PERSPECTIVES
protein5. The power of a model lies in identi-
OPINION
The rise of computational biology
Denis Noble
The year 2001 saw a remarkable burst of
interest in biological simulation, with several
international meetings on the subject, and
the inclusion, by journals, of web site
references from which published models
can be downloaded. So, why has all this
happened so suddenly?
The last half of the twentieth century saw the
phenomenal success of the reductionist
approach. The structures of macromolecules
were unravelled, the chemical nature of
DNA was discovered, and the genome
sequences of several organisms were largely
or completely determined. We are witnessing
monumental achievements. But this success
has created a huge challenge: what do all
these data mean? It is possible that with this
information and limitless computing power
we could simulate, almost mindlessly, in a
bottom-up fashion (FIG. 1), the complete
functioning of an organism?
A biological determinist would hope that
the answer is yes. Isnt life just the product of a
one-way upward causation from genes to
cells, organs, systems and whole organisms?
Perhaps the most uncompromising statement
in support of this view is that from Richard
Dawkins1: They [genes] are in you and me;
they created us, body and mind; and their
preservation is the ultimate rationale for our
existence. Interestingly, the very concept of
the selfish gene is based on a beautiful exam-
ple of computational biology, that of the
mathematics of kin selection as the basis of
social behaviour2: helping near relatives
favours the selection of our own genes.
There is, however, an alternative view,
which is that biological systems are too inter-
active between levels for a one-way framework
to be possible. There is so much feedback from
higher levels controlling gene expression
levels and their interactions with the integra-
tive properties of the organism and its envi-
ronment that it would be just as valid, and
certainly equally as colourful, to represent
genes as prisoners that are trapped inside the
successful physiological systems that express
them. To understand their roles in this con-
text, we need to unravel the higher logic of life,
and as organisms are what live and die, natural
selection must operate at this level.
460 | JUNE 2002 | VOLUME 3
The protagonists of these two camps
would agree on one thing whichever way
the causation runs, biological systems are
highly complex. Beyond a certain level of
complexity (and in mathematical terms this
could mean something as simple as a pair of
differential equations), qualitative thinking
fails us. In other sciences there is already an
answer to this problem become quantita-
tive and calculate!
The growing realization that this is neces-
sary explains the sudden explosion of interest.
In 2001, the first international conference on
computational biology was held in the United
States3. The Institut National de la Sant et de
la Recherche Mdicale (INSERM, France), the
Medical Research Council (MRC, UK) and
the National Institutes of Health (NIH, USA)
held strategy meetings on this emerging field,
while the Novartis Foundation held a land-
mark symposium entitled In silico simulation
of biological processes4. Biology is set to
become a highly quantitative science. In the
present century, it will also become the most
computer-intensive science.
I discuss first the question of how model-
ling relates to biological levels, and illustrate
this using the heart as an example, before gen-
eralizing to the simulation of biological path-
ways, cells and systems and the applications to
drug development. I conclude by asking the
deepest question of all: could there be a theo-
retical biology?
Levels of modelling
Where should modelling begin? Could we
start with the individual molecules and
exhaustively compute their interactions?
There is, of course, a computer that does this:
the body itself! But there are problems with
trying to copy nature so completely.
Even if we were to succeed, the result
would not be a model in the strict sense.
Models are partial representations. Their aim
is explanation: to show which features of a sys-
tem are necessary and sufficient to understand
it. So, although we could try to understand
cardiac rhythm as the interaction of the few
thousand types of protein that are in any cell,
we can in fact understand most of what we
wish to know about pacemaker activity from
the interaction of around a dozen types of
2002 Nature Publishing Group
fying what is essential, whereas a complete
representation would leave us just as wise, or
as ignorant, as before.
The important concept here is modularity.
Function emerges from the interactions of
groups of proteins in which the genes are usu-
ally selected together6. Determining the logic
of such modules and their interactions would
be one of the steps towards creating a funda-
mental theory of biology. It will be particu-
larly interesting to determine the extent to
which modularity at higher, functional levels
matches that identified by proteomics6.
The opposite of bottom-up top-down
(FIG. 1) risks being either empty (reformulat-
ing interactions at a higher level does not guar-
antee that we will find the correct lower-level
mechanisms) or incomplete. Genes (and pro-
teins), after all, do not come with their own
functional labels. We have to work them out
(see online link to the Gene Ontology
Consortium, which systematically documents
information on gene functions), and in most
cases the functionality will be both multiple
and extensively crosslinked. The discovery that
there might be many fewer genes than proteins
reinforces this point, although the precise
number of genes is still a matter of debate7.
Could a combination of these two
approaches a kind of outside-in (FIG. 1)
work? This is the way we often think about
the relationships between molecular biology
and systems biology. Even the most ardent
Physiological systems and function
'Top-down'
Systems Organs
Tissues 'Middle-out' Cells
Pathways Organelles
'Bottom-up'
Molecular data and mechanisms
Figure 1 | Levels of modelling. Should biological
simulation start from the bottom level of
molecules and work upwards to systems and
whole organisms, or from the top (physiological
function) and work downwards to the underlying
molecular mechanisms? How would they be
guaranteed to meet? Would a combination of the
two (outside-in) be guaranteed to meet in the
middle? Alternatively, there is a pragmatic option,
middle-out, which starts at any level (pathways,
organelles, cells, tissues, organs or systems) at
which there are sufficient data and reaches (up,
down and across) towards other levels and
components.
www.nature.com/reviews/molcellbio
 PERSPECTIVES

