philosophy-of-physiology

Lemoine
Time is ripe to complement the question “what is health

and disease?” in philosophy of medicine with a “philosophy
of physiology.” Indeed, the actors in this debate share the
conviction that a “foundational” concept dictates to this
scientific field what is to be considered healthy or pathological
and leaves it to explore only facts and mechanisms. Rejecting The Philosophy
this presupposition, philosophy of physiology accepts that of Biology
biomedical sciences explore and redefine their own object: the
healthy, the pathological. Indeed, various theories of disease
and health, that philosophers have rarely studied, form the core
of biomedical research, too hastily considered as a science
Philosophy of
Philosophy of Physiology
“without theories.” The Element identifies them, and clarifies
their content, presuppositions, and scope. Finally, it proposes a
new question about the unity of the pathological phenomenon:
Physiology
not “what do all diseases have in common?” but rather, “why
is the susceptibility to disease a universal and necessary
characteristic of living beings?”
About the Series Series Editors

This Cambridge Elements series provides Grant Ramsey
concise and structured introductions to KU Leuven
Maël Lemoine
all of the central topics in the philosophy Michael Ruse
of biology. Contributors to the series Florida State
are cutting-edge researchers who offer University
balanced, comprehensive coverage
of multiple perspectives, while also
developing new ideas and arguments
from a unique viewpoint.
Cover image: Ascidiae from Kunstformen der Natur (1904)

by Ernst Haeckel, public domain
ISSN 2515-1126 (online)
ISSN 2515-1118
Downloaded from https://www.cambridge.org/core. IP address: 78.199.203.225, on 29 Jan 2025 at 22:37:59, subject to the Cambridge (print)
Core terms of use,
available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781009370394
Downloaded from https://www.cambridge.org/core. IP address: 78.199.203.225, on 29 Jan 2025 at 22:37:59, subject to the Cambridge Core terms of
use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781009370394
Elements in the Philosophy of Biology
edited by
Grant Ramsey
KU Leuven
PHILOSOPHY OF
PHYSIOLOGY
Maël Lemoine
University of Bordeaux
Shaftesbury Road, Cambridge CB2 8EA, United Kingdom
One Liberty Plaza, 20th Floor, New York, NY 10006, USA
477 Williamstown Road, Port Melbourne, VIC 3207, Australia
314–321, 3rd Floor, Plot 3, Splendor Forum, Jasola District Centre,
New Delhi – 110025, India
103 Penang Road, #05–06/07, Visioncrest Commercial, Singapore 238467
Cambridge University Press is part of Cambridge University Press & Assessment,

a department of the University of Cambridge.
We share the University’s mission to contribute to society through the pursuit of
education, learning and research at the highest international levels of excellence.
www.cambridge.org
Information on this title: www.cambridge.org/9781009486583
DOI: 10.1017/9781009370394
© Maël Lemoine 2025
This publication is in copyright. Subject to statutory exception and to the provisions
of relevant collective licensing agreements, no reproduction of any part may take
place without the written permission of Cambridge University Press & Assessment.
When citing this work, please include a reference to the DOI 10.1017/9781009370394
First published 2025
A catalogue record for this publication is available from the British Library
ISBN 978-1-009-48658-3 Hardback
ISBN 978-1-009-37037-0 Paperback
ISSN 2515-1126 (online)
ISSN 2515-1118 (print)
Cambridge University Press & Assessment has no responsibility for the persistence
or accuracy of URLs for external or third-party internet websites referred to in this
publication and does not guarantee that any content on such websites is, or will
remain, accurate or appropriate.
Elements in the Philosophy of Biology
DOI: 10.1017/9781009370394
First published online: January 2025
Maël Lemoine
University of Bordeaux
Author for correspondence: Maël Lemoine, mael.lemoine@u-bordeaux.fr
Abstract: Time is ripe to complement the question “what is health and

disease?” in philosophy of medicine with a “philosophy of physiology.”
Indeed, the actors in this debate share the conviction that
a “foundational” concept dictates to this scientific field what is to be
considered healthy or pathological and leaves it to explore only facts
and mechanisms. Rejecting this presupposition, philosophy of
physiology accepts that biomedical sciences explore and redefine their
own object: the healthy, the pathological. Indeed, various theories of
disease and health, that philosophers have rarely studied, form the core
of biomedical research, too hastily considered as a science “without
theories.” The Element identifies them, and clarifies their content,
presuppositions, and scope. Finally, it proposes a new question about
the unity of the pathological phenomenon: not “what do all diseases
have in common?” but rather, “why is the susceptibility to disease
a universal and necessary characteristic of living beings?”
Keywords: health, disease, physiology, medicine, evolution
© Maël Lemoine 2025

ISBNs: 9781009486583 (HB), 9781009370370 (PB), 9781009370394 (OC)
ISSNs: 2515-1126 (online), 2515-1118 (print)
Contents
1 From Philosophy of Medicine to Philosophy

of Physiology 1
2 Disease Entities and Pathophysiological Processes 17
3 How Generalizable Are Disease Theories? 27
4 Toward a Theory of the Pathological Phenomenon 41
5 Toward a Theory of Physiological Health 53
6 Conclusion 67
References 69
Philosophy of Physiology 1
1 From Philosophy of Medicine to Philosophy of Physiology

A huge body of scientific literature describes how organisms function – how
bacteria reproduce, how photosynthesis happens, how bears survive during
hibernation, how humans sleep – as well as how they typically dysfunction
via infection, dehydration, starvation, insomnia, scurvy, diabetes, cancer,
multiple sclerosis, and so on. The former is called “physiology,” the latter
“pathophysiology,” though both are typically subsumed within an expansive
understanding of “physiology.” Physiology (in this broader sense) is not an
exclusively medical science, but it certainly is a core science for medicine.
As with any other science, physiology is likely to raise conceptual problems.
For instance, why are some bacteria called “pathogens” if they never produce
symptoms or shorten lifespan in some individuals? Is cancer one or many
diseases? What does it mean for an organism to “repair itself”? Is disease
a universal and necessary fact of life? How can we measure degrees of
“health,” are there mechanisms of health, and what exactly is the difference
between health and fitness? If you are interested in these questions, it seems
natural to turn to philosophy of medicine. But this section argues that this is
not the best place to start. Instead, it proposes an alternative approach, one
centered on the philosophy of physiology, and argues that this is a better path
to understanding health and disease.
1.1 A Short Overview of the Health and Disease Debate

in Philosophy of Medicine
If you are diagnosed with major depressive disorder, you may protest and argue
that in fact, the world is depressing and that you are not sick – only lucid.
Psychiatrists would be encouraged to label this behavior “poor insight” (that is,
a weak degree of the patient’s awareness of their symptoms). On the Hamilton
Depression Rating Scale, a standard tool in psychiatry, that would be a sign of
the severity of the disease. This is just one of the many examples where doctors
seem to be entitled to decide factually how you should be treated. What justifies
such authority of medical science?
Sociologists have described the social process that leads to this authority, and
called it “medicalization” (Conrad 2007), that is, the social consensus that a problem
should be dealt with by medicine. In philosophy of medicine, the question raised is
the justification of this authority. This question has been interpreted as a question of
definition. Indeed, with a correct definition of health and disease, we would have
criteria to decide what really is a disease.
2 Philosophy of Biology
In recent history, philosophers of medicine have polarized into two camps:
- Naturalists define “health” and “disease” in terms of biological functions

and dysfunctions. The knowledge of biological facts justifies that you have
a disease (or not).
- Normativists claim that “health” and “disease” definitions reflect social
values. The observation of what is deemed to be “harmful” in a society
justifies that you are judged sick (or not).
This alternative is deeply ingrained in the health and disease debate: most
contributions in philosophy of medicine dealing with the definition of disease
either endorse, reject, or combine these positions.
Undoubtedly, the champion of naturalism is Christopher Boorse. His seminal
paper, “Health as a Theoretical Concept” (Boorse 1977), has both initiated this
debate and proposed a complete, naturalistic definition of health. It is called the
“Biostatistical Theory of health and disease” (BST). According to the BST,
“Theoretical health (. . .) is the absence of disease; disease is only statistically
species-subnormal biological part-function; therefore, the classification of
human states as healthy or diseased is an objective matter, to be read off the
biological facts of nature without need of value judgments” (Boorse 1997). In
other terms, physiology determines the nature and statistically normal level of
efficiency of all functions of the parts of an organism in a given species, or, more
precisely, in the various “reference classes” in a species – that is, mainly, groups
defined by being either male or female and child, adult or elderly. Thus, basic
concepts of physiology determine the generic criteria for specific conditions to
be considered real diseases.
Although a majority of articles endorse normativism, there is no dominant
version of normativism. Some forms of normativism draw criteria of health and
disease either from values (Engelhardt 1996), requirements of human action
(Clouser et al. 1981), or conditions for happiness (Nordenfelt 1995).One com-
mon form of normativism consists simply in counter-arguments to naturalism
without clear endorsement of normativism (e.g., Kingma 2010).
Hybrid positions have also been held. Focusing on mental disorders, Wakefield
has proposed that the two requirements of harm and biological dysfunction must
both be met for a condition to truly be pathological (Wakefield 1992).
The development of these views and their criticism has fed a voluminous
literature which has now reached a certain level of sophistication, sufficient to
scare off many newcomers. At the same time, skepticism has grown over the
possibility or utility of a definition of health or disease (Hesslow 1993;
Worrall & Worrall 2001). Somewhat paradoxically, the number of articles
dedicated to the question has substantially increased.
1.2 Philosophy of Medicine Is Not the Philosophy

of the Sciences of Health and Disease
How and why doctors judge that you have depression and treat you is a question
about practice. Practice is one thing. Among the many reasons why doctors
judge and treat depression as they do, one is science itself. But science is another
thing. Is science justifying practice? To answer that question, it is necessary to
investigate the science of diseases itself. Perhaps it contains no scientific
argument to justify that a condition is a disease. At the very least, one needs
to examine this literature to answer the question. There is no other reason why
recent handbooks see philosophy of medicine essentially “as part of the
Anglophone philosophy of science tradition” (Solomon et al. 2017, 2).
Medical science is not one discipline, but many. The core science of health
and disease is physiology. A surprising fact is that, on average, philosophy of
medicine about health and disease is only superficially interested in its core
science, as compared to how much philosophy of biology is interested in
biology, philosophy of physics in physics, or even the rest of philosophy of
medicine is, for instance, in scientific debates about causality or evidence in
medicine. To get a sense of the level of engagement of philosophy of medicine
with science, let us have a look at citations and references of articles in the
health and disease debate. Citations are mentions by other articles, while
references are mentions to other articles. A two-dimensional measure of the
integration of the health and disease debate consists in counting how many
citations and references are scientific (see Figure 1). For instance, “Health as
a Theoretical Concept” (Boorse 1977), which is one of the top three papers
cited in philosophy of science journals between 1977 and 2017, is marginal in
medical science (with about fifty citations, by papers rarely cited themselves).
This may sound unproblematic. After all, why should philosophers be cited by
other disciplines if only philosophers truly understand what they do? In
principle, this is valid. Yet in comparison, philosophers of biology, physics,
or even medicine more broadly, do get more scientific attention (even if this
remains modest). What may seem more problematic are the references. One
third of the 110 articles about the health and disease debate used in the
preparation of this Element do not cite any scientific article at all. Scientific
references constitute less than 20 percent in two thirds of these articles.
References often provide examples of diseases that could have been replaced
by other examples and are not even always the standard or expected references
about the disease in question.1 As an example, Boorse’s article cites mostly
1
One exception to this situation is Jerome C. Wakefield’s work on the definition of mental disorder,
both mainly published in science journals and cited and discussed by psychiatrists.
Figure 1 Bibliometric isolation of the health and disease debate from medical
science, as compared to philosophy of physics relative to physics, philosophy of
biology to biology and philosophy of medicine to medical science. Along the X-axis
is Average Ratio of Citation (ARC) in science (Pradeu et al. 2024). An ARC of 1.00
means as many citations in a scientific field on a given year as the average article in
that domain (an ARC of 0.5 means half as many and an ARC of 2.0, twice as many).
Along the Y-axis is the proportion of references to science articles. Dark circles
represent the 10 articles in philosophy of biology that are most cited by articles
published in philosophy of science journals; light squares, in philosophy of physics;
dark diamonds, in philosophy of medicine (except the health and disease debate);
light triangles, in the health and disease debate. The corresponding bigger figure
represents the average in each field. Philosophy of biology is the most integrated in
science, the health and disease debate is the least integrated.
bibliometrically marginal articles from science journals or articles written by

philosophers themselves.2 Yet practically all of the 110 articles mentioned
here cite Boorse’s. This does not pose a problem for seeing how philosophy of
health and disease forms a part of philosophy of medical practice. But it is very
problematic for seeing how philosophy of health and disease forms a part of
philosophy of science. Indeed, in contrast, philosophers of biology, physics, or
2
Checked on the Web of Science on April 1, 2021.
epidemiology frequently refer to scientific sources directly, and generally cite

standard or expected articles in science journals, not anecdotal or illustrative
articles. Consequently, if you are interested in physiology, philosophy of
medicine is not likely to be the place where you want to invest too much
time (some exceptions notwithstanding).
This is, of course, a criticism of the health and disease debate in philosophy of
medicine. However, one possible response is to claim that the real focus is on
medical practice. In fact, some would even argue that, in the case of the health and
disease debate, philosophy of medicine is not part of philosophy of science
because medicine is not a science. However, not many would argue that physi-
ology is not a science. However, many would argue, with some strong reasons,
that the basic concepts of physiology – precisely, health and disease – are not
scientific, and for that reason, there cannot be much philosophy of science in the
philosophy of health and disease. If philosophy of physiology is what you are
interested in, this discrepancy does not matter much. Surely, if “health” and
“disease” were not scientific concepts, there would be other scientific concepts
in physiology. This is the starting point for this Element. In fact, it will show that
physiology offers no scientific definition of health and disease as philosophers of
medicine would like it, that is, a straightforward justification that the conditions
we call diseases really are diseases based on explicit and undisputable criteria. But
that does not mean that physiology does not contain conceptually elaborated
concepts that are crucial to the explanation of health and disease, and even,
theories and concepts of health and disease. In fact, this is the core question: Are
philosophers of medicine right in supposing that a definition of health and disease
is independent from how these phenomena are described and explained, and even,
that this definition must predate and predetermine our explanations of health and
disease? Or is there a theoretical definition of health and disease to be found in the
physiological literature?
Before we get to this key question, it is useful to get acquainted with the most
influential article in philosophy of medicine: “Health as a Theoretical Concept”
(Boorse 1977).
1.3 A Brief Presentation of Naturalism in Philosophy of Medicine

When I teach an introductory class on the health and disease debate, I play
a little game with students. On the whiteboard, we draw both a table (just like
Table 1) and a Venn diagram (just like Figure 2). I ask students to think of
conditions that are or are not diseases according to them, and potential criteria
that fit with all diseases and diseases only. We fill in the table and the Venn
diagram at the same time in search for a correct definition.
Table 1 Possible criteria of health and disease and uncontroversial conditions of health and disease
(after Boorse 1977). The corresponding numbers (E01, E02, . . .) are reported in Figure 2.
Table 1 (cont.)
Note: Grey cells represent that Boorse does not give any explicit example.
Figure 2 A Venn diagram presenting the results of the definition of “disease” in

Boorse (1977). Conditions listed in Table 1 (E01, E02, etc.) are represented in
extension. The central set contains diseases.
This is a rigorous reconstruction of what Boorse did many decades ago. The
definition he proposed was based on a systematic confrontation of a set of forty-
one types of conditions with a set of twenty-nine general candidate criteria for
health and disease (Table 1). He first showed that none of the latter correctly
covers all of the former (and only the former). For example, if you want to
define a disease as “what a physician treats,” you will run into the objection that
“circumcision, cosmetic surgery, elective abortion and the prescription of
contraceptives” (Boorse 1977) are medical treatments of conditions that are
not diseases. Taking the time to go through this table is the best way to
understand how the health and disease debate works.
Then the BST paves its way out of this morass by combining some of these
criteria in a very elegant way. Recall that it defines “disease” as “a type of
internal state which impairs health, i.e., reduces one or more functional abilities
below typical efficiency” (Boorse 1977). This definition can be reconstructed as
follows. First, it relies on three basic concepts: contribution, variation, and
statistical normality. A contribution is what a part of an organism may do to
the survival or reproduction of the organism. A variation is the existence, in
a species, of differences in the same trait and, possibly, in its contribution.
Statistical normality is the fact that the most frequent values of a variable trait
are concentrated into a small interval as compared to the interval of possible
values, for example, that most humans in a given class have systolic blood
pressure of around 12 mmHg (the pressure of the blood in the arteries during
contraction as measured in millimeters of height in a standard column of
mercury) while some show extreme values as low as 7 mmHg or as high as
20 mmHg. Given these three concepts, it is possible to exclude some traits from
the set of diseases according to the following six principles:
(1) no trait contributive to survival or reproduction is pathological

(2) some traits not contributive to survival or reproduction are not pathological
(3) no invariant trait is pathological
(4) some variable traits are not pathological
(5) no statistically normal trait is pathological
(6) some statistically abnormal traits are not pathological
Additional, more local concepts (intrinsic health, functional readiness, poly-

morphic traits, asymptomatic disease, universal disease, etc.) are necessary to
eliminate further subsets of cases from the set of diseases, while some of these
concepts are defined by other concepts (e.g., variation by “species design” and
“statistical normality” by efficiency and reference class). The results are sum-
marized in Figure 2.
For anyone interested in how this beautiful reconstruction stands the test of
counterexamples and counterarguments, the best option is to read the articles by
Boorse provided in the references of this Element. Boorse also summarizes
most objections and answers them. What we are interested in is why the BST is
not a good basis for philosophers of physiology, in spite of its apparently
scientific terms (“function,” “statistical normality,” “reference class,” etc.)
and concrete examples.
1.4 Naturalism Does Not Investigate the Science of Health

and Disease
Here is a puzzling question. On the one hand, when scientists investigate
a phenomenon X, they must rely on some definition of X that determines what
they consider to be cases of X. On the other hand, a definition of X must rely on
some knowledge of X that is obtained through investigation. There are two ways
out of this circle. The first is that the phenomenon is defined a priori, that is,
clearly and once and for all, by more general properties that have been investi-
gated by broader disciplines. The second way out of the circle is that definition
and investigation progress together, and that definitions are temporary and
hypothetical until knowledge is stabilized. Are health and disease concepts of
the first sort or of the second sort?
Most contributions to the health and disease debate endorse the first view.
Philosophy of physiology starts when one embraces the second view. I call the
first view foundationalism about health and disease, which holds that health and
disease are basic, non-empirical, and invariable concepts that frame medical
science and practice. Let us investigate these claims in turn.
First, health and disease are non-empirical concepts. This claim relies on two
ideas, (1) that medical science contains fine-grained descriptions of specific
diseases and the corresponding normal processes but never elaborates any
encompassing conception of what a disease in general (or health) consists in,
and that (2) such a general conception of disease is independent from these
descriptions of particular diseases. As a consequence, the empirical details are
irrelevant to a description of what disease is in general, even for a naturalist.
This thus requires an elaboration of the concept of disease that is based on
concepts external to physiology. This is indeed what normativists do, consist-
ently, when they describe “disease” as a disvalued, or harmful state of the body
(or mind) that impairs our ability to be happy, and so on. The situation is trickier
for naturalists, who want both to define health and disease a priori and in
physiological terms.
To solve this problem, Boorse has used some non-specifically physiological
concepts such as “function” and “statistical normality” that are indeed used in
physiology. He has also invented abstract concepts that are supposed to describe
the foundations of physiology, such as “reference class” and “species design.”
A reference class is defined as a “natural class of organisms of uniform
functional design,” with “characters [that] occur together” (Boorse 1977), and
which provides standards to establish a statistically normal level of efficiency.
This term is forged by Boorse against objections such as: it is statistically
normal for an adult woman, not for a man, to have ovaries – a man without
functional ovaries has no disease. Yet “reference class” seems to substitute for
the epidemiological concept of a population, and it has been shown not to be
very useful – indeed, any class could, in principle, become a reference class, and
anything be deemed normal or abnormal accordingly (Kingma 2007).
A “species design” is “the typical hierarchy of interlocking functional systems
that supports the life of organisms of that type” (Boorse 1977). It is therefore
normal for a frog not to fly, because this is not a part of the “species design.”
However, if medical scientists really used such a concept, it would be biological
nonsense (Ereshefsky 2009). Indeed, the physiological description of an organ-
ism is not committed to the existence of a “species design.” Moreover, most
physiological functions are shared widely across all mammals. The existence of
most biological functions has even been established in small samples of organ-
isms of the same or of different species, then extrapolated, and their “level of
efficiency” is not known. The “typical hierarchy of interlocking functional

