model organisms and behavioral genetics: a rejoinder
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Model Organisms and Behavioral Genetics: A Rejoinder*
Kenneth F. Schaffner†
Medical Humanities
and
Department of Philosophy
George Washington University
___________________________________________________________
* Received 1/17/98
†Reprint requests to the author at University Professor of Medical
Humanities, 714T Gelman, George Washington University, Washington,
DC 20052. E-mail: [email protected]
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ABSTRACT [if needed]
In this rejoinder to the three preceding comments, I provide some
additional philosophical warrant for the biomedical sciences’ focus on
model organisms. I then relate the inquiries on model systems to the
concept of ‘deep homology’, and indicate that the issues that appear to
divide my commentators and myself are in part empirical ones. I cite
recent work on model organisms, and especially C. elegans that supports
my views. Finally, I briefly readdress some of the issues raised by
Developmental Systems Theory.
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1. Introduction. The three sets of preceding comments raise important
questions not only within the philosophy of biology, but also for current
biomedical research programs more generally. Two of the papers (Gilbert
and Jorgensen and Wimsatt) question the biological utility of a focus on C.
elegans and other “simple systems” or “model organisms.” This
criticism presumably also applies to highly directed research by
biomedical scientists on Drosophila and the mouse (Mus), and probably
also to investigations on E. coli, yeast, the plant, Arabidopsis, the
zebrafish, and primates. Griffiths and Knight’s paper does not dispute my
essay’s focus on C. elegans, but does question one of my conclusions
regarding the heuristic priority of DNA-based analyses.
In what follows, I will first discuss two general strategies of research
in the biomedical sciences and provide a twin philosophical rationale for
the simple systems approach. More specific replies to the comments are
then offered.
2. Two Strategies of Research in the Biomedical Sciences. To
a first approximation, inquiry in the biological sciences can take two
contrasting approaches, that we might term (1) narrow but deep (ND), 3
and (2) broad but shallow (BS). The ideal approach would be both deep
and broad, but for practical reasons that is most likely to be a “long run”
strategy. The first type, ND analysis, mobilizes the biomedical
community’s resources around a few prototype organisms, some of which
are “simple” (phage , E. coli, and C. elegans) and some that are more
complex (Mus and various primates). BS inquiries on the other hand
highlight biological variation and diversity, both within and among
organisms and environments, and urge we attend to many different
species simultaneously in biological investigations. Both Gilbert and
Jorgensen and Wimsatt in their comments seem to strongly favor the BS
approach, arguing (or implying) that the ND approach is misleading and
gives a false picture of biological complexity, particularly as involves
organism and species plasticity. In my article, I argue for a ND “model
system” approach (pp. 000-000), both in biology and in the philosophy of
biology, but I did not discuss a background rationale, and that now seems
useful to do in the light of the thrust of many of the commentaries.
Bruce Alberts, a noted biologist, current President of the U. S.
National Academy of Science, and an author of a highly influential
textbook, The Molecular Biology of the Cell (Alberts et al., 1995), recently
asked a rhetorical question about C. elegans studies. He wrote:
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Why should one study a worm? This simple creature is one of
several “model” organisms that together have provided
tremendous insight into how all organisms are put together. It has
become increasingly clear over the past two decades that
knowledge from one organism, even one so simple as a worm, can
provide tremendous power when connected with knowledge from
other organisms. And because of the experimental accessibility of
nematodes, knowledge about worms can come more quickly and
cheaply than knowledge about higher organisms. (1997, xii)
Alberts adds:
...we can say with confidence that the fastest and most efficient
way of acquiring an understanding of ourselves is to devote an
enormous effort trying to understand these and other, relatively
“simple” organisms. (1997, xiv)
I think this statement is representative of a broad consensus among
contemporary biological researchers, but it will be useful to examine why
a “model organism” approach is so widely accepted in contemporary
biology.