Box 1 | Linking genetics to physiology between different parts of the heart. These are
important in explaining pacemaker behav-
a b iour, the electrocardiogram1517 and several
WT KPQ KPQ 0
C
CL = 400 ms CL = 400 ms CL = 600 ms disease states, including cardiac arrhythmias
EAD mV B (BOX 1). Some of these cardiac arrhythmias are
A
AP genetically determined811,17.
40 mV 100
A
The other level is the organ level: the three-
0
B dimensional anatomy of tissues and of the
whole organ1826. Linking these two levels
pA
INa C cells to organs enables us to reconstruct the
4AF1
200 ms spread of excitation through the heart, and
100 ms 1,000
makes it possible to reconstruct some of the
Connecting genetics to physiological function at cellular and other levels is an exciting new life-threatening arrhythmias. The whole-
development in which simulation is helping to unravel complex behaviour that results from simple organ model has even been inserted into an
changes at the genetic level. The heart-model simulations shown here uncover the arrhythmogenic electrical model that represents the tissues of
effects of two types of mutation in the sodium channel gene SCN5A. In both parts of the figure, the the upper part of the human body27. FIG. 2
top records show membrane potential (AP, action potential), while the bottom records show sodium shows a frame from such a simulation.
current (INa ). In part a of the figure, the left graph shows the control situation (WT, wild type). The
simulated mutation was the KPQ mutation, a three-amino-acid deletion Pathways, cells and systems. Integrative interac-
(lysineprolineglutamine) that affects channel inactivation and is associated with a congenital tions between proteins might be the basis of
form of the long-QT syndrome LQT3. Long-QT refers to prolongation of the electrocardiogram the following: a metabolic pathway28,29; a sig-
interval between excitation of the ventricles (Q) and their repolarization (T) a phenomenon that nalling cascade (BOX 2; also see online link to
can indicate life-threatening arrhythmias. The simulations show that the mutant channel (shown in the Alliance for Cellular Signaling); the control
the middle and right graphs) generates a persistent inward sodium current during the AP plateau in of the cell boundaries (membrane transporters
the mutant cell. At long cycle lengths (CLs), this generates an early after-depolarization (EAD, of many kinds); cellular functions, such as
shown in the right graph)8, so delaying repolarization and prolonging the QT interval. Part b of the secretion and electrical activity; and multicellu-
figure shows the effects in a guinea-pig ventricular-cell model of shifting the voltage-dependence of lar functions, as in kidney tubules or cardiac
sodium-channel inactivation, and trace A shows the control situation. A 12-mV shift simply conducting pathways. In this way, integrative
prolongs repolarization (B), but an 18-mV shift produces an EAD (C). This mimics part of the interactions between proteins act through the
experimental effect7 of a missense mutation that underlies Brugada syndrome, an inherited
various levels to affect whole organs and sys-
condition in which sudden fatal ventricular fibrillation can occur in people who show no other
tems. Ultimately, some people conceive that it
manifestation of heart disease9. For further information see online links to the Luo-Rudy dynamics
will be possible to construct a virtual human.
