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Cancer
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Stanford Encyclopedia Cancer is a worldwide epidemic. It is the first or second leading cause of
death before age 70 in ninety-one countries, as of 2015. According to the
of Philosophy International Agency for Research on Cancer, “there will be an estimated
18.1 million new cancer cases and 9.6 million cancer deaths in 2018,” and
cancer is expected to be the “leading cause of death in every country of the
world in the 21st century” (Bray, et al. 2018). While overall cancer
mortality has declined in the U.S. annually since 2005, progress has been
slow in some cases, and mortality is rising in others. In particular, “death
Edward N. Zalta Uri Nodelman Colin Allen R. Lanier Anderson
rates rose from 2010 to 2014 by almost 3% per year for liver cancer and
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by about 2% per year for uterine cancer,” and, “pancreatic cancer death
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https://plato.stanford.edu/board.html rates continued to increase slightly (by 0.3% per year) in men” (Siegel, et
al. 2017). Perhaps not surprisingly, then, cancer is a central topic of
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ISSN: 1095-5054
biomedical research, drawing millions of federal dollars annually. In 2019,
the U.S. National Cancer Institute (NCI) will allocate $5.74 billion in
Notice: This PDF version was distributed by request to mem- federal dollars, a $79 million increase over 2018 (NCI, 2019—see the
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SEP Society and obtain authorized PDF versions of SEP entries, Despite this, cancer—and scientific research on cancer—has received
please visit https://leibniz.stanford.edu/friends/ . relatively little attention from philosophers of science. However, this is
starting to change, as cancer, and scientific research on cancer, raises a
Stanford Encyclopedia of Philosophy
Copyright c 2019 by the publisher variety of compelling philosophical questions. This entry will focus on
The Metaphysics Research Lab four topics, which philosophers of science have begun to explore and
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debate.
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Cancer First, scientific classifications of cancer have as yet failed to yield a unified
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Anya Plutynski taxonomy. There is a diversity of classificatory schemes for cancer, and
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while some are hierarchical, others appear to be “cross-cutting,” or non-
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1
 Cancer
nested. Initially, researchers investigating cancer genomics seemed to
think such issues might be resolved by molecular “subtyping”. However,
genomic sequencing and its sequelae—transcriptomics, proteomics,
epigenomics, etc.—have, if anything, complicated cancer classification.
This literature thus raises a variety of questions about the nature of the
disease and disease classification: Are there some classifications that are
more useful, or better than others? What makes a classification a good
one? What does it mean to track more or less “natural” distinctions in the
context of disease? Is such talk of the “naturalness” of disease categories
simply confused? The problem of cancer classification is complicated by
the fact that cancer progression is a process with a complex natural
history. Thus, cancer serves as a challenging case for disease
classification, and also for demarcating disease from health, raising
intriguing questions about the potential role(s) of precautionary values in
cancer diagnosis.
Second, philosophers of science have historically taken the aim of science
to be arriving at true theories. However, scientists studying cancer come
from a variety of disciplines, with different scientific as well as practical
aims. Perhaps it is not surprising, then, that historians and philosophers of
science do not seem to agree on how best to characterize the aim and
structure of cancer research; it is far from clear whether the appropriate
characterization of the aim is arriving at true theories, or even whether the
proper units of analysis are “theories”, or instead, “models”, “explanatory
frameworks”, “research programs”, “paradigms”, or perhaps,
“experimental traditions”. With the rise of “big data” science—such as the
Cancer Genome Atlas Project (or TCGA)—and “systems” approaches to
the study of disease, both philosophers and historians of science are
rethinking how best to describe and explain these distinctive kinds of
scientific inquiry.
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Anya Plutynski
Third, cancer is in part a byproduct of our developmental and life history,
as well as our evolutionary history. Cancer progression can be compared
to a reversion of development, or, to the evolution of multicellularity.
Thus, cancer raises intriguing questions about how we conceive of
“functions”, “development”, and the role of our evolutionary history and
particularly, selective trade-offs, in vulnerability to disease.
Last but not least, cancer research provides a case study for consideration
of the roles of values at the science-policy interface. Epidemiological and
toxicological research on cancer’s causes informs toxics law and
regulatory policy, which raises a variety of questions about the nature of
evidence and inductive risk in such contexts. Cancer research also
provides a test case for debates about the challenges facing translational
medicine and precision medicine. Moreover, the complexity of cancer
causation provides an opportunity and a challenge for those who take data
and theoretical integration to be an ideal for science. With so many, and
such diverse types of cancer research, integration presents many
challenges. Indeed, this is one of the many reasons why translating “basic”
science into the clinic can be enormously difficult.
1. Defining and Classifying Cancer
1.1 Cancer’s Intrinsic Heterogeneity
1.2 Cancer’s Variable Natural History
2. Explaining Cancer: Theories, Models and Mechanisms
2.1 The Mechanistic Picture of Cancer
2.2 Complicating the Mechanistic Picture: Tissue Organization,
Stem Cells and Systems Theory
3. Cancer as a Byproduct: Evolution, Development, and Aging
4. The Science-Value Interface and Aims of Cancer Research
Bibliography
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Related Entries
1. Defining and Classifying Cancer
What is cancer? Is cancer one disease, or many? If many, how many
cancers are there? One might think that such questions are merely
empirical. However, it turns out that defining and classifying cancer is
contested, for at least two reasons. First, there is little agreement on how to
classify disease, more generally. Second, cancer itself poses a variety of
challenges—both in terms of its intrinsic heterogeneity, and in light of its
variable natural history. In section 1.1, we will consider challenges facing
cancer classification in light of cancer’s intrinsic heterogeneity, and in
section 1.2, we will consider challenges facing cancer classification in
light of its variable natural history.
Prima facie, what distinguishes diseases are typical symptoms, disease
course, and a common cause. The last criterion—common cause—is
inherited from a model of disease classifications that grew in part out of
the successes of the germ theory of disease (Carter 2003). Following
Koch’s postulates (1884), what enables one to distinguish diseases is the
ability to isolate a causal agent as present in each and every case of
characteristic symptoms. Unfortunately, such a model of disease is not
terribly helpful for cancer. Cancer can be present without clinically
detectable symptoms, has variable disease course, and is a “multifactorial”
disease—there are many causes of cancer. It is rather difficult to pick out a
“causal bottleneck” uniquely necessary for cancer, let alone each cancer
type and subtype. While cancers are typically classified by their cell-of-
origin—or the tissue, or organ, and cell-type where they originated (e.g.,
squamous cell carcinoma of the skin or ovaries), it turns out that cancers
can contain mixes of different cells of origin, and cancers arising in the
same cells or tissues can have very different features. Moreover, cancers
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Anya Plutynski
with many of the same features (at least initially), may evolve in different
ways, and have different vulnerability to treatment (Marusyk, et al. 2012).
How, then, are we to classify such poorly behaving kinds?
Classifications of cancer have largely been in service of diagnosis,
prognosis, and treatment decisions. Oncologists, surgeons and pathologists
typically classify cancer types and subtypes, in light of organ and tissue
type of origin (such as leukemia, or glioma), broadly shared signs and
symptoms, disease course, gross histopathology (size, shape and rate of
division of cells), and “biomarkers” (e.g., estrogen sensitivity, genetic
profile). Solid tumors (of the lung, for instance) may be classified as either
“benign,” or “malignant,” and malignant cancers can present at different
“stages” and have different “grades.” Pathologists use various measures
(e.g., size, extent of lymphatic involvement, number of metastases,
number of lymphocytes (white blood cells)) to estimate stage of
progression of the disease. “Grade” is a term used to classify solid tumors
in light of other measures (e.g., degree of “dedifferentiation” of cells in a
tumor—or loss of characteristics typical of a breast, prostate, or colon
cells and tissue) and is taken to indicate likely disease course. Decisions
about staging criteria are conventionally agreed upon by specialists in
oncology and pathology, though informed by the best available evidence.
Early stage disease can be very difficult to classify, and thus also to know
whether (or how) treat. And, some cancers seem particularly recalcitrant to
treatment. This led researchers to ask: Are there distinctive genetic or
molecular “signatures” of each cancer that can help us estimate risk of
progression, or chances of recurrence, as well as predict responses to
treatment? Perhaps these molecular signatures are the key to a natural
taxonomy of cancer types and subtypes?