.?.Endnotes:
. The question could be framed more broadly than I have the
possibility of doing so here, to include historical and sociological factors — a
variant of Gilbert and Jorgensen’s question “why do genes sell?” perhaps —
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I want to argue first that the structure of biological knowledge, from
both epistemic and logic-of-explanation perspectives, is organized
differently from what we find in standard accounts of the physical
sciences. In physics the main “explainers” are theories viewed as
collections of a small number of interrelated universal statements (e.g.,
Newton’s 3 or 4 laws, Maxwell’s 4 or 6 equations, or the 3 axiom version
of quantum mechanics) , a notion I have called the “Euclidean Ideal”
(Schaffner, 1986). In contrast, with a few (important) exceptions,
biological knowledge and biological explanations seem to be framed
around a few exemplar subsystems in specific organisms, and perhaps
even in specific strains. Examples include the Jacob-Monod lac operon in
E. coli K12, Mendel’s pea “factors,” Morgan’s white-eyed male mutant in
Drosophila, Guyton’s dog model in cardiophysiology, and Kandel’s Aplysia
model for learning in neurobiology. These exemplar subsystems are used
as (interlevel) prototypes to organize information about other similar
(overlapping) models to which they are related by analogical reasoning
and to ask “why model organisms sell?” These broader types of questions
have and will continue to be investigated in science studies (see Clarke and
Fujimura 1992).
.?.. This is a view I have held for about twenty years, since I first wrote
on theory structure in biology (Schaffner, 1980). An updated version, and an
extension of the view, appear in chapters 3 and 5 of my 1993 book.
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rather than deductive elaboration. I would speculate that the very
existence of confusing diversity and variation in biological organisms and
processes forces a focus toward simplifying prototypes that can be used
to convey information, and laboratory techniques, in a less bewildering
way. On such a view — one that mirrors Alberts’ account, but more
epistemically and as related to the logic of explanation — model systems
are a powerful heuristic for biological research.
Such prototypes of necessity need to be representative — to
connect analogically to other prototypes — if they are to do their job(s)
as surrogates for what theories do in other sciences, since they putatively
function as the (nearly) common element relating a variety of organisms
or biological processes. Though the organisms are typically chosen for
partly idiosyncratic historical reasons, there are some general reasons for
“model” organism choice, including short life cycle, ease of stock
maintenance, and experimental tractability (see Ankeny 1997, but also
Bolker and Raff 1997). The hope, of course, is that such chosen
organisms and subsystems, when probed deeply and broadly enough, will
disclose “widely conserved” mechanisms of general applicability,
sometimes called “high connectivity models” or “deep homologies.”
Interestingly, the test for the conservation is initially in other model
.?.. To be sure, deductive reasoning will be used in working problems,
checking consistency, within causal models, etc.
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organisms, with Homo sapiens being the ultimate pragmatic application,
typically in the medical context.
The terms “high connectivity” and “deep homology” are worth
some brief additional consideration. In their overview of the utility of C.
elegans as a model organism, Riddle et al. (1997) write that C. elegans,
in addition to yeast, Drosophila, and a few other model systems, is a
“high connectivity model,” using a term initially introduced by Morowitz’s
1985 report on models in biomedical research. In such models,
“knowledge gained in one area of research ultimately “connects” with
research in other areas. This connectivity both expands and reinforces
understanding and speeds research progress” (1997, p. 6). Riddle et al.
cite “parallels between the development of the body plan in nematodes,
.?.. Wimsatt suggests (p. 000) that one of my heuristics for finding
common pathways where only a few genes will explain behavior will not
work unless these pathways are “widely distributed phylogenetically.” But
this misunderstands my sense of “common,” which at that point is meant to
describe a coming together of diverse inputs into a common pathway that
may account for those rare (?) circumstances in which one or a few genes
have a strong effect on a trait of interest. Moreover, these pauci-genetic
explanations could be extremely important even if not “widely distributed
phylogenetically,” if they accounted for a human disease, such as
schizophrenia.
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flies, and mice” and also the similarity of proteins used for programmed
cell death in both nematodes and humans.
