Biological Computation

Denis Noble, University Laboratory of Physiology, Oxford, UK

Simulation of biological processes is increasingly important. The vast amount of data that needs interpretation requires quantitative integration to enable us to understand it. Fortunately, there is now the computing power necessary to achieve this, and it is predicted here that relevant software will also become widely available. Biology is set to become a computer-intensive quantitative science.

Special Essay article

Article Contents
. Introduction . Role of Models . Theory and Computation . Data and Modelling . Preventing the Tower of Babel . Drugs and Devices . Conclusion

Introduction
Computer modelling will even provide the tools with which to perform in silico clinical trials, based on whole organ body models that test for everything. (Pharma 2005, PriceWaterhouseCoopers report, 1998)

. Acknowledgements

When Pharma 2005 was published 3 years ago, that prediction must have seemed simply a dream. Yet today there is a Grand Challenge, the Physiome Project (see www.physiome.org), launched by the International Union of Physiological Sciences (IUPS) (see www.IUPS.org) to facilitate the international academic funding and collaborations required. And there are biotechnology companies already developing the technologies required to achieve it (see the websites of Entelos (www.entelos.com), Pharsight (www.pharsight.com), Physiome Sciences (www.physiome.com), Simulations Plus (www.simulationsplus.com)). What has changed? Here I will try to explain why biological computation is becoming a hot topic. Three major national funding agencies, NIH (National Institutes of Health), MRC (Medical Research de la Council) and INSERM (Institut National de la Sante dicale), held strategy meetings on it during Recherche Me 2001, while the rst International Conference on Computational Biology also took place in 2001 (Carson et al., 2001). I will discuss what the problems are, and why computational biology will have a profound and pervasive impact on biology in the twenty-rst century. Computers are used today in all aspects of biology. It would be impossible to review the whole of this range, which involves analysis of experimental data, development and management of databases, including of course gene and protein databases, imaging, statistical analysis _ the list is almost endless. There is hardly anything in biological science today that has not been computerized. I will not deal with any of these subjects. This article focuses rather on computer modelling of biological processes, not analysis, storage and systematization of data. At the end of this article I will, though, discuss how systematization of data and modelling of processes must interact. Even within this topic though, I will be fairly restrictive. I will not deal with modelling of biological molecules, protein structure, etc. These are important applications of

computational modelling, but they can be viewed as a branch of theoretical chemistry. Biology begins when biological function emerges, and this is above the level of individual molecules. It lies at the level at which proteins interact to produce phenomena like the hearts pacemaker activity, the secretion of insulin (Chay, 1997), the functioning of the immune system etc. In each of these functions large numbers of genes interact in complex ways. Biological computation seeks to understand and predict this complexity by modelling it (Platt, 1964; Bray, 1995; Fell, 1996; Bassingthwaighte, 1997; Kohl et al., 2000; Hunter et al., 2001; Kitano, 2002). The molecular biologist Sydney Brenner gave the fundamental reason for biological modelling when he wrote Genes can only specify the properties of the proteins they code for, and any integrative properties of the system must be computed by their interactions (Brenner, 1998). Brenner meant not only that biological systems themselves compute these interactions but also that in order to understand them we need to compute them, and he concluded this provides a framework for analysis by simulation.

Purpose of Biological Computation

In general, computer models are used when the complexity of a system is too great to grasp intuitively. This has increasingly become the case in biology proteins can interact with many other proteins depending on time and place, individual molecules may participate in multiple pathways, and the background against which protein function is expressed can change dynamically with sex, age, disease and environment. Models are used to aid data interpretation, to hypothesize new approaches, and to identify where gaps in knowledge exist. A modeller can take a set of existing data and determine whether those data are sucient to generate the output of the system under study. If they are not, the modeller can then suggest specic directions for further study as well as make predictions
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about possible results. Most importantly, computer models enable the researcher to fail under controlled conditions. Trying ideas out in a virtual environment where the possible impact of dierent conditions can be tested systematically allows the researcher to anticipate problems and to select the best overall design principles in advance of costly real life studies. Biological function emerges at many dierent levels. Integrative interaction between many proteins may be the basis of a metabolic pathway (Schilling and Palsson, 1998; Schilling et al., 1999; Edwards and Palsson 1999, 2001), a signalling cascade (see www.afcs.org and Shimizu et al., 2000), control of the cell boundaries (membrane transporters of many dierent kinds), cellular functions like secretion and electrical activity, multicellular functions as in kidney tubules or cardiac conducting pathways, through the various levels to whole organs and systems. Ultimately, some even conceive the possibility of constructing a virtual human. A partial virtual heart already exists (Nielsen et al., 1991; Winslow et al., 1991, 1993; Hunter, 1995; Costa et al., 1996; Hunter et al., 1997; Holden and Panlov, 1997; Chen et al., 1998; Smith et al., 2000, 2001). Other organs and systems are beginning to be represented in the same way (Howatson et al., 2000). Connecting them together in appropriate anatomical and biochemical frameworks is indeed not inconceivable. A partial virtual human (partial because probably with not much of a brain! at least for the foreseeable future) may seem a long way o, but such a project, once it has gathered momentum, would be using vast arrays of biological information, much of which already exists. The greatest challenge will lie in connecting it all together. The scale and necessity of this task can be judged by the fact that the Human Genome Project has so far located around 40 000 genes (but see Hollon, 2001 for the debate on this gure), yet there may be as many as 250 000 dierent proteins. Another striking statistic is that the mouse genome has the same number of genes, with 96.5% similarity to the human genome! The task of working out proteinprotein interactions and the role of their environment is, therefore, of crucial importance. However much experimental data we may accumulate on these interactions, computation must be an essential part of the task of unravelling such complexity.

