becomes systemic sepsis, this also has a
deleterious effect on cell metabolism.
When cytokines increase in circulating blood, they exert a double effect, at local
and systemic levels. Locally, they attack the pathogen, allowing eradication of the
local infection; at the systemic level they induce an increased catabolic activity,
whose physiological function is to prepare the organism as a whole for the microbial
aggression. The rise in systemic catabolism is an adaptive response, as patients
failing to show this effect—as a consequence, say, of cardiovascular impairment or
lack of mediator activation—are more likely to have an unfavourable short-term
prognosis.
Hypercatabolism during infection is a complex mechanism, branching out into
many organs and tissues. I shall limit myself to briefly considering muscle tissue:
with the increase of cytokines in the bloodstream, muscle proteins are broken down
into aminoacids, which can support the peripheral neosynthesis of acute phase
proteins and anticorpal proteins. Muscle tissue catabolism may thus help systemic
response to infection.
However, this physiological defense mechanism plays—at the same time—a
prominent pathological role, too. Muscle protein hypercatabolism (graphically
called ‘‘septic autocannibalism’’ by Cerra et al. 1980) induces manifold damage to
the organism: muscle proteolysis and increase of toxic catabolites in the circulating
blood cause damage to the renal parenchyma. When this functionally ambiguous
sequence crosses a critical threshold, a purely pathological mechanism occurs, with
impairment of one or more organ functions until a point of no-return is reached,
with multiorgan failure syndrome leading to the patient’s death.
As far as the formal features of this pathological mechanism are concerned, it is
important to stress that tissue damage is not due to direct microbial aggression, but
to the homeostatic response. Unlike autoimmune diseases, septic shock shows no
real qualitative abnormality in the defense mechanisms, which seem appropriate to
their role in contrasting microbial invasion; except that every protective mechanism
must pay a metabolic price, which might be too high. Thus the response is both
physiological and potentially pathological at the same time.

Antagonism between pathological mechanisms

Evolutionary and historical concepts can be relevant to identifying and understand-

ing pathological mechanisms. In some unfavourable environmental conditions
different pathological mechanisms may be mutually antagonistic; evolutionary
pressure may then favour the less severe condition, if it can have a protective role
against the more impairing one.
Sickle cell anemia is an inherited disease. Due to a congenital defect in the
synthesis of hemoglobin chains, red blood cells become fragile, sticky and shaped
like crescents. The pathological red blood cells have a decreased capacity to carry
oxygen, tend to occlude small vessels, causing thrombosis and bone or chest pain,
and easily undergo massive destruction (hemolytic crisis). Cerebrovascular strokes,
hypersplenism and renal failure result in the more severe cases, with a significant
decrease of life expectancy. Among children and adults with sickle cell anemia

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(homozygous for sickle hemoglobin), the median age at death is 42 years for males
and 48 years for females (Platt et al. 1994).
The regions where sickle cell anemia is more common coincide almost exactly
with areas where malaria was more endemic and severe (Fig. 1); the subsequent
spread to areas where malaria is not present may be the effect of migration of people
with sickle cell trait (heterozygous for the gene), who usually have few or no
symptoms.
It has been demonstrated that Plasmodium malariae, the etiologic agent of the
disease, is carried by normal red blood cells, but cannot infect sickle cells.
Therefore, patients with clinically evident sickle cell anemia are protected against
malarial infection.
Now, malaria is a prominent cause of child mortality in the African regions we
are considering. Children who become infected with malaria usually do not survive
to leave offspring, while patients with sickle cell anemia have more chance of
reaching fertile age. Natural selection therefore spread the inherited pathological
mechanism, as it proved to be protective against the infection mechanism. As in
autoimmune diseases, the mechanism as a whole has changed its character, this
time, however, in the opposite way: a pathological mechanism may play a
physiological role in an environment, where it antagonizes another pathological
mechanism.

Fig. 1 Gene frequencies of deletional a-thalassemia in various African populations. The map also shows
the distribution (shaded area) of malaria (Plasmodium falciparum) in Africa (from: Mouélé et al. 2000)

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Conclusion

The idea of mechanism is ubiquitous in biological practice. In recent years, much

attention has been paid to the theoretical concept of mechanism as a convincing
model of biological explanation, especially when the explanatory interest is not
focused on the evolutionary history of the system. This approach is more
appropriate when biological research aims to find causal relations between single
events, or when the overall behavior of the system is to be explained by appeal to its
constituents.
I have tried to show that this approach is highly fruitful when adopted in the
applied sciences, such as medicine. Evolutionary arguments have little direct
application in medical practice. But thinking in terms of mechanisms is an effective
way of describing causal relations amongst pathological events and providing
possible hints for therapeutic intervention.
However, the pragmatic peculiarities of medicine call for a shift in the point of
view when considering malfunctions. Since pathological entities and their treatment
are the main object of medical research, putting physiological mechanisms at the
centre of the stage with malfunction lurking in the background would seem
perverse; as if pathology could be identified just as a failure in one or more
physiological steps. The opposite is true: in medicine malfunction is the focus of
explanatory interest, and the character of normal functioning mechanisms is a
necessary background assumption of medical research. Instead of considering
malfunction as a by-product of identifying physiological mechanisms, one should
interpret it as an autonomous pathological mechanism. I have tried to show some
peculiarities of such pathology mechanisms compared to their physiological
counterparts. Outcome variability, lack of a regulating range, and mechanism
ambivalence are some of them.
If the approach defended here is the right one, further extensions of the concept
may be possible. For example, the idea of pathological mechanism sheds a different
light on the notions of disease and recovery inasmuch as they may be interpreted
with reference to causal pathological mechanisms. Any transition from pathological
mechanisms to physiological ones and vice versa follows a specifiable pattern.
Other possible fields of application of the concept may be: (a) a more appropriate
account of the relationship between allopathic medicine and alternative therapies, in
order to establish a demarcation criterion between them; (b) a theoretical framework
for evaluating ‘‘surrogate endpoints’’ in pharmacological research.
If this account is correct, medical research progress may be interpreted as an
uneven road towards specifying new submechanisms for each step of the
pathological mechanism. This increasing refined mechanistic hierarchy may
eventually bottom out at elementary biochemical events of little or no interest to
the researcher. Explanatory interest is the only limiting factor in the exploration of
the hierarchical chain of pathological mechanisms.

Acknowledgments I would like to thank Carmen Dell’Aversano for many insightful remarks on earlier
drafts, Guglielmo Tamburrini for his friendly encouragement to the study of scientific explanation, and a
referee of this journal who helped to significantly improve the readability of this paper.

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228 M. Nervi

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