“Deep homology” identifies the same set of near “universals,” but
adds the beginnings of an explanatory dimension. The term “deep
homology” refers to widespread conservation, by descent, of gene
sequences, together with identification of functional similarity across
many organism types (see Fitch and Thomas 1997, 830). Molecular
biologists currently search gene data banks for homologous genes as
part of their fundamental inquiries into gene function (see the discussion
in my paper and the example in my fn. 35). Though the concept of
‘homology’ admits of a number of different senses (see Hall 1994), the
core idea seems to involve some intuition of “sameness.” Hillis argues
that “molecular biologists may have done more to confound the meaning
of the term homology than have any other group of scientists,” adding
that “in many circles of molecular biologists, homology has come to
mean “similarity”: a simple quantifiable relationship, for which the word
similarity adequately suffices” (1994, 339-340). But what this tells us, in
my view, is that molecular biology has extended the original concept of
homology to include elements of its initial contrast concept, analogy,
because of the power of widely conserved genes to identify similar
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functions. Whether this account of deep homology is a useful one is in
part an empirical matter, which I address further below.
What is wanted is a further explanation of the power of model
systems including the features of high connectivity and deep homology. I
think that it is here that Wimsatt’s concept of “generative entrenchment”
can, as he suggests, play an important role. Other like concepts are
Waddington’s “canalization” (1958), Riedl’s “burden” (1978), Kauffman’s
self-organizing properties (1993) , and Wagner’s “generative” and
“morphological” constraints (1994). All of these appear to seek ways in
which genetic and epigenetic factors restrict variation and make some
nearly universal mechanisms more likely.
There is a separate but related issue regarding model systems
raised by Gilbert and Jorgensen’s comment that “the very richness of life
that the Developmentalist Challenge claims has been hunted down and
eliminated from C. elegans research” (1998, 000). Actually, if this was
the intent of the “hunters,” they failed. It is ironic that such a highly
inbred and simple system exemplifies many of the Developmentalist
Systems Theorist’s (or DST) principles —a result that, as Wimsatt
mentions (1998, 000), was surprising to me. But I take a different
message from the C. elegans’ community’s attempt to restrict variation
in the organism — a message that does not relate to DST at all. To me, 10
models are not only intended to be representative prototypes, but also to
be “idealized” in the sense of sharpened and more clearly delineated.
The value of sharpened, simplified idealizations is a lesson that the
physical sciences can still teach us, and it is evident in the idealizations
found in simple subsystems in biology as well, such as in the original
operon model for E. coli K12 (Jacob and Monod, 1961). Once simple
prototypes are preliminarily identified (for example, the so-called “wild
type” of subsystem and some key mutants), then variations (often in the
form of a spectrum of mutants) are sought (or re-examined) to elucidate
the operation of simple mechanisms. For examples of this strategy in the
operon area see my 1993, 76-82. In point of fact, Griffiths and Knight
(1998) themselves, as spokespersons for DST, do not object to my focus
on the worm.
The bottom line it seems to me, after these philosophical
preliminaries have established a rationale and a context, is whether the
model systems approach can be supported by empirical facts, and it is to
this issue that I now turn.
3. Empirical Support for the ND Approach in C. elegans That
Points Toward Variation and Richness.
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A. Phylogeny and Strain and Species Variation. Wimsatt cites Bolker
and Raff ‘s 1997 criticism of the model systems approach as subscribing
to a “great chain of being” myth. But in actuality, the place of the worm
in phylogeny is the subject of empirical investigation, as well as some
controversy. Fitch and Thomas (1997) offer three cladistic possibilities as
represented in figure 1 (a,b,c), and argue that the data available to them
supports 1a. If so, this would license the use of the worm as a predictor
for humans (Fitch and Thomas 1997, 817), in agreement with Wimsatt’s
suggestion that model systems proponents need to take evolution into
account. But quite recently, Aguinaldo et al. (1997) have argued that
their data analysis of ribosomal 18S rDNA supports something more like
figure 1b, and state that “... it had been assumed that developmental
mechanisms common to Caenorhabditis and to Drosophila originated
before the protostome-deuterostome divergence and hence should also
be found in Homo sapiens. Our results imply that mechanisms found in
both nematodes and fruit flies will not necessarily be found in humans”
(1997, 492). Fitch (personal communication) believes that 18s rDNA
evolves too rapidly in nematodes to be of much use as a phylogenetic
instrument, particularly as regards the deep divergences to which it has
been applied by Aguinaldo et al. (1997).