Levels of modelling bottom-up, topdown _ or middle-out?

But before getting too carried away by such grand possibilities as a virtual human, let us consider some of the diculties. One of these concerns the level at which modelling begins. There are several dierent approaches to this question. One might be called the Laplacian view, following Laplaces famous statement that provided we
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knew the positions and velocities of all the components of a system we must in principle be able to foresee all its subsequent states (though Heisenbergs uncertainty principle reminds us that there are strict limits to this, at least on a small scale). An extreme reductionist view is that we should begin with the properties of the individual molecules in a biological system and then exhaustively compute their interactions (see Bock and Goode, 1998 for a lively debate on reductionism in biology). There is, of course, a computer that does this. It is the body itself! This is the rst sense of Sydney Brenners use of the term biological computation. But there are several problems with trying to copy nature so completely in our own simulations, to create a complete computational clone. The rst is that, even if we were able to succeed, the result would not be a model in the strict sense of the term. Models are always, necessarily, partial representations of reality. Their aim is understanding and explanation in a simplied representation, and this must consist partly in determining what features of a system are necessary and sucient to understand it. Thus, we could try to understand pacemaker function in the heart by computing the interactions of the few thousand protein types that must be involved in making any cardiac cell. In fact, however, this is not necessary. We can understand most of what we wish to know about pacemaker activity by computing the interactions of only around 1020 protein types (Garny et al., 2002). That is the power of a model. It identies what is essential. A complete representation a clone of reality would not do that. It would leave us just as wise, or as ignorant, as before. The second problem is that of computability. Such a complete representation of a biological system, from the bottom upwards, would require more computing power than we are likely to achieve in the foreseeable future. It is estimated that to compute the folding of a single protein from the rst principles of theoretical chemistry will require a years work on Blue Gene, the one-million processor supercomputer being built by IBM (see www.research.ibm.com/bluegene/). Yet, there may be more than 100 000 proteins in the body. Even before we start computing proteinprotein interactions, we would already have many years to wait! If we are really talking about simulation, not re-creation, then it is probable that we will not have enough components to build the monstrous computer that would be required to simulate in a complete bottom-up way. Third, and most fundamentally, bottom-up is not the only rule that nature itself follows. At all levels there exist feedback loops from higher function to lower level activity. Gene expression is not a static property. It is dynamically related to the environment in which genes operate. Genes are as much prisoners of the successful physiological systems that carry them (Noble, 2002), as selsh determinants of what that system will do.