systems” itself remains largely unknown. In fact, physiology simply proposes
hypotheses on how things work, not norms on how they should work.
Another such abstract concept discussed by naturalists is “situation-
specificity,” that is, the fact that the level of a function is normal or pathological
depending on the situation (or environment) of the organism. Philosophers of
medicine use this concept to deflect the objection that it is normal for a poisoned
digestive system not to be able to digest, or for the heart rate to be high during
strenuous exercise (Hausman 2011). This concept as well may make the concept
of health and disease intractable (Kingma 2010, 2016). The term seems to
summarize key experimental concepts such as factors, parameters, and expos-
ure. It is normal that organisms shiver when exposed to cold; social life is
a factor of the normal duration of sleep, which also varies because of some
individual physiological parameters. However, this does not mean that physi-
ologists must establish normal values for each specific situation, but that they
must explain how normal organisms adapt as a function of factors, parameters,
and exposure. Physiology investigates biological functions in all their vari-
ations, that is, with the idea that there is not one normal reaction for each
situation, but one normal function adapting to various degrees to various
situations. Physiology thereby establishes values that likely indicate health in
a limited set of defined, standard situations – not normal values for every
possible situation. The idea of “situation-specific” norms is an exaggerated
account inspired by the idea that medical science is all about establishing
norms. In general, the reason for the introduction of such artificial terms as
“reference class,” “species design,” and “situation-specificity” in the descrip-
tion of physiology, is not exactly to account for health and disease as physiology
describes them. Instead, it is to defend or attack the presumed objectivity of
proposed criteria of health and disease. Most of these supposedly defining
concepts are ad hoc creations for that purpose.
The second claim is that health and disease are invariable concepts. All the
recent developments of medical science are supposed to fall inside this sup-
posedly perennial framework and simply provide further technical details. To
put it bluntly, the exact same description of the naturalistic concepts of health
and disease could have been given at the time of Galen, based on the descrip-
tions of diseases in the medical science of imperial Rome. In fact, it has:
Surely whenever there is no impediment in any of the activities of all their

bodily parts, people say that they are healthy and think that they have no need
of doctors; but whenever they become aware that some one of their natural
functions is beginning to perform either badly or not at all, they consider
themselves to be sick in that section of the body whose activity they see to be
impaired and they call upon the aid of a doctor to cure it. I see all men using
the nouns “health” and “sickness” thus; and this is the conception which
I claimed that everyone observes in the case of these words and furthermore
in addition to them no less in the case of all nouns and verbs which are
cognate with them. (Galen 1991)
Boorse explicitly roots his “Biostatistical Theory” of health and disease in this
Galenic tradition, citing it favorably at the beginning of his major article (Boorse
1977). Consequently, conceptual analysis in philosophy of medicine does not
require any specific, or historically updated, medical knowledge, whereas it
would in philosophy of biology or philosophy of physics. All you need to know
is a sufficient number of conditions with their status and, at best, main dysfunction
(if any). Remember my whiteboard exercise. To play the game, you simply need
to know that pregnancy is not a disease, but diabetes is, and so on, and that
pregnancy consists in bearing a future child, while diabetes consists in having too
much sugar in your blood. Based on that, you are simply looking for common
criteria that fits with the status of these three conditions and many more, or object
to your opponent’s definition by simply finding a counterexample (detailed
descriptions can be found in Schwartz 2007; Lemoine 2013).
This “game,” as Boorse himself once called it, has been criticized for many
reasons. One is that not many concepts can be defined by necessary and sufficient
conditions (Schwartz 2007; Sadegh-Zadeh 2008). Another line of criticism is that
conceptual analysis gives priority to folk notions of health and disease. Some
have explicitly investigated the folk “models” of health and disease in medical
practice (Hofmann 2005). Many more contributions in philosophy of medicine
have implicitly done the same: analyze intuitions of medical doctors, rather than
basic concepts of medical science. Yet, as observed by Murphy and Woolfolk,
“from the point of view of the philosophical analysis of scientific terms, the
scientific illiteracy of everyday intuitions is just unfortunate for lay concepts”
(Murphy & Woolfolk 2000). A third line of criticism is that conceptual analysis
cannot rule out artificial definitions or decide between conflicting definitions that
fit with the accepted examples (Lemoine 2013). Plato has famously proposed the
definition of a “man” as a “featherless biped.” Conceptual analysis may lead to
such artificial definitions simply because there is no rule that imposes the usage of
terms of the art. A last line of criticism is that it is, in fact, impossible to determine
whether a condition is a disease or not independently from the knowledge of this
disease. For instance, atherosclerosis is traditionally defined as “a condition in
which an artery wall thickens as a result of the accumulation of fatty materials
such as cholesterol” (ICD-11). This makes it problematic as a bona fide case of
disease because it is structural, universal, progressive with age, and comes in
degrees of severity (Boorse 1977). Yet, since the 1980s, dramatic redefinition of
these conditions has focused less on occlusion by fat deposit, atheroma, and
structural degradation, and focused instead on homeostatic functions of the
endothelium related to vasoconstriction (e.g., Deanfield et al. 2007). Some have
proposed the hypothesis that an equilibrium, described as the homeostatic endo-
thelium, is disrupted, and replaced by a noxious feedback process. Not every
thickening of the artery is pathological in this view and this affects how you
classify the condition, which in turn affects the exact boundaries of the class.
Finally, this may also affect the criteria of your definition. If all this is true,
boundaries cannot be invariable, and a definition must take into account scientific
knowledge of those conditions.
The third claim of foundationalism is that health and disease are basic concepts
for medical science. This means that they are not established inductively, that is, by
generalization from facts that medical science progressively discovers about dis-
eases. Instead, these concepts can only be clarified by deduction from even more
general concepts, and more specific diseases should be established as such by
deduction from the broad concept of disease. The apparently “inductive” approach
Boorse (and others) adopt consists only in checking whether the general features of
“health” and disease” they hypothesize a priori indeed fit with the various condi-
tions medical science defines as diseases – is condition X “dysfunctional,” “statis-
tically abnormal,” “maladaptive,” “harmful,” and so on. Instead, a truly inductive
approach would admit that “health” and “disease” are not defined once and for all
and that they depend on the discovery of various mechanisms at play in the
pathophysiology of various diseases. A philosopher endorsing this inductive
approach would consider these mechanisms as the true content of the concept of
disease, and the description of the physiology of the body as containing the
mechanisms that should define “health.” For instance, if we found that in nine
cases out of ten, diseases are caused by a recently discovered process that is rarely
present in what we call healthy conditions – say, inflammation – this would not
change the definition of “disease” according to foundationalism. While medical
researchers may consider this a theory of disease, from which a powerful definition
of disease follows, and may consider non-inflammatory conditions to be defined
differently, foundationalism would simply see this as a theory of how some
diseases work. Indeed, the foundationalist concept of disease cannot be changed.
It can simply be properly analyzed, that is, derived from broader concepts such as
“incapacity,” “harm,” “typical,” and “situation.” The function of this concept is to
justify that a medical theory really is a theory of a disease, and the foundationalist
credo is that nothing else can, so that without such a basic concept, anything would
count as a disease if doctors, or pharmaceutical companies, so decided.
Yet, medical researchers typically use an inductive strategy to establish whether
a controversial condition is, or is not, a disease. In a controversial condition, they
look for material, generic processes that underlie other known diseases, and for
specific variations in the process that explains this disease only. Typically, schizo-
phrenia has been hypothesized to be a specific form of homeostatic dysregulation of
dopamine, or a fetal infection by Toxoplasma gondii, or a genetically predisposed
deficiency in the treatment of information by the brain. In any of these options,
schizophrenia would belong to a set of uncontroversial diseases. A foundationalist
would object that such processes as “infection” must be established as pathological
in the first place. For medical scientists, however, a process is preliminarily
hypothesized as pathological because it explains statistically abnormal levels of
efficiency or harmful conditions – or for any vague and general feature generally
found in diseases. That would be the case for infection. However, once it is
sufficiently documented in accepted pathological conditions, that is, precisely and
specifically, it serves as sufficient evidence in itself that any new condition that
involves it is actually a disease, even if it is not statistically abnormal or harmful. On
the contrary, as long as no explanation can be found in terms of infection, for
example, a condition will remain controversial.
Why is naturalism so far away from physiology? The reason is that it has
never evolved from a polemic question of the 1970s into a single field of
investigation. Although naturalism confronts normativism with the claim that
having a disease essentially relies on the existence of biological dysfunction
rather than on a value judgment, naturalism is still, essentially, about the role of
values in medical practice. For Boorse, the raison d’être of “naturalism” is to
establish that disease is “a value-free concept,” not to establish with exactness
what we know about the biological fact of disease (see Lemoine & Giroux
2016). This question about practice is still pervasive and seems to frame the
health and disease debate. In comparison, philosophers of biology may have
practical goals (like opposing creationism or criticizing the moral consequences
of essentialism), but their legitimacy in doing that as philosophers of science
necessarily relies on the pursuit of a theoretical goal, that is, clarifying scientific
concepts as they are used in contemporary science. In the health and disease
debate, the practical goal is explicit in 62 of the 110 articles mentioned earlier.
A total of 79 articles out of 110 explicitly take a side, naturalism, or normati-
vism, and 47 of them develop anti-naturalistic arguments without necessarily
endorsing normativism explicitly. In other terms, philosophers of medicine,
including naturalists, are interested in discussing the justification for medical
judgments rather than in examining the nature of the phenomena of health and
disease. This is legitimate if the goal is to discuss the implications of having
concepts of health and disease. But this is at odds with discussing related
concepts within the medical sciences.
1.5 The Idea of a Philosophy of Physiology

Medical researchers investigate fascinating processes such as infection and
inflammation mentioned earlier, but also dysbiosis, auto-immunity, neoplasm,
proteopathy, endothelial dysfunction, decompensation, homeostasis, mainten-
ance, repair, regeneration, and so on, and properties such as virulence and
pathogenicity, penetrance, genotoxicity, teratogenicity, and resilience. In this
Element, I will present some of those processes and properties. They explain
what is happening in the many diseases we all know or have heard of. They
together constitute the field of the pathological phenomenon – the natural
phenomenon of disease, as it exists on our planet in all its diversity. They also
raise many conceptual difficulties. This is the field that us philosophers of
physiology want to investigate. We are interested in conceptual questions
about how disease, but also health, are explained. We think that if there is
any scientific definition of health and disease, it is to be found in how they are
explained.
As a guide to this vast field, we will follow the thread of a question: is there
a theory of disease and a science of health in physiology? In medicine, it is true that
no theoretical part of medicine discusses “health” and “disease” the way theoret-
ical biology discusses “organism,” “function,” “metabolism,” or the origin of life
(Hesslow 1993). However, it is indeed “health” and “disease” that are indirectly
elaborated through more technical and seemingly local concepts. These discus-
sions have consequences for the empirical content of theories. They are necessary
to understand physiological science and they organize a body of knowledge. They
are used in biomedical theories and they are necessary to identify theoretically
important problems. They do everything the concepts of health and disease,
themselves, according to Hesslow, do not. In fact, a mistake of skepticism is to
conclude that they do not play a major role in medical science because they do not
play the role of foundational concepts. The fact is that the concepts of “health” and
“disease” are progressively defined, in medical science, by induction and recur-
sion, through a set of more precise and specific concepts. In this Element, we will
call these more precise and specific concepts – inflammation, infection, dysbiosis,
pathogenicity, neoplasm, and so on – disease-related concepts.
I will try to convince you that the search for a theory that explains health and
disease is a constant preoccupation of medical researchers. Far from neglecting
this question and leaving it aside for philosophers to deal with, they are much
more aware of how difficult the question is. In their collective quest for an
answer, they are progressively naturalizing the concepts of health and disease,
that is, they are transforming two terms that originate in commonsense, are
vaguely defined or even rigorously redefined by philosophers, into a precise,

technical, operational, and scientifically useful set of concepts based in natural
science (Lemoine 2014). They are not “presupposing” any preliminary definition
in any strong sense of “presupposing.” They are certainly leaning on intuitions,
but it is not to justify these intuitions by scientific theories; indeed, they are very
likely to go beyond these intuitions or prove them wrong. A handful of philo-
sophers of medicine have endorsed this description of naturalization in the health
and disease debate (Griffiths & Matthewson 2016; Fuller 2018; Sholl 2020;
Sholl & Okholm 2021). If I fail to convince you that physiology is building
a theory of health and disease, I hope to have at least convinced you that this field
is full of interesting conceptual issues for philosophers of science to investigate.
In short, the goal of the present section was to show how futile it may be to
investigate definitions of health and disease without any consideration for how
they are explained in medical science. The rest of this Element investigates
these disease-related concepts at various levels of generality called “disease
entities,” “theories of diseases” (in the plural) and, finally, “theories of disease”
(in the singular), and the science of health.
2 Disease Entities and Pathophysiological Processes

There are 17,000 diseases in the last version of the International Classification
of Diseases (ICD-11). A typically philosophical question is: what do they have
in common, if anything? Commonsense would propose a set of intuitive
answers: they are unpleasant, incapacitating, dysfunctional, or harmful. Is that
all there is to diseases?
Let us investigate one of them. Diabetes mellitus is a disease, a recognizable
condition diagnosed in many human patients. To diagnose a condition, doctors
must know typical signs and symptoms of that condition and, on this basis,
distinguish it from conditions it closely resembles. Symptoms are often defined
as reported, or experienced, by the patient (e.g., pain, fever, swelling, incapacity
to walk), while signs are often defined as found by the doctor through an
investigation of some sort (e.g., high blood pressure, high sugar level in the
blood, abnormal spot in X-ray imagery, subtly abnormal motor control of
hands). To predict and treat a condition, doctors also need to know its causes
and how it works. For instance, diabetes mellitus type 2 (T2D) is, most often,
a late-life and progressive condition of chronically high blood glucose (and
other signs), caused by diet and lifestyle and, to some extent, reversible by strict
change in diet and lifestyle, while diabetes mellitus type 1 (T1D) is, generally,
an early-life condition of chronically high blood glucose (and other signs), with
more sudden onset, caused by irreversible, autoimmune destruction of beta cells
in the pancreas. What any diseases have in common must be causes, process, or
manifestations.
The diagnostic science of diseases is called “semiology,” that is, the “science of
the signs” of diseases. There is also a biological science of the processes of
diseases, called “pathophysiology.” The process itself is also called the patho-
physiology of, say, T2D. What doctors call a “disease entity” is a specific form of
pathological phenomenon ideally characterized both by specific signs and by
a specific pathophysiology – present in all patients with that disease. However,
semiology and pathophysiology of a disease are rarely specific. Many signs can
be observed in many diseases. Many pathophysiological processes enter in the
pathophysiology of many diseases. Surely, some are exclusive. For instance,
“insulin resistance,” the progressive unresponsiveness of cell receptors to insulin,
when chronic, is a pathophysiological process supposed to be specific to T2D. It
causes hyperglycemia and exhausts insulin secretion, which are two pathophysio-
logical processes known to be shared with T1D. Another component of both types
of diabetes mellitus is chronic inflammation, a pathophysiological process also
common to many other disease entities. In fact, if many pathophysiological
processes participate in the pathophysiology of many diseases, a disease entity
is characterized by a specific nexus of pathophysiological processes. For that
reason, pathophysiology can either be conceived as the science of distinct and
separate disease entities, or as the science of pathophysiological processes inter-
acting with one another in many ways. These distinct views are not opposed.
However, they provide different perspectives on “the pathological phenomenon”:
on the one hand, there are thousands of typical abnormal conditions with many
shared properties but none in common with all, apart from trivial features like
“incapacitating,” “dysfunctional,” or “harmful,” and the more we get fixed on
specific disease entities, the more precise the diagnosis; on the other hand, there
are at most a few dozen common pathophysiological processes, caused by, or
causing, more specific processes, and the fewer there are, the simpler the explan-
ation. In the latter perhaps lies a unitary view of disease.
2.1 Robust Disease Entities Rely on the Description of Specific

Pathophysiological Processes
In Harrison’s Principles of Internal Medicine,3 there is one description for both
diabetes mellitus types 1 and 2. It is divided up into classification, epidemi-
ology, diagnosis, “regulation of glucose homeostasis,” pathogenesis, and the
presentation of some monogenic forms of diabetes mellitus. However, there is
no canonical way the knowledge about a disease entity is supposed to be
3
https://accessmedicine.mhmedical.com/book.aspx?bookid=2129 (last access on May 27, 2021).
organized. In the same handbook, the descriptions of breast cancer and influ-
enza are organized differently. That said, an analytic definition of “disease
entity” can be:
the description of a specific disease type that consists in:
(1) pathogeny, that is the process where a set of causes external to the disease
itself triggers it (these causes are called the “etiology of the disease”),
(2) the various mechanisms composing the process of the disease itself
(pathophysiology),
(3) signs and symptoms (pathology and semiology), including
a. alternative combinations of signs and symptoms that sometimes mani-
fest in different ways (clinical forms),
b. characteristic courses (natural history), for example, initial rash peak-
ing with a high fever and improving until complete remission, leaving
scars,
c. a set of explicit, sufficient differences from other disease entities (dif-
ferential diagnosis),
d. the capacity to clearly group a certain set of individual cases (nosology),
(4) the ability to explain why and how the disease happens in relation to why
and how it can, or cannot, be treated, and with what expected effects
(therapeutics, including prevention).4
The main goal of disease entities is to organize knowledge. Most studies in

medical science, whether they are investigating the pathophysiology of
a disease, the sensitivity and specificity of a diagnostic test, or the efficiency
of a treatment, are generally led in groups of patients that share the same disease
entity. Although doctors may treat patients even when they cannot fit their state
with any disease entity, the reliability, safety, and scientific nature of medicine
depends upon disease entities. Consequently, a crucial task for science is to
correctly distinguish different disease entities. The International Classification
of Diseases summarizes official disease entities. It provides a short description
of the specificity of the disease, an explicit but stipulated inclusion of various
forms of the disease and exclusions of other disease entities, and possible
pathological manifestations. See Table 2 for an example.
The key feature of any nosological system, that is, a list of disease entities, is
the distinctions it allows to make between these disease entities. The distinc-
tions can be designed to optimize many properties of such a system, as philo-
sophers of medicine have pointed out, including observational fidelity,
explanatory power, predictive power, or correspondence to available treatments
4
A simpler version of this template is proposed in Thagard (1999). See also Whitbeck (1977).
Table 2 The ICD description of “Diabetes mellitus type 2”

(consulted on May 26th, 2021).
Description
Diabetes mellitus type 2 (formerly noninsulin-dependent diabetes mellitus
(NIDDM) or adult-onset diabetes) is a metabolic disorder that is character-
ized by high blood glucose in the context of insulin resistance and relative
insulin deficiency.
Inclusions
• non-insulin-dependent diabetes of the young
Exclusions
• Diabetes mellitus in pregnancy (JA63)
• Diabetes mellitus, other specified type (5A13)
• Idiopathic Type 1 diabetes mellitus (5A10)
Coded Elsewhere
• Pre-existing type 2 diabetes mellitus in pregnancy (JA63.1)
Has manifestations
• Acute complications of diabetes mellitus
• 5A44 Insulin-resistance syndromes
• 8C03.0 Diabetic polyneuropathy
• Mononeuropathy
• 8D88.1 Autonomic neuropathy due to diabetes mellitus
• 9B10.21 Diabetic cataract
• 9B71.0 Diabetic retinopathy
• 11 Diseases of the circulatory system
• 13 Diseases of the digestive system
• EB90.0 Diabetic skin lesions
• 15 Diseases of the musculoskeletal system or connective tissue
• FA38.0 Diabetic arthropathy
• FA38.1 Neuropathic arthropathy
• 16 Diseases of the genitourinary system
• GB61 Chronic kidney disease
• MC85 Gangrene”
(Tsou 2012; Tabb 2015, 2020; Keuck & Hauswald 2016). Another requirement
for any good nosological system is that they respect two principles stated by
Hucklenbroich (2014):
(1) “Principle of completeness”: Every case of disease is a case of a specific

disease. An unspecified case of disease is either an unknown case of
a disease, or a case of an unknown disease.
(2) “Principle of unambiguousness”: Every case of a disease is a case of one

disease only. Patients may nevertheless be affected by two diseases at the
same time.
Which of the necessary components of a disease entity justifies that a set of

pathological manifestations be grouped into a specific disease entity? Some
philosophers have proposed original views on this question,5 but the scientific
consensus is rather that specificity relies on pathophysiology. There are, in fact,
relatively few symptoms of disease, and few sets of symptoms that are specific to
a given disease. For that reason, diagnosis relies more solidly on specific signs.
The specificity of signs increases with their centrality in the pathophysiological
process. Signs of systemic inflammation (e.g., in the blood) are not very specific
to any condition, while signs of local inflammation (a red, swollen, hot protuber-
ance under the skin) are more specific, and the detected presence of a certain toxin
on the inflammatory spot is perfectly specific. Thus, the pathophysiology of
a disease entity justifies that it is considered as a specific disease entity. When it
turns out to be the same in two disease entities, they merge into one with different
clinical forms. When it turns out to be different in two clinical forms, they are
defined as separate disease entities. These questions are related to the debate
between “lumpers” and “splitters” in psychiatry (Craver 2009) or elsewhere.
A good test of how important pathophysiological processes are is to consider
how some areas of medicine are doing without solid knowledge of these
processes. Psychiatry, as a matter of fact, does not offer disease entities robustly
based on known pathophysiological processes. As a result, its nosological
system is subjected to more controversies than other fields of medicine. Some
of the conditions it diagnoses as pathological are controversial because of the
very relevance of seeing them as such (see the historical controversy about
homosexuality), others, because of the criteria that are used to diagnose them
(e.g., how do psychiatrists diagnose a “major depressive episode”?). That said,
it is interesting to see how researchers have tried to bypass pathophysiological
processes to build nosological systems anyway. These debates revolve around
the notion of a “crisp” diagnosis, that is, one that distinguishes who has disease
X from who does not. The opposite of a crisp diagnosis is a fuzzy diagnosis, that
is, a diagnosis that cannot always tell with certainty that you have disease X or
not. To improve crispness, researchers may try to improve 5 properties of their
proposed diagnostic criteria:
5
Philosophers have defended original versions of the specificity of disease entities based on
etiology (Whitbeck 1977), natural history (Hucklenbroich 2014), or “reasonable applicability”
and “reasonable predictability” (Severinsen 2001) of the manifestation-specificity of disease
entities.
- Operationality: explicit, person-independent, verifiable nature of