model of the mammalian ventricular action potential and the Cardiac Mechanics Research Group.
Reprinted with permission from REF. 40 1999 The Physiological Society.
There is already a partial virtual heart (see
above), and other organs and systems for
example, the lung30 are beginning to be rep-
resented in the same way. Connecting them
reductionists are not blind to functional available. This might be a biochemical path- together in appropriate anatomical and bio-
descriptions of biological processes, even if way, a cell-signalling mechanism (BOX 2), a chemical frameworks is indeed not inconceiv-
they might dream of replacing them, although whole cell, a tissue, an organ or a system able, but this will be one of the greatest chal-
no systems biologist today can be satisfied wherever the relevant information on which lenges for biological computation.
with explanations that do not connect to the the modelling is based is most detailed. This
underlying mechanisms and even to the inevitably leads to the concept of a hierarchy Applications to drug development. Simulation
genome level811 (BOX 1). Could we therefore of models, and one of the main challenges will at the protein level is highly relevant to the
imagine a kind of double tunnelling, in which be how to link them together. pharmaceutical industry, as this is the level at
the teams start from both sides and meet in which many drugs act. An important use in
the middle? Examples of modelling the case of the heart is in assessing drug
Unfortunately, in biology there isnt a sin- The heart. Modelling the heart shows the safety. More than half of the drug with-
gle predetermined meeting point, or even just middle-out approach elegantly, because there drawals that have occurred in recent years are
one way of describing the meeting points. are at least two middle levels of data-rich sim- attributable to cardiac side effects, frequently
Because genes have more than one function, ulation: the cellular level, at which we model manifested as effects on the electrocardio-
functions depend on many genes, and because the properties of proteins, including those that gram and an increased risk of arrhythmia. As
there is feedback between the levels, there will transport ions, catalyse reactions and generate virtually all the ion transporters that are
be many ways of dividing the system up. force; and the organ level at which detailed involved are now modelled, and as very real-
These issues were recently debated in a anatomical models have been built. Linking istic simulations of the electrocardiogram
Novartis Foundation symposium on biologi- these two levels together has produced some can be obtained when these models are
cal complexity12. The outcome was that mod- spectacular results13 (BOX 1 and FIG. 2). incorporated into three-dimensional tissue
elling has to be middle-out (see online link to There has been a long period of interac- simulations (FIG. 2), it is possible to use in silico
the Encyclopedia of Life Sciences: Biological tion between experiment and simulation in screens for drug-safety testing31.
computation), which means that computation the case of cellular-level models14. All Another use is in screening drugs for multi-
inevitably focuses on a level between genes excitable cell types have been modelled, as ple actions. Very few drugs bind to just one
and function at which experimental data are have the fine variations in expression levels receptor. Usually two, three or even more