1.1 Cancer’s Intrinsic Heterogeneity
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The Cancer Genome Atlas (TCGA) project, a federally funded U.S.
research program, supported jointly by the National Cancer Institute (NCI)
and National Human Genome Research Institute (NHGRI), sought to
characterize the genomic features of each cancer type and subtype,
resulting in thirty-three “marker” papers, laying out molecular features of
each cancer type, often yielding novel subclassifications of each type. For
example, in 2016, a working group affiliated with TCGA published
“Comprehensive Pan-Genomic Characterization of Adrenocortical
Carcinoma,” which identified three subtypes of adrenocortical carcinoma,
and in 2015, another working group published “Comprehensive Genomic
Characterization of Head and Neck Squamous Cell Carcinomas,” which
identified specific mutations associated with human-papillomavirus-
associated versus smoking-related head and neck cancers. While TCGA
did result in a more comprehensive understanding of cancer biology, it
also raised many questions. One particular challenge has been determining
which mutations to which genes are the “drivers” of cancer, or which ones
enable cancer cells to “succeed” in an environment that would (ordinarily)
prevent their growth. Cancer genomes have many mutations, so a central
puzzle has been determining which among the many changes to cancer
genomes are causally relevant to cancer progression. Solving this puzzle
has been difficult, because cancers are far more heterogeneous than they
initially anticipated. Or, perhaps it is better to say: sorting the “signal”
from the noise has proven more difficult than anticipated, as Meyerson, et
al. (2010) explains, paraphrasing Tolstoi:
… normal human genomes are all alike, but every cancer genome
is abnormal in its own way. Specifically, cancer genomes vary
considerably in their mutation frequency,… in global copy number
or ploidy, and in genome structure… (Meyerson, et al. 2010)
In other words, there are very different rates, numbers and types of
mutations across and within different cancer types and subtypes. Which
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Anya Plutynski
ones matter, how, and how much, in different cancer types and subtypes,
and indeed, over the course of cancer progression, is a difficult puzzle to
solve. Complicating this further, a cancer may contain several
subpopulations of cells (or, multiple evolving lineages), with different
numbers and types of mutations within each lineage. That is, cancers have
varying types and degrees of “intratumor heterogeneity.” So, samples of a
tumor taken when cancer is first diagnosed may be representative of only
one subpopulation of an early stage of a dynamic process. Such samples
may not be representative of the genomic changes of greatest relevance to
treatment-resistant late stage disease. Yet, it is late-stage disease that we
need better tools to more effectively intervene upon; most cancers—if
caught early—can be treated relatively effectively.
All this would be challenging enough as it is, but there is a yet further
challenge to cancer classification. Cancers arising in the same tissue or
organ can be more genetically dissimilar than cancers arising in different
tissues or organs. Or, “cell-of-origin influences, but does not fully
determine, tumor classification” (Hoadley, et al. 2014, 2018). Genomic
information, far from providing a way to sort all cancers into a Linnean
hierarchy, instead yields what philosophers have called cross-cutting
classifications (Khalidi, 1998). One might think genetic profile should
trump tissue or cell of origin for purposes of classification. But it turns out
that where a cancer arises in the body is rather important to know.
Characteristics of the tissues and organs in which a cancer arises shape the
course of disease in a complex fashion (Öhlund, et al. 2017; Fessler, et al.
2016). Moreover, the rise of epigenomics, proteomics, and
transcriptomics, and “regulomics” generates further challenges with
classification, suggesting genomic information needs to be supplemented.
For instance, it turns out changes in microRNA in cancer cells—non-
coding RNA, which affects the expression of genes—can affect cancer
initiation, progression, and responses to drugs (Hrovatin, et al. 2018). This
is just one of several “extra-genomic” factors that play an important role in
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cancer causation and thus, presumably, ought to play at least a partial role
in informing cancer taxonomy.
This does not exhaust all factors of causal relevance to cancer onset, and
thus also (at least potentially) classification. Family history and inherited
(as opposed to somatic) mutations, life history (e.g. parity, or number of
children, and age at first birth), environmental exposures, and histories of
infection, inflammation, and immune response, contribute differentially to
cancer’s age of onset, rate of progression, histopathology, and response to
treatment. For instance, infectious agents (e.g., HPV- or HCV-) are
associated with cervical and liver cancers, and some proportion of
esophageal cancers (Cancer Genome Atlas, 2015). Cancers of the prostate
and breast are associated with hormonal environments, which are in turn
affected by parity (number of pregnancies). “Pregnancy-associated” breast
cancers are cancers that arise during or shortly after pregnancy (see, e.g.,
Schedin 2006). The “same” cancer in the same tissue or organ can be
classified as either “somatic,” or “familial”—due in part to whether the
patient possesses inherited mutations, such as those with Li Fraumeni
syndrome. Smoking associated lung cancers and non-smoking associated
lung cancers are distinct genetically, epigenetically, and phenotypically
(i.e., in terms of both gross pathology, and course of progression, as well
as response to treatment). Which of these several causal factors ought to
figure centrally in classification? Depending upon how fine-grained a
characterization of the causal basis of cancer one adopts, there could be
hundreds or thousands of cancer types and subtypes. It’s far from clear
whether there is one obvious choice of causal basis that best reflects
anything like a “natural” division of type and subtypes. Indeed, this case
raises the larger question of whether one can or should expect a univocal
classification of multifactorial disease, or indeed, of disease more
generally. Are diseases, such as cancer, “natural” kinds? Or, are they
simply ways of carving up the world that we happen to find useful? Is the
‘naturalness’ of a classification in science a matter of degree?
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Several philosophers have weighed in on the matter of the nature of
disease and disease classification (see, e.g., Ereshefsky, et al. 2015; Lange
2007; Broadbent 2009 and 2015; Williams 2011; Khalidi 2013; Sorenson
2011). The questions these authors are addressing are both epistemic—
what warrants choice of criteria of classification of disease—and
metaphysical—given diseases like cancer lack “essential” properties, is it
correct to think of disease “kinds” as “natural”?
Lange (2007) for instance, argues that, “a disease is a natural kind of
incapacity that features in interesting function-analytic explanations of
other unhealthful incapacities”(Lange, 2007, 266). Cancer is not a “natural
kind,” in his view, because the “typical patterns of disruption of cell birth
and death” characteristic of cancer are multiply realized. Categories like
“breast cancer” or “lung cancer” seem to be increasingly replaced in
modern medicine by appeal to molecular subtypes. Molecular subtypes of
cancer are not, however, “natural kinds of incapacity,” on Lange’s view,
and so are not distinct diseases. Indeed, many “disease kinds” lack
unifying “function-analytic” explanations. Thus, modern medicine has, in
a sense, led to the “end of diseases” as natural kinds. In a similar vein, but
for very different reasons, Sorenson (2011) argues that diseases are “para-
natural” kinds. Insofar as diseases are “deficiencies,” or “departures from
the norm,” they lack the “integrity” or “internal nature” characteristic of
natural kinds. Diseases are “reflections” of natural kinds of process. They
“inherit the lawfulness and projectability of the natural kinds that shape
them.” In other words, both Lange and Sorenson seem similarly skeptical
that diseases are natural kinds.
In contrast, while Broadbent (2009, 2015), Williams (2011), and Khalidi
(2013) agree that diseases lack essential properties, they claim that disease
classifications in light of distinctive causes, or types of cause, either pick
out distinctive “deviations from normal functional ability,” or (in Khalidi's
case) homeostatic property cluster kinds. For instance, Broadbent’s (2009,
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2015) “contrastive” model of disease classification roughly takes diseases
to be distinct in light of distinctive causes. Where there is a difference in at
least one of a set of causes shared by “controls” and “cases” (where cases
are identified in light of “parts and processes deviating (negatively) from
normal functional ability”), we have a distinct disease. Broadbent takes
this account to explain why, for instance, “cervical cancer is a disease, but
HPV-itis is not.” Though, it’s not clear that HPV-itis is not properly
regarded as a legitimate disease category; or, at least, this case raises an
interesting question as to whether potential, rather than overt, dysfunction
is more central to disease designation. In public health contexts, whether a
strain of HPV causes cancer or not is not as important as deploying
interventions that limit the spread of HPV more generally. Strains of HPV
that do not currently cause cancer could well evolve the capacity to do so.
So, perhaps from a public health perspective, “HPV-itis” is a perfectly
legitimate disease category. That is, from a preventive medicine
perspective, what matters is that a disease category is a good one for
predicting and intervening, even where functional disruption does not
always (or even most of the time) eventuate. Which choice of
classification we ought to make in demarcating disease types, in other
words, might depend on not only on which contrast we are interested in
explaining retrospectively, but also which kind of intervention we wish to
promote prospectively.
Khalidi (2013) argues that cancer might be a homeostatic property cluster
kind. Khalidi argues that cancer is driven by “homeostatic” mechanisms—
namely, mutations to “caretaker” genes, or genes that play a “gatekeeping”
role in preventing or permitting the emergence of a tumor. Acquisition of
mutations to specific “caretaker” genes, on this view, serve a function akin
to Boyd’s (1999) “homeostatic mechanisms,” in that they permit the
further acquisition of “hallmark” properties of cancer cells. Khalidi is
drawing upon a very common view of cancer, articulated by two famous
cancer researchers, Hanahan and Weinberg (2000, 2011). They identify
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Anya Plutynski
what they take to be the “hallmarks” of cancer: “a small number of
molecular, biochemical, and cellular traits—acquired capabilities—shared
by most and perhaps all types of human cancer.” They identified these “six
essential alterations in cell physiology that collectively dictate malignant
growth” as: self-sufficiency in growth signals, insensitivity to antigrowth
signals, evasion of apoptosis (cell death), sustained angiogenesis (the
ability to develop a blood supply), tissue invasion and metastasis
(Hanahan, et al. 2000, 57). By way of example of a caretaker, TP53 is
called a tumor suppressor, because it carries the function of sensing and
responding to signals associated with cell damage, typically inducing
apoptosis, or cell death. It is one of the only genes mutated in a majority of
cancers sequenced (Bailey, et al. 2018), and Weinberg (2013) characterizes
it as “master guardian and executioner,” in that it prevents further
mutations by inducing cell death where there are signs of trouble. On
Khalidi’s view, one ought to understand disruption of these very specific
capacities as a “homeostatic mechanism” for cancer.