a criterion to reduce vagueness, that is, observable ambiguities and relative
inapplicability, with a tradeoff between reliability and validity (Millon et al.
2010, 175), as well as a risk that the early operationalization of a concept
leads to diagnostic rigidity (Maj and Gaebel 2002, 21; Millon et al. 2010,
178–179). This is just to avoid divergence between doctors that would add
to the divergence between criteria and factual differences in pathophysi-
ology (if any exist, that is).
- Theory-independence: atheoretical, neutral criteria (American Psychiatric
Association 2000, xvii–xviii), in particular, “with regard to etiology”
(American Psychiatric Association 1987, xxiv). On the contrary, when
the physiopathology is correctly hypothesized, a theory-dependent criter-
ion is obviously much better.
- Categorical or dimensional: determining membership according to binary
properties (e.g., present/absent), or thresholds in quantitative values (Kendell
and Jablensky 2003; Cooper 2007, 53). If a pathophysiological process is
known, it is also known whether the process is pathological when the
outcome is quantitatively out of range (e.g., blood pressure), or when the
process does not take place in a healthy body at all (e.g., viral infection).
When the pathophysiology is unknown, this choice comes down to a best
guess.
- Monothetic or polythetic: necessary (and jointly sufficient) for a situation to
qualify as a case or determining alternative sets of criteria. Polythetic
concepts are liable for a greater heterogeneity of the delimited class, and
increase the risk of false positive cases (Helzer et al. 2008, 21), but may be
a necessary evil in the face of individual variation (Millon et al. 2010, 89).
This is a clever way to deal with diagnosis when pathophysiology is
unknown. When it is known, it is most often not necessary.
- Prototypicity: a set of highly characteristic features, or an individual
characteristic case, or series of cases, with a degree of closeness or resem-
blance that defines membership to the class (see Westen’s section in Millon
et al. 2010). Prototype approaches are probably a better match with how the
clinician naturally diagnoses, but do not necessarily produce crisper diag-
nostic sets. They reflect how doctors spontaneously categorize abnormal
conditions, but not necessarily the underlying abnormal pathophysiology.
Disease entities have mostly been controversial where pathophysiological know-

ledge is insufficient. Alternative formal approaches to disease entities have
generally been proposed to make for insufficient knowledge, without much result.
Overmedicalization has prompted reflection on the need for sophisticated
thresholds for diagnostic and therapeutic decisions, while debates between lump-
ers and splitters have fueled the usage of statistical tools and fuzzy logic.
This is enough to show how crucial the knowledge of pathophysiology is to
medical science and how distinct this is from the terms of the health and disease
debate.
2.2 The Pathological Phenomenon Consists in a Small Number

of Pathophysiological Processes
If pathophysiology unifies each disease entity, does anything unify the patho-
physiology of all disease entities? Obviously, the concept of disease does, at
least in a trivial way. We have seen that philosophy of medicine has traditionally
answered that question with the presupposition that disease is some sort of
a priori notion imposed on medical science. Let us investigate deeper into this
question. For example, when you go to the doctor with some pathological
condition, you can be in one of two situations. First, you, and possibly the
doctor, acknowledge that you are sick, which means that you present some of
the few well-known, unspecific signs and symptoms of disease (pain, fatigue,
weakness, nausea, fever, rash, swelling, etc.). The doctor may at the same time
not know which disease to diagnose, and simply acknowledge that something is
going wrong. They may even treat the sickness without a diagnosis – for
instance, prescribe an anti-inflammatory drug to alleviate the symptoms and
hope they simply go away soon enough. Second, the doctor may diagnose
disease X, that is, conclude that the corresponding pathophysiological process
is developing in your organism. In this situation, you may not even feel sick.
Philosophers have traditionally distinguished between “illness” – which is
what you mostly have in the first situation – and “disease” – which is what you
have in the second situation. Generally, this is interpreted as a distinction
between the subjective and objective, or values and facts, or commonsense
and science (Boorse 1975). On the one hand, the unity of the concept of disease
is defined by what is common to illnesses – for example, the experience of harm.
On the other hand, it is defined by what is common to all disease entities, for
example, that they involve some form of dysfunction. Here, we are stuck in the
debate between normativists and naturalists mentioned in the previous section.
In light of the previous subsection, the difference between “being sick” and
“having a disease” can be more precisely interpreted as a difference between
manifestations and their underlying processes, description, and explanation.
From a scientific point of view, unifying the field of the pathological by its
manifestations makes less sense than unifying by its explanations. As seen in
the previous section, naturalism has failed to consider this possibility because it
has presupposed that the concept of disease should somehow be a priori, and
that the specific diseases are diseases only because they match the criteria of
disease in general.
A useful phrase to introduce at this stage is “the pathological phenomenon,”
to refer to all the pathological phenomena collectively. The pathological phe-
nomenon is not a concept with an extension to possible or conceivable condi-
tions – as if we had a definition that could work with any possible disease in any
possible organism living in any possible world. Instead, it is a fact as we observe
it in organisms in this world, even if we do not conceptualize it clearly. This fact
is biologically important as a collective fact. There are diseases. What there is to
disease is not one and the same thing, such as “diseasehood” (Sadegh-Zadeh
2008), that is supposed to be instantiated in each disease entity. Instead, it is
a fact of life as we know it. All living organisms are vulnerable to disease. This
collective term, “the pathological phenomenon,” refers to a fact that scientists
sometimes study collectively, without any reference to the subdivision into
many disease entities. For instance, epidemiology refers to “morbidity” or to
the “burden of disease” when addressing all or many diseases at the same time.
Recently, some have proposed the concept of the “diseasome” to refer to all the
interactions between genes involved in all diseases (Loscalzo et al. 2007). As
they grow old, many human beings suffer from multimorbidity, that is, the
conjunction of several chronic diseases.
The starting point for the philosophical problem of the unity of the science of
disease should be that “disease” is de facto defined by: “disease1 or disease2 or . . .
diseasen” and that these diseases are defined by the concrete description of the
processes that underlie them, rather than by abstract and trivial criteria. Indeed,
“disease” refers to the pathological phenomenon, which consists in the gigantic
disjunctive domain of all specific diseases. It is important to start with that simple
idea, even if just to acknowledge that there are too many diseases for any scientific-
ally meaningful unifying conception to be immediately obvious. Disease is a fact
before it is a unified notion.
For the pathological phenomenon to be conceived and defined, the disjunc-
tion must be reduced as much as possible (but not necessarily to one category).
However, a focus on explanation seems to lead to the self-defeating conse-
quence that there is no meaningful concept of disease for the science of diseases,
only a huge list of heterogeneous conditions that may have nothing to do with
one another – and this would not prevent doctors from doing a good job after all.
That said, the focus on pathophysiological processes that explain specific
diseases allows for an important reduction in the number of criteria necessary
for this otherwise intractable disjunction. In other terms, if the pathological
phenomenon is to be theorized and “disease” to be defined meaningfully, it has
somehow to be as a disjunction of pathophysiological processes: “process1 or

process2 or . . . processm” instead of a disjunction of disease entities: “disease1
or disease2 or . . . diseasen” given that there are many fewer processes than
entities (m ≪ n).
Note that this reduction is already at play in the broader categories used in
classifications of disease entities. For instance, a set of patients suffer from T2D,
T2D is one of the forms of diabetes, diabetes is a metabolic disease, a metabolic
disease is a somatic disease, and somatic disease is one of the two forms of
disease (along with mental disorders). At each step, the problem is to model
a type of process that explains all diseases in the group, not simply find common
features that may be accidental or simply appear to be the most common to all
other diseases. For instance, in the face of the description of T2D, it will not
explain much about the disease to focus on trivial features such as “dysfunction”
or “harm.” Instead, the question is how the description of T2D participates in
a hypothesized set of diseases so that a common process is revealed, which
would not have been apparent otherwise. For instance, T1D and T2D involve
similar disruptions in the regulation of glycemia. Grouping them reveals how
T2D can evolve toward insulin dependence. Then grouping diabetes with other
metabolic diseases like hyperlipidemia reveals their relation to a common
higher regulatory system, its various vulnerabilities, and how different meta-
bolic diseases may interact (e.g., in the so-called “metabolic syndrome”). Thus,
the primary problem with generalization is not counterexamples, as is the case
for conceptual analysis, but sterile or misleading hypotheses about types of
disease. As hypotheses are many, the insight they provide consequently comes
in various forms and degrees. A choice between explanatory models need not be
made until everything that is explained in one is also in the other. In ICD-11,
“type 2 diabetes mellitus” is currently categorized as an endocrine disease but
described as a metabolic disease without much explanation. Obviously, it is
both. It is also a nutritional disease in many cases. Each of these conceptualiza-
tions casts a different light on the disease. The problem is empirical, but also
entrenched in important conceptual questions – what process characterizes all
endocrine diseases? Metabolic diseases? Nutritional diseases? How should they
be modeled and defined, and what should they include?
Indeed, nosology is not like the periodic table of elements, that is, final, give or
take a handful of newly discovered elements. Yet, the formal structure of nos-
ology remains relatively stable. What is constantly changing, however, are the
descriptions of processes, how they explain a disease, and the types of diseases
they justify. The extension of a disease changes, sometimes with philosophical,
ethical, economic, and social considerations, always with a change in the descrip-
tion of processes. For instance, “insulin resistance” was once a description of
a process specific to diabetes (Matthews et al. 1985). However, research deals

with questions such as: Is “insulin resistance” an accurate or sufficient description
(Goel 2015)? What is an accurate description of “insulin resistance” and does it
happen in all patients with diabetes and only them (Bugianesi et al. 2005)? Only
in the context of such discussions about a disease entity can other considerations
be relevant in contemporary medicine.
From the point of view of the processes they share or not, diseases are
grouped in tree-shape nosological structures. It is unlikely, but possible, that
some groups of diseases are entirely distinct from the rest, that is, share no
common process with any other disease. This may be the case for mental
disorders. If it were the case, the science of such a separate group of diseases
would be entirely independent.
It seems safe to hypothesize, on the contrary, that all diseases share common
processes with other diseases. On the further hypothesis that these processes
causally interact with one another, individual diseases can be described as the
many specific manifestations of a network of pathological processes. This
network can consist in a handful of major nodes and belts of minor ones, with
a thicket of edges – one specific disease consisting in one of the many pathways
in the network (Figure 3). Another possibility is that the network has the strong
hierarchical structure of a tree with all specific diseases branching out of the
same trunk through further ramifications. This is what a successful “theory of
Figure 3 The pathological phenomenon as a bush of pathological processes.

The more frequent a process, the bigger the node, and the more frequent the
association between two processes, the thicker the edge. In lighter grey, we
approach one disease.
disease” could ultimately discover (see Section 3). Whatever the situation, all
diseases together do not simply form a class of phenomena with similar
properties. Instead, they form one “pathological phenomenon” with infinitely
many variations and manifestations in individuals. This concrete fact is what
pathophysiology is keen to theorize.
In this section, we have uncovered the object of pathophysiology, namely, the
“pathological phenomenon.” We now want to know whether it simply consists
in the juxtaposed knowledge of all the many diseases and underlying processes
we have observed, or whether it can be unified into one theory – or whatever we
want to call it.
3 How Generalizable Are Disease Theories?

When you are sick, you expect the doctor to diagnose a specific disease entity
among thousands of possibilities. However, entire sets of these possible
diseases have a lot in common. To describe a crucial process shared by a set
of diseases, physiology resorts to a specific form of theories – disease theor-
ies. For instance, there are many infectious diseases – malaria, the flu, tuber-
culosis, syphilis, AIDS, to cite only a few – but a theory of infectious diseases
is intended to describe the core process they all share and its many variations.
Such disease theories have important functions in physiology as well as in
medical science.
A first function is to provide the right description of a causal process. It should
be generalizable, that is, it expands our knowledge of some specific diseases by
analogy and is in contrast with what is known in other specific diseases of the
same type. One common process to all infectious diseases is proliferation of
a micro-organism (the “agent”) in a “host organism” (e.g., the lung, the brain, the
skin or the immune system of humans, or mammals, or specific species), trigger-
ing some form and degree of defense in the host, with the whole process
explaining “virulence,” that is, the sum of pathological effects caused in an
organism or population. Since we know that, in a specific disease, the virus that
causes it cannot enter a human cell and replicate in its nucleus without a specific
receptor, this suggests both how other viral infections may occur and how they
may differ. In other words, a disease theory illuminates the key parameters that
diseases share or not, explaining both their specificities and commonalities, why
they can cause disease (pathogenicity), and have such and such effects to a given
degree (virulence). In so doing, such a theory establishes the boundaries of
a disease type. The discovery of Helicobacter pylori, an agent that can settle in
the stomach and cause damage in its tissue, transformed peptic ulcer from
a psychosomatic into an infectious disease (Thagard 1999).
A second function is to establish that a condition is indeed a disease, if it

proves to be undergirded by a typical pathological process and is explained by
a disease theory. In Section 2, we mentioned the existence of an infectious
theory of schizophrenia. While schizophrenia has long been somewhat contro-
versial, evidence that it is specifically caused by an infectious agent would have
been considered evidence that it is a disease. Another somewhat controversial
condition is fibromyalgia. Fibromyalgia is defined as a form of widespread pain
in muscles and joints that is not explained yet by any specific known factor.
Some think that it is a rheumatic, autoimmune disease, others, that it is psycho-
genic – that is, the expression of a mental disorder – and others even think that it
is just a way to express human distress (e.g., extreme fatigue or demotivation),
which is not particularly pathological. However, most skeptics would be forced
to capitulate if a specific virus was shown to be active in most people suffering
from fibromyalgia, and almost only in them.
A third important function is for a disease theory to actively expand into
a “theory of disease.” By theory of disease, I mean a construction that describes,
explains, and predicts all diseases by a specific pathological process. A theory
of disease is a disease theory that works for all diseases – for instance, expand-
ing the infectious theory of diseases to claim that all diseases are caused by
some infection. Such a theory of disease, if it existed, would unify the field of
pathophysiology in a very strong sense, even if it did not work for a few
diseases. It would describe the “pathological phenomenon,” as it is called in
the previous section, in its entirety. A definition of “disease” would follow
that would be based on what scientists know of disease, not on what folk
representations are. Even if this extreme possibility is unlikely, it is nevertheless
an important feature of disease theories that they keep expanding until they
reach the limits of their generalizability, which could attain universality.
In this section, we will focus on the first and third functions of disease
theories in turn, introducing nine disease theories that have been proposed in
pathophysiology, and then discussing how a disease theory can be generalized
into a theory of disease.
3.1 How Disease Theories Differ in Explaining a Disease

Disease theories describe, explain, predict, and support therapeutic intervention
on pathophysiological processes more or less specifically involved in some
diseases.6 Note that diseases are sometimes grouped after a common property
that is not, properly speaking, a process: for example, mental disorders,
6
A pioneering epistemological work on the particular structure of these theories in medical science
can be found in Schaffner (1986); see also Sadegh-Zadeh (1999, 2012).
Table 3 Nine disease theories. The theory is given a name (in bold). Note that
alternative names always exist. In italics, technical terms describe the core
process that is the object of the theory.
• In the formal sense, the homeostasis theory of disease describes disease as

the disruption of a mechanism with a role or function of active regulation or
maintenance of a broader system of parts with functions or roles, through
signaling, control, and mediation, in the face of stress and with a margin of
tolerance (see Section 5.2 for more).
• According to the infectious theory of disease, a disease is the colonization by
a pathogen of a host that generally mounts up a response of the form of a
defense, involving a nonnull degree of virulence.
• The genetic theory of disease distinguishes two cases of genetic disease. In a
strong sense, a genetic disease is a (generally rare) Mendelian disease that
only a defined mutation can cause by compromising a specific step in a
determined pathway and producing a recognizable phenotype. In a weak
sense, a genetic disease is a (often frequent) complex (Botstein & Risch 2003)
disease, the risk of which is increased by an indefinite number of undeter-
mined genes, possibly in an undetermined way.
• The stress theory of disease is that psychosocial stressors during childhood
or adulthood (trauma) trigger a mechanism of vulnerability (diathesis)
mediated by neuroendocrine or neuroimmunological loops, which accumu-
late a deleterious factor, sometimes called allostatic overload, and which is
responsible in turn for an increased risk of many diseases – defined as the
effects of this same cause.
• In the immunological theory of disease, an immune disease is defined as a
process of either immunodeficiency or autoimmunity or excessive response,
often (but not always) associated with inflammation, as observed in the innate
and/or adaptive immune system of the host.
• The microbiota theory of disease originates diseases in dysbiosis, which is
generally defined either as the presence of a keystone pathogen (Hajishengallis
et al. 2012) that causes an imbalance in the composition of the microbiota as
assessed by its metagenome, or as an imbalance of undetermined cause, which
is either the cause of, or associated with, a specific disease. Alternative versions
of the theory avoid the term “dysbiosis” (Olesen & Alm 2016).
• The theory of the developmental origin of health and disease (DOHaD)
proposes that early exposure during development tracks individual organisms
into a given phenotype that explains their (low or high) susceptibility to
various diseases through phenotypic plasticity.
• The geroscience theory of disease sees the accumulation of unrepaired
damage as the main common cause of all forms of structural decay, func-
tional decline, and increased incidence of disease and risk of death with age.
It not only applies to the diseases of the aged, but also proposes to see forms of
Table 3 (cont.)
accelerated aging in diseases of the young and does not consider aging at the
level of the organism only, but also at lower levels.
• The evolutionary theory of disease investigates why disease exists to clarify
how diseases work, more specifically, how fitness is compatible with an
imperfect degree of health. It proposes environmental mismatch, antagonistic
pleiotropy, arms races, and life history tradeoffs as important explanatory
concepts for all diseases.
neurological disorders, and skin diseases. In this case, there is no object for
a disease theory.
Table 3 proposes a list of 9 disease theories of broad scope. Although they are
ubiquitous in medicine, there is no article or textbook to list them as such.
Sometimes, some of them are presented in an article as concurrent or comple-
mentary theories of the same disease. For that reason, the list is open to
discussion, and intended only to provide an idea of the scope of concepts and
theories yet to be explored by philosophers of physiology.
When confronted with a disease, scientists have a choice between these various
theories (and certainly others) to determine which explains the disease better.
Take T2D again. It fits with the theory of disrupted homeostasis (of glucose
availability) and has traditionally been thus conceived – Cannon developed the
example of the regulation of glycemia (i.e., level of glucose in the blood) in his
article on homeostasis, and also mentions diabetes (Cannon 1929). It is still
common to think of diabetes as the following process: glycemia cannot be
maintained within the margins of tolerance of normality because of insulin
resistance, which is an acquired insensitivity to insulin signaling. However,
there has also been an important trend in research to look for genes that make
some humans more susceptible to T2D than others. So far, a genetic approach has
failed to significantly discriminate and predict which humans would develop
a complex genetic disease such as T2D but it has been more successful in the case
of Mendelian diseases. Obviously, the evolutionary, homeostasis, and genetic
theories are generally not in competition over the explanation of T2D. While the
former is focusing on the pathophysiology of diabetes (how it works), the latter is
focused on its pathogeny (how it is brought about). If one fails, the other does not
necessarily prove stronger. However, they are in competition to define the
specificity and the timeframe of T2D. If conceived as the disruption of homeo-
stasis, everything before glucose levels are chronically high is better conceived as
a part of the etiology and not of the pathophysiology of the disease. If conceived
as a genetic disease, the pathophysiology may remain undetectable for a much

longer time and the disease may start even when the deleterious effects of genes
can still be compensated naturally so that no traditional sign shows. In the end,
a focus on pathogeny has the effect of redefining the pathophysiology of the
disease. In this, these two theories are in competition. This competition between
these two theories also exists over many diseases, such as cancer, cardiovascular
diseases, and neurological diseases.
These various theories also differ over the pathology-specificity of the process
they describe as their object. More concretely, we may not want to consider any
disruption of homeostasis as pathological. Perhaps hyperglycemia in type 2
diabetes is adaptative. After all, many have noted how robustly hyperglycemia
is actively maintained in diabetes itself, as if it were a homeostatic process
(Bernard-Weil 1999). On the other hand, if a set of mutations, or an infectious
agent, or a specific property of the immune system, or of the microbiota, and so
on, perfectly discriminated between those who would develop T2D and those
who would not ceteris paribus, the process would indeed be specific, and the
pathological status of the condition would be considered largely established. This
problem exists for many other diseases which are controversially considered to be
diseases – late-onset, chronic conditions such as hypertension or abnormal tissues
that are sometimes labeled as “precancerous.” Interestingly, the geroscience
theory of disease focuses on how the specific ways in which cells and tissues
are altered while we age can cause these various diseases. Many in this research
program have rejected the relevance of discriminating between aging and age-
related diseases on the ground that aging itself can (and should) be treated – and
thus considered a pathological process, if not a disease. Others have tried to
discriminate between normal and pathological aging. So far, this has mostly been
speculative and has not cast much light on these questions. The reason is certainly
that it has failed, so far, to concretely describe, rather than verbally refer to, the
pathophysiological process of aging that is supposed to cause all these late-onset
diseases.
In general, there is no space here to fully develop how these theories differ
and compete over which diseases. Endorsement of one or the other explains
much of the theoretical controversies, and divergences in research programs,
over many diseases.
3.2 Generalizing Disease Theories

