Magazine
R51
Theory in Biology
Systems biology
versus molecular
biology
Charles F. Stevens
Systems biology and molecular
biology can answer the same
question in quite different ways,
and frequently the answers given
by one sub-discipline seem no
answer at all to the other. For many
molecular biologists, a systems-
level explanation leaves them
feeling that, until the underlying
molecular mechanisms are known,
the approach is hopelessly
superficial. For systems biologists,
on the other hand, an account of
the genes and gene interactions
responsible for a phenomenon is
just a list, and they hunger for the
underlying principles that make
sense out of the list. I believe that
these two styles of answering
questions are complementary; at
best, a more complete
understanding is reached when the
two approaches are unified.
I shall illustrate how these two
approaches differ by considering
the different answers they give to
two questions. Why do separate
neocortical areas exist? And why
are the cortical areas arranged in
the way they are? The example I
give is flawed, however, and the
nature of the flaw is revealing
about the challenges facing
systems and molecular biology.
Since Brodmann [1], we have
recognized the existence of many
anatomically and molecularly
distinct neocortical areas, each
with a different function. About 100
areas have now been identified in
the human cortex, ranging from the
primary visual cortex (V1) through
temporal and frontal lobe language
areas. The first question, then, is:
why are the neurons responsible
for a particular calculation grouped
together in one region of cortex? A
given area, V1 for example, varies
considerably in size and in its
precise location from one
individual to the next (and from one
species to the next), but its
relations to other areas never
change. For example, V1 is always
next to V2 and never next to V3 (V2
and V3 are other areas devoted to
vision). The second question is:
why are these neighbor relations
the same from one individual to the
next?
Molecular biology answers
Patterning in developing cortex
[2,3], like that elsewhere in the
embryo, is believed to be governed
by a coordinate system established
by concentration gradients of
signaling molecules. Different
concentrations of these signaling
molecules are thought to activate
different combinations of
transcription factors, giving rise to
the various distinct areas of the
mature cortex. The molecular
nature of at least some of the
anterior-posterior and medial-
lateral signals has been tentatively
identified, and a large number of
genes appear to be involved in
specifying cortical areas and their
pattern of arrangement.
To explain the existence of
cortical areas and their
arrangement, then, one must
identify: first, the genes that
instruct newborn neurons to adopt
a cortical fate; second, the genes
that define the coordinate system;
and third, the transcription factors
that specify the positions of areal
boundaries, and the combinations
of genes and gene expression
levels that define the specific
areas. Once we know the genes
responsible for cortical patterning
and all interactions between them,
the molecular biologist has
answered the questions of why we
have areas and why the areas are
arranged as they are.
Systems biology answers
Each neocortical area sends
information to about ten other
areas and receives information
from about ten areas, generally not
just the same areas to which
information is sent. The axons
carrying this information usually
run in the white matter, and most
of the white matter volume is made
up of these intercortical axons. In
the human brain, about 40% of the
entire volume consists of white
matter, so it would seem that
arranging cortical areas in a way
that minimizes the volume of the
interconnecting axons would be
advantageous; because the cranial
volume is limited, minimizing the
volume taken by the ‘data buses’
leaves more space for the brain’s
computational elements. The
systems biologist, then, would say
that the cortical areas are arranged
by evolution as they are to optimize
the use of space in the head.
This idea has been tested for 11
areas in monkey prefrontal cortex
for which all or most of the
intercortical connections are
known [4]. Just under 40 million
arrangements of the 11 areas, all of
the possible arrangements, were
examined by computing the
volume of interconnecting axons
required for each arrangement.
Every alternative was found to be
worse than the actual area
arrangement, in the sense that the
actual arrangement required the
least volume of intercortical
connecting axons.
This systems-level explanation,
then, holds that areas have evolved
an arrangement that minimizes the
volume of white matter required for
intercortical communications,
conferring a selective advantage
over evolutionary alternatives with
less efficient use of cranial space,
and the fact that the actual
arrangement is better than any of
the approximately 40 million
possible alternative patterns gives
strong support to the white matter
minimization hypothesis.
This discussion gives an answer
to the second question, and
suggests one to the first: grouping
the most highly interconnected
cells (those with the same function)
together to form a cortical area
saves space by minimizing the
volume of axons needed to
construct the computational circuit
for a particular function. This notion
is, however, hard to test and I
consider an alternative, somewhat
deeper, explanation for why we
have separate cortical areas.
The cortical neuropil can be
divided conceptually into
conducting (‘wire’) and non-
conducting (‘non-wire’)
components: axons and dendrites
conduct information over
relatively long distances, whereas
glia, extracellular space and
synapses can be thought of as
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non-conducting components
(although they, too, are involved
in signaling). An optimality
argument — sketched below —
holds that axonal conduction
delays and dendritic signal
attenuation are minimized and
synaptic density maximized when
the conducting components take
up 3/5 of the cortical volume [5].