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Biological Computation

Pure bottom-up therefore is neither feasible, nor would it necessarily be explanatory. What about the opposite of bottom-up: top-down? The idea here is that, since any model must extract from reality the essential features necessary for an explanation, we might as well start with the function we want to explain and burrow down to the underlying mechanisms. This, at least, ensures that we will focus on the biological phenomena we are trying to explain. But it also runs the risk of being either empty (reformulating interactions at a higher level does not guarantee that we will hit upon the correct lower-level mechanisms) or seriously incomplete. Genes (and proteins), after all, do not come with their own functional labels. We have to work them out, and in most cases the functionality will be both multiple and extensively crosslinked. The discovery that there may be many fewer genes than proteins reinforces this point. Top-down also carries a further risk, which is that we may be misled by the prejudices that are inevitably built in to a preconceived idea of functionality. A top-down approach must operate within the boundaries predetermined by the system we think is complete. Recent biological research has thrown up countless examples of underlying processes that we did not know were there, and certainly could not have predicted from a purely functional-level description. Compare any textbook of cell biology with its counterpart of 20 years ago to see the point. Could a combination of top-down and bottom-up approaches work a kind of outside-in? This is the way we often think about the relationships between molecular biology and systems biology. How else can we conceivably span the whole range from genes to functions? So, there cannot be much doubt that this dialectical way of thinking will inform our eorts in computational biology. Even the most ardent reductionist is not blind to functional descriptions of biological processes even if he or she might dream of replacing them, while no systems biologist today can be fully satised with explanations that do not connect to the underlying mechanisms and even to the genome level (e.g. Clancy and Rudy, 1999). Could we therefore imagine a kind of double-tunnelling, a bit like the construction of Eurotunnel linking Britain and France, where the teams started from both sides and met in the middle? The problem with this approach is that, unlike tunnelling, there is not a single predetermined meeting point, or even just one way of describing the meeting points. Because genes have multiple functions, and functions depend on many genes, and because there are feedbacks between the levels (gene expression depends itself on functionality), there will be many ways of dividing the system up at the intermediate levels. Modellers will choose between these according to their own aims. Someone interested in reconstructing electrical activity will describe proteins primarily in terms of their ionic transport properties, whereas someone interested in uxes and energy expenditure may even regard the electrical properties as a side

eect. There will also be dierent ways of conating individual protein functions at the higher levels. Electrophysiologists are already familiar with this problem. Reduced systems of equations (van der Pol and van der Mark, 1928; Nagumo and Sato, 1972) can only be said to represent protein activity by combining the eects of several proteins together in a single computed parameter. There are many ways in which this can be done. There will therefore be a multiplicity of parallel models at the intermediate levels, all of which will have their strengths and weaknesses. This raises the important question of mapping. One way to analyse this heterogeneity of models will be to map models onto each other, something that is rarely done, but which can in fact be highly instructive. One of the major controversies in cardiac modelling was resolved by this approach (DiFrancesco and Noble, 1982). We need to think about the ontology of models. These issues were recently debated in a Novartis Foundation symposium on biological complexity (Goode, 2001). The outcome was the proposal that if the various outside-in options (including bottom-up and top-down) have so many diculties, there was only one remaining alternative: modelling had to be middle-out, meaning that computational models inevitably focused on a functional level between genes and function at which they were most detailed. This might be a biochemical pathway, a cell signalling mechanism, the whole cell, a tissue, an organ, a system etc. The level of focus can be characterized as that at which the relevant information on which the modelling is based is most detailed. This inevitably leads to the concept of a hierarchy of models, and one of the major challenges will be how to link them together.

Role of Models
Analogy with the role of modelling in the physical sciences is helpful. In particular it is important to recall that, here also, there has been a long period of iterative interaction between computation and observation. No-one today builds a new aircraft, for example, without rst modelling designs and functions on computer systems. Once, this was done laboriously with wind tunnels. Models of the universe have gone through many stages of development, as astronomy has provided more and more data. In turn, models have suggested new aims for observation. Some of these developments, particularly the iterative nature of the interaction between theory and experiment (see e.g. Noble and Rudy 2001), have obvious parallels in the biological sciences. What makes the situation look so dierent is that the sheer complexity of biological systems, and the recent discovery of much of the relevant data during the molecular biological revolution, means that we are at an earlier stage of development in biology. To some extent,
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the dierences will become less obvious with time as the eld develops. But there will also be some respects in which biological computation must be fundamentally dierent. Ideally, biological models need to span at least three levels.

Level 1: descriptive as much data as possible

There must be a level somewhere between that of the gene and that of the whole organism at which the input to a computational model is simply descriptive. At this level, far from minimizing parameters, we need to incorporate as much data as possible. Biological systems are data-rich, whether at the level of genomes, proteins, pathways, cells or whole organs. At this level, models must also be responsive to the need to introduce new data and data formats to permit rapid model development. The data deluge is one of the key problems computational biology has to address. Modelling should be exible enough to cope with this.

Level 2: integrative how elements interact

From this rich data-descriptive level, we then develop equations for ways in which the elements interact. The object here must be to integrate, in order to simulate the way in which the biological system itself computes the interactions. The criterion for success at this level will be how much biological function can be reconstructed.