Remember that diseases entities are grouped into types – infectious diseases,
metabolic diseases, cardiovascular diseases, and so on – and that most disease
theories are introduced as theories of types of disease, not as theories of disease
in general – although researchers expand them as much as they can. A common

idea is indeed that an indefinite number of types of diseases happen to exist, and
there are causes for why they exist, but no reason for why them and not others.
However, it would be naïve to believe that a disease is assigned once and for
all to a disease type. In fact, theories of disease-types are possibly generalizable
to more diseases than currently known. For instance, the literature on stress and
diseases is huge and includes mental disorders (Heim et al. 2008; McEwen et al.
2015), cancer (Reiche et al. 2004; Heikkila et al. 2013), metabolic disorders
(Karatsoreos & McEwen 2011), cardiovascular diseases (Steptoe & Kivimäki
2012), autoimmune diseases (Webster et al. 2002), and neurodegenerative
disorders (Viau 2002). However, many researchers are wary of it because of
the lack of experimental support of the hypothesized mechanisms and the
weakness of epidemiological evidence. In contrast, the field of immunology is
based on well-established mechanisms and strong epidemiological evidence. In
the recent years, immunology has considerably extended its scope from
a territory of diseases involving immunodeficiency, autoimmunity and exces-
sive immune response, to an undetermined number of diseases previously
categorized as neurodegenerative (Heneka et al. 2014; Heppner et al. 2015),
neoplasic (Schreiber et al. 2011), metabolic (Osborn & Olefsky 2012) or
vascular (Hansson & Libby 2006). Major therapeutic applications substantiate
the claim, which typically involve the development of immunotherapies in new
fields. Likewise, many papers have investigated the causal role of the compos-
ition or biological activity of the microbiota in diseases as different as T2D (Qin
et al. 2012), cancer (Schwabe & Jobin 2013), cardiovascular diseases (Koeth
et al. 2013), and autoimmune and inflammatory diseases (Belkaid & Hand
2014), but also the efficiency of immunotherapies on cancer (Routy et al.
2018) and the regulation of the immune system (Honda & Littman 2016).
More specifically, a disease theory is justified in the case of a disease
D inasmuch as the process it describes is (a) necessary to D and (b) specific to
the pathological phenomenon in general (i.e., takes place in diseases only).
Table 4 represents how necessary the process described by each disease theory
is to explain each type of disease. In this table, the darker the average color of the
column, the more diseases a theory may explain. The darkest shade represents the
original scope of the theory while the other colors represent its expansion. The
expansion of a theory may be based on articles that apply it, or on the existence of
elements to hypothesize that the process is necessary to all diseases of a type,
although no article does it explicitly and systematically. Take the example of
infectious diseases. The so-called Koch’s postulates stipulate that a disease is
infectious if and only if an infectious agent is found in all patients, is not found in
subjects without the disease, and is a sufficient condition to develop the disease if
Table 4 The scope of disease theories. In columns, disease theories as listed earlier.
Table 4 (cont.)
Lines represent types of disease after ICD-11. Shades represent how well the theory accounts for a type of disease according to the literature. More
specifically, they represent
– the existence of at least one current paper that presents the process as 1) necessary and sufficient (darkest) or 2) necessary (dark) to account for all diseases
of the type;
– the absence of such articles, with the conclusion that the process is 3) possibly necessary to account for all diseases of the type (medium),
or 4) not necessary to some diseases of the type (light), or 5) not necessary to any disease of the type (white).
For instance, the infectious theory of disease amounts to the claim that infection may be necessary (yet undetected) in almost all types of disease, while the
evolutionary theory of disease claims on theoretical ground that one of the processes it describes is necessary and sufficient or necessary in many more types
of disease.
inoculated. There are many formulations of these postulates, but whatever the
formulation, they do not allow for a disease to be formally characterized as
infectious before a pathogen is identified. However, this allows for reasonable
hypotheses that a pathogen may be involved in many apparently non-infectious
diseases – think again of the example of the explanation of schizophrenia by
Toxoplasma gondii. Beyond this, of course, there would be the merely heuristic
hypothesis that any disease could be explained by a specific infectious agent.
Finally, some theories have been proposed as a broad explanation of all diseases
of a certain type, for example, the microbiota theory of disease has been applied to
all neurological disorders (Cryan et al. 2019).
The extension of various theories of disease should be interpreted differently
depending on the grade of necessity of the condition described for the group of
diseases. Indeed, it is hard to assess how much of a disease, or of diseases,
a theory can explain. An illustration of the problem is the geroscience theory of
cancer: how many aspects of cancer initiation and development can the normal
aging of tissues explain? Some think aging is a marginal risk factor for cancer
that increases with time (e.g., through the phenomenon of inflammaging, that is,
a common phenomenon of chronic inflammation with no specific reason) or that
most of the causal contribution of aging is already considered in traditional
theories of cancer (e.g., via the accumulation of random mutations in cells).
Others consider that cancer should be conceptualized as the effect of the
combination of several processes involved in the aging of a tissue. This problem
of explaining a disease is frequently raised in terms of the nature of the
interaction between the supposed explanatory factor, for instance, between
microbiota and host (Tremaroli & Bäckhed 2012), or under the question of
whether there is causation or simply association between dysbiosis and disease
(de Vos & de Vos 2012). It is obviously more difficult to assess the generaliz-
ability of very recent research programs. The DOHaD agenda was named after
a general explanation for metabolic disorders like T2D (Bateson et al. 2004),
and it was initially applied to cardiovascular diseases (Barker 1986) before it
was hypothesized to be important also for immunological and neurological
disorders (Fleming et al. 2018), as well as cancer (Ekbom et al. 1992).
However, the evidence is still scant. Similarly, the scope of age-related diseases
is arguably limited: infectious diseases, cancer in infants, congenital disorders,
and most mental disorders cannot be described as effects of aging, although
aging aggravates the effects of many diseases that are not strictly speaking age-
related diseases.
Importantly, disease theories do not have mutually exclusive extensions in
principle – quite the contrary. In the previous subsection, I explained that the
homeostasis and the genetic theories of T2D focused on different processes, and
that this led to competition about where the specificity of the pathophysiology
really lies. Another reason for their coexistence is that each disease theory
focuses on one necessary condition – and can rarely establish that it is sufficient.
If your theory is that T2D is caused by chronic nutritional imbalance, you would
have to explain why some people exposed to the same or similar cause escape
the effect. The same goes if your theory is that it is genetic. For that reason, there
can be as many theories of processes involved as necessary conditions of a type
of disease.
Most of the hype of a “new” disease theory comes from the uncertain extension
of its domain of application. Just like the enthusiasm about the genetic theory of
disease peaked with the achievement of the human genome project (the integral
sequencing of the human genome), and the subsequent flurry of “genome-wide
association studies” (systematic search for all genetic differences between popu-
lations with a disease and populations without), there has been a lot of enthusiasm
around the microbiota theory of diseases, revolving around how many diseases,
and how much of these diseases, it would ultimately explain.
The general point of this subsection is to warn you against the opposite,
equally hasty conclusions, that the latest theory in town will necessarily explain
more diseases than the previous ones or that it is bound to fail to explain all
diseases. The truth is that there is no way to predict how far a theory goes. The
field of physiology develops by expansion, speculation, waning, and fixation of
successive research programs around specific disease theories, each of which
could (in principle) be a theory of a disease type as well as a theory of disease.
3.3 Issues with the Generalization of Disease Theories

Before we get to the examination of this goal of a truly general theory of disease
in the next section, it is useful to examine some issues with the potential
generalization of theories of disease types.
Let us begin with a general observation. A theory of disease types usually
does not come in the exact same version (TA, TB . . .) when applied to different
diseases (D1, D2, . . . Dn). Take the example of homeostasis, a venerable and
arguably general account of many diseases. Possibly all diseases can be
explained as instances of disruption of homeostasis on some level, from dia-
betes to Down syndrome. However, applied articles with a limited scope (one
form of homeostasis or one family of diseases) are much more cited than
theoretical articles with a broad scope (on homeostasis in general) – including
Cannon’s original paper (Cannon 1929). Indeed, there is no visible overarching
theoretical literature on homeostasis, as if everyone knew what it is, or
conversely, considered it useless to the explanation of specific diseases. On the

contrary, theories of homeostasis as one specific phenomenon are partial gener-
alizations (e.g., Kotas & Medzhitov 2015), visible at most in one field. Another
example is genetic theories of disease types. The genetic theory of hereditary
and congenital iron deficiency (TA of D1 and D2) is not the same as the genetic
theory of infectious diseases (TB of D3). While the former defines a genetic
disease as a process that will invariably take place, will probably take the same
form since birth, and for everyone with the corresponding mutation, the latter
defines a genetic disease as a susceptibility to some infectious diseases that will
depend upon the encounter with the pathogen and may vary considerably
depending on the strain of the pathogen and the host’s age, compensatory
mechanisms, and other factors. Is that really the same theory? How should it
be phrased? What these two theories that apply to different diseases have in
common may be much less than a unified or common theory – perhaps, simply,
a vague appeal to the same ultimate explanatory terms, in this case, “gene.” It is
important that a common theory can be explicitly phrased. It is unavoidable that
it is constantly rephrased to account, as accurately as possible, for as many
phenomena as possible. For instance, a description of the process of an infec-
tious disease, based on a currently widely accepted understanding, could be “the
colonization by a pathogen of a host that generally mounts up a response in the
form of a defense, involving a nonnull degree of virulence.” This description
may, or may not be true of cancer, depending on whether infection by pathogen
X, Y, Z, cause cancer in all cases (Becsei-Kilborn 2010). But it may, or may not
be true of cancer depending on how the process of infectious disease is itself
described (Liu et al. 2016). For instance, it is currently not considered that any
disease where a microbe intervenes is fruitfully described as an infectious
disease. For instance, oncovirus-induced cancer is generally not described as
such, which suggests that it may be better to describe an infectious disease as the
process of colonization rather than as the simple triggering of the disease by an
infection. Is this the best choice, or should the theory be rephrased in order to
gain extension? No one can say before it has been tried.
More generally, the phrasing of a global disease theory faces three major
conceptual difficulties that are well known to philosophers.
An extension problem consists in determining whether a technical term used
in the description of a theory clearly applies to specific facts. For instance,
“homeostasis,” “allostasis,” “allostatic overload,” and “disruption of homeosta-
sis” are ambiguous in many cases – is insulin resistance a case of “disruption of
homeostasis” or a case of “pathological homeostasis” (Bernard-Weil 1999)?
There is a theoretical discussion about whether “allostasis” really refers to
something else than “homeostasis” (Day 2005). A major concept both in the
evolutionary theory of disease and in the geroscience theory of disease is

“antagonistic pleiotropy” (Williams 1957): namely, the hypothesis that
a genetic trait has been selected for a (even modest) beneficial effect on
reproduction early in life, in spite of a (even catastrophic) deleterious effect
later in life. Classic but disputed examples are Huntington’s disease (Shokeir
1975) and inflammation related to cancer (Campisi 2013; see the philosophical
argument in Giaimo & d’Adda di Fagagna 2012). In general, it proves very
difficult to determine whether a given gene is an example of antagonistic
pleiotropy. “Stress” is also a notoriously difficult term to use unambiguously.
What a “pathogen” is is a matter for discussion (e.g., Virgin et al. 2009). So is
“mismatch” in evolutionary medicine (crucial clarification in Bourrat &
Griffiths 2021). Some fields of science, like immunology, have already contrib-
uted theories meant to encompass a wide array of immune phenomena and
processes as applied to many different diseases, but the exact scope of some
concepts – for example, “disease tolerance” (Medzhitov et al. 2012) – remains
to be investigated.
A focal adjustment problem consists in the choice, for a term, between a very
accurate meaning with a restricted scope and a very broad scope with a vague
meaning. The stress theory is highly disputed for its conceptual vagueness, which
is in turn related to its potentially very broad scope. Although stress has since
come to be understood as any deleterious factor acting at any level, from proteins
to organisms, a properly speaking “stress theory of health and disease” is
restricted to the influence of psychoneuroendocrine stress on the pathogenesis
of multiple diseases. In its recent, more specific version of the allostasis theory of
health and disease (McEwen 2007), it is maybe more precise but also restricted to
the explanation of fewer diseases. Note that it is sometimes hard to define the
conceptual framework itself in fields that tend to expand before they get precise,
as is the case for DOHaD (Gluckman & Hanson 2006b). In the end, the choice of
a meaning is a matter of stipulation. It should be strategic and fruitful and is
always tentative. For instance, many diseases have been described as “genetic”:
cancer (Vogelstein & Kinzler 2004), but also bipolar disorder, coronary artery
disease, Crohn’s disease, rheumatoid arthritis, T1D and T2D (Wellcome Trust
Case Control Consortium 2007), and many others. Philosophers have investi-
gated both the notion of causal selection in the case of genetic diseases (Hesslow
1984; Magnus 2004) and the concept of genetic disease (Smith 2001; Darrason
2013), with particular attention to the question of the reduction to genetic
explanations. They have shown that many so-called “genetic diseases” are not
genetic in a strong sense, but in a weak sense in which every disease is genetic
(e.g., cancer, see de Magalhães 2022). While the strong sense is both restricted to
a small number of diseases and generally uncontroversial, most, if not all,
diseases are likely to be of a type between pure Mendelian and “complex” in

the vaguest way (Lemoine 2016). However, Darrason has proposed an ori-
ginal contribution by discussing not genocentrism, but the genetic theory of
disease. Taking the example of the genetic theory of infectious diseases, she
shows that infectious diseases are genetic as well, but not in a trivial sense.
A consistency problem consists in defining the key terms of a disease theory
together in a coherent, but not circular way. The definitions of “pathogen,”
“infection,” and “virulence,” should be consistent with one another, but each
should refer to a proper set of facts so that bringing them together does not
simply follow from analysis but leads to a set of explanations and predictions.
Indeed, there is a developed and precise theoretical literature in evolutionary
biology, in epidemiology and in immunology that defines the basic concepts of
infection. They include “pathogen” (Méthot & Alizon 2014), “host” and “para-
site,” “response,” “defense” (Akira et al. 2006), “resistance,” and “virulence”
(Frank 1996). Scientists, as well as philosophers, have pointed out problems in
the consistency of the microbiota theory of disease: the definition of dysbiosis,
the problem of causation, and the focus on taxonomic rather than functional
decomposition of the metagenome (Hooks & O’Malley 2017; Lynch et al. 2019;
Greslehner 2020). The field of geroscience is not yet investigated by philo-
sophers of science, although theoretical questions have already been listed
(Lemoine 2020). A handful of philosophers have likewise discussed and con-
tributed to the conceptual elaboration of the evolutionary theory of disease
(Méthot 2011; Cournoyea 2013; Griffiths & Matthewson 2016). The microbiota
theory of diseases, if it exists, still needs clarification of its main terms and their
relations (Sholl et al. 2021).
Before we get to the next sections, it is useful to take stock by comparing,
once again, the point of view of philosophy of physiology on the question,
“what is disease?” with the point of view of traditional philosophy of medicine.
The latter embraces foundationalism – the idea that the term “disease” should be
defined once and for all for the field of medicine independently from its
empirical discoveries – and discards disease theories. The former embraces
the examination of disease theories – as potentially developing into theories of
disease – and discards foundationalism. This is enough for philosophy of
physiology to exist as a field, without needing to ever address such a general
question as: “what is disease?” However, we also want to know what such an
approach would have to say on this. Predictably, it is a much harder question to
answer if you renounce foundationalism, but we are now sufficiently prepared
to tackle it in the next section.
4 Toward a Theory of the Pathological Phenomenon

An intriguing fact about the pathological phenomenon is that while perhaps no
specific disease will strike all individuals in a population, certainly no individual
in a population will escape all diseases. Developing some diseases at some points
in life seems to be a trait of all living organisms. Here are a few facts to illustrate
the importance of this paradox. First, congenital diseases necessarily develop in
some individuals, obviously not all of them. More generally, are some individuals
bound to develop, say, cardiovascular diseases or cancer, while others are immune
to these (but not others), and what roles do genes and environments play in this?
Second, some diseases that happen frequently in some species, like sarcoids,
a form of tumor of the skin found in horses, may be impossible in other species as
far as we know. What are the physiological facts that explain these differences in
the susceptibility to some disease? Third, some speculate that all human organ-
isms – maybe mammals, animals, or even all multicellular organisms – frequently
initiate cancer but efficiently inhibit its development or eradicate it most of the
time. However, most admit that there is some randomness involved, so that of two
individuals with the exact same genes living in the exact same environment, one
may develop cancer while the other does not. How much of the pathological
phenomenon depends on random events in general, how much on necessitating
causes? Fourth and finally, even if it is extremely unlikely that you never catch
a cold in your whole life, it is not inconceivable that you may, like it is that
a human may breathe under water or survive without ever eating. If we eliminate
the possibility of extreme luck, what are the differences between the hypothesis
that something is missing in your physiology to develop a given disease, and the
hypothesis that you have some protective mechanism actively inhibiting some
part of the pathophysiological process?
I summarize these questions as follows: what makes succumbing to disease
a necessary trait? A necessary trait is a trait whose presence can be derived from
theoretical premises. For instance, if a sufficient cause of cancer is a certain
combination of mutations (premise #1), and if there is no restriction of possible
mutations (premise #2), then given infinite time, any organism will necessarily
develop cancer eventually. We are interested in a set of theoretical claims that
would explain why it is necessary that organisms have diseases in general –
more specifically, why organisms are susceptible to disease. Understanding the
necessity of disease that befalls living organisms is a better first step toward one
theory of the pathological phenomenon, than is finding some universal feature –
typically, ultimate consequences like suffering, dysfunction, or incapacity.
4.1 Why One Theory for All Diseases Sounds Unlikely

and What It Could Achieve
Most scientists would be wary of the idea of one theory for all diseases. There are
solid reasons for such skepticism. Think again of the huge variety of diseases. It is
unlikely that biological properties that are common to all diseases are ever found,
including those apparently so different from one another as schizophrenia and
cancer. Moreover, the history of medicine strongly warns against theories of
disease supposed to describe the cause of all diseases. The Hippocratic theory
of dyscrasis explained all diseases by an ill-balanced mix of “humors,” that is,
imaginary components of the blood. The lesion theory of disease sought to
explain all diseases by lesions – but some diseases appear not to be caused by
any observed lesion. The same problem occurred for the germ theory of disease
(“all diseases are infectious”), the psychosomatic theory of disease (“all diseases
have a psychological cause”), or the genetic theory of disease (“all diseases are
caused by genetic mutations”). Finally, contemporary medical research is mas-
sively specialized for a reason: the heterogeneity, complexity, and specificity of
pathophysiological processes. In cancer research, for instance, one must special-
ize in the study of a form of cancer or even in a precise, limited process involved
in a form of cancer. Even if it is still possible that encompassing theories unify
pathophysiology again, specialization makes such unity both unlikely to happen
and idle to seek for. So, maybe philosophers of medicine are wise to omit the
possibility that a common property defines the pathophysiological, and focus
instead on broad concepts like “dysfunction,” or even “harm.” Maybe “dysfunc-
tion” is as indifferent to the nature of many diseases as “money” is to its
realization under the forms of coins, strips, cows, sheet of paper, and so on
(Fodor 1974). Maybe “harm” is the same form of encompassing concept for well-
established categories of diseases as the concept of “weed” is for diverse forms of
plants that have nothing to do with one another biologically (Cooper 2005).
However, we have seen in Section 2 that the huge variety of specific diseases
results from the many combinations of relatively few unspecific pathophysio-
logical processes. We also emphasized that these processes are causally con-
nected. We entertained the view of the pathological phenomenon as one “bush”
of connected processes, and concluded that in this case, the unity of pathophysi-
ology is not to be sought in analogous features of infinitely varied diseases, but
in their underlying, causal processes. We also insisted that it is natural and
useful to try to extend to other diseases a theory that explains some diseases
well. The proposal, in the present section, is not to focus on a unitary patho-
physiology of all diseases, but on the common causes to all pathophysiological
processes – a theory of these causes would be a theory of disease.
4.2 The Conceptual Necessity of the Pathological Phenomenon