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This debate will continue, and the relation of C. elegans
mechanisms to developmental mechanisms in the mouse, that argues
against Aguinaldo et al.’s 1997 position, will be cited below. But the
general point to be made here is that the relationships among model
systems is not viewed in terms of some philosophical great chain of
being, but is a matter that is in part an empirical investigation, in which
awareness of alternative possibilities are actively pursued.
Another point at which empirical results can help us sort out the
value of the ND and BS approaches is in connection with experimental
testing of putative “deep homologies,” such as mentioned in the previous
section. Perhaps the most interesting area in C. elegans deep homology
involves developmental and pattern-forming mechanisms. There is
evidence that C. elegans uses the same mechanism as does Drosophila
and the mouse for cell-fate specification (Fitch and Thomas 1997, 830;
Manak and Scott 1994). Fitch and Thomas suggest that a “tool kit” of
“basic regulatory mechanisms” is used by all species evolutionarily
proximal to C. elegans. They also state that “the most striking evidence
for the conservation of function is the ability of a molecule from one
species to function in a different species as its endogenous homologue,”
and cite the ability of human blc-2 to regulate cell death in C. elegans,
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and also the interspecies substitutability of the hox genes between
worms and fruit flies (1997, 831).
Thus, in contrast to Wimsatt’s 1998 (and Gilbert and Jorgensen’s
1998) concerns about the nonrepresentativeness of C. elegans, these
results actually suggest C. elegans could help Wimsatt to confirm his
belief that the hox gene example is paradigmatic of generative
entrenchment.
Finally, readers should be aware of the preliminary inquiries
currently under way to investigate strain and environmental variations in
C. elegans, and similar investigations in the nematodes in general. Fitch
and Thomas (1997) point out that there are 17 Caenorhabditis species
that are known, though only four are currently easily available, and that
initial comparisons suggest considerable genetic variation between
species in spite of morphological similarity. Fitch (1997) has issued a
request to the C. elegans community for information about available non-
elegans strains so as to share them more broadly. Further, more than 20
different C. elegans strains have been identified in the soil of four
different continents, and are under investigation to examine genetic
diversity and phylogeny (see Fitch and Thomas 1997, 825-830). Thus C.
elegans researchers are not solely interested in hunting down and
eliminating variation, but wish to use the information generated by 14
detailed investigation of the N2 Bristol strain for comparison with other
organisms, both reasonably closely related, as well as phylogenetically
more distant classes.
B. Genes, Neural Plasticity, and Behavior. A related concern about
the elimination of variation in model systems, but in studying the
relations of genetics to behavior, is expressed at several points by Gilbert
and Jorgensen (1998, 000, 000). I disagree with Gilbert and Jorgensen’s
claim that worm behavioral geneticists can only study traits that are
present and absent (p. 000), and thus will miss any subtle variation.
Behavioral assays can identify a number of fairly complex behaviors (see
Gannon and Rankin 1995). Furthermore, subtly different chemotactic and
thermotactic behaviors in the worm are modified by experience, and
these effects have been extensively studied and related to a variety of
genes in C. elegans (Bargmann and Mori 1997). Also, various protocols to
examine associative learning have and continue to be explored in C.
elegans, as Gilbert and Jorgensen know well (see Jorgensen and Rankin
1997, 787-790). Interestingly, Jorgensen himself, writing with Rankin
(1997) on neural plasticity in the worm, states that that “Once well-
defined learning paradigms become established in C. elegans, genetic
analysis of this organism may resolve several long-standing issues in our 15
studies of learning and memory” (790). Jorgensen and Rankin also write
that “in the future, genetic analyses of the mechanisms involved in the
long- and short-term memory phases of habituation should lead to
additional insights into the similarities and differences between memory
processes in this simple nervous system [C. elegans] and in more
complex organisms such as Drosophila, Aplysia, and mammals” (787).