Level 3: explanatory biological insight

Finally, there is the level (or better still, the levels) at which the models can be used to help achieve biological understanding. This will include the unravelling of counterintuitive properties, the making and experimental testing of predictions, and, most importantly, the probing for failure. A point that is not yet properly appreciated in biology is that one of the functions of models is to fail. It is the way in which they fail that can be illuminating, leading on to new experiments, new models and new ideas in a continuous interactive manner. All models must eventually fail for the simple reason that they are always partial representations of reality and there must therefore be phenomena that are not within their range of prediction. A good modeller is a kind of detective, looking for inconsistencies in the story, where the failure of the logic of a model leads to uncovering new or hidden knowledge.

Theory and Computation

There is yet another important respect in which computational biology diers from computational works in the physical sciences. This is that there are established elds
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that call themselves theoretical physics and theoretical chemistry on which computational work in the physical sciences is based. Is there, then, a theoretical biology which can act as the base for computational biology? Note, rst, that there is an important dierence to be drawn between computational biology and mathematical biology. The latter is a branch of mathematics applied to biology. Its role is to discover explanations, not just numerical solutions. There is a good tradition in many aspects of mathematical biology (Murray, 1983; Keener and Sneyd, 1998), some of which does form a base for computational biology. In the theory of excitable cells there is a substantial literature (Jack et al., 1975; Hunter et al., 1975; DiFrancesco and Noble, 1980; Hinch, 2002) on analytical solutions to problems in excitation theory. Unfortunately, the sheer power of modern computing has sometimes overshadowed the more purely mathematical approach. So, some areas of biological computation 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 the answer to that question must be no (see also Bray, 2001). If there is to be a theoretical biology, it will have to emerge from the integration of many pieces of the reconstruction of living systems. This question touches on the very nature of biology as a science. Of course, there are theories in biology many of them! There is also a central theory that of evolution. So why do I conclude that theoretical biology does not yet exist? The rst reason is that much of the increasingly spectacular modelling of biological processes does not use anything called theoretical biology; it uses the basic theories of chemistry and physics. Reconstructions of the electrical activity of nerves, muscles and organs like the heart, for example, use the well-known laws of electricity and conservation of mass and charge, while a reconstruction of its blood ow uses the equations of uid dynamics. There are biological data in such models but there is no sense in which the equations used can be said to come from a theoretical biology. The second reason is that we still have not resolved some fundamental questions within the central theory of biology, that of evolution. Has that process been essentially one of chance, dependent on contingent events such as weather change, meteorite impacts, etc., with no overall trend? Or are there features that would inevitably emerge in any such evolutionary process? Part of our trouble is that we have only one experiment to judge by, and even if we discover life on Mars or elsewhere, it may well not be a fully independent evolutionary event. Yet this question (of contingency or necessity) must be fundamental to any emergence of a subject that could call itself theoretical biology. If we are dealing mostly with the consequences of contingent events, then a level of massive and exhaustive description will always and necessarily

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remain at the heart of biological computation. Whereas, if there were to be some general principles (what some would call the Logic of Life (Boyd and Noble, 1993)), then these, in their quantitative formulations, would eventually become the basis of a fully theoretical biology. One of the big future challenges for computational biology will be to try to identify these rst principles. We are in a similar situation to that of the theoretical cosmologists. So far as we know, they also are dealing with only one actual event, the evolution of the universe we know. But computation gives us the possibility of exploring many other dierent possibilities. I believe that will one day be true of biological computation. Can we foresee the ways in which computational biology might eventually identify the principles of a theoretical biology? This is where I can see a role for what I called earlier the ontology of models. I am not a good enough mathematician to see clearly what might be done here, but I have the intuition that by mapping alternative models, and exploring the ontologies of models at dierent levels we may begin to reveal at least one thread of the theoretical rules for biological processes.

not fail if we could with reasonable certainty identify these small groups of individuals (and they will be dierent for dierent drugs, of course) and allow the great majority who could benet to do so.