At first blush, this seems a vivid case of a homeostatic property cluster
kind. However, demarcating mechanisms is far from straightforward.
Where we take a mechanism to begin and end is in large part a pragmatic
matter (Craver 2009); so, depending upon how we carve up the
“homeostatic mechanisms for” cancer, we can yield many or few cancer
subtypes. As perhaps may have been expected, Hanahan and Weinberg’s
initial picture has been complicated since 2001. In 2011, Hanahan and
Weinberg updated their hallmarks to include four more: “genome
instability, which generates the genetic diversity that expedites their
acquisition, and inflammation, which fosters multiple hallmark
functions… reprogramming of energy metabolism, and evading immune
destruction.” And, “In addition to cancer cells, tumors exhibit another
dimension of complexity: they contain a repertoire of recruited, ostensibly
normal cells that contribute to the acquisition of hallmark traits by creating
the tumor microenvironment” (2011, 646). In other words, hallmarks of
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cancer appear to no longer involve all and only intrinsic properties of
cancer cells, but also dynamic interactions between cancer cells and the
immune system and extra-tumor environment. This may not be such a
serious challenge to Khalidi’s view that caretaker mutation are
mechanisms for cancer; one could, arguably, just expand the mechanisms
for homeostasis to the tumor microenvironment. However, such a strategy
is complicated by the context-sensitivity of mechanism activation. Many
cells on the surface of the skin as we age possess as many mutations to
“caretaker” genes as those in a breast tumor, but most such skin cells are
shed (Martincorena, et al. 2015). The “same” mechanisms may well lead
to harm in one context, and be entirely harmless in another.
The larger concern cases like this raise is whether there is one way to
privilege choice of causal basis for classifying diseases like cancer.
Different choice of temporal or spatial scale, or more or less fine-grained
characterization of causal processes, might yield multiple, overlapping
disease classifications. While some may be willing to bite this bullet, and
indeed, endorse pluralism and non-hierarchical classifications (see, e.g.,
Khalidi 1998, 2013), others might be concerned that this would yield too
permissive an array of disease types. More generally, whether and how
scientific researchers and clinicians are likely to to converge on a common
classification for cancer raises some interesting puzzles about the aims and
methods of classification in the biomedical sciences more generally. That
genomic features of cancer are unlikely to unproblematically yield a
natural taxonomy suggests that a reductive picture of disease classification
is more generally implausible. It seems that classifications of disease like
cancer form a kind of ‘hybrid’—they are intended to capture natural
regularities and their causes, but also to be of use for a wide array of
agents with different purposes. It’s unclear whether all these purposes can
be served by one univocal method or set of classificatory criteria.
1.2 Cancer’s Variable Natural History
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Anya Plutynski
One further complication surrounding classification in the case of cancer,
is that cancers have variable disease course (Foulds 1958; Cairns 1975;
Lynch 2007; Bertolaso & Dupré 2018). Not all cancers progress uniformly
to metastasis and death; some growths progress slowly or not at all. Some
very common cancers (in the prostate and thyroid) are either slow
growing, or tend to remain “indolent” (Esserman, et al. 2013; Siegel, et al.
2017). There is some disagreement in the medical community about how
to characterize such cases; it’s unclear in many cases whether they are best
viewed as very slow growing precancerous lesions, or perhaps ought not
be characterized as “cancer” at all. Such cases raise a host of practical
questions about the merits of screening, and the risk of overdiagnosis—the
diagnosis of disease that might never have progressed in the lifetime of the
patient (see, e.g., Walker & Rogers 2016; Hofman 2017; Esserman, et al.
2013; Welch & Black 2010), but they also raise interesting philosophical
questions about the nature of disease.
Some philosophers (Schwartz 2014), drawing upon the biostatistical
theory of disease as departure from age and sex-typical function (Boorse
1977), argue that we ought to classify such early stage cancers as risk
factors, rather than disease. Such growths are not disease, on this view,
because they are not atypical and do not as yet impair function—in fact as
many as one half of men over 60 have some lesions the prostate (Welch &
Black 2010). Reclassification of such cancers as mere risk factors, it’s
hoped, will prevent overdiagnosis and overtreatment. Other philosophers
less sympathetic to the biostatistical approach (e.g., Reid 2016) argue that
this approach fails to acknowledge how the practice of diagnosis is itself a
sort of risk-benefit calculation, informed in part by our knowledge of the
prevalence of early stage growths like DCIS (ductal carcinoma in situ), or
indolent prostate disease, and in part by more or less precautionary values.
As we’ve learned how common such indolent diseases are, with the
growing realization that many such growths do not progress, it seems that
they fall into some further (and less well-defined) category. It seems this
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debate is not only a scientific or empirical one, but also a normative one;
much like debates about PTSD or obesity, there are normative dimensions
to how we define and classify disease. Labeling can have both positive and
negative consequences for patients, clinicians, insurers, not to mention
developers and producers of screening, medical device, and
pharmaceuticals (Ereshefsky 2009). Overdiagnosis of early stage disease
can lead to serious harms; not least, treating a “cancer” that may or may
not progress in the lifetime of a patient is costly and harmful to quality of
life.
One hope driving the precision medicine research program is that the
identification of biomarkers of aggressive disease will resolve these
ambiguities with respect to early stage disease, as well as identify targets
of effective treatment (see, e.g., Collins, et al. 2005). However, as we have
seen, interpreting genomic data has been far from straightforward, and
classifying cancer types and subtypes by appeal to genomic information
alone can lead to a loss of important information. While genomic and
molecular data is no doubt useful, it is not necessarily decisive.
In sum, much like genes and species, diseases like cancer lack essences,
are heterogeneous, blur together at the edges, are caused in many different
ways, and have variable dynamics. Perhaps inconsistent classifications are
simply to be expected in such cases. That this is so does not (necessarily)
show that we ought to give up on realism about disease kinds; indeed,
perhaps we ought to endorse “promiscuous realism” (Dupré 1996). As
knowledge has grown, and practical interests shift, on this view,
classifications can multiply and even cross-classify the same kinds. This is
nothing to fear, so long as the kinds we countenance do the predictive or
explanatory work intended for them, in the context intended. Others have
a somewhat less permissive view, however, arguing that there need to be
some empirical constraints or other on classification of “scientific kinds,”
whether or not these categories count as examples of “natural” kinds
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Anya Plutynski
(Slater 2014; Ereshefsky, et al. 2015). For instance, Ereshefsky, et al.
(2015) argue that all and only categories that serve the needs of
“progressive” research programs are legitimate.
Given the complex causal pathways and heterogeneity of cancer, perhaps
it is not surprising that, as Bertolaso (2016) argues, the history of attempts
to identify defining features of cancer, let alone arrive at a unified theory,
have floundered. Either cancer is defined so vaguely as to include non-
pathological states, or focused so narrowly on a specific class of causes as
to rule out cases that might otherwise be included. Among the many
definitions she canvases are: “abnormal proliferation,” “unregulated
growth,” “a disease of cell differentiation rather than multiplication,” “the
result of destruction of tissue architecture,” “a systems biology disease,”
“blocked ontogeny,” a disease of “suppressed (sic) immune function,” a
“metabolic” and of course, a “genomic” disease. Such a variety of
definitions is, Bertolaso argued, due to the fact that cancer has many
causes, and many effects; moreover, it involves many different types of
dysregulation, at a variety of temporal and spatial scales. Suffice it to say,
it is no small challenge to identify defining features of cancer, let alone
arriving at a unified “theory” of disease etiology.
One might well ask, however, whether the lack of a unified theory of
cancer is a cause for concern? Is this a sign of immature science? Kincaid
has argued to the contrary (2008), “biomedical science can make
significant progress without precise definitions of disease, without full-
fledged theories of disease and of normal biological functioning, and
without disease entities being natural kinds” (p. 368). Pointing out how
tumor microenvironment shapes how cancer cells behave as they do,
Kincaid argues that “There is no clear definition of what constitutes a
cancerous cell in terms of necessary and sufficient conditions. However,
no one thinks that cancer research should stop until we get this definition
settled, or that creating linguistic uniformity is important for
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understanding the science. The science certainly makes progress
nonetheless… Likewise, there is no parsimonious theory of the disease
and the normal functioning from which it is a deviation. Instead, we have
piecemeal causal explanations” (p. 373). Kincaid is correct. Much of
cancer research is piecemeal in character, offering partial and locally
constrained characterizations of the loss or promotion of some particular
activity of a cell associated with this or that mutation typical of cancer
cells. Whether we require a unified theory of cancer remains an open
question. Or, at least, the question of what function such a unified theory
might serve is a matter of some debate. This is reflected in the fact that the
research program seeking to identify genetic mechanisms associated with
cell birth and death has received so many different names: the “oncogene
paradigm,” (Bishop 1995; Morange 1997) “vision,” (Morange 1997),
“theory,” (Sonnenschein & Soto 2008), “model” (Temin 1974; Vogelstein
& Kinzler 1993), “theory-method package” (Fujimura 1988, 1992), and
recently, “framework” (Blassime, et al. 2013).
