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PERSPECTIVES

protein5. The power of a model lies in identi-


OPINION fying what is essential, whereas a complete
representation would leave us just as wise, or
as ignorant, as before.
The rise of computational biology The important concept here is modularity.
Function emerges from the interactions of
groups of proteins in which the genes are usu-
Denis Noble ally selected together6. Determining the logic
of such modules and their interactions would
The year 2001 saw a remarkable burst of The protagonists of these two camps be one of the steps towards creating a funda-
interest in biological simulation, with several would agree on one thing whichever way mental theory of biology. It will be particu-
international meetings on the subject, and the causation runs, biological systems are larly interesting to determine the extent to
the inclusion, by journals, of web site highly complex. Beyond a certain level of which modularity at higher, functional levels
references from which published models complexity (and in mathematical terms this matches that identified by proteomics6.
can be downloaded. So, why has all this could mean something as simple as a pair of The opposite of bottom-up top-down
happened so suddenly? differential equations), qualitative thinking (FIG. 1) risks being either empty (reformulat-
fails us. In other sciences there is already an ing interactions at a higher level does not guar-
The last half of the twentieth century saw the answer to this problem become quantita- antee that we will find the correct lower-level
phenomenal success of the reductionist tive and calculate! mechanisms) or incomplete. Genes (and pro-
approach. The structures of macromolecules The growing realization that this is neces- teins), after all, do not come with their own
were unravelled, the chemical nature of sary explains the sudden explosion of interest. functional labels. We have to work them out
DNA was discovered, and the genome In 2001, the first international conference on (see online link to the Gene Ontology
sequences of several organisms were largely computational biology was held in the United Consortium, which systematically documents
or completely determined. We are witnessing States3. The Institut National de la Sant et de information on gene functions), and in most
monumental achievements. But this success la Recherche Mdicale (INSERM, France), the cases the functionality will be both multiple
has created a huge challenge: what do all Medical Research Council (MRC, UK) and and extensively crosslinked. The discovery that
these data mean? It is possible that with this the National Institutes of Health (NIH, USA) there might be many fewer genes than proteins
information and limitless computing power held strategy meetings on this emerging field, reinforces this point, although the precise
we could simulate, almost mindlessly, in a while the Novartis Foundation held a land- number of genes is still a matter of debate7.
bottom-up fashion (FIG. 1), the complete mark symposium entitled In silico simulation Could a combination of these two
functioning of an organism? of biological processes4. Biology is set to approaches a kind of outside-in (FIG. 1)
A biological determinist would hope that become a highly quantitative science. In the work? This is the way we often think about
the answer is yes. Isnt life just the product of a present century, it will also become the most the relationships between molecular biology
one-way upward causation from genes to computer-intensive science. and systems biology. Even the most ardent
cells, organs, systems and whole organisms? I discuss first the question of how model-
Perhaps the most uncompromising statement ling relates to biological levels, and illustrate
in support of this view is that from Richard this using the heart as an example, before gen- Physiological systems and function

Dawkins1: They [genes] are in you and me; eralizing to the simulation of biological path- 'Top-down'

they created us, body and mind; and their ways, cells and systems and the applications to Systems Organs
preservation is the ultimate rationale for our drug development. I conclude by asking the
existence. Interestingly, the very concept of deepest question of all: could there be a theo-
the selfish gene is based on a beautiful exam- retical biology? Tissues 'Middle-out' Cells
ple of computational biology, that of the
mathematics of kin selection as the basis of Levels of modelling
social behaviour2: helping near relatives Where should modelling begin? Could we
Pathways Organelles
favours the selection of our own genes. start with the individual molecules and
There is, however, an alternative view, exhaustively compute their interactions? 'Bottom-up'
which is that biological systems are too inter- There is, of course, a computer that does this: Molecular data and mechanisms
active between levels for a one-way framework the body itself! But there are problems with
to be possible. There is so much feedback from trying to copy nature so completely. Figure 1 | Levels of modelling. Should biological
simulation start from the bottom level of
higher levels controlling gene expression Even if we were to succeed, the result
molecules and work upwards to systems and
levels and their interactions with the integra- would not be a model in the strict sense. whole organisms, or from the top (physiological
tive properties of the organism and its envi- Models are partial representations. Their aim function) and work downwards to the underlying
ronment that it would be just as valid, and is explanation: to show which features of a sys- molecular mechanisms? How would they be
certainly equally as colourful, to represent tem are necessary and sufficient to understand guaranteed to meet? Would a combination of the
genes as prisoners that are trapped inside the it. So, although we could try to understand two (outside-in) be guaranteed to meet in the
middle? Alternatively, there is a pragmatic option,
successful physiological systems that express cardiac rhythm as the interaction of the few
middle-out, which starts at any level (pathways,
them. To understand their roles in this con- thousand types of protein that are in any cell, organelles, cells, tissues, organs or systems) at
text, we need to unravel the higher logic of life, we can in fact understand most of what we which there are sufficient data and reaches (up,
and as organisms are what live and die, natural wish to know about pacemaker activity from down and across) towards other levels and
selection must operate at this level. the interaction of around a dozen types of components.

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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

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

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PERSPECTIVES

Theoretical biology Computational biology will then simply have the Heart (eds Panfilov, A. & Holden, A.) 6569 (Wiley,
Chichester, UK, 1997).
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13. Kohl, P., Noble, D., Winslow, R. L. & Hunter, P. Foundation, Medical Research Council, Wellcome Trust and
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method. When we have pieced together H1365H1378 (1991). CellML: http://www.cellml.org
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enough of the complete organism, a pattern Computational models of the mammalian cardiac sinus Biological computation
might emerge. It would be very surprising if node implemented on a Connection Machine CM-2. Med. Entelos, Inc.: http://www.entelos.com
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Biology of the Heart (eds Panfilov, A. & Holden, A.) http://www.physiome.org.nz
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