Preventing the Tower of Babel

One of the reasons computational biology has not played a major role in the past is that it has been largely the preserve of the high priests of the art. I remember the excitement generated in the world of physiology when Hodgkin and Huxley (1952) published their Nobel prize-winning analysis of the nerve impulse. There was breathtaking admiration for this early demonstration that biology could be quite as quantitative as physics or chemistry, but there was also the perception that such achievements were beyond the ordinary mortals of biological science, most of whom have little training in mathematics, let alone in computer programming. It took Andrew Huxley around 6 months to do the computations (with a mechanical, hand-operated calculator I was once the proud possessor of such a machine, a Brunsviga, myself, later abandoned in favour of an electronic computer (Noble, 1962)). It was also a major achievement to get time allocated on the precious mainframe computers of the 1960s and 1970s, vast machines that cranked away at a speed that even handheld machines can exceed today. But that is my point! At a time when nearly everyone has powerful computing at their ngertips in the form of a PC or workstation, any remaining justication for treating the eld as a black art has gone. Recall that even the simplest PC today is much more powerful than the computers with which NASA achieved a trip to the moon. Computational modelling should be a natural tool of analysis available to everyone. This aim is in the process of being achieved. Several laboratories have made their software widely available (examples include OXSOFT HEART, Virtual Cell (see www.nrcam.uchc.edu), e-cell (see www.e-cell.org and Tomita et al., 1999), JSIM, Luo-Rudy), and a major part of the Physiome Project is to encourage the development of meta-languages (such as CellML (see www.cellml.org) and SBML (see www.cds.caltech.edu/erato)) that dispense with the need to write specic computer code, and which will enable models to connect with each other more readily. Developments of this kind will be essential if the immense potential for biological computation is to be achieved. We need standardization, facilitation of exchange and the ability to merge point solutions into highly integrated formulations.

Data and Modelling

At the beginning of this article, I said that I would return to the question of the connection between data and biological computation. It will be evident from what I have said about levels of modelling, and about the lack of a theoretical biological framework, that reconstruction from rst principles will certainly not be possible in the near future, and certainly not until (if ever) the principles of a theoretical biology emerge. Either way, we are stuck with the prospect that biological computation will need to relate to vast databases of information. In principle, this could be turned to advantage. Individuals dier not in the general principles by which a body is made, but rather in the details that are attributable to dierent genomes and dierent environmental inuences. This is why identication of individuals is possible from DNA sequence measurement, and why we are able to trace the history of populations (see e.g. Sykes, 2001). Some therefore predict that we will all eventually carry our own personal information (genome, expression levels etc.) in some form of information card. This is one of the aims of the development of what are called biochips. If connected to biological modelling or to other forms of in silico technology, it is possible that we will not only have access to such information but will also be able to feed it directly into simulations that could, in principle, advise us which treatments would be most suitable. Patient stratication is then a possibility. The implications of this kind of development are immense, both technically and ethically. To give one example: many drugs fail because in clinical trials a tiny fraction of the population reacts badly to them. They need

Drugs and Devices

It would take another article to deal properly with this subject (see e.g. Noble et al., 1999; Noble and Colatsky,
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2000). Here I will simply note that biological computation is not just of theoretical interest. The reason that biotechnology companies exist that are built on in silico simulation technology (see the introductory remarks to this article) is that the potential for application to the processes of drug discovery and device development is immense. Virtually all pharmaceutical companies now have or are developing in-house eorts in this direction, sometimes in collaboration with biotechnology companies and with university teams. Leading medical device companies are also involved in modelling.

Conclusion
Biological computation is at an early stage of development, one at which it relies heavily on well-established principles from the physical sciences, combined with huge and rapidly growing databases of biological information. I predict that the eld will grow rapidly as the techniques became easy to use and as widely available as are powerful computers today. Within probably only 10 years or so, biology will become suciently quantitative that it will be as unthinkable not to formulate hypotheses in a mathematical form, as it is now to be purely qualitative in our descriptions of biological data. The sheer complexity of the functional level of biology will force us to think in terms of models that address this complexity in a way that the unaided brain cannot possibly do. Conceivably, but not necessarily, out of this will eventually emerge the principles of a theoretical biology. At present it is impossible to tell whether such a discipline exists and how it will take shape. Either way, though, the impact of biological computation will be extensive. Integrative biology will increasingly depend on it, and if a theoretical biology does eventually emerge, biology will never be the same again. Some have surmised that with the sequencing of the genome we have seen the last major revolution in biology. I believe the contrary: that immense achievement is only the beginning of an even bigger revolution: not just to describe, but to understand.

Acknowledgements
I would like to acknowledge the support of the British Heart Foundation, MRC and The Wellcome Trust.

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Further Reading
Bock G and Goode J (Eds) (2002) In Silico Simulation of Biological Processes. Novartis Foundation Symposium 247. London: John Wiley. Csete ME and Doyle JC (2002) Reverse engineering of biological complexity. Science 295: 16641669. Noble D (2002) The rise of computational biology. Nature Reviews Molecular Cell Biology (in press). Noble D (2002) Modelling the heart: from genes to cells to the whole organ. Science 295: 16781682.

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