One suggestion that seems plausible is that a better way of framing the
project of cancer research involves commitment to an “explanatory
framework.” For instance, Blassimie, et al. (2013) characterize the search
for oncogenes as an “explanatory framework”: “causal patterns, schemata
(in the sense of Darden 2002), intuitions, hypotheses, evidential standards
and various bits of evidence and data coming from different experimental
settings and instrumental devices,” which “establish selective and local
criteria of causal relevance that drive the search for, characterization and
use of biological mechanisms.” Rather than consisting of sets of laws or
general principles, such frameworks help generate strategies in the search
for causes, and narrow the field of inquiry. Blassime, et al. argue that
“explanatory frameworks allow for changes of scientific perspective on
the causal relevance of mechanisms without necessarily fully replacing
previous explanatory frameworks” (p. 375). Explanatory frameworks, in
other words, can “coexist” or be “gradually displaced,” rather than stand
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in mutually exclusive relations with one another. As new questions arose,
and new information was discovered, this explanatory framework became
elaborated; depending upon how permissive or restrictive our
characterization of this framework, it need not be viewed as at odds with,
for instance, attention to the tissue microenvironment in cancer. This sort
of multifaceted approach is perhaps what one ought to expect for such a
heterogeneous disease, where causes and effects can be described at very
different temporal and spatial scales. Much like other complex,
multifactorial diseases, cancer is not a single phenomenon, but a
heterogeneous class of disease processes, with few definitive properties or
unique causes. This makes not only classification, but also explanation,
enormously difficult, as we will see below.
2. Explaining Cancer: Theories, Models and
Mechanisms
What does it mean to explain cancer? The question is ambiguous, and
fraught. For, by “cancer” one could have several targets of explanation in
mind: the transformation of a cell into a “cancer cell,” the (general)
process of carcinogenesis, the process of invasion and metastasis in solid
tumors, the emergence and roles of intratumor heterogeneity, differential
rates of incidence of different cancer types, patterns of cancer incidence or
mortality in different environments, socioeconomic groups, races, ages, or
sexes. Each of these explanatory targets arguably calls for quite different
kinds of explanation and not only different explanatory information.
Cancer scientists make appeals to generalizations of wide scope, for
instance, and will also offer detailed, specific mechanistic explanations of
specific outcomes. The fact that these explanations are different in kind
may (in part) explain why there appears to be such a variety of views
amongst philosophers concerning the aim and character of explanation and
progress in cancer research. There is, of course, a long history of debate
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among philosophers of biology concerning norms of explanation. It’s still
hotly debated whether, for instance, all explanations in the biological
sciences must identify causes, or mechanisms, or whether “mathematical”
or “equilibrium” explanations are distinct in kind, and how “network”
models or “systems theoretical” explanations are distinct from other kinds
of explanation, are all live debates (See the entries on scientific
explanation and philosophy of systems and synthetic biology). However,
there is also a history of dispute amongst cancer scientists about both
competing research agendas and explanatory strategies.
2.1 The Mechanistic Picture of Cancer
As mentioned above, for most of the last twenty or so years of the 20th
Century and the first decades of the 21st, the central concern of the
majority of cancer researchers seems to have been identification of
mechanisms at the cell and molecular level that regulate cell birth and
death. Two characteristic features of cancer cells are their uncontrolled
growth, and failure to undergo cell death. This is often accomplished via
changes to the “cellular machinery,” or mutations and associated
disruption of pathways associated with regulation of cell division or cell
death (Hanahan & Weinberg 2001). So, it is natural to assume that
explaining cancer requires identifying the chromosomal alterations,
mutations, and epigenetic changes to cells that give them distinctive
capacities of a cancer cell, as well as describe the ways in which these
mutations systematically yield these effects. This framework for
explaining cancer has been characterized as “somatic mutation theory,”
insofar as cancer is viewed as a product of a series of mutations to cells
during somatic cell division. Onset of cancer, on this view, may be
accelerated either by inheritance of “oncogenes” or “tumor suppressors,”
or by damage to DNA, for instance, due to smoking or UV radiation.
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This picture of cancer was pieced together over decades from various
sources of evidence—from Virchow’s observations of chromosomal
abnormalities in cancer cells, to epidemiological patterns of incidence in
cancer, to the discovery of the “src” gene—one of the first mutations
found to be associated with cancer. This vision of cancer as the product of
oncogenes replaced a “regulatory” view of cancer, according to which
cancer was a “breakdown in normal constraints on growth” (for a history,
see, e.g., Morange 1993, 1997, 2003). Not coincidentally, the “oncogene
paradigm” arose at the same time that some of the first bioengineering
technologies, which enabled early cancer researchers to use the techniques
of molecular biology to study identify genes associated with cancer
progression (Fujimura 1987). While this is a reductionist research
program, in the sense that the aim is to decompose the system of interest
and understand the parts in operation, not all early advocates of the
multistage theory were cell and molecular biologists. Two of the first
advocates of a multi-stage theory of carcinogenesis—Armitage and Doll—
found that curves of average lifetime incidence of lung cancer in smokers
appeared to have the same shape as that of nonsmokers, simply shifted to
earlier ages. This suggested that cancer could arise from a rate-limited
series of insults acquired over the life course. Since the 1980s, hundreds of
genes have been identified, mutations to which are associated with the
hallmarks of cancer. Carcinogenesis, on this view, results from damage to
DNA, or errors in the process of cell division, as well as either
endogenous factors (various hormonal or other factors that promote cell
growth), or exogenous factors (infection, and inflammation), which over
time can lead to dysregulated cell growth.
In one paradigmatic example, Vogelstein and his group collected tissue
samples (premalignant polyps) from patients with a familial or inherited
form of bowel cancer (FAP, or familial adenomatous polyposis). They
discovered that mutations to genes associated with various cancers
accumulated in series of steps, what has been called the “Vogelstein
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cascade.” The study of familial or strongly inherited forms of cancer
(cancers that appear at relatively young ages, and occur in families) has
enabled the identification of several genes, mutations to which (whether
inherited or acquired during somatic cell division) play a role in cancer:
APC, RB, and p53 (associated with familial adenomatous polyposis,
retinoblastoma, and Li Fraumeni syndrome, respectively).
This picture of explaining cancer might be expected to resonate quite well
with the picture of scientific explanation advocated by what has been
called the “new mechanists.” According to this view, one of the central
aims of biological scientists is the identification of mechanisms. The
biological sciences, on this view, are unique in their focus on mechanisms,
rather than laws or general principles, of the sort (typically imagined) to
be central to the physical sciences. A mechanistic explanation identifies
parts and processes that typically yield specific outcomes of interest
(Machamer, et al. 2000). If we wish to understand regulation of apoptosis
(cell death), for instance, we might identify particular genes and proteins
that play an important role in cell senescence, and determine how their
activity and organization yield (or fail to yield) a given outcome. This
mechanistic picture of the aims and character of explanation in the
biological sciences seems prima facie to characterize current cancer
research quite well, or at least the past 25 years of this research.
However, several philosophers have argued that this picture fails to
capture the diverse explanatory strategies carried out by cancer scientists,
at least currently. For instance, some have argued that this fails to take into
consideration more “organicist” or “holistic” views of cancer causation,
which they contrast with a “reductionist” approach in cancer research
(Bertolaso 2009). Some also argue that apparently competing perspectives
can be fruitfully integrated (Bertolaso 2011; Marcum 2005; Malaterre
2007).
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Even advocates of the mechanistic perspective have argued that it needs to
be amended to accommodate the complex causal processes involved in
cancer’s etiology. For instance, according to Bechtel (forthcoming), a
linear picture of mechanisms for cancer leaves out an important
dimension. He characterizes the mechanisms associated with apoptosis,
for instance, as made up of two types: “primary” and “control”
mechanisms. Failure to respond to signals promoting apoptosis in cancer
may be a result of disruption in either one (or both) such mechanisms.
Advocates of the mechanistic perspective have failed, Bechtel argues, to
attend to the complex negative feedback processes of control and
constraint affecting primary mechanisms. As evidence of the significance
of such control mechanisms, he points out how cancer researchers utilize
novel methods, such as network analysis to identify regulatory networks
or feedback loops, associated with specific functions. Bechtel’s distinction
between “primary” and “control” mechanism raises some interesting
questions about the organization of causal pathways in cancer. Whether
such pathways are, for instance, relatively fixed or static in organization, is
an open question. Moreover, the category of “controller” versus “primary”
mechanism itself may be relatively fluid, or context dependent. The
“same” mechanism in a different environment might exert different
controls, and, control mechanisms may themselves be viewed as primary,
given one’s characterization of the function that is the subject of inquiry.
