Forthcoming in Endeavour (accepted June 2013)
Title: What Makes a Model Organism?
Sabina Leonelli*
ESRC Centre for Genomics in Society
Department of Sociology and Philosophy
Byrne House, St Germans Road
University of Exeter
Exeter EX4 4PJ UK
[email protected]
Rachel A Ankeny
School of History & Politics
423 Napier Building
University of Adelaide
Adelaide 5005 SA AUSTRALIA
[email protected]
*Corresponding author
Keywords: model organisms, experimentation, genetics, history, science policy
Introduction
Model organisms are usually defined as non-human species that are extensively studied in
order to understand a range of biological phenomena, with the hope that data, models and
theories generated will be applicable to other organisms, particularly those that are in some
way more complex than the original. The selective use of organisms has been critical in
biology for centuries, as underscored by the commonly cited August Krogh principle: ‘For a
large number of problems, there will be some animal of choice, or a few such animals on
which it can most conveniently be studied’ [1]. In many cases, the selection of particular
organisms was fortuitous rather than carefully planned, as the organisms were already in use
or familiar to the researchers, and some of their advantageous features only emerged in
retrospect [2-4]. The most widely acknowledged inventory of model organisms, compiled by
the U.S. National Institute of Health, comprises only thirteen species, including the yeast
Saccharomyces cerevisiae, the fruitfly Drosophila melanogaster, the nematode worm
Caenorhabditis elegans, the plant Arabidopsis thaliana, the zebrafish Danio rerio and the
mouse Mus musculus [5]. Yet, since the advent of the large-scale genomic sequencing
projects, the term “model organism” has become ubiquitous in biological discourse, and is
increasingly used to describe any experimental organism utilised to investigate a particular
biological process or system. Examples of this tendency include recent laboratory manuals on
“emerging” model organisms ranging from honeybee to wallaby [6]. Many research groups
are experiencing pressures as a result of the popularity of the term, for instance due to
competitive granting systems that force researchers to focus on these organisms or to
rationalise proposed research work on a particular organism by claiming that it is, in some
sense, a “model organism” [7, 8]. The model organism concept has thus been accused of
“swamping out” research agendas, making it difficult to get funding to do research on nonmodel organisms [9]. Critics also questioned the scientific validity of model organisms as
research tools, pointing out that their use emphasises unity across life instead of exploring
diversity, and genetics over all other organismal features or levels of analysis [10]. These
critiques are largely justified, yet fail to recognise the important role as reference points that
model organisms have acquired in contemporary biological research, the complex factors that
have led them to have this status, and the implications for research and funding. This
commentary proposes a view of model organisms that explains their key role within
contemporary large-scale biological research, while at the same time acknowledging their
limitations as biological models.
From experimental to model organisms
The list of organisms deemed to be well-suited for research purposes includes hundreds of
species, such as for instance the sea urchin for development; Planaria for inheritance;
Chlamydomonas reinhardtii for photosynthesis; Dictyostelium discoideum for cellular
differentiation/communication; Aplysia for neurobiology; the dog for physiology and
haematology; the mouse in fields ranging from physiology to immunology and oncology; and
the rat in nutrition, neurology and behavioural psychology (e.g. [11,12]). What we wish to
contend here is that not all of these organisms have played the same role within experimental
research. In particular, not all experimental organisms have become model organisms.1
Experimental organisms do not necessarily have to be representative of species other than
themselves. They are studied either as (1) a means to investigate a specific phenomenon or as
(2) interesting organisms in and of themselves. Prominent early examples of (1) include the
frog and the guinea pig. Dating back to the late 1600s, the frog was used to study muscle
action, circulation and respiration because it was considered a highly experimentally tractable
and accessible animal [13]. The guinea pig was first adopted to investigate anatomical
structures, and later for the establishment of the germ theory, the discovery of vitamin C and
vaccines, and in toxicology [14,15]. Both organisms were chosen because they had
characteristics relevant to studying a particular process or disease (for example, guinea pigs,
unlike pigeons, acquire scurvy-like diseases when subjected to particular types of diet). A
clear example of (2) is the study of malaria plasmodium and its mosquito carrier, which are
extensively researched primarily because of the threat they pose to humans rather than
because they provide experimental access to specific phenomena (though of course such
organisms do function as models for processes such as the lifecycle of parasites).
