Model organisms: There's more to life than rats and flies

Article (PDF Available)inNature 491(7422):31-3 · November 2012with175 Reads
DOI: 10.1038/491031a · Source: PubMed
The tiny number of model organisms constrains research in ways that must be acknowledged and addressed, warns Jessica Bolker.
HISTORY A masterful take
on the age-old allure of
alchemy p.38
mind extract meaning from
language? p.36
DEVELOPMENT Science must
inform UN sustainability
goals p.35
POLITICS US abortion lobby
set to clash with prenatal
diagnostics p.33
or most experimental biologists, life
revolves around a handful of species:
the mouse (Mus musculus), the nema-
tode worm (Caenorhabditis elegans), the
fruitfly (Drosophila melanogaster) and
the thale cress (Arabidopsis thaliana). We
assume that model organisms offer universal
insights, and funding agencies largely sup-
port work on a shortlist of favoured species
Scientists who submit grant proposals
for a project using a standard model organ-
ism need not use up space to explain their
choice. By contrast, choosing a less common
model that is uniquely suited to the research
demands a lengthy justification to convince
sceptical colleagues. Proposals for projects in
unusual species are often returned with the
suggestion that the applicant use a standard
organism instead, because any worthwhile
question should be accessible in a well-
established model.
Investments in research with a handful of
models have returned rich dividends in basic
knowledge and medical progress. And many
careers, labs and journals are built on the pri-
macy of the fly, mouse and worm
But studying only a few organisms limits
science to the answers that those organisms
can provide. The extraordinary resolving
power of core models comes with the same
trade-off as a high-magnification lens: a
much reduced field of view. For instance, tra-
ditional models for developmental biology —
such as the fly — were chosen because their
phenotypic traits directly reflect their geno-
type, with minimal environmental input.
These models are poorly suited to questions
asked by scientists in emerging fields such
as ecological developmental biology —
eco-devo’ — which focuses on external influ-
ences on developing phenotypes.
Theres more to life
than rats and flies
The tiny number of model organisms constrains research in ways that
must be acknowledged and addressed, warns Jessica Bolker.
1 NOVEMBER 2012 | VOL 491 | NATURE | 31
© 2012 Macmillan Publishers Limited. All rights reserved
Such limitations have serious
consequences. Disparities between mice and
humans may help to explain why the mil-
lions of dollars spent on basic research have
yielded frustratingly few clinical advances
Narrowing the research focus too far limits
basic understanding, in ways that can lead
directly to clinical failures. For example, an
experimental treatment for multiple sclero-
sis that, in inbred mice, improved symptoms
of induced disease produced unpredicted
— and sometimes adverse — responses in
human patients. The
inbred mouse model
failed to represent the
genetic and immu-
nological diversity of
human cells, a short-
coming that was obvi-
ous in retrospect
It is time to think
more critically about
how we use models. This means articulat-
ing tacit assumptions, such as the adequacy
of rodent models to fully represent specific
human diseases. It means looking hard at
how we select and use our favoured model
species, and acknowledging both their
strengths and their limitations. And it means
mainstream funders and journals welcom-
ing work in non-standard organisms.
How did a handful of species become
central models? Sometimes it was more about
convenience than strategic planning. Dros-
ophila rose to prominence in the early 1900s
in part because its short generation time was
handy for student projects and its four pairs
of large chromosomes were ideal for the study
of eukaryotic genetics
. Yeast, mice, chickens
and other domesticated species became lab
favourites because they were already familiar
and accessible. The existence of lab popula-
tions of frogs (Xenopus laevis) for use in preg-
nancy tests led to their recruitment as a model
for developmental research.
As model-based science grew, these few
species became increasingly dominant,
despite the sometimes haphazard way that
they had initially been chosen. We have now
reached a point where, if researchers cannot
tackle a problem using a familiar species,
they may not study it at all
Take modern developmental biology. The
field has centred on small, rapidly develop-
ing organisms with short generation times
— most typically, Drosophila and C.elegans.