In general I read Gilbert and Jorgensen’s comments as largely in
agreement with the main messages of my essay, though we occasionally
use somewhat different language in our formulations of the issues. In
addition to issues about model organisms in general already reviewed
above, Gilbert and Jorgensen (1998) ask whether worm research can say
anything useful about interesting research on human cognition, and
argue that it essentially cannot ([ref. To Gilbert and Jorgensen, 1998] p.
000). My answer to this question, as indicated in my paper, is more
positive. Part of the answer is contained in the comments about deep
homology made earlier, but part of the value of C. elegans studies is also
methodological. Worm studies will not tell us anything about
consciousness or intention or agency ([ref. To Gilbert and Jorgensen,
1998] p. 000), for complexities exist in humans not found in simpler
organisms. And some of these complexities will include the interaction of
linguistic and socio-cultural factors with biological developmental 16
processes (see Deacon 1997 for an elaboration of such a view). But some
fundamental mechanisms, including simplified analogues of real
biological neural nets are emerging in C. elegans studies (see my
references to Lockery’s research program in my paper and also Wicks et
al. 1996). Furthermore, it appears that the molecules and mechanisms
of neurogenesis are phylogenetically conserved among worms, flies, and
vertebrates” ( Fitch and Thomas 1997, 831; also see this page for
supporting references).
The types of influences that genes can have on human behavior
are outlined in section 6 of my paper. Where Gilbert and Jorgensen and I
may disagree on some useful extrapolations to humans lies in the area of
psychiatric genetics. There is already a useful homologue available in C.
elegans that relates to Alzheimer’s disease (Levitan and Greenwald,
1995). And the model system approach is only in the early stages of
application to such other serious diseases as schizophrenia, where a
potentially suggestive mouse model has recently been identified (the
dishevelled gene), that also has some ties back to Drosophila (Lijam et
al., 1997). A worm is not a human, but worm studies may offer important
lessons about human psychopathology if yoked to other model systems.
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4. Developmentalism: Pros and Cons. Griffiths and Knight close
their comments by anointing me as a developmentalist (p. 000). It should
be clear from my paper, and Griffiths and Knight’s excellent summary of
the themes I sketched, that I am sympathetic to some of those themes.
In particular, I think that the DS theorists have provided important
criticisms to philosophers’ — and biologists’ — overly restricted attention
to genetics and the role(s) of DNA. Griffiths and Knight do criticize me for
one of my exceptions to the Developmentalist creed, however, namely
my views about the heuristic and epistemic priority of DNA and its
informational content. In response, I would reiterate my comments on pp.
000-000 of my paper that I think are powerful arguments, but would also
add that I have already acknowledged the importance of epigenetic
inheritance factors, albeit briefly, where I touch on the importance of
“maternal effects” (p. 000).
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The sense of ‘information’ I intend is related to the question what
molecule types account best for individual and species differences.
Though it is possible that we may find extensive variations in molecules
other than DNA that constitute the set of severally necessary and jointly
sufficient conditions for embryogenetic differences, at present the
variations among individuals and species seem largely resident in the
DNA. Of course, as Griffiths and Knight suggest, this may because this is
only where we have looked for causes —there is (as yet) no Human
Phenome Project, that might focus on molecules other than DNA and on
higher order properties. Sarkar (1996), whom Griffiths and Knight cite as
critical of the informational concept of the gene, also seems to be
struggling to capture this sense of information, though he does also does
not find any plausible, developed account that characterizes it (see
especially pp. 222-223 for his possible alternatives to DNA-based
biology).
Developmental Systems Theory may be one of those possible
alternatives (though not one that Sarkar mentions or seems to favor).