Distinct areas exist, according to
this argument, because
separating highly interconnected
neurons, those participating in
the same computation, would
depart from this optimal
arrangement of components and
would, therefore, be
disadvantageous.
Where does the 3/5 come from?
The idea behind the optimality
argument is illustrated by a
thought experiment in which the
diameters of all of the axons in a
cubic millimeter of cortex are
imagined to be reduced to zero,
with the other elements pressed
together to take up the spaces
created by shrinking the axons
which, we imagine, are also
shortened to run as directly to their
targets as possible. The imagined
cortical cube would not function
because conduction delays from
one particular point in the circuit to
another would be infinite. This is
true because the conduction
velocity of unmyelined axons is
proportional to the square root of
their diameter: zero diameter
means zero conduction velocity
and infinite conduction delays.
Now suppose we smoothly
increase the axon diameters,
moving the other components
apart to make room. A plot of
conduction delay versus axon
diameter shows that delays first
decrease as the diameter (and
conduction velocity) increase, but
they reach a minimum and then
start to increase. Why is there an
optimal diameter? As the axon
diameter is increased and the
axonal volume grows, the other
elements are pushed apart and
axons have to become longer to
reach their targets in the cortical
circuit. The conduction delays are
inversely proportional to the
square root of the axon diameter
but directly proportional to the
length of the conduction path so
the longer path starts to dominate
when the volume contributed by
the axons becomes large enough.
A simple mathematical argument
shows that the conduction delays
are least when the conducting-
element volume is 3/5 of the total,
and extensions of this type of
analysis shows that signal
attenuation by dendrites is
minimum and synaptic density is
maximum at the same point.
Is this explanation correct?
Quantitative study of various
cortices in the mouse shows that,
in each case, the conducting
components indeed occupy 3/5 of
the volume, although the fraction
of the volume taken by each
component varies from one
cortical type to another [5]. The
systems biology explanation for
why cortical areas exist, then,
depends on the notion that the
cortex, as a computing machine,
should be optimal; this optimality
drives evolution to select
developmental rules that group the
most highly connected neurons
together, and thus gives rise to the
cortical areas.
Unification
Molecular biology and systems
biology provide answers to the
same questions, but the answers
are quite different for the two
approaches and are, on the
surface, unrelated. The molecular
biological answers are arguably
more fundamental and are unique,
but alternative systems biology
answers are possible — consider
the two systems-level answers to
the first question. Nevertheless, the
systems-level answers can be in
some sense more satisfying,
because you feel you have an
explanation you can understand
and use to make testable
predictions; a list of genes together
with their interactions is perhaps
preferred, but much harder to
grasp, explain and remember.
That the two types of answer
seem to be unrelated reveals an
essential flaw in the example I have
used. In a really good example, the
two levels of explanation would be
unified so that the molecular
biology explanation would also
include the systems biology
answers, and vice versa. In our
example, the molecular biologist
would not only have to identify the
genetic networks responsible for
cortical patterning, but would also
have to discover the molecular
basis for the rules that lead to the
optimal arrangement of cortical
areas and to understand the
mechanisms used by the
developing cortex to ensure
conducting components occupy
3/5 of the volume so that cortical
function is optimal. Even if you
know all the genetic and epigenetic
mechanisms that result in 3/5 of
the cortical neuropil volume being
conducting components, you still
can ask why evolution selected
that particular mix of mechanisms.
The systems-level approach
explains the molecular biologist’s
answer to this question by appeal
to a general principle: evolution
selects an optimal partitioning of
components.
The challenge for systems
biology is to discover answers to
biology’s questions, and the
challenge for the molecular
biologists is not only to provide
answers to these questions, but
also to explain the answers given
by systems biology. And after
molecular biology has given its
final answers, the systems
biologist must identify the general
principles that lead to the actual
combination of molecular
mechanisms. At its best, then,
systems biology and molecular
biology work hand-in-hand to
provide a complete picture of how
and why Biology is the way it is.
References
1. Brodmann, K. (1999). Localization
in the cerebral cortex (London:
Imperial College Press).
2. Grove, E.A., and Fukuchi-
Shimogori, T. (2003). Generating
the cerebral cortical area map.
Annu. Rev. Neurosci. 26, 355-380.
3. O’Leary, D.D., and Nakagawa, Y.
(2002). Patterning centers,
regulatory genes and extrinsic
mechanisms controlling
arealization of the neocortex. Curr.
Opin. Neurobiol. 12, 14-25.
4. Klyachko, V.A., and Stevens, C.F.
(2003). Connectivity optimization
and the positioning of cortical
areas. Proc. Natl. Acad. Sci. USA
100, 7937-7941.
5. Chklovskii, D.B., Schikorski, T., and
Stevens, C.F. (2002). Wiring
optimization in cortical circuits.
Neuron 34, 341-347.
The Salk Institute, PO Box 85800,
Molecular Neurobiology Laboratory,
San Diego California 92138-9216, USA.