NATURE REVIEWS | MOLECUL AR CELL BIOLOGY VOLUME 3 | JUNE 2002 | 4 6 1

2002 Nature Publishing Group

PERSPECTIVES

Box 2 | Simulating signalling pathways

Biological pathways often encompass the interactions of many
molecular species. Although in vitro approaches to studying
pathways are essential, and can provide kinetic data, they are
unfortunately limited to analysing only a small section of a
given pathway at any one time. By contrast, mathematical
models of biological processes allow scientists to monitor and
visualize the interactions of many molecular species
simultaneously, and help to foster an understanding of the
effects of a particular entity in a complex system.
The screen shots in the image from PathwayPrism a
software application from Physiome Sciences, Inc. show the
representation of the signalling modules nuclear factor-B
(NF-B) and inhibitor of NF-B kinase (IKK) within the larger
pathway of the signal-transduction processes that are involved
in stress signalling. The topological representation of the
pathways is automatically converted into a set of mathematical
relationships that can be simulated. Algorithms in the software
can check for overlap, redundancy and other similar problems
in merging pathway models. Pathways can also be linked to the
modelling of cell behaviour, such as the electrophysiology of
ion channels. This figure is reproduced with permission from Physiome Sciences, Inc. (see online links).
Modelling biological complexity requires that we make such tasks relatively easy, and that laboratories communicate with each other without having to
re-code their equations. The Physiome Committee of the International Union of Physiological Sciences is encouraging the development of common
standards through the use of open mark-up languages, such as CellML (see online link to the The Physiome Markup Languages). CellML stores a
model as a network of individually connected components, and contains a complete definition of a model, so that no assumptions are made by the
software as to how to reconstruct it.

receptors are affected32. Moreover, multisite
action might be beneficial33,34. This will be one
of the ways in which simulation could lead to a
more rational drug-discovery process. In regu-
lating cellular function, nature has developed
many multiple-action processes. So in seeking
more natural ways of intervening in disease
states, we should be seeking to manipulate the
multitude of proteins in more subtle ways.
Towards a theoretical biology?
Simulation in the physical sciences is based on
the long-established fields of theoretical
physics and theoretical chemistry. Is there a
theoretical biology that acts as the basis for
computational biology (FIG. 3)?
It is important to distinguish between com-
putational biology and mathematical biology.
The latter is a branch of mathematics. Its role is
to discover explanations by finding mathemat-
ical not just numerical solutions.
Mathematical solutions provide a basis for
generalization, which is an essential step
towards developing a theory, whereas compu-
tational biology seeks particular numerical
results. There is a successful tradition in many
aspects of mathematical biology35,36, so some
areas of biological computation, which range
from biochemical reactions to the function of
the nervous system36, are already well based in
mathematical biology. Does the existence of
mathematical biology necessarily entail that
something called theoretical biology should
also exist? At this stage, I believe not37. If there is
to be a theoretical biology, it will have to
emerge by integrating many pieces of informa-
tion on the reconstruction of living systems.
This touches on the very nature of biology as a
science. Of course, there are theories in biology.
There are many of them, including the central
theory of evolution. So, why do I conclude that
theoretical biology does not yet exist?
The main reason is that we do not yet use
anything called theoretical biology; instead we
apply the basic theories of chemistry and
physics to biology. Reconstruction of the elec-
trical activity of nerves and muscles38, for
example, uses the well-known laws of electric-
ity and conservation of mass and charge. There
are biological data in such models, but there is
no sense in which the equations used can be
said to have come from a theoretical biology.
Moreover, we have not resolved funda-
mental questions in the central theory of biol-
ogy, that of evolution. Is it dependent on con-
tingent events such as weather change or
meteorite impacts with no overall trend, or
are there features that would inevitably emerge
in any evolutionary process? Part of our prob-
lem is that we have only one experiment to
judge by, and even if we discover life on Mars
Figure 2 | A model of the human torso used
to reconstruct the electrical field changes
that create the electrocardiogram (ECG).
This anatomical model27 of the upper part of the
body represents the varying electrical
conducting properties of the tissues, such as
skin, bone, muscle and lung. The heart
generates electrical fields in the torso, which
are represented here in colour (red represents
positive potentials, whereas blue represents
negative potentials). This frame from the
simulation is taken at the time of the peak
voltage change during the ECG. Reconstruction
of the ECG is important for pharmaceutical
applications, as many drugs have side effects
that alter the ECG17. This figure was kindly
provided by C. P. Bradley, University of
Auckland, Australia and University of Oxford,
United Kingdom.