1
As we make clear below, the categories of ‘experimental’ and ‘model’ organisms can and
indeed often morphed or evolved over time. Our distinction thus is not meant to apply
universally and atemporally, but rather can be used to identify and evaluate specific moments
of the history of the use of an organism in biological research.
Model organisms, such as the ones listed by the NIH, have different key characteristics. First,
they are always taken to represent a larger group of organisms beyond themselves, and serve
as the basis for articulating processes thought to be shared across several (or all) other types
of organism, particularly those processes whose molecular bases can be articulated. Because
of their use in the human genome projects and biomedical research, model organisms are
often claimed to be representative of processes that it is hoped will be shared by higher level
organisms, especially human beings. These organisms are not being studied primarily
because they are interesting in their own right (though they may well be) but because of the
value they can have for investigating processes that can be generalised: ‘the fish is a frog…is
a chicken…is a mouse’ [16].
Second, model organisms are selected and used to study whole, intact organisms, in other
words as models for a range of systems and processes that occur in living organisms,
including genetics, development, physiology, evolution and ecology. This approach allows
pursuit of one key, long-term goal of this type of research: that of promoting large-scale,
comparative work across species by integrating a range of disciplinary approaches. This goal
is achieved using a specific strategy, which is first to gather resources and build
interdisciplinary infrastructure on individual organisms, and then to compare across species
using the original organism as a reference point [17]. So for instance, as is well-known, a
number of homologous genes have been identified across a range of model organisms,
although of course questions remain in many cases about the correlation between sequence
and function. Nonetheless researchers conceptualise identification of these homologues as a
key step in producing knowledge about the molecular basis of phenotypes, particularly of
variations that cause disease (e.g., the gene BRCA1 whose homologue has variant forms in C.
elegans and the mouse), and also for gathering information about the evolutionary histories of
these organisms, particularly speciation.
Third, model organisms have experimental characteristics that closely relate to their power as
genetic tools: small physical and genomic sizes; low costs to breed, maintain and transport;
short generation times and life cycles; high fertility rates; and high mutation rates or high
susceptibility to techniques for genetic modification. Indeed, model organisms have been
developed using complex processes of standardisation that allow the establishment of one or
more strains which then serve as the basis of future research. The standard strain,
paradoxically referred to as “wild type,” is a token organism developed through various
laboratory techniques so that it possesses features valued by researchers and can be
reproduced with the least possible variability across generations, for example through cloning
[18,19]. Processes of genetic standardisation are essential because model organism research
hinges on developing a detailed genetic account of the organism; this characteristic is not an
“in principle” requirement, but rather one derived from the historical context in which this
type of research developed. In contrast, standardisation is not a defining, generic feature of
experimental organisms: how standardised the organism is (in genetic or other terms) is a
function of the question under investigation, and has considerable epistemological
consequences especially with regard to the translation of results from model organisms more
generally and especially to humans [20].
Infrastructure is critical
The material features necessary for pursuing integrative research on model organisms may
arise casually, but they require the establishment and maintenance of a range of
infrastructures enabling cross-disciplinary communication and the exchange of standardised
materials and instruments, as well as specific social structures for the models to retain their
scientific value. Model organism research has depended critically on building infrastructure,
including stock/strain centres and cyberinfrastructure such as databases for communication of
results. Hence another essential feature which contributes to the characterisation of a model
organism is the distinct infrastructure that surrounds these organisms. The value of model
organism research was clearly recognised by granting bodies in the 1980s, leading to the
awarding of large-scale funding to the genome sequencing projects in the 1990s, as well as
“community resources” such as stock centres (e.g., C. elegans and Arabidopsis) and
community databases such as Flybase, The Arabidopsis Information Resource (TAIR), and
WormBase. This infrastructure contributed significantly to these communities’ abilities to
foster communication and collaboration, and hence to conduct their research efficiently and
effectively. Due to their capacities for bringing results, people and specimens together,
community databases and stock centres have come to played crucial roles in defining what
counts as knowledge of organisms in the post-genomic era [21, 22].