Before we investigate general causes of the pathological phenomenon, we must
examine one important consequence of the variability of traits for the necessity of
disease.
Organisms of the same species are similar but not identical – some have bigger
bodies, move their wings faster, reproduce more quickly, are more vulnerable to
cold, operate photosynthesis more efficiently, and so on than others. These are
variations in traits. Any population of living organisms presenting variations in
traits can be represented as a distribution of the probability that the bearer
survives, or reproduces, or that the traits are more frequent in the next generation.
Physiology is not primarily interested in whether a trait tends to be more frequent
in a population with time – this is a crucial question for evolutionary biology.
Physiologists are primarily interested in whether variations affect individual
survival (and possibly, reproduction). An important consequence is that there
will necessarily be a lower tail of contributive traits – that is, some variations will
perform poorly as compared to others. Diseases fall in the category of variations
that perform comparatively poorly.
This fact has been taken as a defining feature of disease, creating unsolvable
problems. Should we, or should we not, call all extreme variations that are
deleterious to survival “diseases,” or should we introduce a threshold and/or
standard environmental conditions? If we accept the premise, then disease is
conceptually necessary for trivial reasons. For instance, if we imagine that all
the diseases we know were made impossible in some mutant organism, a new
population of such mutant organisms that present variations in performance
affecting survival would be sufficient to reintroduce disease susceptibility.
Reciprocally, in that view, it is conceptually impossible that a specific, con-
genital disease is universal – indeed, there is always an upper end to the
distribution of any functional trait, except when a radical change in the
environment universally reduces the probability of survival to zero.
Our perspective should be different. Variability in traits contribution to
survival is one of the theoretical premises from which the necessity of disease
derives. However, it would be completely trivial if we took the lower-end tail to
be the defining feature of disease. In any possible world where there is variabil-
ity in trait contribution, there would be diseases. We are interested instead in the
natural world where other, more specific and less trivial conditions make
susceptibility to disease a necessary fact and explain the variations of that
susceptibility across species and populations. We should therefore extend our
investigation beyond this premise and its necessary consequence.
4.3 The Fourfold Root of the Natural Necessity

of the Pathological Phenomenon
The investigation of general, common causes of the existence of the patho-
logical phenomenon has been initiated by evolutionary medicine. Evolutionary
medicine is a research program defined as “a growing and central discipline that
applies evolutionary knowledge to the understanding of human biology, both
normal and abnormal. It is an essential science, necessary for a holistic percep-
tion of how health and disease emerge.” (Gluckman et al. 2009). Here, we will
focus on the natural causes that make disease necessary in any, or most, species.
If the pathological phenomenon in any species can be represented as a bush, we
may compare its general causes to the roots. Many contributors have listed these
general causes differently. As an introductory hypothesis to illustrate this
approach to a theory of disease, I propose to reinterpret the original quadriparti-
tion proposed by Williams and Nesse (1991) in their seminal paper. The four
roots of the pathological phenomenon, that is, the causes that make us neces-
sarily vulnerable to diseases, I will propose, can be described under the labels of
“mismatch,” “infection,” “disposability” and “senescence.”
Mismatch is a crucial concept for evolutionary medicine. Because species
evolve and environments change, mismatches between organisms (or genes)
and environments are unavoidable. Most famously, contemporary humans present
maladapted traits selected in the environment of the Pleistocene (i.e., the
Environment of Evolutionary Adaptedness, or EEA, which ended some 12,000
years ago). Yet their environment has massively changed: climatic stability,
changes in nutritional patterns due to the emergence of agriculture, food abun-
dance, sedentary life, social demands, and so on have generated several cases of
mismatch responsible for frequent diseases – typically, metabolic diseases, hyper-
tension, cancers, and so on. Importantly, diseases are necessary because mis-
matches are unavoidable. There is no way organisms can be equally fit in all
possible environments. Adaptation through evolution by natural selection will
take time. Philosophers have clarified this concept of mismatch and insisted on
how sound a theoretical basis it provides to the development of evolutionary
medicine (Bourrat & Griffiths 2021). Importantly, note that the conceptual neces-
sity of a distribution of differential fitness superimposes on the unavoidability of
mismatch. Indeed, even widespread “maladapted” traits such as tooth decay due to
excess sugar intake, blood pressure due to salty diet, and so on are unevenly
distributed in a population. Maladaptedness is therefore a doubly relative concept:
as compared to the average EEA human, and within current human populations.
However, note that a radical mismatch can strike a whole population relatively
evenly through extreme environmental change. Mismatch is the first root of the
pathological phenomenon and the first principle to account for its necessity.
Infection is the second root of the pathological phenomenon and the second cause
that makes disease necessary. Williams and Nesse have insisted on the concept of
“arms race” between host and pathogen, but they have not really addressed
the question of the necessity that there are infectious diseases. A hypothesis is
that infection is made possible by common ancestry of all living organisms.
Consequently, species can hardly be so heterogeneous as to not interact chemically
with one another. They use the same resources and build similar molecules thanks to
largely identical processes – for instance, viruses share RNA or DNA molecules
with mammals and plants. For that reason, molecules built by some species can be
used by others, and processes performed in some can be hijacked by others to the
former’s profit, with the outcome of disease for the latter. In fact, this form of disease
is not necessary in a strong sense, as shown by the possibilities of mutualism or
symbiosis. Yet, as there is reciprocally no necessity of mutualism or symbiosis and
a very high number of occurrences of such chemical competition, an infectious
disease is so likely to occur at some point that it can be considered a necessity in
practice. Moreover, as there are populational variations in responses to infection and
in virulence, the lower-tail view of disease also applies to infectious diseases – some
will be affected, others not enough to be considered sick. Note also that not every
individual is necessarily infected at a given time, but that all can be and thus
a disease can be universal. Although infection can be conceptualized as a specific
form of mismatch, it is a root of its own regarding the necessity of disease.
The third root of the pathological phenomenon can be called disposability.
Indeed, organisms have to face physical and chemical forces of destruction in
general – the evolutionary cause of disease Williams and Nesse call “injuries and
intoxications.” There is no way they could evolve perfect defenses against all
injuries. Not only is this unlikely to be physically feasible, but natural selection
would favor any improvement in individual reproductive value over any
improvement of longevity, in the face of any trade-off between these two traits.
This is the idea of the so-called “disposable soma theory” (Kirkwood & Holliday
1979).7 In a nutshell, an optimal balance is selected, in the variations of a species,
between investing resources in immediate reproduction and investing resources
in individual maintenance and repair that increases lifespan and chances of future
reproduction. The necessity of reproduction and the challenges it faces together
explain that a species must limit repair and maintenance to the strict minimum
7
More specifically, the disposable soma theory claims that senescence is explained by disposabil-
ity. For that reason, it was introduced as a theory of aging. Here, I simply follow Williams and
Nesse, and propose that the disposable soma theory is better understood as the expression of this
third root of the pathological phenomenon than as an explanation of the necessity of aging.
required to ensure reproduction, depending on their vulnerability to their envir-

onment. This necessary fallibility of repair and maintenance partially overlaps
with two forms of mismatch, “developmental” and “physiological mismatch”
(Bourrat & Griffiths 2021). Just like infection, the disposability of individual
organisms can be interpreted as a form of mismatch. However, just like infection,
it is a distinct root of the necessity of disease. Moreover, the conceptual necessity
of a distribution in a population also applies to disposability. That is, individuals
may have different abilities to maintain or repair, or to invest in repair or
maintenance at any stage of their life, or in the face of a specific challenge. In
the end, variable disposability also explains in part how organisms respond to,
and survive, infectious diseases. Indeed, either infection or a response to infection
generally involves tissue destruction.
The fourth root of the necessity of disease is senescence. It is also the only one
not to be universal. Indeed, not all species are senescent. There can be no age-
related diseases in non-senescent species (by definition). Reciprocally, there must
be age-related degradations, dysfunctions, or diseases, in senescent species.
Senescence may have emerged from a form of antagonistic pleiotropy – as
a trait with early beneficial effects on development and reproduction and late
deleterious effects on survival (Williams 1957). “Early” and “late” are defined
relative to the reproductive period of life. A senescent trait is indeed unlikely to
ever produce its late deleterious effect, while its early, favorable effect is readily
selected. During evolution, senescence thus appeared as the side effect of mul-
tiple ways to lower the risk of early death, including of early disease, whatever its
form. Senescence is also yet another form of mismatch, but a specific cause of the
necessity of diseases – the diseases that are commonly called “age-related” (in
relevant species). Moreover, it interacts with both infectability and disposability.
Lastly, the lower-tail conception of disease also applies here. First, variations
in a population of all ages also produce a distribution, which is likely to corres-
pond to the distribution of individuals of that population according to age. More
specifically, the lower tail of the distribution is likely to coincide with the old. In
a longitudinal perspective, all individuals are less functional than they used to be
when they enter old age. Second, in a subpopulation of the old, there is, again,
a distribution – the lower tail of which can be interpreted as that of the diseased.
For these two reasons, the conceptual necessity of disease introduced in the
previous subsection is the source of a classical controversy over whether aging
is a disease. Individuals decline over time and the lower tail of distributions of
traits corresponds to the old or to the worse off of the old, which leads to
interpreting the processes that explain their conditions as diseases.
Figure 4 graphically represents the action of the four roots of the pathological
phenomenon, along with the lower-tail aspect of disease, as they are traditionally
Figure 4 Represents how the various evolutionary answers to the question: “why
are there diseases?” (a) Changes in genes or environment (arrows) affect the level
of dysfunctional traits. When more frequent, mismatch ensues. (b) Hosts and
parasites necessarily compete for resources, which leads to host infectability. With
changes of the balance, selective pressure increases alternatively on one or the
other, representing the “arms race” of the “red queen hypothesis.” (c) Disposability
is the fact that replicated proteins at generation qi are not identical to proteins at
generation qi–1 resulting in a loss of accuracy. This is necessary because an increase
in accuracy is useless for reproduction (after Kirkwood 1977). (d) Senescent traits,
that is, with late onset deleterious effects, cannot be eliminated due to the decrease
of selective pressure at the time in life when they appear – the “selection shadow.”
(e) With time and circumstances, distribution of levels of performance may change
(from t0 to either t1 or t'1), but there always is a Gaussian distribution.
represented in the scientific literature. However, there is still some way to go

toward a theory of the pathological phenomenon. I have sketched how these roots
may intermingle into the production of some of the properties of the pathological
phenomenon. This is enough to substantiate the idea of a theory explaining why
diseases are necessary.
The next question is that of a unified theory of disease. Figure 5 represents
three possibilities. The “one trunk” theory of disease (Figure 5, top) suggests
that all the roots of the pathological phenomenon combine into one process from
which all types of diseases branch out. This strong claim would undoubtedly
establish the unity of the phenomenon and justify the idea that there is one
theory of disease. The “few offshoots” theory of disease (Figure 5, middle) is
that a limited number of combinations of the four roots explain why the diseases
that we know exist. It is still compatible with the claim that there is one theory of
disease, provided that the combinations are not too many. Finally, the “many
offshoots” theory of disease (Figure 5, bottom) is the least favorable to the
existence of one theory of disease. According to this theory, the causes of the
necessity of disease do not account for their variety in any significant way.
4.4 The Idea of Disease Profiles

Why there is disease at all, is not the only question we can profitably ask
a theory of disease to answer. We can also ask more specific questions, such
as why certain diseases are more or less frequent in a given population.
Indeed, populations, human or otherwise, have specific “disease profiles,”
that is, a pattern of diseases with their prevalence, incidence, average age of
onset, lethality, and so on. Such a disease profile also characterizes a space of the
possible states of disease, and likely trajectories in this space, for individuals in
the population. Obviously, the distribution of the various diseases is not ran-
dom, that is, they are not equally frequent. Some underlying causes must
produce patterns with a certain degree of necessity, notwithstanding a certain
variety of disease profiles.
Let’s take a specific example. Aging is a major determinant of the distribution
of diseases in senescent species (as is obvious in Figure 6b in the case of
humans). Physiological reasons would explain why the same age-related dis-
eases may not strike all species in the same proportions in protected environ-
ments. While infectious diseases kill more individuals in aged populations than
in the young, the proportion of death by infections remains surprisingly constant
after the first year of life (see Figure 6a). These are some of the causes of the
disease profile of a population. A disease profile has also specific, necessary
consequences. In human populations, what is called the “burden of disease”
Figure 5 Three versions of the roots of disease, (a) with a universalized disease
theory (“one trunk theory”), (b) with several disease theories (“few offshoots
theory”), and (c) with no general disease theory but many specific disease
theories (“many offshoots theory”).
measures some of them. Whereas the risk of a disease for a given age is
a probability measured by incidence, the burden of disease for a given age
takes incidence, prevalence, fatality, impairment, and social and economic costs
into account. It can be estimated for a specific disease – say cancer (Thun et al.
2018) – or all diseases. Finally, a disease profile is also characterized by
Figure 6 Death by disease in the E.U. between 2011 and 2017. (a) Proportion of
causes of death according to age, (b) frequency of causes of death according to age
01 All extrinsic causes of death; 02 Other symptoms, signs and abnormal
clinical and laboratory findings (remainder of R00-R99; 03 Ill-defined and
unknown causes of mortality; 04 Sudden infant death syndrome; 05 Symptoms,
signs and abnormal clinical and laboratory findings, not elsewhere classified
(R00-R99); 06 Congenital malformations, deformations and chromosomal
abnormalities (Q00-Q99); 07 Certain conditions originating in the perinatal
period (P00-P96); 08 Pregnancy, childbirth and the puerperium (O00-O99); 09
Diseases of the genitourinary system (N00-N99); 10 Diseases of the
musculoskeletal system and connective tissue (M00-M99); 11 Diseases of the
skin and subcutaneous tissue (L00-L99); 12 Diseases of the digestive system
(K00-K93); 13 Non-infectious respiratory; 14 Ischaemic heart diseases;
15 Diseases of the circulatory system (I00-I99); 16 Diseases of the nervous
system and the sense organs (G00-H95); 17 Mental and behavioural disorders
(F00-F99); 18 Endocrine, nutritional and metabolic diseases (E00-E90);
19 Diseases of the blood and blood-forming organs and certain disorders
involving the immune mechanism; 20 Non-malignant neoplasms
complex interactions between the various diseases that strike a population in

a given time and place – what the historian of medicine Mirko Grmek called
“pathocenose” (Grmek 1969).
Aging explains important properties of the disease profile of senescent species
(see Figure 6b again). Biodemography is the biological investigation of the
demography of human longevity as compared to longevity in other species (for
a survey of the field, see Wachter 2008). It studies the patterns and causes of death
in a population. Biodemography has been built around the Gompertz-Makeham
model of mortality (Olshansky 2010). According to this model, mortality is
explained by the combination of two factors: extrinsic and intrinsic causes of
death. Extrinsic causes of death are contingent and environmental. They group
factors such as predation, hunger, thirst, poisoning, or injuries. Their incidence
does not depend on age, at least in adult life. Intrinsic causes of death are necessary
and organismal. They comprise aging and diseases.8 The incidence of intrinsic
causes of death tends to increase exponentially with age in a senescent population.
This makes disease a necessary cause of death in two different senses. In both non-
senescent and senescent species, it is necessary by chance that individuals die from
a disease in the long run (as a face will sooner or later obtain in an infinite series of
rolls of the dice). In senescent species alone, as humans are, disease is a necessary
cause of death simpliciter, that is, it determines, independently of circumstances,
a maximum lifespan of the species.
A major effect of diseases in human populations is indeed death. While envir-
onmental mismatch, infectious diseases, injuries and intoxication are major killers
in most species, including senescent species, age-related diseases have become the
major cause of death in human populations of developed countries. In fact, the
three other causes of death are extrinsic and highly controllable; aging is not – or
not as easily. Moreover, remarkably few diseases kill the aged in such populations
(see Figure 6a). There may be a necessity that, in a shielded environment, most
humans die from neoplasm, arterial lesions, or infections of the upper respiratory
tract; some inbred strains of lab mice also die particularly frequently of neoplasm
(Szymanska et al. 2014).
Caption for Figure 6 (cont.)

(benign and uncertain); 21 Neoplasms; 22 Infectious respiratory;
23 Certain infectious and parasitic diseases (A00-B99)
(Source: Eurostat. Design by Peppina Zimmermann).
8
Biodemography considers infection as an intrinsic cause of death, but the cause of infection as
environmental. On the other hand, it does not consider poisoning or injuries as the trigger of an
intrinsic cause of death.
4.5 A Shorthand Recapitulation on Disease

It may be useful to summarize the synoptic view of disease we have sketched in
this section and put it into some perspective.
(1) Disease is a necessary, not contingent, cause of limitation of the longevity

of all living beings. It results from natural selection. In non-senescent
species, this limitation is extrinsic but will necessarily happen in the long
run under one form or another, for example, due to environmental mis-
match, infection, or imperfect repair. In senescent species, an additional,
intrinsic cause of limitation to longevity is aging. It makes disease physio-
logically necessary in these species. These four roots of disease are inde-
pendent, but as factors, they combine and, generally, potentialize one
another. In principle, all diseases should stem from (at least one of) these
four roots (see Figure 5).
(2) The question of one theory of disease is whether these four roots join into
a single trunk before they branch into specific diseases, combine into
a limited number of trunks, thus giving few types of diseases, or produce
an indefinite number of trunks, mostly indifferently to how the necessity of
disease is accounted for.
(3) The high diversity of diseases in a population should not hide the regularity
necessitated by deep causes common to all diseases. Aging is one obvious
cause of such regularity. It explains that the incidence of diseases, and the
incidence of lethal diseases, increases exponentially with time. It combines
with disposability to produce “age-related diseases.” It also casts light on
the difference between easily controllable diseases – mainly, due to extrin-
sic causes – and uncontrollable diseases – due to intrinsic causes. This
difference explains the so-called epidemiological transition (from acute to
chronic disease as the main cause of death in human populations).
(4) Disease is also the conceptually necessary result of the existence of vari-
ability in functional traits. Variability is an important and almost universal
factor of disease. Some propose that the least functional variations are
always defined as diseases, and no matter how highly functional a species
may become, it will always be composed of a lower tail of less functional
individuals. Others require an additional condition to restrict this lower-tail
conception to some phenomena only.
This sketch should not be taken as a hypothetical definition to be proven right

or wrong by cases traditionally considered to be “diseases.” Rather, it may
prove a starting point for theorizing about the pathological phenomenon in all its
generality and in its necessity.
5 Toward a Theory of Physiological Health

If you go to a doctor for a check up, and the doctor says you are healthy, what they
generally mean is that you simply have no disease they can detect. In this sense, it
seems that “health” does not really refer to some present property, process, or
thing, but to the absence of many – diseases that you do not have. A common and
apparently reasonable interpretation is thus to assume that if diseases are certainly
an object of physiological science, health is not. “Strictly speaking, there is no
science of health” (Canguilhem 1991). Many doctors would admit that they know
what diabetes or cancer is, but not what health is. However, health itself surely is
a natural fact as well, and not only a concept. First, health is the functioning of the
body when there is no disease, or it is related to a certain subset of these functions.
Second, health is what you want to improve through diet and physical activity.
Moreover, you may want to improve specific aspects of your health. If you run
long distance, you may want to improve your maximum oxygen consumption,
which in turn should reflect your endurance, as it depends on your cardiovascular
health. If you practice rugby, you may want to increase your muscle mass. In the
former case, you will also want to lose weight to the level compatible with your
best speed, while in the latter case, you may prioritize a gain of weight compatible
with a sufficient level of speed. These are different forms that health can take.
Each state we may want to reach relies on physiological interdependencies that
can be investigated and make them realizable or not, with a certain number of
short-term and long-term consequences we may also want to know. In investigat-
ing these interdependencies and consequences, we are investigating health itself.
In all its generality, health is about how organisms breathe, digest, perceive,
move, and grow. Even with a disease, health is present in an organism. This is
the object of physiology. In a narrower sense, your health is only a subset of
physiological capacities – namely, your capacity to maintain, preserve, restore all
physiological capacities, as it is supported by specific mechanisms.
In this section, we investigate physiology – now, as the science of health. We
should expect it to be very different from the concept of health central to other
disciplines such as population health and public health. Philosophers have already
proposed multiple explications of this population concept of health: the “welfare
theory of health” (Nordenfelt 1995), the capability conception of health
(Whitbeck 1981; Venkatapuram 2013), conative theories of health (Raibley
2013) or life course theory (Valles 2018). Such conceptions may be involved in
important questions in public health (Kershnar 2016) and are crucial in the
interpretation of various measurements in population health (Hausman 2012). In
this section, we want to examine a different concept of health than public/
population health, namely: physiological health (Ayres 2020). I first distinguish
health as normal physiology from dedicated functions intended to restore it when

it is challenged (5.1), then investigate them in turn as what I respectively call
“material homeostasis” (5.2) and “mechanisms” of health (5.3). The last three
subsections introduce vexed conceptual questions for scientists: the variability of
health (5.4), the limits of the concept of homeostasis (5.5), and the relationship
between health and the evolutionary concept of fitness (5.6).
5.1 The Two Objects of a Physiological Science of Health