2.2 Complicating the Mechanistic Picture: Tissue Organization,
Stem Cells and Systems Theory
Some critics of the somatic mutation theory and its associated search for
mechanisms of cancer at the cell and molecular level are far more radical
in their ambitions. In the late 1990s, and early 2000s, two researchers
proposed what they took to be an alternative theory or “paradigm” to the
“somatic mutation theory” (SMT), namely, the Tissue Organization Field
Theory (or, TOFT) (Soto & Sonnenschein 2000). Soto and Sonnenschein
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object not only to reductionist methodology, but reductionist assumptions
about the causes of cancer. That is, their concern is not only with
experimental approaches that focus on dysregulated growth of cancer cells
in cell culture, but also with the claims regarding the role of mutations in
cancer. In their view, cancers are not the result of mutations, but instead
“alterations in the communication among cells and tissues that affect
tissue architecture” (2013, p. 90). On this view, mutations do not lead the
way—or, directly affect these signaling pathways—but follow upon
disruptions to tissue organization. It is these alterations of patterns of
interaction between cells that leads to “downward causation effects” on
cells and cellular components, inducing aneuploidy and mutations (Soto &
Sonnenschein 2006; Sonnenschein & Soto 2008). Arguments such as this
one raise several interesting philosophical questions. First, Soto and
Sonnenschein are skeptical of the scientific methodology supporting SMT.
They bring attention to some interesting broader questions as to when are
we warranted in inferring from cell culture or model organism work to
general claims about cancer etiology.
Given that the development of cancer is an immensely complex causal
process that cannot be observed directly, many scientific claims about
cancer’s causes are based on indirect inference, using model organisms or
cells in culture. For instance, tumors are grown in nude mice using
xenotransplantation, or, tumors are observed to grow in mice in which
“driver genes” are “knocked out.” Soto and Sonnenschein have argued that
the artificial experimental circumstances that have enabled or promoted
the study of cancer “genes” render judgments about their causal efficacy
suspect; in principle, they claim, it’s consistent with these experiments to
suggest that these mutations are mere effects of the true causes of
carcinogenesis. Whether or not one agrees with their conclusions about
TOFT v. SMT, they do raise methodological questions worth exploring
about the scope and limitations of model organism work. Germain (2013)
points out that cancer in these xenotransplantation experiments are “highly
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artificial” contexts, and echoes concerns of researchers that the use of
immunodeficient mice to study cancer stem cells, for instance, may or may
not warrant the conclusions they claim to establish. Xenotransplantation,
for instance, has been used to articulate and test hypotheses about
“intrinsic tumorigenicity” of some cells, particularly cells expressing a
particular antigen, ABCB5+, which were then designated “cancer stem
cells” in light of their capacity to form tumors in nude mice (Germain,
2013, p. 9). The problem with using these tools, however, is that the
matter of when and whether a cell is “tumorigenic” varies across different
backgrounds—in immune deficient mice, lacking a particular receptor
(interleukin-2 gamma receptor, or Il2rg), tumors will grow, but not in mice
with such a receptor. Which experimental context is relevant to
understanding how and why cancer is caused by “stem cells,” thus
depends upon which causes we wish to isolate, and how. As Germain
points out,
On the one hand, human tumors do not develop “in the void”:
cancer patients are seldom so immunodeficient, and immune
response is an important part of cancer development and of
variability in outcomes. A notion of tumorigenicity independent of
this pressure seems to be an idealization that lacks practical
relevance. On the other hand, it seems scientifically worthwhile to
isolate the different components influencing the malignancy of
cancer cells, so that we might exclude the effects of the immune
system; tumorigenicity is one thing, evasion of immune
surveillance is another. (Ibid, p. 10)
A second question that Soto and Sonnenschein's work raises is whether
“downward causation” is at work in cancer. Several philosophers have
weighed in on this question (Malaterre 2011; Bertolaso 2016; Green
2019). Malaterre (2011) argues that advocates of TOFT need not commit
to non-reductive physicalism, or emergent properties. Instead, he argues,
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Soto and Sonnenschein are drawing attention to dynamic relationships
between variables that supervene over molecular and cellular activities,
and a “higher level,” or less granular explanation of cancer etiology may
be preferred in some contexts, both for pragmatic and epistemic reasons.
Malaterre makes appeal to Woodward’s (2010) argument that choice of
causal variables often involves appeal to something like a notion of
“proportionality,” such that, depending on the target of inquiry, we may be
“led to the incorporation of more fine-grained detail in the specification of
causes […] or toward specifications that abstract away from such detail”
(2010, 299).
Soto and Sonnenschein would likely reject this analysis, insofar as their
argument was not simply that tissue organization is deserving of our
attention, for pragmatic reasons, but “that carcinogenesis resulted from the
disruption of the reciprocal interactions between stroma and epithelium.”
Or more precisely, “the cancer phenotype is an emergent phenomenon
occurring at the tissue level of organization” (2006, p. 371). What
evidence is offered up for this kind of causal relationship? There are three
sources of evidence that Soto and Sonnenschein have emphasized as of
relevance to their defense of “organicism” and TOFT:
Embryonal cells can produce neoplasms when misplaced in adult
tissues, and revert to normalcy when placed in an early embryo
(Stewart & Mintz, 1981). In other words, the neoplastic phenotype
can be both induced or normalized or reversed, without any change in
the cell itself. According to critics of the somatic mutation theory,
such outcomes cannot be explained on the somatic mutation theory,
since there is no intrinsic mutational change in such cells.
Some neoplasms tend to arise in areas of contact between two types
of epithelium. During development and adult life, there can be
changes of tissue organization at just such points of interaction,
which may well be responsible for the induction of tumors in these
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cases.
Proteins in the extracellular matrix affect self-organization of
mammary epithelial cells in culture (Bissell 1981; Weaver, et al.
2002; Nelson, et al. 2006). That is, tissue organization can suppress
or promote the neoplastic behavior of malignant cells (Weaver, et al.
1997, 2002). For instance, Paczek (2005) shows that the malignant
phenotype can be altered by stiffness of the extracellular matrix, in
colonies of mammary epithelial cells (MECs).
All of these phenomena are taken as evidence that there are features of the
tissue microenvironment that affect either the induction of or progression
of cancer, and such features are not reducible to, or explainable in terms of
properties or processes at or below the cell and molecular level. Further,
Soto and Sonnenschein claim that the somatic mutation theory cannot
account for these observations, and that they can only be accommodated
on a view that takes that tissue architecture itself as causally relevant to
the progression of disease, which is described in this case as downward
causation.
Do such cases genuinely count as downward causation in, for instance,
Kim’s (1999) sense? After all, strictly speaking, the idea that causation is
synchronic across the whole and part of the same entity seems
contradictory. Soto and Sonnenschein accept this criticism, and propose
that the kind of causation they are invoking is not synchronic, but
“diachronic emergence”: “cellular and tissue events occurring before the
expression of a particular set of genes takes place may act downwardly
modifying the expression of these genes at a later time” (Soto, et al. 2008,
271).
This, however, seems to be not as radical a metaphysical thesis as talk of
downward causation may initially suggest. Indeed, Soto and Sonnenschein
seem to simply refer to a form of constraint. Green (2019) takes
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“downward causation” to mean just this: “the role of solid-state tissue
properties in tumor progression can be interpreted as a form of downward
causation, understood as constraining relations between tissue-scale and
micro-scale variables” (p. 1). She notes that while this suggestion is “a
‘weaker’ form of downwards causation than the one Kim (2000) and
others oppose,” and so departs from standard use of the expression (at
least among philosophers of mind), the advantage of this weaker notion
that it better captures what scientists have in mind when arguing for the
“necessity of higher-scale features for the realization and understanding of
biological phenomena.” Similarly, Bertolaso (2016) argues that:
The biology of cancer shows that the stability of constitutive
elements depends on the organization, and that there is a source of
regulation in the biological context. Cells change their behavior
depending on their functional integration in the tissue. Alteration in
cell communication alters gene expression, and the loss of
integration of cells within a functional tissue leads to genetic
instability and apoptosis. The collapse of levels, as characterized in
cancer, results from the loss of general functional integration of a
biological entity. This means that the structure itself, once
constituted, determines the relationships among the parts and the
stability of the parts… The dynamic structure has… causal
relevance. (2016, p. 87)
She characterizes this as an instance of synchronic reflexive emergence
—“a different mode of causation. In such a mode, effects are not
expressed in terms of a progression of events, but of maintenance of states
at different levels of biological organization” (Bertolaso 2016, p. 95).
It seems that each of these authors is pointing to an important role for
structural organization in the maintenance of homeostasis as playing an
important role in carcinogenesis. Indeed, evidence provided by Bissell’s
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lab (Weaver, et al. 1997, 2002) seems to indicate that structural features of
the extracellular matrix somehow either prevent the emergence of disease,
or can accelerate it. It seems such examples do not point to “downward
causation,” but instead suggest that we need to expand our understanding
of the causes of cancer to include maintenance of tissue integrity. That is,
the case of cancer seems to require a richer, more integrative and
interdisciplinary approach to investigating cancer.