462 | JUNE 2002 | VOLUME 3 www.nature.com/reviews/molcellbio

2002 Nature Publishing Group


Theoretical biology
Mathematical biology
Theoretical physics Theoretical chemistry
Computational biology
Biological data
Figure 3 | Towards a theoretical biology? How
does computation relate to mathematics, and
could either eventually lead to a subject called
theoretical biology? Here, computation is
regarded as the bottom level, that of detailed
simulation using biological data. Mathematical
biology tries to generalize the results in the form of
explanatory equations, usually those of theoretical
physics and chemistry. Theoretical biology would
be a set of principles and mathematics that are
specific to biology. At present, we have only
tentative ideas on what this set of principles might
be, but they would include evolution and the
theory of complex systems.
or elsewhere, it might turn out not to be a fully
independent evolutionary event.
If we are dealing mostly with the conse-
quences of contingent events, then a level of
detailed description will always remain at the
heart of biological computation. Whereas, if
there were to be some general principles
(what some would call the logic of life39),
then these in their formulations as equa-
tions would eventually become the basis
of a fully theoretical biology. One of the
biggest future challenges for computational
biology will be to try to identify these first
principles. There are several ways in which
they might emerge.
The first, and probably the most secure,
method would be the piecemeal reconstruc-
tion of successful components of the whole.
This approach might be called the jigsaw
method. When we have pieced together
enough of the complete organism, a pattern
might emerge. It would be very surprising if
something like this does not happen. Nature
has, surely, re-used the same tricks many times.
Some kinds of biological laws must exist.
The other extreme would be the appear-
ance of a biological Einstein capable of math-
ematical insight into the central theory of evo-
lution. It is encouraging to see how many
excellent mathematicians are being attracted
to this field. My hunch is that the twenty-first
century will witness the consummation of the
marriage of mathematics and medicine.
NATURE REVIEWS | MOLECUL AR CELL BIOLOGY
2002 Nature Publishing Group
Computational biology will then simply have
been a stepping stone to an even greater trans-
formation of biological science.
Denis Noble is at the Department of Physiology,
University of Oxford, Parks Road,
Oxford OX1 3PT, UK.
e-mail: denis.noble@physiol.ox.ac.uk
doi:10.1038/nrm810
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Acknowledgements
Work in the authors laboratory is supported by the British Heart
Foundation, Medical Research Council, Wellcome Trust and
Physiome Sciences. D.N. was a scientific founder of Physiome
Sciences, Inc.; however, the companys contibution to the
funding of research in his laboratory is less than 5%. Most of
the laboratorys funds come from the British Heart Foundation,
the Medical Research Council, the Royal Society and the
Wellcome Trust. The work of D.N.s research group is all in the
public domain.
Online links
DATABASES
The following terms in this article are linked online to:
OMIM: http://www.ncbi.nlm.nih.gov/Omim
Brugada syndrome | LQT3
Swiss-Prot: http://www.expasy.ch/
SCN5A
FURTHER READING
Alliance for Cellular Signaling: http://www.afcs.org
Cardiac Mechanics Research Group:
http://cmrg.ucsd.edu/modelling/modelling.html
CellML: http://www.cellml.org
Encyclopedia of Life Sciences: http://www.els.net/
Biological computation
Entelos, Inc.: http://www.entelos.com
Gene Ontology Consortium: http://www.geneontology.org
IBMs Blue Gene Project:
http://www.research.ibm.com/bluegene/index.html
Luo-Rudy dynamics model of the mammalian ventricular
action potential:
http://www.cwru.edu/med/CBRTC/LRdOnline
Pharsight Corporation: http://www.pharsight.com
Physiome Sciences, Inc.: http://www.physiome.com
Simulations Plus, Inc.: http://www.simulationsplus.com
Systems Biology:
http://www.cds.caltech.edu/erato/index.html
The Human Physiome Project:
http://www.bioeng.auckland.ac.nz/physiome/physiome.php
The Physiome Markup Languages:
http://www.physiome.org.nz
The Physiome Project: http://www.physiome.org
Access to this interactive links box is free online.
VOLUME 3 | JUNE 2002 | 4 6 3