What is physiological health?
A first, natural interpretation is that “health” refers to the normal functioning of
organisms, which is the primary object of physiology. So far, we have focused on
pathophysiology, which is a part of physiology (in the broad sense). The physio-
logical science of normal functions is often called “physiology” (in a stricter
sense), and, rarely, “normophysiology.” In fact, scientists sometimes say that
a process is “physiological” to emphasize that it is healthy or normal or, at least,
not pathological.9 In this general sense, “health” is how organisms survive and,
maybe, reproduce. Physiology (in the strict sense) is the science of breathing and
digesting, of moving and perceiving, and so on; the science of what epithelia in the
lungs and stomach, the muscular tissue and the sensory and motor nerves, and so
on, do; the science of what the cells that constitute these tissues, organs and
systems, contribute.
Following that interpretation, many have considered that, just as in medical
practice, “health” simply refers to the privation of disease. In physiology,
“disease” becomes the privation of health. More specifically, you can infer
that someone is probably healthy from the absence of any detectable disease,
but you must determine what the normal physiology should be if you want to
define a process as pathophysiological. Based on that observation, an appar-
ently sound inference is that the two concepts are complementary and per-
fectly reversible. Yet this is inaccurate, as several philosophers have noted
(Whitbeck 1981; Nordenfelt 1995; Lemoine 2009). Surely, it is difficult to
think of one physiological function for which there is no known corresponding
dysfunction, so that our knowledge of functions seems to be implied in our
knowledge of dysfunctions. Moreover, it is true that, in theory, any function
can fail. However, the science of health and the science of disease are to some
extent independent. First, there are many non-pathological variations in
“health” in this broad sense that we seek to understand – sports physiology,
9
More specifically, “physiology” both refers to a method of explanation and to an object of
scientific investigation, that is, the biological phenomena that can be healthy or pathological
(Lemoine & Pradeu 2018).
which studies how and why some run faster or longer than others without the
latter having diseases, for instance, is a good example of a part of the science
of physiological health that has no pathophysiological counterpart. Second,
there are many possible dysfunctions for the same normal function (e.g., there
can be several causes for why a patient cannot move a finger), so that knowing
normal function will not be sufficient to deduce any knowledge of dysfunc-
tions. Even more specifically, a pathophysiological process has its own course
which is not strictly determined by, and could therefore not have been pre-
dicted from, the normal physiology of the organism (Nervi 2010): for
instance, cancer development has its own logic (if any “logic” at all) that is,
precisely, no more contained in the normal functioning of the tissue, than you
could deduce that something is shifting from red to blue from the fact that it is
“not white.” Finally, it makes sense, and is certainly useful, to consider that
health and disease may both be found in the same organism at the same time,
even if they antagonize one another: “a high degree of health is compatible
with some degree of disease, injury and impairments” (Whitbeck 1981).
More recently, a different interpretation of “health” has emerged in physio-
logical science (Ayres 2020; López-Otín & Kroemer 2021). As opposed to the
whole functioning of organisms, “health” may refer to a specific subset of
adaptive capacities – intuitively, the capacities to recover, repair, regenerate,
and self-maintain. During most of their life, humans have imperfect repair
mechanisms (e.g., leaving scars in wounded tissues) and no regeneration
mechanisms (they do not grow limbs back). Having no bauplan, sponges
can alternatively regenerate a damaged area or grow in some other direction.
Planarians can and will regenerate entirely from a small subset of cells. This is
one way these different metazoans actively maintain their health. Why do
humans maintain theirs differently? For instance, why can skin cells of
placental animals efficiently repair some DNA damage but not UVA damage
to pyrimidine while other animals, plants and fungi use photolyase to that end
(Miles et al. 2020)? These are questions about health in this stricter sense. In
this sense, health is an even more independent object from disease than in the
broader sense: it is a specific subset of mechanisms, whose function is
precisely to deal with diseases and injuries. “The evolved mechanisms of
health are distinct from disease pathogenesis mechanisms,” notes Ayres, so
that we should “develop an understanding of the biology of physiological
health” (Ayres 2020). In this sense again, there can even be “diseases of
health,” that is, dysfunctions of the mechanisms of health (e.g., the inability
to repair UV damage or to form a scar).
5.2 Homeostasis
“Homeostasis” is the technical translation of the vernacular concept of health,
both in the broad and in the narrow sense, as defined earlier – a physiological
reconstruction of “health.”10 A simple example of homeostasis is the regulation
of body temperature. Some animals, called “homeotherms,” have mechanisms
to actively regulate their body temperature so that it is maintained within
a certain range, increased when it is cold outside (e.g., by shivering), decreased
when it is hot (e.g., by sweating): this balance is called “homeostatic.” This
captures the broad sense of “health” because all functions are maintained by
some sort of homeostasis, and the narrow sense because all the mechanisms of
health just defined actively produce a form of homeostasis.
“Homeostasis” is also understood in two senses: formal and material. In the
formal sense developed in cybernetics (Wiener 1948; Bertalanffy 1969), the term
refers to any type of process where a feedback loop actively intervenes to restore
a given variable to a given range of values (a thermostat, climate, and many more
systems, living or not, are homeostatic in that sense). In the material sense,
“homeostasis” refers to one specific, optimized balance an organism can sup-
posedly remain in indefinitely, which includes defined processes and a precise
range of quantitative values. The science of material homeostasis is the science of
the specific ways organisms have evolved homeostasis, related to precise vari-
ables, and certain effects – from how cells maintain the level of proteins they need
(“proteostasis”) or their pH, to how ecosystems regulate populations.
In the formal sense, it is easy to define and detect homeostasis. In fact, it is so
easy that characterizing a system as “homeostatic” does not say much. Surely,
health is homeostatic, but so are many pathological conditions as well, such as
metabolic syndrome, cancer, but also hypertension and hypothyroidism. These
pathological states keep their own balance. In the last two examples, the range
of base values and the boundaries that serve as reference – of blood pressure and
thyroid hormones respectively – is simply shifted to the right.
In the material sense, homeostasis in an organism is one complex, multidimen-
sional balance that encompasses a range of coordinated states of the various
components of the organism at any level. By definition, these states exclude
pathological states that are homeostatic in the formal sense, like metabolic
syndrome, hypertension, hypothyroidism, and cancer, because they will disrupt
material homeostasis sooner or later (or at some level). In the material sense,
10
Boorse has left the meaning and role of homeostasis unclear in his account of health and disease,
first rejecting it somewhat surprisingly (Boorse 1977), then acknowledging its importance and
claiming that it was implicit in his account (Boorse 1997). An explication of Boorse’s biostatis-
tical theory of health and disease in terms of homeostasis has been proposed (Dussault & Gagné-
Julien 2015).
homeostasis is difficult to define and detect (and may not even exist). A complete
description would require that the whole of physiology is integrated.11 In fact,
hypothesizing that a number of processes and values are a part of homeostasis in
that sense is crucial to medicine. Think of the use made of “homeostasis” in
intensive care, which involves a limited list of vital signs (O2 saturation, heart
rate, blood pressure, temperature, calcium level, etc.). It is a reasonable hypoth-
esis that when values of these vital signs are controlled, the patient is “stable” and
will survive. However, any doctor knows that this hypothesis is a simplification,
as many more unknown determinants can defeat the prediction. One of the results
of progress in medical science is to provide a still more comprehensive and
predictive description of homeostasis.
It is the material sense, not the formal sense of homeostasis, that explains why
humans can survive circumstance X but not circumstance Y, how long they live,
why some can perform certain functions at such a level while others cannot, and
why the phenomenon of disease impairs various abilities.
One major difference between the formal and the material sense of homeo-
stasis, is that while in the formal sense, any balanced or self-regulated subsys-
tem of an organism can be properly called homeostatic in itself, in the material
sense, this subsystem may only participate in homeostasis – or not. A striking
illustration is when the same variables are balanced differently in different
subsystems of the same organism. Tissue homeostasis in the liver involves the
same actors and processes as tissue homeostasis in the epidermis, muscle,
bone marrow, or epithelium of the gut: stem cells, differentiated cells, apop-
tosis, proliferation, senescence, and inflammation, to mention a few. Yet in
each of these systems, the balance is different, with different effects, for
example, on the rate of cell renewal. While inflammation is generally not
a constant component of homeostasis in most organs, it is constantly partici-
pating in it in the liver or the gut. While the formal sense would hardly help
determine whether cell renewal is too quick or inflammation too high in
a system that is homeostatic all the same, the material sense will determine
how the same components should behave homeostatically in different tissues.
Moreover, physiology in general, and medicine in particular, would be
deprived of a major concept if it could not determine what the contribution
of one system can be to homeostasis and thereby how long a regime of life can
last with what consequences.
11
One possible complete material description is: growth and development, macro-/micronutrient
and vitamin regulation, socialization, thermoregulation, energy balance – appetite, energy
balance – body composition, detoxification, osmoregulation, acid–base balance, and oxygen-
ation (Ayres 2020).
5.3 Mechanisms of Health

The two articles mentioned earlier (5.1) converge in trying to push the science
of homeostasis further by detailing what the mechanisms of health are. That
said, their scope is different. López-Otín and Kroemer have the broadest view
on the mechanisms of health while Ayres goes further in the direction of
theorizing them.
Ayres’ proposal is not a full-fledged theory of health but consists in theoret-
ical distinctions that are preparing such a theory. She introduces the theorization
with the striking results of an experiment her team carried out: when healthy,
genetically identical rodents are faced with the challenge of a dose of the
pathogen C. rodentium sufficient to kill half of them stochastically, the half
that shows no sign of disease and survives has the same high pathogen burden as
the half that is deteriorating and eventually dies. To fully understand this, she
introduces this notion of health mechanisms as distinct from disease mechan-
isms. What explains the difference in survival must be a difference in the health
mechanisms. More generally, she proposes to distinguish two broad types of
mechanisms of health. On the one hand, defensive health mechanisms, that are
active only against a challenge, and on the other hand, homeostatic health
mechanisms, that are always active. In the experiment earlier, both may explain
the difference, but defensive health mechanisms are more likely to explain it.
These defensive mechanisms in turn either antagonize or withstand insults.
They antagonize insults by avoidance – a behavioral mechanism to stay away
from, say, a pathogen – or resistance – a mechanism to eradicate a pathogen
once infected. Neither explains what happened in the experiment. Defensive
mechanisms withstand insults by tolerance – compensating for the effects of the
disease – or neutralization – for instance, detoxifying by purifying the blood
from the toxin produced by a pathogen (but not the pathogen itself). Either one
or the other must have happened in this experiment. These mechanisms of
defensive health either produce maintenance – the level of health remaining
the same throughout the challenge – or resilience – the capacity to recover
health after the challenge has impaired it. In turn, homeostatic mechanisms
include homeostatic control mechanisms – mechanisms that actively restore an
intrinsic variable (e.g., heart rate or blood pressure) – and homeostatic tolerance
mechanisms – mechanisms that compensate for the failure to maintain or restore
the normal value of an intrinsic variable. Homeostatic mechanisms have the
effect of promoting vigor (health under normal unchallenged conditions) and
apparent vigor, that is, vigor maintained at the cost of some other detrimental
change, for example, cardiac hypertrophy is the enlargement of the heart that
may happen to maintain cardiac output when compensating for high blood
pressure, with lethal long-term consequences. Note also that these homeostatic
mechanisms participate in homeostasis but are not homeostasis itself – namely,
a general mechanism of balance that is, in physiology, the naturalized version of
“health,” in the broader sense of normal functioning just explained.
López-Otín and Kroemer distinguish three families of “stigmata” of health:
spatial compartmentalization, maintenance of homeostasis over time, and adequate
responses to stress. Spatial compartmentalization contains both the integrity of
barriers at all levels of the organism (think of the membrane of the nucleus within
our cells, of the cell membrane, of an epithelium consisting in tightly jointed cells,
of the blood vessels, the skin, etc.) and the containment of perturbations, that is,
active processes that antagonize the spread of a harmful process (the formation of
a cyst, the destruction of an infected cell, the formation of a scar, etc.). Maintenance
of homeostasis over time consists in mechanisms of recycling and turnover (as most
of the components of a part of the organism need to be replaced at some point),
integration of circuitry (as systems must communicate within the organism) and
rhythmic oscillations (many processes must keep a regular pattern – think of the
alternance of wake and sleep). Finally, responses to stress contain repair and
regeneration, hormetic regulation – hormesis is usually defined as the prop-
erty of improving through exposure to limited stress – and homeostatic
resilience. These distinctions come as an open list where Ayres’ distinctions
look more systematic and exhaustive. However, Ayres’ distinctions are some-
what dependent on the specific context of immunology, and it is not always
clear how other mechanisms would fit into her classification. In contrast,
López-Otín and Kroemer give very diverse examples from different fields
and at all levels of organization. Either paper illustrates how vast and rich
a science of physiological health in this narrow sense can be. Their approach
also emphasizes that health can be considered an evolved (complex) trait, not
just a label that summarizes all the physiology of normal functions.
5.4 Does Homeostasis Capture the Variability of Health?

As you may know from your own experience, blood pressure, heart rate, and
sweating must generally increase to sustain physical effort. During pregnancy
as well, or sleep, or digestion, or exposure to cold weather, and so on, a whole
range of variables are maintained within different boundaries than the usual
values. You may think that your health is unlikely to be one perfect and ideally
invariable balance. Certainly, these are all homeostatic in the formal sense, but
the material sense of homeostasis seems to grossly contrast one ideal state with
all other possible states, without accommodating for individual specificities,
degrees, multiplicity, or adaptability. In this sense, homeostasis may be, at best,
a pragmatic simplification for clinical use – useless or maybe misleading for the
researcher.
First, it is important to correctly understand why medical scientists favor the
hypothesis that health corresponds mostly to one homeostatic state. Indeed, it is
not because of some conceptual presupposition, but because of strong factual
causes that restrain variability. Some think that we take the most frequently
observed form of homeostasis, with all its statistically normal values, to define
health because it is frequent. In this view, health is stipulated as the most frequent
state, which is probably not always beneficial to individuals – what if some are
better off with different values than the average, because of some idiosyncrasies?
Some think that medical doctors or scientists presuppose that all individuals
should have the same blood pressure, level of blood sugar, and so on, because
of their concept of health as “statistical normality.” This is wrong, as many have
noted since Canguilhem. The truth is that there are strong constraints on what
material homeostasis can be and how much it can vary. There are so many nested
and interlocking systems in an organism that the constraints they put on one
another perhaps do not leave so many different possibilities for the organism to
survive optimally. The statistical consequence is frequency. Conversely, display-
ing the most frequent form of balance as compared to a population, that is,
conformity to a statistical standard of homeostasis, is generally a reliable sign
that an organism is healthy. However, material homeostasis is not defined as
normal because it is frequent, but because the complexity of homeostasis in any
organism of the same species does leave some, but not much, room for variability.
For this reason, it is often safe to extrapolate from the values generally seen in
healthy individuals to the values that correspond to what health should be in one
deviant individual. For instance, the level of homeostatic blood pressure can be
constitutively higher in an individual, say, due to idiosyncratic variations in the
rate of secretion of angiotensin. It is likely that this is a threat to long-term
homeostasis because it is unlikely that other idiosyncratic variations counterbal-
ance the risk associated with higher blood pressure. Yet statistically normal values
only play a heuristic role in hypothesizing risk: durability of homeostatic state,
not statistical deviation, is the reason why the corresponding states are deemed
less healthy. Finally, it is important to emphasize that the many constraints on
material homeostasis do not make individual variability impossible, but likely to
be very limited.
Second, material homeostasis also explains the variability in the degrees of
health – far from denying that there are such degrees. Indeed, typical organisms
of a given species necessarily achieve homeostasis to a certain degree, if they
live. They are healthy insofar as they self-maintain, no matter for how many
cycles and at what cost to perform them. However, they can be more or less
healthy, depending on how long and how robustly they achieve homeostasis.
Note that in principle, predictions could be made about the longevity, resistance,
and so on, of individual organisms based simply on a thorough understanding of
their homeostasis, that is, without any statistical extrapolation from observa-
tions on other organisms of the same constitution. For instance, knowing what
the formula is for ideal blood pressure to maximize longevity, one could
calculate ideal blood pressure for a specific organism with its variations. In
other terms, beyond the statistical, heuristic simplification of health, the notion
of homeostasis is useful precisely because it can be realized multiply in different
organisms (or even in the same organism). Without this notion of homeostasis,
differences in performance or longevity would be attributed to the variation of
traits rather than to the balance they form together.
Third, there is no presupposition that homeostatic states of an organism should
be perfect, or that they all have the same consequences. Indeed, homeostasis
seems to imply “integration,” that is, coordination of different interlocking
systems in the same organism, at the same level or at different levels. An
important question is about two (or more) interlocking systems that alternatively
balance values so that homeostasis of one disrupts homeostasis of the other.
Examples are the suspension of digestion during physical exertion – a fact you
are familiar with if you are a long distance runner of the Médoc marathon in
France, proposed to drink wine at every stop and eat 12 oysters at kilometer 40 –
but also the fact that stress produces immunosuppression, explaining why you are
more vulnerable to infection, or the fact that muscular exhaustion happens before
fainting due to the priority of the brain over any other part of the organism to
receive available glucose from the blood. To be maintained and balanced as such,
physical exertion, stress and the activity of the brain require conditions that
disrupt other systems. If normal, this situation seems to challenge the material
conception of homeostasis and make it a useless abstraction. Indeed, either such
a situation is healthy because normal, but not homeostatic, or it is unhealthy
because not homeostatic, but normal. In fact, the correct interpretation is not that
this is a limitation to the explication of health in terms of homeostasis, but
a limitation of health itself due to the constraints of homeostasis. In some cases,
an equilibrium results from competition between systems, all of which will
function at a suboptimal level. In other cases, one system takes priority over the
others. In all cases, trade-offs are involved, which concretely limit what an
organism can do or can stand. Health is not ambiguous but limited because an
organism cannot do X and Y at the same time – homeostasis even explains why
that is. The normal situation when two systems cannot function optimally at the
same time is a limitation of health and the requirements of homeostasis in both
systems, and in the system they together form, explain why they cannot.
A qualified notion of homeostasis is even necessary for the researcher to bear in

mind that the system they study is never isolated from the rest of the organism.
It is useful to emphasize one last difference between the material and the
formal sense of homeostasis regarding nested levels of homeostatic processes.
Homeostasis can indeed be described at various levels. Let us keep in mind
here that in the material sense, a “homeostatic” subsystem (cell, tissue, organ,
etc.) is a subsystem that participates in homeostasis of the organism. As an
example, the size of an adult human organism is regulated by simultaneous,
antagonistic processes of growth and destruction (Yu et al. 2015). This relies
on the homeostatic regulation of the size of organs which, in turn, depend on
“tissue homeostasis,” including the regulation of the number of cells in
a tissue. In some tissues, this relies on cell quiescence, that is, a state of
balance between growth/proliferation and senescence/apoptosis. Growth and
proliferation are under the control of several pathways, one of which is the
Hippo pathway, which contains a self-regulatory, negative feedback loop
between proteins called YAP/TAZ and LATS1/2. All these processes are
homeostatic in some sense. At any of these levels, homeostasis supposedly
captures the “health” of the corresponding entity. In many cases, disease is
understood as involving a disruption of homeostasis at a given level and,
consequently, at higher levels. Typically, the overexpression of liver-specific
YAP/TAZ in genetically modified mice leads to a dramatically oversized liver.
Conversely, so many diseases have roots in the disruption of cell homeostasis
that when a given disease is described as a disruption of homeostasis at a given
level, the causes are often investigated in the disruption of homeostasis at the
lowest level inside of cells. Thus, in many forms of cancer, YAP/TAZ is found
to be overexpressed.
However, a conception of fully nested homeostasis in health and of perfect
correspondence, at a given level, between a healthy component and homeo-
stasis in that component is misleading, yet frequently assumed.12 First,
homeostasis at a given level may occur without any significant condition in
homeostasis at a lower level and disruption of homeostasis at a given level
may not depend on disruption of homeostasis at a lower level. For instance, the
regulation of blood pressure indeed depends on the number of cells in the
blood (among other things), but it is largely independent from many intracel-
lular mechanisms in blood cells. Besides, many causes of its disruption, like
12
An example is: “The control of each of these variables is dependent on homeostatic control
mechanisms that operate at each level (molecular, cellular, tissue, organ, physiological), each
contributing to homeostasis at the next level that ultimately translates to vigor at the organismal
level” (Ayres 2020).
hemorrhage, do not originate in the disruption of intracellular homeostasis.