Another major research program that in some ways challenges a
mechanistic picture of cancer (or at least some (Laplane, 2016) see as
opposed to the “classical view” of cancer) is the “cancer stem cell” theory
(CSC). However, the idea of cancer stem cells has been somewhat
controversial, in part due to the experimental models used to establish and
identify cancer stem cells. Fagan (2016) characterizes the notion of a
cancer stem cell, as well as the current state of the field, succinctly as
follows.
Cancer stem cells (CSCs) are thought to be a small subpopulation
of self-renewing stem cells within a tumor or blood-borne cancer,
which are responsible for maintaining and growing the
malignancy. This idea has significant clinical implications. If the
CSC model is correct, the current clinical strategy of seeking to
eradicate all cancer cells should be revised, to specifically target
CSC.
The cancer stem cell theory in part is descended from the view that
cancers are in several ways akin to ordinary tissue (though distorted),
containing a mixture of proliferating stem cells and their more
differentiated products. This view played an important role in cancer
research in the 1960s and 1970s, and is sometimes called the
“developmental” theory of cancer, in light of the fact that it takes cancer to
be a disease of “development,” or cellular differentiation in particular
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(Pierce & Speers 1988, Morange 2015, Laplane 2016). This model of
cancer etiology was revived in the 90s, when Lapidot, Bonnet, and Dick
identified “leukemic stem cells” (Lapidot, et al. 1994, Bonnet and Dick
1997), and was expanded upon in the early 2000s with the identification of
an analogous cell population in breast cancer, suggesting that CSCs are a
general feature of all cancers (Al-Hajj, et al. 2003).
The notion that there are subpopulations of cells within a tumor that play a
distinctive role—either in initiating a cancer, or in seeding new cancers,
has been influential in current research, suggesting new avenues for both
treatment and prevention. Historically the cancer stem cell theory (CSC)
was framed in opposition to the somatic mutation theory (e.g. Reya, et al.
2001; Wicha, et al. 2006; Shipitsin, et al. 2007). Laplane (2016) has
argued that the cancer stem cell theory (CSC) has various advantages over
the alternative, which she calls the “classical” theory. Laplane takes the
following to be the four fundamental theses of CSC theory:
1. CSCs are capable of self-renewal, thus producing new CSCs.
2. CSCs are capable of differentiation, thus producing cells of different
phenotypes.
3. CSCs represent a tiny subpopulation of cells, distinct from other
cancer cell populations and are, in theory, isolatable.
4. CSCs initiate cancers.
The first two claims concern the concept of a stem cell; the latter two
claims concern carcinogenesis itself: how cancer arises. It’s the latter two
theses that Laplane takes to be in tension with the “classical” theory.
Laplane argues that CSC theory is more “parsimonious”, because it
“explains cancer development, propagation and relapse” from a “limited
number of hypotheses” (Laplane 2016, 28). In contrast, the classical view
neither predicts nor explains cancer heterogeneity, or relapse, but must
invoke special (“additional” or “ad hoc” theories) to explain them, in
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Anya Plutynski
particular, evolutionary processes. Moreover, the CSC theory has the
advantage that it “connects basic research and intervention by suggesting
new therapeutic strategy” (Laplane 2016, 28)
Fagan (2016) argues, to the contrary, that on a “model-based” approach,
it’s not clear that these two theories are inconsistent. Indeed, Laplane
(2017) has more recently pointed out how the CSC can serve to
supplement the evolutionary perspective. The presence and number of
cancer stem cells can, it has been suggested, affect the rate and nature of
evolutionary change in a population of cancer cells. Essentially, if all cells
in a tumor are descended from one or a few cancer stem cells, this restricts
population size, and thus suggests that to a large extent cancer progression
is driven by drift, rather than selection. Rather than see the two theories as
mutually exclusive, in other words, we might see the two as
complementary, in the process of integration, or overlapping models.
All this discussion of the role and nature of cancer stem cells, however, is
complicated by the fact that there is a great deal of dispute around what
counts as a cancer stem cell. Both Laplane and Fagan draw attention to the
fact that the concept of cancer stem cell is multiply ambiguous, in at least
the following ways:
First, when we speak of cancer stem cells, we may be referring to
their capacities or properties, or to their historical role or genealogy,
i.e., to the fact that they were the cells from which other cancer cells
originate. That is, some take cancer stem cells to be defined in terms
of their distinctive capacities and some in terms of their relationship
to other cells—in particular, to their ancestor-descendent
relationships in a population of cells in a tumor. The “cancer stem
cell model” is sometimes simply taken to refer to any model of a
tumor that treats the population of cells as having a hierarchical
relationship, where one or a few cells propagate the tumor, whether
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or not those cells have distinctive properties that cause them to stand
in that relationship.
Second, there are several different kinds of historical role that CSCs
might play: They may be all and only those cells that initiate a cancer
under natural conditions, they may be those cells which propagate a
cancer in situ, or they may be those cells that are capable of
propagating a cancer in an experimental animal.
Third, some take the concept of CSC to be restricted to normal stem
cells, which some believe are the most likely precursors to cancer.
Others hold that cells that originate a tumor have stem-like properties
but may or may not derive from normal stem cells.
What’s clear is that some populations of cells in a tumor appear to have
“stemness” properties—the ability to renew oneself. What is less clear is
whether these capacities are context sensitive, and how and by which cells
they may be acquired. The plasticity of many types of cancer cells
suggests that they may acquire a stemness phenotype, and even shift back
to non-stem phenotype. Given this, it appears that the CSC is just one of a
continuum of general views, some of which take only specific types of
cells to be precursors to cancer and others which grant that many different
types of cells have the potential to develop such properties. That is, the
real question at issue is whether the cells that initiate a tumor are in some
way distinctive or require distinctive precursors, and how properties of
stemness are acquired. Whether stemness is intrinsic or acquirable, niche-
dependent or independent, moreover, will drastically change the
therapeutic strategy. The CSC model (the idea that CSC are at the origin of
cancer development, resistance to treatment, and relapse) might be true
and yet CSC-targeting strategy might fail. Indeed, what kind of property
“stemness” is may vary across cancers, and even over time within a cancer
(Laplane and Solary 2019).
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Anya Plutynski
In sum, there appear to remain several open questions about the nature of
cancer stem cells, and more generally, how to best intervene upon cancer
to successfully eradicate the disease. According to the model of the
disease inherited from the latter third of the 20th Century, somatic
mutations, acquired over a lifetime, to the acquisition of cancer’s
“hallmarks.” So, the best strategy for intervention may be targeting
specific pathways associated with these hallmarks. In contrast, according
to the Tissue Organization Field Theory (TOFT), changes in tissue
organization yield carcinogenesis. Thus, the best strategy for intervention
might be finding ways to intervene in the tissue microenvironment, so as
to create an environment less hospitable to the growth of cancer cells.
According to the cancer stem cell theory, cancer arises in cells that have
distinctive properties: continuous renewal, and indefinite growth,
permitting the emergence of new disease. On this view, eradicating these
stem cells seems essential to cancer treatment. Philosophical work on
cancer causation and explanation can better illuminate the competing
presuppositions of different approaches, clarify their commitments, and
offer insights into fruitful integration of new data. It is already clear that
philosophical discussions of ambiguities in how we define and measure
stemness is essential to understanding how best to prevent recurrence and
treat the disease (Clevers 2016).
Philosophical discussions of how and why TOFT and CSC challenge a
simple reductionist picture of cancer etiology are only two of several
examples. Other philosophers have described (or critiqued) evolutionary
explanations of cancer (especially models of multilevel selection)
(Germain 2012a; Lean and Plutynski 2016; Germain and Laplane 2017;
Plutynski, 2018). Still others emphasize systems biology-based
approaches to cancer (Bertolaso 2016; Plutynski & Bertolaso 2018), or the
important role of a developmental perspective (Laplane 2016, 2018; Fagan
2017). Others still emphasize how one might model cancer as an
infectious disease (Liu, et al. 2017), and or an evolutionary-developmental
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process (Liu 2018). What all these philosophers seem to emphasize is that
the study of mechanisms associated with cancer at the cell and molecular
level requires supplementation to better predict and explain the origin of
the disease, and design effective therapies. In addition, Pradeu
(forthcoming) has recently pointed out how the immune system plays an
apparently “paradoxical” dual role in cancer, both acting to prevent and
promote cancer. This raises interesting questions about the function of the
immune system, as well as the appropriate way of understanding
“organism,” “self” and “non-self” in biological contexts. There remain
interesting questions about how to integrate various perspectives on this
complex disease.
3. Cancer as a Byproduct: Evolution, Development,
and Aging
Dobzhansky (1973) wrote that “nothing in biology makes sense except in
light of evolution.” Can evolutionary thinking shed light on cancer? After
all, cancer is ordinarily understood to be a case of failure of otherwise
functional controls on cell birth and death. At first pass, this view seems
fundamentally at odds with taking an evolutionary perspective on cancer.