The community ethos
There are three additional distinctions about what makes something a model organism. First,
research groups who use various organisms do not tend to have strong social ties simply
because they work on the same organism, unlike those who work with model organisms
where there are relatively delimited and unified research communities. Second, the explicit
and implicit rules that govern work with model organisms are better articulated (particularly
for publicly-funded research) than in other areas of biology. These communities have a strong
ethos of sharing resource materials, techniques and data, and of making materials and data
available across the community almost immediately. The communities associated with
particular model organisms thus have become models for certain behaviours within science,
described as the “share and survive” ethos [23]. Finally, those who participate actively in
model organism communities are expected to contribute material to the stock centres, support
the community databases by providing data and other information, and perhaps even assist in
database curation, in exchange for being critically dependent on the specialised information
and resources available through the community. Hence the material practices of model
organism research are defined much more closely than those associated with experimental
organism research. Creating a model organism is itself a powerful incentive for research
communities to adopt norms of reciprocal sharing and investment in communal
infrastructure. Thus, what constitutes a model organism is itself determined, at least in part,
by the social norms established and fostered by the research communities involved (which of
course depend in turn on the broader infrastructures, funding strategies and policy mandates
within which these communities are located).
Conclusion
We have argued that there is something special about model organisms compared to
experimental organisms more generally: model organisms are understood as representing a
larger group of organisms beyond themselves, often by functioning as genetic models for
fundamental processes of interest; they serve as models for whole, intact organisms, in other
words for a range of systems and processes which occur in living organisms, and hence
support large-scale, comparative work, by members of a well-defined community, across
species integrating a range of disciplinary approaches.
Currently there is inadequate understanding among researchers, science administrators or
historians/philosophers of science about the implications of using the term “model organism”
and the deep epistemic and other commitments that necessarily accompany it. By invoking
and analysing the term, we do not intend to endorse the idea that integrative, comparative
research necessarily needs to start with strict focus on individual organisms and gathering
resources on a massive scale. Instead, we are arguing that we need to understand the
epistemic and social characteristics of this form of “big science,” given this idea has already
been implemented on a wide scale by scientists and science administrators. In order to make
wise use of existing resources, researchers now find themselves committed to carrying out
this specific, long-term vision about the “right way” to do biological research, with its
accompanying assumptions. Our aim is to provide clarity to recent debates around the claim
that too much funding has been invested in the best-established model organisms (e.g., [24])
through our arguments regarding the appropriate characterisation of the key features of model
organisms.
As pointed out by model organism researchers and other commentators [25], sudden cuts of
funding for model organism research would run counter to its long-term interdisciplinary and
comparative goals, potentially undermining all the efforts to date. However, the use of
experimental organisms for the investigation of specific questions within well-defined
contexts is just as important as the use of model organisms for integrative and comparative
research. Thus there is no scientifically or epistemologically grounded justification for recent
efforts to transform experimental organisms that are popular within specific disciplines into
model organisms (the so-called ‘emerging model organisms,’ [6]), although there may be
good political and economic reasons why researchers wish to do so. For such organisms to
succeed as model organisms, a range of features would be required that are typically not in
evidence in such organisms. Distinguishing the specific characteristics of model organism
work involves recognising that this type of research may be inappropriate for research
questions or programs where the processes of interest are much more delimited or can be
usefully studied in isolation [10]. It also is the case that some useful lines of research will be
neglected if we continue to focus solely on current model organisms. Hence the time has
come to exploit the resources and knowledge accumulated using model organisms to study
more diverse groups of organisms.