The dangers of DST in its present form, as I see it, is that it gives too
much to “context,” see Griffiths and Knight’s 1998, 000-000 comments,
and needs to formulate its categories of interactions more clearly, but
that is not a point I can elaborate in this reply. It is not helpful to assert 19
that everything interacts with everything else, but that could be a
problem for DST unless it provides us with some form of prioritized
ontology. It would be interesting to see what an NIHish DST research
grant program announcement and request for proposals would look like,
and I would encourage Griffiths and Knight, and other developmentalists,
to consider proposing one.
5. Conclusions. This set of excellent comments has pushed me to
consider a number of foundational issues that were only implicit in my
paper. There is much more to be done. For example, Gilbert and
Jorgensen ask “Why do genes sell?” — and also to whom do I need to tell
this story about DST and the extent to which it is supported by C. elegans
results. (More colorfully, they ask on whose door should I nail these
theses, p. 000, suggesting behavioral geneticists and journalists need to
know.) I would agree that those groups are prime audiences, but for a
different type of paper than this one was intended to be. Other papers
and projects currently under way will likely be the source of messages to
these and other policy-making groups.
My paper and this rejoinder are primarily directed at the philosophy
of science community, and at those scientists who have an interest in
philosophical issues. It is my hope that this symposium will raise the 20
discussion of genetics and behavior to a new level in terms of
philosophical clarity married to scientific detail. Certainly the
commentators have accomplished that, and I hope that I have as well.
21
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.?.. There are two factual points where Gilbert and Jorgensen provide
appropriate corrections to statements I made in my paper. (1) I used the
odr-7 gene as an example of gene-neuron behavior specificity, whereas they
cite the odr-10 locus (1998, 000). It has turned out that odr-7 is a control
gene for odr-10 that codes for a receptor, so though the former has the
specific effects on the AWA neuron I mentioned, the site of action is earlier
in the pathway (see Bargmann and Mori 1997). (2) Gilbert and Jorgensen
say (p. 000) it is sometimes unclear whether I am talking about a worm’s
attractant detection ability or a worm’s ability to move towards an
attractant. I do not believe that I conflate these two notions, and allow the
context to make the distinction. But that distinction could be masked in the
experimental population if the appropriate controls were not provided. See
Sengupta (1994) for an account of those comparative controls and possible
alternative explanations, esp. 971-973, 975, and 977.
.?.. Harold Morowitz told me (personal communication) that the
bioinformatics community has become interested in “phenomics” and that
there is some discussion of trying to identify “physiomes” that would
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implement this possibility. A number of members of this community think
that this type of inquiry might lead to a successor to the human genome
project. See
http://nsr.bioeng.washington.edu/NSR/physiome/files/Petrodvoret.1997/
summary.html for details
”?.. See Günter Wagner’s discussion in his 1994.
.?. . More accurately, this is a partly empirical investigation, given the
extensive number of methodological and philosophical assumptions that
underlie phylogeny. This has been written on extensively in philosophy of
biology by David Hull, Elliott Sober, and many others, but this is not the
place to discuss this.
?.. I thank Manfred Leibichler for bringing this article to my attention.
.?.. One paper jointly authored with a psychologist (Irving Gottesman)
and a behavioral geneticist (Eric Turkheimer) has already been delivered in
oral form to an audience of bioethicists (Joint Meeting of the American
Association of Bioethics and the Society for Health and Human Values,
29
Baltimore, November, 1997). A project on which I have agreed to consult
and that will be directed toward improving the lay public’s understanding of
behavioral genetics is in the process of submission to the NIH by the
Hastings Center and the AAAS.
Figure 1 Legend (from Fitch and Thomas 1997, 818):
Figure 1. Three possibilities of relationships of C. elegans ("the"
nematode) to Drosophila melanogaster ("the" arthropod) and Mus musculus
("the" vertebrate): (a) nematodes as an outgroup taxon to vertebrates and
arthropods; (b) nematodes more closely related to arthropods than to
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vertebrates; (c) nematodes more closely related to vertebrates than to
arthropods. Obviously, these hypotheses (like the model systems
themselves) are overly simplistic representations for enormously diverse
phylogenetic groups. Although present data favor a or b, robustly
distinguishing which hypothesis is most likely depends on the accumulation
of much more data.
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