For, how can something that is an exemplary case of “dysfunction” count
as an evolutionary process or product of adaptive evolution? Moreover,
how ought we to square this picture of cancer with the fact that cancer
cells seem to co-opt developmental processes—i.e., the process of “de-
differentiation” typical of early embryonic cells? Is cancer a byproduct of
development? Finally, cancer seems to increase in incidence as we age. Is
cancer simply a byproduct of aging? Relatedly, if—as some argue—aging
itself is selected for (a contested question!), is cancer in some sense
“adaptive”? All these perspectives on cancer require us to perhaps rethink
the nature of function and dysfunction, or at least better understand how
there are trade-offs in fitness at different temporal and spatial scales over
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Anya Plutynski
the course of our life and evolutionary history. The best perspective to take
on this may be a “multilevel” evolutionary perspective—i.e., thinking of
evolution by natural selection as operating at different temporal and spatial
scales, both sequentially, and in some cases, simultaneously, sometimes
yielding unfortunate “cross-level byproducts” of selection at one temporal
and spatial scale, for entities or processes at other temporal or spatial
scales (cf. Okasha 2007).
First, it is relatively uncontroversial that understanding a species’
evolutionary history, and the selective trade-offs they face over the course
of their life history, can inform our understanding of how and why they are
more or less vulnerable to disease. For instance, some species are more
vulnerable to cancer than others. Why? Comparative biology—the
comparison of different species—may help us identify mechanisms
associated with disease vulnerability, onset and progression, when they
arose, where and why they are shared, as well as how they have diverged
(Aktipis, et al. 2015). Comparing and contrasting how development,
immunity, and other mechanisms of suppression of cancer across species
can help cancer researchers identify targets of opportunity for either
treatment or prevention of cancer. In addition, we can look to unique
features of our own evolutionary history in order to explain patterns of
disease incidence, suggesting selective “mismatches” with our ancestral
environment, a kind of “byproduct” explanations of our vulnerability to
diseases. This enterprise is broadly characterized as “evolutionary
medicine” (Crespi, et al. 2005; Gluckman, et al. 2009; Stearns & Koella
2008; Sun, et al. 2014).
While the broad principles behind evolutionary medicine are relatively
uncontroversial—we all are evolved organisms after all—philosophers of
biology have been skeptical of particular claims about how our
evolutionary history has shaped our vulnerability to disease. Some such
claims have been particularly contentious, either because the nature of the
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disease itself is not well characterized (especially mental illness, for
instance), or evidence in support of evolutionary “mismatch” with our
ancestral environment is both scant and disputed. Particularly where
alternative explanations may well involve attributing responsibility to,
e.g., pollutants, or choices in lifestyle that are politically or socially
sensitive, philosophers of science have been particularly skeptical. Some
have argued that many arguments in evolutionary medicine make
“adaptationist” assumptions, i.e., assumptions that a given trait is adaptive,
or selectively advantageous, founded on at best “just so” stories (Valles
2011; see also Murphy 2006).
Of course, there are better and worse such arguments; the best arguments
consider not only the widest array of evidence, but also trade offs in
fitness, as well as the role of constraints arising out of development and
life history. For instance, traits adaptive early in life may yield fitness costs
later in life. A vivid example of a trade-off in fitness is androgenic
hormones; such hormones predispose men to higher prostate cancer risk,
but they may also yield an advantage early in life, in terms of increasing
sperm production, relative growth and size at sexual maturity, and thus
(potentially) access to mates and resources. Some defenders of
evolutionary perspectives on medicine claim that high prostate cancer risk
in taller men may thus be a case of a “mismatch” between our ancestral
and current contexts (see, e.g., Summers, et al. 2008 for discussion).
Presumably, philosophers are likely to contest such arguments on a variety
of grounds—either speculative assumptions about the adaptive advantage
of size or early age of sexual maturity in our evolutionary past, or
concerns about how or how much variability in hormones contributes
either to body size or cancer risk. Though, this provides an interesting case
study for considering how hypotheses about the role of sex and age in
disease risk are tested, an area of growing interest.
34 Stanford Encyclopedia of Philosophy
Anya Plutynski
“Mismatch” hypotheses suggest that traits that may have been adaptive in
the past leave us vulnerable to disease in our current environment. For
instance, many advocates of evolutionary medicine have argued that the
high correlation between nulliparity and cancer risk might be explained by
our evolutionary history. The argument is that women in the evolutionary
past were pregnant for much of their lives, starting at an earlier age; breast
development and differentiation was thus adapted to a lifetime of frequent
pregnancy and nursing. Delaying or avoiding pregnancy changes the
developmental processes typical for our species, and might expose women
to more cycles of estrogen, which could increase breast cancer risk. Of
course, such hypotheses are contentious; there is always the potential for
confounding causes (in this case, of increased cancer risk due to a variety
of risk factors at work in modern society) (Greaves 2000). Nonetheless, it
has been known for centuries that nulliparity (not having children) raises
breast cancer risk, and since at least the 1970s, it’s been widely known (at
least in the cancer research community) that the more children one has,
starting at a younger age, the lower the risk of breast cancer. In a 1970
case-control study conducted at eight different locations around the globe,
a WHO group led by McMahon et al., estimated that “breast cancer risk
for women having their first birth under the age of 20 years is about half
that for nulliparous women,” and that “women having their first child
when aged under 18 years have only about one-third the breast cancer risk
of those whose first birth is delayed until the age of 35 years or more.”
Evolutionary “byproduct” explanations appeal to our evolutionary history
to explain this observation.
Another type of “byproduct” explanation of cancer—though one that
appeals to a much more distant event in our evolutionary history—is that
cancer is a product of the emergence of multicellularity. At one point in
the very distant past, single celled organisms formed collectives that
cooperate; these collectives eventually became multicellular organisms.
Any collective of cells, especially collectives whose survival and
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reproductive success depends on functional organization, are potentially
vulnerable to breakdown in cooperative organization. On this view, then,
cancer is a product of breakdown in mechanisms that permitted the
emergence of multicellularity—the mechanisms that protect us from
“revolt from within” are not error-free, and over time will fail. According
to Greaves and others (Greaves, et al. 2012; Merlo, et al. 2006) the
evolutionary picture of cancer dovetails nicely with the somatic mutation
theory; somatic cells divide and acquire mutations during our lifetimes;
some of these mutations involve failures in regulatory pathways that
ordinarily “enforce” functional organization, and thus cooperation. In this
way, an evolutionary perspective—understanding how evolution of
multicellularity required the emergence of cooperative organization—is
essential to understanding cancer. Moreover, on this view, cancer itself
may be viewed as an evolutionary process—the emergence of adaptive
features of cancer cells, where these “adaptations” enable short term
“fitness,” or relative success at survival and reproduction. Several
scientists have developed theoretical models of this process, linking it to
empirical data, e.g., on the emergence of chemotherapy resistance (Frank
2007; Wodarz & Komarova 2015).
On this view, cancer is a both a process and byproduct of multi-level
selection, where selection may be understood as operating at several levels
of biological organization simultaneously, or sequentially (Damuth, et al.
1988; Lean, et al. 2016). That is, cancer cells may bear adaptations, and,
they are also evolutionary byproducts of selective processes at other level
of organization. It appears that cancer cells co-opt or hijack otherwise
adaptive features of organisms. Signaling pathways that are ordinarily in
service of adaptive functions in early stages of development or wound
healing are reactivated in (some) cancer cells, in service of the transition
to metastasis. This is a classic example of a cross-level selective byproduct
(Okasha 2005, 2006). Traits advantageous at one level in the organization
of multicellular organisms may be coopted by component parts. Some of
36 Stanford Encyclopedia of Philosophy
Anya Plutynski
the capacities that invasive cancer cells acquire (the capacity to invade and
metastasize) are in fact due to a change in phenotype from epithelial to
mesenchymal type cells, and losing adhesive properties enables such cells
to invade the lymph and blood system. Lean and Plutynski (2016) have
argued that cancer may in some ways parallel the patterns of emergence of
multicellularity as characterized by Damuth and Heisler (1988), shifting
over the course of emergence of disease from a simple selective process
between individual cells to several kinds of multilevel selective process
(MLS1 to MLS2). Critics contest that the process of metastasis only
weakly mimics MLS2, however (Germain, et al. 2017).
To be sure, there are both analogies and disanalogies between evolution in
whole organisms, and the evolving population of cancer cells in a tumor
(Germain 2012). However, thinking of cancer as a dynamic, evolutionary
process, has great potential for applications in cancer treatment, and
perhaps also, in prevention. For instance, some have suggested that we
might give young girls drugs or nutritional supplements that remodel the
breast in ways akin to pregnancy, as a way to prevent the emergence of
breast cancer (Katz, et al. 2015). Others suggest that modeling the
evolution of multi-drug resistance may help prevent one of the major
causes of cancer mortality. Drugs can be more or less effective in different
patients, and lose their effectiveness over time. An evolutionary
perspective on cancer may shed light on how drug resistance comes about,
in patients with more or less intratumor heterogeneity (Greaves 2000,
2007; Frank & Nowak 2004; Merlo, et al. 2006; Greaves and Maley,
2010).