Second, and more importantly, some forms of homeostasis at a lower level in
a system contribute to a disruption of homeostasis at a higher level. For
instance, senescent cells are homeostatic in their own way, resisting apoptotic
signaling, being pro-inflammatory, and inducing neighboring cells into senes-
cence as well. Generally, homeostasis at this lower level is not defined as the
“health” of the corresponding component (e.g., the cell) even if there is, for the
cell itself, nothing wrong in the way it works. It is often not even called
“homeostasis.” Finally, some processes are healthy and not homeostatic at
a given level but participate in homeostasis at a higher level. For instance,
apoptosis, one of the forms of programmed cell death, is not homeostatic at the
level of the cell but is an essential part of “tissue homeostasis” in normal adult
tissue. Implicitly, it is then considered that a condition for the health (or even
homeostasis) of a component of the organism at level n is that the way it works
does not disrupt homeostasis at higher levels (in particular, at the level of the
organism). At least four conceptions of health in terms of homeostasis are thus
possible:
(1) health of X at level n requires the homeostasis of X at n,

(2) health of X at level n requires one of the homeostatic states (or processes) of
X at n that guarantee some homeostatic state (or process) at the level of the
organism,
(3) health of X at level n requires a state (or process) of X that guarantees some
homeostatic state (or process) at the level of the organism,
(4) health is the state (or process) that results from homeostasis at all lower
levels.
Conception (1) relies on the formal definition of homeostasis. Conception (4)

wrongly presupposes that health is the balance that results from a series of
nicely nested systems, that are all homeostatic. Only conceptions (2) and (3)
reflect a relevant conception of material homeostasis. The difference between
them depends on whether a component at a level n can be called “healthy” if
a non-homeostatic process at this level contributes to homeostasis at the level
of the organism. Conception (3) is likely to be preferable.
Homeostasis is often understood as an individual organism’s functional state
that can last indefinitely. Subsystems that compose this fictional-functional state
should be called homeostatic not because they self-maintain, but because they
participate in the maintenance of homeostasis. Homeostasis does not necessarily
characterize one possible state of the system against all others. It need not be
perfect, nor do the multiple homeostatic states of an organism necessarily have
the same effects, nor are all the subsystems of the homeostatic state of an
organism necessarily self-maintained.
The material concept of homeostasis describes how, in one organism of
a given species, the various systems are balanced, nested, integrated, all to
a certain, imperfect degree, and with idiosyncratic variations. This set of
mutual constraints is called the state of health. In this important sense, health
does not disappear, but is impaired in disease. Health is necessary for clinical
action. After all, “homeostasis” is less the translation of “health” in physi-
ology, than the explanation of why a certain state should be called “healthy.”
This concept is not dispensable for physiological research. That said, this
subsection should have illustrated how interesting the variations of material
homeostasis are, and what an interesting concept it still is for philosophical
investigation.
5.5 Health beyond Homeostasis

Many have doubted that the health of living organisms is entirely accounted for
by homeostasis. Its focus on the self-maintenance of values within boundaries
accounts for how organisms can stand some environmental changes (e.g.,
thermoregulation and external temperature), but not so obviously how they
adapt by changing the reference point of balance. For instance, under the
influence of fear, awareness is raised above its normal level, and so is readiness
for action – thus shifting the balance of metabolism, neurotransmission, and
immunity. This new balance may, of course, still be called homeostatic. But the
very ability to shift from one balance to another is a part of health. It has been
called “allostasis” (Sterling & Eyer 1988) to insist on the irreducibility of this
ability to obtain homeostasis, while others have rejected the term, claiming that
the notion of homeostasis already captures this very ability (Day 2005). In
a sense, it is not clear that predictive behavioral changes like those induced by
fear are not themselves overriding usual levels of homeostasis to re-establish
some undetermined, priority balance.
Allostasis has been understood in a formal and in a material sense just like
homeostasis. In a formal sense, it is virtually applicable to any homeostatic
system that can, temporarily or permanently, change its reference value in
adaptation to environmental challenges. This is what largely triggers the dispute
about the reducibility of allostasis to homeostasis.
However, the material sense of allostasis has been the most useful to under-
stand the links between behaviors, physiology, mental disorders, health and
disease. A clear definition of allostasis in this sense is “regulatory systems in
which (1) there is no clear set point, (2) there are individual differences in
expression (. . .), (3) the behavioral and physiological responses are anticipatory
(. . .), and (4) there [is] a vulnerability to physiological overload and the break-
down of regulatory capacities” (Schulkin 2012). The last two points are particu-
larly important. The notion of an anticipatory physiological response focuses on
the interlocking of cognitive and physiological processes. Rats build nests when
temperature drops, blood pressure increases in anticipation of action, many
animals overeat in anticipation of fasting. An anticipatory response does not
necessarily involve cognition and can evolve by natural selection (see the
example of the water flea in Matthewson & Griffiths 2017). If we call cognition-
based anticipatory responses “predictive,” we can understand how cognition is
rooted in physiology thanks to the notion of allostasis. This also casts light on
some aspects of mental health, particularly those associated to the risk of so-
called “psychosomatic disorders.” Maladapted behaviors of many sorts take a toll
on physiology through the protraction of allostatic state – a notion dubbed
“allostasis overload” (Korte et al. 2005). Allostasis is a further possibility of
adaptation – in this sense, it is just one additional capacity to preserve homeostasis
in the long run. Allostatic overload refers to its costs. It has been investigated for
itself under the form of a mechanism underpinned by chronically high cortisole-
mia, the epidemiology of which has been studied (McEwen & Seeman 1999), in
association with many diseases and risk factors, some mental, like addiction
(Koob & Le Moal 2001), depression and anxiety disorders (McEwen 2007),
and others physiological, like obesity, hypertension, and Alzheimer’s disease.
Conceptual developments around allostasis may suggest an original concep-
tualization of mental health. Indeed, two models have been mainly discussed:
analogy and integration. By analogy, mental health is the same kind of balanced
state as somatic health, only, at a different level. By integration, mental health is
a necessary part of health together with somatic health. An example of the latter
approach is the biopsychosocial model of health (Bolton & Gillett 2019). With
the allostatic model, understood in a material sense, a material hypothesis,
grounded in evolution, proposes a conception of how cognition emerged as
a mechanism of regulation, but also a view of the necessary trade-offs and risks
involved in such a specific form of regulation.
5.6 Health, Fitness, and Evolution

All these developments give substantial support to the hypothesis that health is,
indeed, a complex evolved trait – which makes it also an object of investigation
for evolutionary biology and philosophy of biology. The investigation of the
biological phenomenon of health in the light of evolution remains marginal in
medical science, but it is an important conceptual question whether this helps
describe basic properties of health. Similar to what was done for disease, let us
ask why has health evolved and sketch some conceptual questions raised by
evolutionary medicine about health.
At first, it may seem difficult to make a distinction between “health” and the
evolutionary concepts of “fitness” or “adaptation.” However, “a common
misconception is that health and fitness are interchangeable, which is not the
case” (Ayres 2020). For instance, in the technical, genetic sense of “fitness” –
reproductive success as measured by the increase of the frequency of a gene in
a population – health is only one of its components, along with mating success
and kin’s reproductive success (Stearns & Koella 2008). Also, some physi-
ologists have insisted on homeostasis being a major factor of evolution by
natural selection (Turner 2010). To begin with, it is a major constraint on
potential mutations – they must certainly make homeostasis evolve in
a different direction, but they must also make homeostasis possible in the
first place. Another fact is that if health contributes to fitness, it is probably not
infrequent that a mutation improves fitness to increase mating success at the
expense of health. Thus, a crucial question that has emerged in evolutionary
medicine is the study of trade-offs between survival and reproduction but also,
more generally, between abilities. The trade-offs evolutionary medicine has
investigated are not limited to “positive health” as Boorse presented it (Boorse
1977), that is, innate or acquired individual improvements in abilities beyond
the species norm, but they also constitute the species norm of health itself.
“Health is commonly perceived as an idealized goal, one that involves optimal
bodily function. (. . .) evolutionary biology offers an insight: concepts of
health must incorporate the physiological constraints and ranges of plasticity
well documented by the biological community. Those constraints include the
idea of trade-offs” (Stearns & Koella 2008).
One important category of trade-offs opposes lifespan and reproduction. In this
perspective, the opposite of “health” is not “disease” but, more generally, “deg-
radation,” or “aging,” understood in a broad sense as the accumulation of damage
(Sholl 2021). Another category of trade-offs involves stages of development as
they are investigated by life history theory (Gluckman & Hanson 2006a). In this
perspective, “health” consists in a predictive strategy of growth, survival, and
reproduction over the lifetime. For instance, key hormones such as testosterone,
progesterone, estradiol, leptin, and prolactin, are in direct control of these trade-
offs, with major impact on health and disease (Bribiescas & Ellison 2007). A third
category of trade-offs involves abilities that increase the chances of survival in
different environments. Whereas the trade-off between metabolic/muscular func-
tion and immune function is often interpreted as an evolutionary trade-off
between reproduction and survival, on the presumption that reproduction depends
mostly on metabolic and muscular function, it is probably more correct to admit

that muscular function can be involved in survival in some circumstances, as
much as in sexual competition. Testosterone increases sexual attractiveness, but
also metabolic rate in muscle cells by 20 percent in a few seconds.
Here we can only catch a glimpse of the extent of the conceptual questions
raised by the evolution of health in general, and human health more specifically.
Far from being a simple label for a non-entity – the absence of disease – health is
a biological fact that can both be studied by physiology and evolutionary
biology, and theorized. In the end, a useful theory of health for medicine must
be a theory of the various forms of human health, in comparison with other
forms of health in nature.
6 Conclusion
Mostly independently from traditional debates in philosophy of medicine about
the definition of terms like “health” and “disease,” this Element has developed
a philosophical approach to health and disease called the “philosophy of
physiology.” We diagnosed a problem with philosophy of medicine, namely,
a foundationalist approach to these concepts, according to which they are
immune to changes in biological and medical science, and an exclusive focus
on whether judgments that something is healthy or pathological are objective,
leaving untouched an entire set of conceptual problems in how diseases are
scientifically explained.
An alternative approach has indeed revealed a set of largely unexplored
conceptual questions about disease entities, disease theories, the pathological
phenomenon itself, and health. We have emphasized the crucial role of theor-
ization in the explanation of the pathophysiological processes that define
disease entities, the existence of partially competing theories to account for an
open set of diseases, the possibility of a unified approach to the necessity and
universality of the pathological phenomenon, and the existence of an evolved
complex trait of health that is not simply the ens rationis of “not having any
disease.”
Theorization is indeed not marginal in medicine. A narrow focus on the part
of medical science that consists in clinical trials may suggest that medical
science is mostly experimental, pragmatic, and atheoretical. Evidence-based
medicine (EBM) is a powerful research agenda that has emphasized the
importance of establishing clinical facts – typically, does a drug really
work? – and not take the existence of a theory – from which it can be inferred
that a drug should work – for evidence of a clinical fact. Fairly enough,
philosophers of EBM have revealed, emphasized, and discussed the theory
of causality that EBM necessarily requires (Russo & Williamson 2007).

However, other philosophers have insisted on the role of formalized models
of physiological and pathophysiological processes in medical science
(Thompson 2011). Physiology may be considered a field of intensive theor-
ization – specific diseases, disease types, and even the pathological phenom-
enon itself, are the object of frequent attempts of explanation and prediction
through causal formalization of the process(es) that specifically constitutes
them. Physiological theories may be of a special type, as was already sug-
gested a long time ago (Schaffner 1986). One theory may one day explain all
diseases. Either way, these are not premises of philosophy of physiology.
What is is that philosophy of physiology sets itself a different goal from
traditional philosophy of medicine about specific diseases, disease theories
and the concept of disease. In philosophy of medicine, the ultimate goal of the
conceptual work on diseases, disease or health, has always been social and
ethical – in the end, it is about judgments and actions. In philosophy of
physiology, the goal of all conceptual work is to push further our understand-
ing of the natural phenomena of health and diseases. It is about explanations
and predictions of the world of health and disease.
References
Akira, S., Uematsu, S., & Takeuchi, O. (2006). Pathogen recognition and innate
immunity. Cell, 124(4), 783–801.
American Psychiatric Association. (1987). Diagnostic and Statistical Manual
of Mental Disorders: DSM-III-R, Washington, D.C.: American Psychiatric
Assoc.
American Psychiatric Association. (2000). Diagnostic and Statistical Manual of
Mental Disorders, Text Revision (DSM-IV-TR), Washington, D.C.: American
Psychiatric Association.
Ayres, J. S. (2020). The biology of physiological health. Cell, 181, 250–269.
Barker, D. (1986). Infant mortality, childhood nutrition, and ischaemic heart
disease in England and Wales. The Lancet, 327(8489), 1077–1081.
Bateson, P., Barker, D., Clutton-Brock, T. et al. (2004). Developmental plasti-
city and human health. Nature, 430(6998), 419–421.
Becsei-Kilborn, E. (2010). Scientific discovery and scientific reputation: The
reception of Peyton Rous’ discovery of the chicken sarcoma virus. Journal of
the History of Biology, 43(1), 111–157.
Belkaid, Y., & Hand, T. W. (2014). Role of the microbiota in immunity and
inflammation. Cell, 157(1), 121–141.
Bernard-Weil, E. (1999). Pathological homeostasis: Its meaning, its inferences.
Medical Hypotheses, 53(1), 24–31.
Bertalanffy, L. von. (1969). General System Theory: Foundations, Development,
Applications, New York: G. Braziller.
Bolton, D., & Gillett, G. (2019). The Biopsychosocial Model of Health and
Disease: New Philosophical and Scientific Developments, Cham: Springer
International. https://doi.org/10.1007/978-3-030-11899-0.
Boorse, C. (1975). On the distinction between disease and illness. Philosophy
and Public Affairs, 5(1), 49–68.
Boorse, C. (1977). Health as a theoretical concept. Philosophy of Science, 44(4),
542–573.
Boorse, C. (1997). A rebuttal on health. In J. M. Humber & R. F. Almeder, eds.,
What Is Disease? Totowa, NJ: Humana Press, pp. 1–134.
Botstein, D., & Risch, N. (2003). Discovering genotypes underlying human
phenotypes: Past successes for Mendelian disease, future approaches for
complex disease. Nature Genetics, 33(S3), 228–237.
Bourrat, P., & Griffiths, P. E. (2021). The idea of mismatch in evolutionary
medicine. The British Journal for the Philosophy of Science, 716543.
70 References
Bribiescas, R. G., & Ellison, P. T. (2007). How hormones mediate trade-offs in

human health and disease. In S. C. Stearns & J. C. Koella, eds., Evolution in
Health and Disease, New York: Oxford University Press, pp. 77–94.
Bugianesi, E., Gastaldelli, A., Vanni, E. et al. (2005). Insulin resistance in
non-diabetic patients with non-alcoholic fatty liver disease: Sites and mechan-
isms. Diabetologia, 48(4), 634–642.
Campisi, J. (2013). Aging, cellular senescence, and cancer. Annual Review of
Physiology, 75, 685–705.
Canguilhem, G. (1991). The Normal and the Pathological, New edition,
Translated by Carolyn R. Fawcett, New York: Zone Books.
Cannon, W. B. (1929). Organization for physiological homeostasis. Physiological
Reviews, 9(3), 399–431.
Conrad, P. (2007). The Medicalization of Society: On the Transformation of
Human Conditions into Treatable Disorders, 1st ed., Baltimore, MD: Johns
Hopkins University Press.
Cooper, R. (2005). Classifying Madness: A Philosophical Examination of the
Diagnostic and Statistical Manual of Mental Disorders, Dordrecht: Springer.
Cooper, R. (2007). Psychiatry and Philosophy of Science, Stockfield: McGill-
Queen’s University Press.
Cournoyea, M. (2013). Ancestral assumptions and the clinical uncertainty of
evolutionary medicine. Perspectives in Biology and Medicine, 56(1), 36–52.
Craver, C. F. (2009). Mechanisms and natural kinds. Philosophical Psychology,
22(5), 575–594.
Cryan, J. F., O’Riordan, K. J., Cowan, C. S. M. et al. (2019). The microbiota-gut-
brain axis. Physiological Reviews, 99(4), 1877–2013.
Clouser, K. D., Culver, C. M., & Gert, B. (1981). Malady – A new treatment of
disease. Hastings Center Report, 11(3), 29–37. https://doi.org/10.2307/3561321.
Darrason, M. (2013). Unifying diseases from a genetic point of view: The
example of the genetic theory of infectious diseases. Theoretical Medicine
and Bioethics, 34, 327–344.
Day, T. A. (2005). Defining stress as a prelude to mapping its neurocircuitry: No
help from allostasis. Progress in Neuro-Psychopharmacology and Biological
Psychiatry, 29(8), 1195–1200.
de Magalhães, J. P. (2022). Every gene can (and possibly will) be associated
with cancer. Trends in Genetics, 38(3), 216–217.
de Vos, W. M., & de Vos, E. A. (2012). Role of the intestinal microbiome in
health and disease: From correlation to causation. Nutrition Reviews, 70,
S45–S56.
Deanfield, J. E., Halcox, J. P., & Rabelink, T. J. (2007). Endothelial function and
dysfunction: Testing and clinical relevance. Circulation, 115(10), 1285–1295.
References 71
Dussault, A. C., & Gagné-Julien, A.-M. (2015). Health, homeostasis, and the
situation-specificity of normality. Theoretical Medicine and Bioethics, 36(1),
61–81.
Ekbom, A., Adami, H.-O., Trichopoulos, D., Hsieh, C.-C., & Lan, S.-J. (1992).
Evidence of prenatal influences on breast cancer risk. The Lancet, 340(8826),
1015–1018.
Engelhardt, H. T. (1996). The Foundations of Bioethics, New York: Oxford
University Press.
Ereshefsky, M. (2009). Defining “health” and “disease.” Studies in History and
Philosophy of Science Part C: Studies in History and Philosophy of
Biological and Biomedical Sciences, 40(3), 221–227.
Fleming, T., Watkins, A., Velazquez, M. et al. (2018). Origins of lifetime health
around the time of conception: Causes and consequences. The Lancet 391
(10132), 1842–1852. https://doi.org/10.1016/S0140-6736(18)30312-X.
Fodor, J. A. (1974). Special sciences (or: The disunity of science as a working
hypothesis). Synthese, 28(2), 97–115.
Frank, S. A. (1996). Models of parasite virulence. The Quarterly Review of
Biology, 71(1), 37–78.
Fuller, J. (2018). What are chronic diseases? Synthese, 195, 3197–3220.
Galen. (1991). On the Therapeutic Method. (R. J. Hankinson, Trans.). New York:
Oxford University Press.
Giaimo, S., & d’Adda di Fagagna, F. (2012). Is cellular senescence an example
of antagonistic pleiotropy?: Cellular senescence and antagonistic pleiotropy.
Aging Cell, 11(3), 378–383.
Gluckman, P. D., Beedle, A., & Hanson, M. A. (2009). Principles of Evolutionary
Medicine, Oxford: Oxford University Press.
Gluckman, P. D., & Hanson, M. A. (2006a). The developmental origins of
health and disease. In E. M. Wintour & J. A. Owens, eds., Early Life Origins
of Health and Disease, Vol. 573, Boston, MA: Springer, pp. 1–7.
Gluckman, P., & Hanson, M. (Eds.). (2006b). Developmental Origins of Health
and Disease, Cambridge: Cambridge University Press. https://doi.org/
10.1017/CBO9780511544699.
Goel, P. (2015). Insulin resistance or hypersecretion? The βIG picture revisited.
Journal of Theoretical Biology, 384, 131–139.
Greslehner, G. P. (2020). Microbiome structure and function: A new framework
for interpreting data. BioEssays, 42(7), 1900255, 1–8.
Griffiths, P. E., & Matthewson, J. (2016). Evolution, dysfunction, and disease: A
reappraisal. The British Journal for the Philosophy of Science, 69, 301–327.
Grmek, M. (1969). Préliminaires d’une étude historique des maladies. Annales,
24(6), 1473–1483.
72 References
Hajishengallis, G., Darveau, R. P., & Curtis, M. A. (2012). The keystone-pathogen

hypothesis. Nature Reviews Microbiology, 10(10), 717–725.
Hansson, G. K., & Libby, P. (2006). The immune response in atherosclerosis: A
double-edged sword. Nature Reviews Immunology, 6(7), 508–519.
Hausman, D. M. (2011). Is an overdose of paracetamol bad for one’s health?
The British Journal for the Philosophy of Science, 62(3), 657–668.
Hausman, D. M. (2012). Measuring or valuing population health: Some con-
ceptual problems. Public Health Ethics, 5(3), 229–239.
Heikkila, K., Nyberg, S. T., Theorell, T. et al. for the IPD-Work Consortium.
(2013). Work stress and risk of cancer: Meta-analysis of 5700 incident cancer
events in 116 000 European men and women. British Medical Journal, 346
(feb07 1), f165–f165.
Heim, C., Newport, D. J., Mletzko, T., Miller, A. H., & Nemeroff, C. B. (2008).
The link between childhood trauma and depression: Insights from HPA axis
studies in humans. Psychoneuroendocrinology, 33(6), 693–710.
Helzer, J. E., Kraemer, H. C., & Krueger, R. F. (Eds.). (2008). Dimensional
Approaches in Diagnostic Classification: Refining the Research Agenda for
DSM-V. Arlington, VA: American Psychiatric Publishing.
Heneka, M. T., Kummer, M. P., & Latz, E. (2014). Innate immune activation in
neurodegenerative disease. Nature Reviews Immunology, 14(7), 463–477.
Heppner, F. L., Ransohoff, R. M., & Becher, B. (2015). Immune attack: The role
of inflammation in Alzheimer disease. Nature Reviews Neuroscience, 16(6),
358–372.
Hesslow, G. (1984). What is a genetic disease? In L. Nordenfelt & B. I. B. Lindahl,
eds., Health, Disease and Causal Explanation in Medicine, Dordrecht, Holland:
Reidel, pp. 183–193.
Hesslow, G. (1993). Do we need a concept of disease? Theoretical Medicine
and Bioethics, 14(1), 1–14. https://doi.org/10.1007/BF00993984.
Hofmann, B. (2005). Simplified models of the relationship between health and
disease. Theoretical Medicine and Bioethics, 26(5), 355–377.
Honda, K., & Littman, D. R. (2016). The microbiota in adaptive immune
homeostasis and disease. Nature, 535(7610), 75–84.
Hooks, K. B., & O’Malley, M. A. (2017). Dysbiosis and its discontents. mBio,
8(5), mBio.01492–17, e01492–17.
Hucklenbroich, P. (2014). “Disease entity” as the key theoretical concept of
medicine. Journal of Medicine and Philosophy, 39(6), 609–633.
Jucker, M., & Walker, L. C. (2013). Self-propagation of pathogenic protein
aggregates in neurodegenerative diseases. Nature, 501(7465), 45–51.
Kannisto, V. (1991). Frailty and survival. Genus, 47(3/4), 101–118.
References 73
Karatsoreos, I. N., & McEwen, B. S. (2011). Psychobiological allostasis:

Resistance, resilience and vulnerability. Trends in Cognitive Sciences, 15(12),
576–584.
Kendell, R., & Jablensky, A. (2003). Distinguishing between the validity and
utility of psychiatric diagnoses. The American Journal of Psychiatry, 160(1),
4–12.
Kershnar, S. (2016). Quantifying health across populations. Bioethics, 30(6),
451–461.
Keuck, L. K., & Hauswald, R. (2016). Indeterminacy in medical classification:
On continuity, interest-relativity, and vagueness. In K. Geert, L. K. Keuck, &
R. Hauswald, eds., Gradualist Approaches to Mental Health and Disease,
Oxford: Oxford University Press, pp. 93–116.
Kingma, E. (2007). What is it to be healthy? Analysis, 67(294), 128–133.
Kingma, E. (2010). Paracetamol, poison, and polio: Why Boorse’s account of
function fails to distinguish health and disease. British Journal for the
Philosophy of Science, 61(2), 241–264.
Kingma, E. (2016). Situation-specific disease and dispositional function. The
British Journal for the Philosophy of Science, 67(2): 391–404. https://doi
.org/10.1093/bjps/axu041.
Kirkwood, T. (1977). Evolution of aging. Nature, 270(5635), 301–304.
Kirkwood, T. B. L., & Holliday, R. (1979). The evolution of ageing and
longevity. Proceedings of the Royal Society of London. Series B. Biological
Sciences, 205(1161), 531–546.
Koeth, R. A., Wang, Z., Levison, B. S. et al. (2013). Intestinal microbiota
metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis.
Nature Medicine, 19(5), 576–585.
Koob, G. F., & Le Moal, M. (2001). Drug addiction, dysregulation of reward,
and allostasis. Neuropsychopharmacology: Official Publication of the
American College of Neuropsychopharmacology, 24(2), 97–129.
Korte, S. M., Koolhaas, J. M., Wingfield, J. C., & McEwen, B. S. (2005). The
Darwinian concept of stress: Benefits of allostasis and costs of allostatic load
and the trade-offs in health and disease. Neuroscience & Biobehavioral
Reviews, 29(1), 3–38.
Kotas, M. E., & Medzhitov, R. (2015). Homeostasis, inflammation, and disease
susceptibility. Cell, 160(5), 816–827.
Lemoine, M. (2009). The meaning of the opposition between the healthy and the
pathological and its consequences. Medicine, Health Care, and Philosophy,
12(3), 355–362.
74 References
Lemoine, M. (2013). Defining disease beyond conceptual analysis: An analysis

of conceptual analysis in philosophy of medicine. Theoretical Medicine and
Bioethics, 34(4), 309–325.
Lemoine, M. (2014). The naturalization of the concept of disease. In G. Lambert,
M. Silberstein, & P. Huneman, eds., Classification, Disease and Evidence:
New Essays in the Philosophy of Medicine, Amsterdam: Springer, pp. 19–41.
Lemoine, M. (2016). Molecular complexity: Why has psychiatry not been revolu-
tionized by genomics (yet)? In G. Boniolo & M. J. Nathan, eds., Philosophical
Foundations of Molecular Medicine, Dordrecht: Springer, pp. 81–99.
Lemoine, M. (2020). Defining aging. Biology & Philosophy, 35(5), 46.
Lemoine, M., & Giroux, É. (2016). Is Boorse’s biostatistical theory of health
naturalistic? In É. Giroux, ed., Naturalism in the Philosophy of Health, Vol
17, Switzerland: Springer, pp. 19–38.
Lemoine, M., & Pradeu, T. (2018). Dissecting the meanings of “physiology” to
assess the vitality of the discipline. Physiology (Bethesda, Md.), 33(4),
236–245.
Liu, K. E., Love, A. C., & Travisano, M. (2016). How cancer spread:
Reconceptualizing a disease. In G. Boniolo & M. J. Nathan, eds., Philosophy
of Molecular Medicine, New York: Routledge, pp. 100–121.
Lock, M. M. (2013). The Alzheimer conundrum: Entanglements of Dementia
and Aging, Princeton, TX: Princeton University Press.
López-Otín, C., & Kroemer, G. (2021). Hallmarks of health. Cell, 184(1),
33-63. https://doi.org/10.1016/j.cell.2020.11.034.
Loscalzo, J., Kohane, I., & Barabasi, A.-L. (2007). Human disease classification
in the postgenomic era: A complex systems approach to human pathobiology.
Molecular Systems Biology, 3, 1–11.
Lynch, K. E., Parke, E. C., & O’Malley, M. A. (2019). How causal are micro-
biomes? A comparison with the Helicobacter pylori explanation of ulcers.
Biology & Philosophy, 34(6), 62.
Magnus, D. (2004). The concept of genetic disease. In A. L. Caplan, J. J. McCartney,
& D. A. Sisti, eds., Health, Disease and Illness: Concepts in Medicine,
Washington, DC: Georgetown University Press, pp. 233–242.
Maj, M., & Gaebel, W. (2002). Psychiatric Diagnosis and Classification,
Chichester: John Wiley.
Matthews, D. R., Hosker, J. R., Rudenski, A. S. et al. (1985). Homeostasis
model assessment: Insulin resistance and fl-cell function from fasting plasma
glucose and insulin concentrations in man. Diabetologia, 28, 412–419.
Matthewson, J., & Griffiths, P. E. (2017). Biological criteria of disease: Four
ways of going wrong. The Journal of Medicine and Philosophy: A Forum for
Bioethics and Philosophy of Medicine, 42(4), 447–466.
References 75
McEwen, B. S. (2007). Physiology and neurobiology of stress and adaptation:

Central role of the brain. Physiological Reviews, 87(3), 873–904.
McEwen, B. S., Bowles, N. P., Gray, J. D. et al. (2015). Mechanisms of stress in
the brain. Nature Neuroscience, 18(10), 1353–1363.
McEwen, B. S., & Seeman, T. (1999). Protective and damaging effects of
mediators of stress: Elaborating and testing the concepts of allostasis and
allostatic load. Annals of the New York Academy of Sciences, 896(1),
30–47.
Medzhitov, R., Schneider, D. S., & Soares, M. P. (2012). Disease tolerance as
a defense strategy. Science, 335(6071), 936–941.
Méthot, P.-O. (2011). Research traditions and evolutionary explanations in
medicine. Theoretical Medicine and Bioethics, 32(1), 75–90.
Méthot, P.-O., & Alizon, S. (2014). What is a pathogen? Toward a process view
of host-parasite interactions. Virulence, 5(8), 775–785.
Miles, J. A., Davies, T. A., Hayman, R. D. et al. (2020). A case study of
eukaryogenesis: The evolution of photoreception by photolyase/crypto-
chrome proteins. Journal of Molecular Evolution, 88(8–9), 662–673.
Millon, T., Krueger, R. F., & Simonsen, E. (2010). Contemporary Directions in
Psychopathology: Scientific Foundations of the DSM-Vand ICD-11, New York:
Guilford.
Murphy, D., & Woolfolk, R. L. (2000). Conceptual analysis versus scientific
understanding: An assessment of wakefield’s folk psychiatry. Philosophy,
Psychiatry, and Psychology, 7(4), 271–293.
Nervi, M. (2010). Mechanisms, malfunctions and explanation in medicine.
Biology and Philosophy, 25(2), 215–228.
Nesse, R. M. (2001). On the difficulty of defining disease: A Darwinian
perspective. Medicine, Health Care and Philosophy, 4(1), 37–46.
Nordenfelt, L. Y. (1995). On the Nature of Health: An Action-Theoretic
Approach, 2nd ed., Dordrecht: Springer.
Olesen, S. W., & Alm, E. J. (2016). Dysbiosis is not an answer. Nature
Microbiology, 1(12), 1–2, 16228.
Olshansky, S. J. (2010). The law of mortality revisited: Interspecies compari-
sons of mortality. Journal of Comparative Pathology, 142(Suppl 1), S4–S9.
Osborn, O., & Olefsky, J. M. (2012). The cellular and signaling networks
linking the immune system and metabolism in disease. Nature Medicine,
18(3), 363–374.
Pradeu, T., Lemoine, M., Khelfaoui, M., & Gingras, Y. (2024). Philosophy in
science: Can philosophers of science permeate through science and produce
scientific knowledge? The British Journal for the Philosophy of Science, 75
(2), 375–416. https://doi.org/10.1086/715518.
76 References
Qin, J., Li, Y., Cai, Z. et al. (2012). A metagenome-wide association study of gut
microbiota in type 2 diabetes. Nature, 490(7418), 55–60.
Raibley, J. (2013). Health and well-being. Philosophical Studies, 165(2),
469–489.
Reiche, E. M. V., Nunes, S. O. V., & Morimoto, H. K. (2004). Stress, depression,
the immune system, and cancer. The Lancet Oncology, 5(10), 617–625.
Routy, B., Le Chatelier, E., Derosa, L. et al. (2018). Gut microbiome influences
efficacy of PD-1–based immunotherapy against epithelial tumors. Science,
359(6371), 91–97.
Russo, F., & Williamson, J. (2007). Interpreting causality in the health sciences.
International Studies in the Philosophy of Science, 21(2), 157–170.
Sadegh-Zadeh, K. (1999). Fundamentals of clinical methodology: 3. Nosology.
Artificial Intelligence in Medicine, 17(1), 87–108.
Sadegh-Zadeh, K. (2008). A prototype resemblance theory of disease. Journal
of Medicine and Philosophy, 33, 106–139.
Sadegh-Zadeh, K. (2012). Handbook of Analytic Philosophy of Medicine,
Dordrecht: Springer.
Schaffner, K. F. (1986). Exemplar reasoning about biological models and
diseases: A relation between the philosophy of medicine and philosophy of
science. Journal of Medicine and Philosophy, 11(1), 63–80.
Schermer, M. H. N. (2023). Preclinical disease or risk factor? Alzheimer’s disease
as a case study of changing conceptualizations of disease. The Journal of
Medicine and Philosophy: A Forum for Bioethics and Philosophy of Medicine,
48(4), 322–334.
Schreiber, R. D., Old, L. J., & Smyth, M. J. (2011). Cancer immunoediting:
Integrating immunity’s roles in cancer suppression and promotion. Science,
331(6024), 1565–1570.
Schulkin, J. (2012). Allostasis, Homeostasis, and the Costs of Physiological
Adaptation, Reprint, Cambridge: Cambridge University Press.
Schwabe, R. F., & Jobin, C. (2013). The microbiome and cancer. Nature
Reviews Cancer, 13(11), 800–812.
Schwartz, P. H. (2007). Decision and discovery in defining “disease.” In
H. Kincaid & J. McKitrick, eds., Establishing Medical Reality, Amsterdam:
Springer, pp. 47–63.
Severinsen, M. (2001). Principles behind definitions of diseases – a criticism of
the principle of disease mechanism and the development of a pragmatic
alternative. Theoretical Medicine and Bioethics, 22(4): 319–336. https://doi
.org/10.1023/A:1011830602137.
Shokeir, M. H. K. (1975). Investigation on Huntington’s disease in the Canadian
Prairies: II. Fecundity and Fitness. Clinical Genetics, 7(4), 349–353.
References 77
Sholl, J. (2020). The sciences of healthy aging await a theory of health.

Biogerontology, 21(3), 399–409.
Sholl, J. (2021). Can aging research generate a theory of health? History and
Philosophy of the Life Sciences, 43(2), 45.
Sholl, J., & Okholm, S. (2021). Taking a naturalistic turn in the health and
disease debate. Teorema, 40(1), 91–109.
Sholl, J., & Rattan, S. I. S. (Eds.). (2020). Explaining Health across the
Sciences, Vol. 12, Cham: Springer International. https://doi.org/10.1007/
978-3-030-52663-4.
Sholl, J., Sepich-Poore, G. D., Knight, R., & Pradeu, T. (2021). Redrawing
therapeutic boundaries: Microbiota and cancer. Trends in Cancer, 8(2), 87–97.
Smith, K. C. (2001). A disease by any other name: Musings on the concept of
a genetic disease. Medicine, Health Care and Philosophy, 4(1), 19–30.
Solomon, M., Simon, J. R., & Kincaid, H. (Eds.). (2017). The Routledge
Companion to Philosophy of Medicine, New York: Routledge, Taylor &
Francis Group.
Stearns, S. C., & Koella, J. C. (2008). Evolution in Health and Disease, 2nd ed.,
New York: Oxford University Press.
Steptoe, A., & Kivimäki, M. (2012). Stress and cardiovascular disease. Nature
Reviews Cardiology, 9(6), 360–370.
Sterling, P., & Eyer, J. (1988). Allostasis: A new paradigm to explain arousal
pathology. In S. Fisher & J. Reason, eds., Handbook of Life Stress, Cognition
and Health. New York: John Wiley & Sons, pp. 629–649.
Szymanska, H., Lechowska-Piskorowska, J., Krysiak, E. et al. (2014). Neoplastic
and nonneoplastic lesions in aging mice of unique and common inbred strains
contribution to modeling of human neoplastic diseases. Veterinary Pathology,
51(3), 663–679.
Tabb, K. (2015). Psychiatric progress and the assumption of diagnostic
discrimination. Philosophy of Science, 82, 1047–1058.
Tabb, K. (2020). Should psychiatry be precise? Reduction, big data, and
nosological revision in mental health research. In K. S. Kendler, J. Parnas,
& P. Zachar, eds., Levels of Analysis in Psychopathology, 1st ed., New York:
Cambridge University Press, pp. 308–334.
Thagard, P. (1999). How Scientists Explain Disease, Princeton: New Ed,
Princeton University Press.
Thompson, R. P. (2011). Models and theories in medicine. In F. Gifford, ed.,
Philosophy of Medicine, Oxford: Elsevier, pp. 115–136.
Thun, M. J., Linet, M. S., Cerhan, J. R., Haiman, C., & Schottenfeld, D. (Eds.).
(2018). Cancer Epidemiology and Prevention, 4th ed., New York: Oxford
University Press.
78 References
Tremaroli, V., & Bäckhed, F. (2012). Functional interactions between the gut
microbiota and host metabolism. Nature, 489(7415), 242–249.
Tsou, J. Y. (2012). Intervention, causal reasoning, and the neurobiology of
mental disorders: Pharmacological drugs as experimental instruments.
Studies in History and Philosophy of Science Part C, 43(2), 542–551.
Turner, J. S. (2010). The Tinkererer’s Accomplice: How Design Emerges from
Life Itself, Cambridge, MA: Harvard University Press.
Valles, S. A. (2018). Philosophy of Population Health Science: Philosophy for
a New Public Health Era, New York: Routledge, Taylor & Francis Group.
Venkatapuram, S. (2013). Health, vital goals, and central human capabilities.
Bioethics, 27(5), 271–279.
Viau, V. (2002). Functional cross-talk between the hypothalamic-pituitary-
gonadal and -adrenal axes: Testosterone and corticosterone interact on HPA
function. Journal of Neuroendocrinology, 14(6), 506–513.
Virgin, H. W., Wherry, E. J., & Ahmed, R. (2009). Redefining chronic viral
infection. Cell, 138(1), 30–50.
Vogelstein, B., & Kinzler, K. W. (2004). Cancer genes and the pathways they
control. Nature Medicine, 10(8), 11, 30–50.
Wachter, K. W. (2008). Biodemography comes of age. Demographic Research,
19, 1501–1512.
Wakefield, J. C. (1992). The concept of mental disorder: On the boundary
between biological facts and social values. American Psychologist, 47(3),
373–388.
Webster, J. I., Tonelli, L., & Sternberg, E. M. (2002). Neuroendocrine regulation
of immunity. Annual Review of Immunology, 20(1), 125–163.
Wellcome Trust Case Control Consortium. (2007). Genome-wide association
study of 14,000 cases of seven common diseases and 3,000 shared controls.
Nature, 447(7145), 661–678.
Whitbeck, C. (1977). Causation in medicine: The disease entity model.
Philosophy of Science, 44(4), 619–637.
Whitbeck, C. (1981). A theory of health. In A. L. Caplan, H. T. Engelhardt, &
J. J. McCartney, eds., Concepts of Health and Disease: Interdisciplinary
Perspectives, Reading, MA: Addison-Wesley, Advanced Book Program/
World Science Division, pp. 611–626.
Wiener, N. (1948). Cybernetics: Or Control and Communication in the Animal
and the Machine, Paris, France: Hermann.
Williams, G. C. (1957). Pleiotropy, natural selection, and the evolution of
senescence. Evolution, 11(4), 398–411.
Williams, G., & Nesse, R. (1991). The dawn of Darwinian medicine. Quarterly
Review of Biology, 66(1), 1–22.
References 79
Worrall, J., & Worrall, J. (2001). Defining disease: Much ado about nothing? In
A.-T. Tymieniecka & E. Agazzi, eds., Life Interpretation and the Sense of
Illness within the Human Condition, Netherlands: Springer, pp. 33–55.
Yu, F.-X., Zhao, B., & Guan, K.-L. (2015). Hippo pathway in organ size control,
tissue homeostasis, and cancer. Cell, 163(4), 811–828.
Acknowledgments
Steeves Demazeux, Jan Pieter Konsman, Simon Okholm, Thomas Pradeu, and
Jonathan Sholl have read the first draft of this Element and have added eight
months of delay to my workload. Thanks, guys. Really. Jonathan Sholl has
kindly edited the final manuscript and made even more useful suggestions.
Philosophy of Biology
Grant Ramsey
KU Leuven
Grant Ramsey is a BOFZAP research professor at the Institute of Philosophy, KU Leuven,
Belgium. His work centers on philosophical problems at the foundation of evolutionary
biology. He has been awarded the Popper Prize twice for his work in this area. He also
publishes in the philosophy of animal behavior, human nature and the moral emotions. He
runs the Ramsey Lab (theramseylab.org), a highly collaborative research group focused on
issues in the philosophy of the life sciences.
About the Series

This Cambridge Elements series provides concise and structured introductions to all of
the central topics in the philosophy of biology. Contributors to the series are
cutting-edge researchers who offer balanced, comprehensive coverage of multiple
perspectives, while also developing new ideas and arguments from
a unique viewpoint.
Philosophy of Biology
Elements in the Series

Biological Individuality
Alison K. McConwell
Human Nature
Grant Ramsey
Ecological Complexity
Alkistis Elliott-Graves
Units of Selection
Javier Suárez and Elisabeth A. Lloyd
Evolution and Development: Conceptual Issues
Alan C. Love
Inclusive Fitness and Kin Selection
Hannah Rubin
Animal Models of Human Disease
Sara Green
Cultural Selection
Tim Lewens
Controlled Experiments
Jutta Schickore
Explanation in Biology
Lauren N. Ross
Biological Organization
Leonardo Bich
Maël Lemoine
A full series listing is available at: www.cambridge.org/EPBY

philosophy-of-physiology

Uploaded by

Copyright:

Available Formats

philosophy-of-physiology

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

philosophy-of-physiology

Uploaded by

Copyright:

Available Formats

Lemoine

Time is ripe to complement the question “what is health

About the Series Series Editors

Cover image: Ascidiae from Kunstformen der Natur (1904)

Cambridge University Press is part of Cambridge University Press & Assessment,

Elements in the Philosophy of Biology

Abstract: Time is ripe to complement the question “what is health and

Keywords: health, disease, physiology, medicine, evolution

© Maël Lemoine 2025

1 From Philosophy of Medicine to Philosophy

2 Disease Entities and Pathophysiological Processes 17

3 How Generalizable Are Disease Theories? 27

4 Toward a Theory of the Pathological Phenomenon 41

5 Toward a Theory of Physiological Health 53

1 From Philosophy of Medicine to Philosophy of Physiology

1.1 A Short Overview of the Health and Disease Debate

In recent history, philosophers of medicine have polarized into two camps:

- Naturalists deﬁne “health” and “disease” in terms of biological functions

1.2 Philosophy of Medicine Is Not the Philosophy

bibliometrically marginal articles from science journals or articles written by

epidemiology frequently refer to scientiﬁc sources directly, and generally cite

1.3 A Brief Presentation of Naturalism in Philosophy of Medicine

Figure 2 A Venn diagram presenting the results of the deﬁnition of “disease” in

(1) no trait contributive to survival or reproduction is pathological

Additional, more local concepts (intrinsic health, functional readiness, poly-

1.4 Naturalism Does Not Investigate the Science of Health

efﬁciency” is not known. The “typical hierarchy of interlocking functional

Surely whenever there is no impediment in any of the activities of all their

1.5 The Idea of a Philosophy of Physiology

vaguely deﬁned or even rigorously redeﬁned by philosophers, into a precise,

2 Disease Entities and Pathophysiological Processes

2.1 Robust Disease Entities Rely on the Description of Speciﬁc

The main goal of disease entities is to organize knowledge. Most studies in

Table 2 The ICD description of “Diabetes mellitus type 2”

(1) “Principle of completeness”: Every case of disease is a case of a speciﬁc

(2) “Principle of unambiguousness”: Every case of a disease is a case of one

Which of the necessary components of a disease entity justiﬁes that a set of

- Operationality: explicit, person-independent, veriﬁable nature of

Disease entities have mostly been controversial where pathophysiological know-

2.2 The Pathological Phenomenon Consists in a Small Number

somehow to be as a disjunction of pathophysiological processes: “process1 or

a process speciﬁc to diabetes (Matthews et al. 1985). However, research deals

Figure 3 The pathological phenomenon as a bush of pathological processes.

3 How Generalizable Are Disease Theories?

A second function is to establish that a condition is indeed a disease, if it

3.1 How Disease Theories Diﬀer in Explaining a Disease

• In the formal sense, the homeostasis theory of disease describes disease as

as a genetic disease, the pathophysiology may remain undetectable for a much

3.2 Generalizing Disease Theories

in general – although researchers expand them as much as they can. A common

3.3 Issues with the Generalization of Disease Theories

conversely, considered it useless to the explanation of speciﬁc diseases. On the

evolutionary theory of disease and in the geroscience theory of disease is

diseases are likely to be of a type between pure Mendelian and “complex” in

4 Toward a Theory of the Pathological Phenomenon

4.1 Why One Theory for All Diseases Sounds Unlikely

4.2 The Conceptual Necessity of the Pathological Phenomenon

4.3 The Fourfold Root of the Natural Necessity

required to ensure reproduction, depending on their vulnerability to their envir-

represented in the scientiﬁc literature. However, there is still some way to go