Biology Reference
In-Depth Information
provide a rich resource for a research community. For
example, the networks capture and summarize a huge
amount of existing biological knowledge and so can be
used to rapidly search for connections between a novel set
of genes, such as those identified in a genetic screen or in an
expression profiling experiment. Moreover, given a set of
genes known to be important for a particular process,
a network can be used to predict new genes that are likely
to function in that process. Search tools such as that
provided for Wormnet (
www.functionalnet.org/wormnet
)
make this process of 'network-guided genetic screening'
straightforward.
These models have highlighted the importance of
a sequential activation of the epidermal growth factor
receptor (EGFR) and LIN-12/Notch signaling pathways,
and how the lack of a delay in signaling results in unstable
fate patterns
[48]
. Moreover, they have also illustrated how
quantitative changes in a common regulatory network may
be sufficient to explain the differences in vulva patterning
that are observed among different species
[179]
.
As in many other multicellular systems, a key limitation
when it comes to constructing dynamical models is the lack
of data on important in vivo biochemical and biophysical
parameters such as rate constants, protein concentrations,
tensions and viscosities. As such, it is likely the combina-
tion of modeling and quantitative experimental validation
will be most fruitful in the immediate future.
Dynamic Models of Developmental Processes
One ultimate goal of systems biology is to produce mech-
anistic and predictive models describing biological
systems. Such mechanistic modeling necessarily involves
considering the dynamics of a system, but dynamical
modeling is, unfortunately, another area where systems
research in C. elegans has rather lagged behind that in the
other two main invertebrate systems of yeast and D. mel-
anogaster. Indeed, only two developmental processes have
received substantial interest from the modeling community:
symmetry breaking in the first cell division of the embryo
[176,177]
, and the early development of the hermaphrodite
vulva
[48,50,51,178
OUTLOOK
In this chapter we have attempted to outline the key
systems-level approaches that have been employed to date
by the C. elegans community, and where future directions
might best be focused. However, our aim has also been to
emphasize that C. elegans is a rather unique animal when it
comes to systems biology. This is not primarily because it is
a relatively 'simple' and highly experimentally tractable
organism, although these are, of course, key advantages.
Rather, it is because 'systems thinking' has existed in the
C. elegans community from its very inception, and because
the phenotype of C. elegans is a uniquely well-defined and
reproducible problem at the cellular level. Only for this
animal is the complete list of cell divisions, movements,
differentiations and deaths known and quantifiable during
development, and only in this animal is the complete
anatomy of the adult, including the nervous system,
described and quantifiable at cellular resolution. We and
others
[182]
would therefore argue that, if our aim is to
achieve a comprehensive and quantitative understanding of
an animal life form, then that animal should be C. elegans.
Brenner famously quips that there are only three
important questions in biology
[183]
: How does it work?
How is it built? And how did it get that way? If we want to
answer these questions in a comprehensive and predictive
manner, then C. elegans was
180]
.
With respect to the first cell division, two elegant
studies have aimed to connect biophysical processes to the
generation of asymmetry, modeling the physical mecha-
nisms by which stable asymmetric distributions of proteins
arise
[176]
, and how cortex
e
microtubule interactions
position the mitotic spindle in response to these polarity
cues
[177]
. Crucially, in both cases the plausibility of the
biophysical models was assessed using quantitative
imaging. For example, in the first study it was shown that
advective transport by the flowing cell cortex, when
coupled to a PAR protein reaction
e
diffusion system, can
be sufficient to trigger polarity in an otherwise stably
unpolarized system
[176]
. This coupling of mechanical and
biochemical modeling is an approach that may be crucial
for building additionally mechanistically grounded
predictive models of development. In general, a better
understanding of biophysical processes during C. elegans
development is required
[181]
.
The second system that has been quite extensively
modeled in C. elegans is the patterning of the precursor
cells during the early development of the hermaphrodite
vulva
[48,50,51,178
e
the most
logical system to study. How does a single cell develop into
an animal? How does the organization of that animal
determine its functions? And how did such an animal come
into being in the first place through the process of
evolution?
We will take it as read that there will be continued
progress in using the worm to unravel the genetic basis for
many complex animal behaviors and processes, from
alternative splicing to the development of the neuromus-
cular system to the role of non-coding RNAs in animal
development. Genetic screens, whether using the classical
and still is
e
e
180]
. Here, six cells of initially equal
developmental potential adopt three different develop-
mental fates, a process that involves the interactions
between at least three different signal transduction path-
ways. Vulva development has been modelled using
a number of different approaches
[48,50,51,178
e
180]
.
e