A third type of byproduct explanation for cancer is the view that cancer is
a disease of aging—that is, cancer incidence by and large increases as we
age, perhaps in part as a byproduct of breakdowns in mechanisms
associated with immune response and tissue integrity. This claim raises
some broader questions about how we assess function and dysfunction, or
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how we assess function at different temporal and spatial scales of analysis,
as well as how we understand the role of the immune system and the
integrity of the organism as an individual. Indeed, all evolutionary and
byproduct explanations of cancer raise similar philosophical questions
about hypothesis testing, as well as definitions of “function” and
“individuality,” both at the individual and group level, and over the course
of one’s life history. On the evolutionary view of cancer, for instance,
cancer cells are in some sense highly adaptive (Hausman 2011; Germain
2012; Godfrey-Smith 2009). One relatively controversial view of aging,
first proposed by August Weisman, is that aging has the evolutionary
advantage—effectively clearing the way for the young. If indeed cancer is
a necessary byproduct of aging, and aging is selected for, then on one
view, cancer may be thought of as adaptive. Such a view raises a variety of
questions about evidence and adaptationist explanations (see SEP entry on
“Adaptation”). They also raise questions about the merits of group versus
individual level selection hypotheses. Moreover, the dual role of the
immune system in both preventing—and paradoxically, in some cases,
promoting cancer—raises interesting questions about the nature of
biological individuality, as well as how we define “immunity” an the role
of the immune system in setting out the boundaries of the organism. (For a
vivid discussion, see, e.g., (Okasha 2006; Godfrey-Smith 2009; Bouchard
& Huneman 2013; Clarke 2011, 2013; Love & Brigandt 2017; Bueno, et
al. 2019; Pradeu 2012, 2013, 2016, 2019).
4. The Science-Value Interface and Aims of Cancer
Research
There are several ways in which biomedical and public health research on
cancer intersects with debates about the proper role of values in science.
First, epidemiological and toxicological research is used in support of
regulatory policy and toxic tort law. Decisions about when and what is
38 Stanford Encyclopedia of Philosophy
Anya Plutynski
“carcinogenic” have significant public health import, and thus raise a
variety of philosophical questions about evidence, values risk, and
precaution (Mayo, et al. 1994; Cranor 1993, 2006, 2011, 2018).
Evidence for such claims is often indirect, and underdetermination is rife.
In tests of carcinogenicity, there is a choice of levels of significance, and
even optimally done epidemiological studies, or toxicological studies, for
instance, at best lend high probability to claims about health risk. In such
contexts, there is “inductive risk”, or the risk of error either in over- or
under-estimation of actual risk of cancer, and thus, room for values to play
a role. Several philosophers of science have weighed in on this matter of
when and whether values ought to play a role in such contexts, as well as
which values, in particular precautionary judgments that may have import
for policy or law (see, e.g., Mayo 1988; Douglas 2000, 2009; Brown 2013;
Steel 2007, 2010, 2015; Elliott 2011; Shrader-Frechette 1993, 1994, 2002,
2004; and Mitchell 2009). As one might imagine, there is also a
substantive history of debate among epidemiologists, public health
scientists, scholars of the law, around when we have good reason to claim
that X or Y is carcinogenic, or what counts as good or “good enough”
evidence, going back to the dispute between Doll and Hill and their
detractors, regarding the causal link between smoking and lung cancer
(Hill, 1965). For a compelling history of this literature, see, e.g., Proctor
(1995), or more recently, Oreskes, et al. (2011). Problems of
underdetermination are no less rife in the context of assessments of
“effectiveness” of cancer screening and prevention (see, e.g., Solomon
2015; Stegenga 2017; Plutynski 2017. (For a discussion, see the entry on
philosophy of medicine.)
Second, much of basic cancer research—e.g., research on the cell and
molecular bases of the disease—is supported by federal funds, which often
are allocated in the hopes that such research will (eventually) yield better
health outcomes. Yet, the relationship between “bench and bedside” is, by
Summer 2019 Edition 39
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all accounts, extremely indirect, and shaped by many factors outside of the
merits of the science itself. So, it’s unclear whether and how “basic”
cancer science ought to be evaluated in light of whether or how it leads to
better health outcomes. However, this is hard to avoid, particularly when
so many lives depend upon a research program’s promised outcomes.
This whole matter is complicated by the fact that the study of cancer is
itself big business. Indeed, some compare cancer research and medicine to
a “medical industrial complex.” Cancer pharmaceuticals, medical devices,
and cancer research more generally, are major drivers of the economy. On
the one hand, given the loss of life due to cancer, one could argue that the
time and energy devoted to cancer care and research is proportional to the
threat. Löwy (1996) in her Between Bench and Bedside characterizes this
as the “white” (optimistic) reading of the situation. Arguably, however,
many other diseases, often those more prevalent in “developing” parts of
the world, cause far more extensive loss of life. As Reiss and Kitcher
(2009) and Reiss (2009) have argued, from a “Millian” perspective, we
ought to be expending our resources on those diseases that proportionally
cause the greatest loss of life, and so, at least from a strictly maximizing
utilitarian perspective, these diseases have a greater claim on our
investments. The vast funds invested in cancer research—at least during
the past 25 years or so—have done very little to shift mortality rates. This
leads to what Löwy might call the pessimistic answer to this question.
According to one line of thinking, the centrality of cancer in biomedical
research is a product of several historical, economic, institutional, and
social forces in combination, some of which are self-perpetuating (Proctor
1995; Fujimura 1996; Clarke & Fujimura 2014). Ever since Nixon’s 1971
call for a “war” on cancer, advertised implications for cancer treatment or
prevention have been used to bolster much of basic research into genetics,
genomics, and cell and molecular biology, fostering investment in
biotechnology. Some have argued that this has led to an unduly excessive,
or disproportionate fear of cancer as a disease, an excess of anxiety, and
40 Stanford Encyclopedia of Philosophy
Anya Plutynski
perhaps also unnecessary or unwarranted use of medical screening and
testing (Aronowitz 2007, 2009, 2015).
On the other hand, cancer research has led to important innovations in
science and medicine with impacts much wider than cancer itself.
Moreover, particularly in the U.S., regulations on research by, e.g., the
FDA on the design and conduct of clinical trials for approval of drugs, for
instance, may in part be slowing research and leading to excessive costs.
Some argue that we ought to lift restrictions on such tests for novel and
more “precise” (or targeted) drugs that might benefit very few. Such
matters are of course intertwined with larger debates among both
clinician-researchers and philosophers of medicine around when and
whether we have sufficient evidence to claim that, e.g., this or that mode
of intervention is effective. In part, such debates are shaped by the
economic costs of large clinical trials, and in part, by epistemic issues
around what and how we can and should measure, in making claims to
“effective” intervention (Ashcroft 2002; Cartwright 2011; Howick 2011;
Stegenga 2015; Teira 2011; Teira, et al. 2015; González-Moreno, et al.
2015; Deaton, et al. 2018).
One area where such questions are particularly fraught is “precision”
medicine; Obama’s Reinvestment act budgeted a significant component
toward cancer genomics, with the idea that a more fine grained analysis of
the molecular and genomic features of cancer would promote more
effective prediction and control of cancer risk, enable detection of cancers
at much earlier stages, and less debilitating, more targeted treatments.
With better technologies and more fine-tuned risk information, the practice
of medicine has been shifting from diagnosis (and treatment) of disease, to
constant surveillance and intervention on disease risk, as well as higher
rates of overdiagnosis and overtreatment (diagnosis and treatment for a
proto-disease state that may never have progressed in the lifetime of a
patient) (Welch, et al. 2011; Esserman, et al. 2014). Moreover, one
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concern some have raised about precision oncology is that it has been less
successful than hoped or advertised (Prasad & Gale 2016, Prasad, et al.
2016). Such skepticism should raise genuine concerns—especially given
the hopes of patients and families hanging upon the promises of such
treatments, and the overall costs of both cancer care, and precision
medicine research. In sum, current practices of cancer research, screening
and treatment raise a number of questions: How ought we to allocate
research funds in cancer research? How is investment in precision
medicine likely to yield the benefits promised? When is medical
intervention on disease risk (rather than disease itself) unduly excessive?
What exactly does it mean to speak of effective medical intervention? Is
overdiagnosis and overtreatment a serious harm, or is it simply an
inevitable byproduct of an otherwise effective strategy—treating disease
risk? How ought clinicians to communicate about risk and benefit of novel
targeted interventions to patients, especially where there are gray areas of
benefit and harm? Are the (frequently) excessive costs of, and inequitable
access to, cancer care, matters of justice?
Cancer research—and especially the hope and hype surrounding precision
medicine—provides a focused lens through which to consider problems
central to critical examination of the concepts and methods of the
biomedical sciences. That is, cancer and the scientific study of cancer
illustrate challenges facing disease classification, fuzzy borders between
disease versus health, the problems with genetic essentialism, the ever-
present reference class problem and ever promised solutions, as well as
specific ways in which underdetermination of evidence in biomedicine
shapes matters of justice in public health. Moreover, it provides a case
study in how matters of evidence, disease status, and questions of values
and justice are deeply intertwined.
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