Much of our current understanding of devel-
opmental principles is based on experiments
in these species. However, evolutionary
selection for rapid development has broad
implications. It seems to favour stronger
genetic control during development and
less plasticity (or flexibility). Compared with
related species, development in the models is
less responsive to external signals, whether
adaptive or disruptive. Because plasticity and
the role of the developmental environment
are particularly hard to study in key mod-
els, these areas receive comparatively little
A similar narrowing has occurred in
biomedical research. In the case of Parkin-
sons disease, potential treatments are often
assessed by measuring motor function in
a lesioned rat. But the rat model does not
clearly represent other significant symptoms
of Parkinsons that occur in human patients,
such as cognitive decline. This may steer
some researchers away from these aspects
of the disease.
Similar biases rooted in the use of par-
ticular models may also contribute to the
translational disconnect’ with regard to
neuro degenerative diseases such as Alzhei-
mer’s and amyotrophic lateral sclerosis
The inability of highly inbred and often
genetically modified rodent strains to fully
represent the diversity of human patients
and symptoms has called the power of
such models into question, even within the
research communities they serve
At the same time, the effects of appar-
ently trivial environmental variations, such
as the details of mouse handling, are often
. Aggression is the key behav-
ioural phenotype in male mice lacking the
enzyme neuronal nitric oxide synthase.
This was not observed — and could not be
seen — until animals were housed in groups
rather than in standard individual cages
Few lab models explicitly account for the
environment of organisms, despite increas-
ing recognition that this may affect the
outcome and replicability of experiments
In short, if we frame a research model or
system too narrowly, leaving out key causal
elements such as environmental influences,
we cannot hope to construct a complete pic-
ture of the mechanisms that underlie crucial
variations, for example in development and
disease. To study environmental influences,
we need to study species in which such fac-
tors matter. So the traits that define a suc-
cessful model must shift as the questions for
which we use them evolve.
Choosing a research model should be more
than a matter of convenience or conven-
tion. Scientists need to ask more questions
— about the goals of a specific experiment,
how suitable a given model is to reach-
ing those goals, and what environmental
or other external factors might be relevant
to how well the model works. For a given
question, it is crucial to determine which
aspects of human biology are essential (for
example, our genetic diversity, unique char-
acteristics of our immune system or particu-
lar disease symptoms) and assess how well
they are represented in a candidate model
(see ‘Choosing the right candidate’). Where
mismatches appear, we must limit our infer-
ences from animal studies accordingly, and
consider when and how to move to research
in humans. For some kinds of biomedical
“To study
we need to
study species
in which
such factors
2 Need for additional models
Example: Where there are known
obstacles to translating results from mice
to humans, how do we develop alternative
routes to find new treatments for human
Key questions
What aspects of human disease are
poorly represented in current models?
How might the utility of current models
be expanded?
What potential new models are available,
or could be developed?
Research objectives
Develop strategies to assess other
aspects of human disease in current
Identify new candidate models for
specific questions.
Develop criteria for selecting new
1 Matching between the model
and what it represents
Example: Does studying immunology in
highly inbred mouse models shed useful
light on the diversity of human immune
function and disease
Key questions
What do we need to know about a
disease to develop treatments?
What mechanisms link disease origin to
Research objectives
Discover aetiology of symptoms.
Compare disease initiation and
progression between models and humans.
Assess whether therapeutic targets are
well represented in specific models.
Identify gaps between models and
patients that may be significant with
respect to basic knowledge and to
treatment approaches.
Choosing the right candidate
32 | NATURE | VOL 491 | 1 NOVEMBER 2012
© 2012 Macmillan Publishers Limited. All rights reserved
research, it may not matter that the
damage or symptoms in the model devel-
oped by a different pathway to that which
occurs in patients — orthopaedic injuries
are one example. But in other areas, such
as epidemiology, it matters a great deal.
Recognizing that standard models have
limitations does not mean we should give
them up. Rather, we should deliberately
account for their limitations as part of
study design — for example, by analysing
the role of a gene in mouse strains with
different genetic backgrounds. No single
species, no matter how highly engineered,
can ever serve as a universal model: every
species has unique features that may be
assets or faults, depending on the ques-
tion being asked. For instance, the lack
of developmental plasticity in Drosophila
and of genetic variability in inbred rats
limit what these models can tell us about
ecological effects on development, but
make them powerful tools for studying
gene function during development.