Acknowledgments: We thank the numerous colleagues and scientists who contributed their
insights to our considerations in this paper, particularly Chris Degeling, Michael Dietrich,
Scott Gilbert, Jane Maienschein, Peter Menzies, Mary Morgan, Staffan Müller-Wille, and
Maureen O’Malley. We also are grateful for very helpful comments from anonymous
reviewers for this journal. SL was funded by the Economic and Social Research Council as
part of the ESRC Centre for Genomics in Society (Egenis). RAA wishes to thank Egenis for
its hospitality and sponsorship in 2011-12, which enabled the preparation of this paper.
References
1. Krogh A. The progress of physiology. Science 1929; 70: 200–4.
2. Kohler RE. Lords of the Fly: Drosophila Genetics and the Experimental Life. Chicago,
IL: University of Chicago Press; 1994.
3. Rader KA. Making Mice: Standardizing Animals for American Biomedical Research,
1900–1955. Princeton, NJ: Princeton University Press; 2004.
4. Sommerville C, Koornneef, M. A fortunate choice: the history of Arabidopsis as a
model plant. Nat Rev Gen 2002; 3: 883–9.
5. National Institutes of Health (NIH) [Internet]. Bethesda, MD: The NIH; n.d. [cited
2010 April 26]. Model organisms for biomedical research. Available from
http://www.nih.gov/science/models/.
6. Cold Spring Harbor Press, editor. Emerging Model Organisms: A Laboratory Manual.
Volumes 1-2. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 2009–10.
7. Sommer RJ. The future of evo-devo: model systems and evolutionary theory. Nature
2009; 10: 416–22.
8. Maher B. Biology’s next top model? Nature 2009; 458: 695–8.
9. Gilbert S.. The adequacy of model systems for evo-devo: Modeling the formation of
organisms/modeling the formation of society. In: Barberousse A, Morange M, Pradeu T,
editors, Mapping the Future of Biology . Dordrecht: Springer; 2009, pp. 57–68, 155–69.
10. Bolker, JA. Model systems in developmental biology. BioEssays 1995; 17: 451–5.
11. Clarke AE, Fujimura JH., editors. The Right Tools for the Job: At Work in Twentiethcentury Life Sciences. Princeton, NJ: Princeton University Press; 1992.
12. Burian RM. How the choice of experimental organism matters: Epistemological
reflections on an aspect of biological practice. J Hist Biol 1993; 26: 351–67.
13. Holmes FL. The old martyr of science: The frog in experimental physiology. J Hist Biol
1993; 26: 311–28.
14. Guerrini A. Experimenting with Humans and Animals: From Galen to Animal Rights.
Baltimore, MD: The Johns Hopkins University Press; 2003.
15. Endersby J. A Guinea Pig’s History of Biology. London: Random House; 2007.
16. Grunwald DJ, Eisen JS. Headwaters of the zebrafish: emergence of a new model
vertebrate. Nat Rev Genet 2002; 3: 717–23.
17. Ankeny RA, Leonelli S. What’s so special about model organisms? Stud Hist Philos
Sci 2011; 41: 313–23.
18. Ankeny RA. The natural history of C. elegans research. Nat Rev Genet 2001; 3: 474–8.
19. Leonelli S. Growing weed, producing knowledge. an epistemic history of Arabidopsis
thaliana. Hist Phil Life Sci 2007; 29: 55–87.
20. Bolker J. Model organisms: There's more to life than rats and flies. Nature 2012; 491:
31-3.
21. Rosenthal N, Ashburner M. Taking stock of our models: the function and future of
stock centres. Nat Rev Genet 2002; 3: 711–7.
22. Leonelli S, Ankeny RA. Re-thinking organisms: the impact of databases on model
organism biology. Stud Hist Philos Sci 2012; 43: 29-36.
23. Rhee SY. Carpe diem: retooling the “publish or perish” model into the “share and
survive” model. Plant Physiol 2004; 134: 543–7.
24. Davies JA. Developmental biologists’ choice of subjects approximates to a power law,
with no evidence for the existence of a special group of “model organisms.” BMC Dev Biol
2007; 7: 40.
25. Petsko GA. In praise of model organisms. Genome Biol 2011; 12: 115.