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: medhum@gwis2.circ.gwu.edu

1

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.

2

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:

4

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 —

5

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.

6

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.

7

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.

8

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

9

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.

11

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).

12

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,

13

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.

17

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).

18

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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27

.?.. 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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