We also need to broaden our range of
models to include species such as Antarc-
tic icefish, comb jellies, cichlids, dune mice
and finches that are naturally endowed by
evolution with features relevant to human
. Studying the basis of unique
adaptive traits in these animals may yield
insight into human disorders such as
osteo porosis, cataracts and cancer.
Immediately and practically, the US
National Center for Advancing Transla-
tional Sciences in Bethesda, Maryland,
should support the development of new
systems for investigating problems that
are not tractable in currently favoured
models. It should also fund investiga-
tions into fundamental questions about
model-based research (see ‘Choosing the
right candidate’). The resulting insights
would help scientists to select the best
models for advancing basic and applied
research, and strengthen the bridges
between them.
Jessica Bolker is an associate professor of
zoology in the Department of Biological
Sciences, University of New Hampshire,
Durham 03824, New Hampshire, USA.
1. Davis, M. M. Immunity 29, 835–838 (2008).
2. von Herrath, M. G. & Nepom, G. T. J. Exp. Med.
202, 1159–1162 (2005).
3. Geerts, H. CNS Drugs 23, 915–926 (2009).
4. Schnabel, J. Nature 454, 682–685 (2008).
5. Kohler, R. E. Lords of the Fly: Drosophila
Genetics and the Experimental Life (Univ.
Chicago Press, 1994).
6. Bolker, J. A. BioEssays 17, 451–455 (1995).
7. Beckers, J., Wurst, W. & Hrabé de Angelis,
M. H. Nature Rev. Genet. 10, 371–380 (2009).
8. Hurst, J. L. & West, R. S. Nature Methods 7,
825–826 (2010).
9. Nelson, R. J. et al. Nature 378, 383–386
10. Maher, B. Nature 458, 695–698 (2009).
n the United States, pro-life advocacy
groups, notably Americans United for
Life, based in Washington DC, have been
making headway in their mission
to limit
womens access to abortions “state by state,
law by law and person by person. In 2011, 24
US states enacted 92 new provisions restrict-
ing abortion — nearly triple the previous
record of 34 in 2005 (see ‘Clamping down’).
One of the strategies of pro-life advocates is
to target the reasons for which a woman can
have an abortion. Meanwhile, a major devel-
opment in prenatal care, called non-invasive
prenatal genetic testing (NIPT), promises to
increase the genetic information available to
women early during their pregnancy.
The US Food and Drug Administra-
tion (FDA) cannot control how people
use information from genetic tests. But
by developing a clear regulatory framework
for NIPT and improving public under-
standing of NIPT’s benefits and limitations,
the agency could help to allay fears that
the tests will lead to a drastic increase
in selective abortions.
NIPT has the potential to improve
womens reproductive autonomy. But if it
is not integrated cautiously into pre natal
care, the technology could be targeted to
support burgeoning strategies to restrict
In recent years, two blood tests combined
with an ultrasound have been the most
common method for determining a fetuss
risk of having a congenital disease such as
Downs syndrome. Results from this type
Politics and fetal
diagnostics collide
Without better regulation, non-invasive prenatal
genetic tests will be targeted by US anti-abortion
lobbyists, argues Jaime S. King.
Pro-choice and pro-life activists clash outside the US Supreme Court in Washington DC.
1 NOVEMBER 2012 | VOL 491 | NATURE | 33
© 2012 Macmillan Publishers Limited. All rights reserved
    • These and other features helped to establish the lamprey as the first (and still the only) vertebrate CNS to fulfill all the NIH criteria (Guth et al., 1980) for demonstration of functional regeneration of axons in the spinal cord (Cohen et al., 1988). It is a fallacy that focusing only on mammalian models will provide adequate preclinical information to predict effects on humans (Bolker, 2012). There are numerous examples of differences in reactions to SCI between mice and rats (Sroga et al., 2003; Byrnes et al., 2010).
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    • One of the central questions in genomics is, which genes influence which phenotypes? Identifying links between genotypes and phenotypes is difficult to do, and must take biological diversity into account to establish how general or specific each link is that is identified in each species. Much of what we have learned in the best studied canonical model organisms applies to a broad diversity of organisms; however, many details are specific to these species and do not describe the biology of other organisms (Bolker 2012). This simple fact about the organisms becomes a problem for the study of biology when 'model organisms' are thought of has models of other organisms rather than as organisms with excellent tools for developing models of certain biological processes (Katz 2016).
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