SUCCESS STORIES IN SYSTEMS BIOLOGY

Project funded by the European Comission under the Seventh Framework Programme for Research and Technological Development Contents

Welcome 2

Research 3

A model that gets to the heart of systems biology 3 Denis Noble, Oxford University

Taking a systems-eye view of cancers in children 5 Walter Kolch, Systems Biology Ireland

Systems biology study points to Turing model of finger formation 7 James Sharpe, Centre for Genomic Regulation

Balancing flavour and texture in tomatoes - with systems biology 9 Stuart Dunbar, Syngenta

Systems X.ch: Swiss bank on systems biology 11 Daniel Vonder Muehll, SystemsX, Gisou van der Goot, EPF Lausanne, Cris Kuhlemeier, University of Bern

Answering big questions with a small bug 13 Luis Serrano, Centre for Genomic Regulation

Blueprints for life 15 Bas Teusink, Netherlands Platform for Systems Biology

Merrimack: Following a systems path to drug discovery 17 Peter Sorger, Massachusetts Institute of Technology, and Birgit Schoeberl, Merrimack Pharmaceuticals

Beating the conundrum of variability in cardiac simulations 19 Blanca Rodriguez, Oxford University

Stats and modelling – a Belgian diagnostic tool for arthritis 21 Thibault Helleputte, DNAlytics

Virtual Liver Network: a collaborative solution to hepatic diseases 23 Adriano Henney, Virtual Liver Network

Tools and Resources 25

SBML: A lingua franca for systems biology 25 Michael Hucka, California Institute of Technology

Model Support: JWS Online and BioModels Database 27 Jacky Snoep, Stellenbosch University, and Henning Hermjakob, European Bioinformatics Institute

SYSMic: An interdisciplinary skills course for biologists 29 Gerold Baier and Geraint Thomas, University College London

COPASI: An open source software package easing the path to modelling 31 Pedro Mendes, University of Manchester

SEEK and ye shall find data 33 Katy Wolstencroft, University of Leiden

1 ISBE - www.isbe.eu Welcome

I am very pleased to introduce this collection of success stories in systems biology, produced as part of the Infrastructure for Systems Biology Europe (ISBE) project and funded through the European Union Seventh Framework Programme. This is just a small sample of the cutting edge BIOGRAPHY research being carried out in systems biology in academic, clinical and industrial settings which is making an increasingly significant impact as we seek to tackle grand societal challenges in areas as diverse as health, agriculture and biotechnology.

In the past fifteen years, systems biology research has become embedded across a range of biological and biomedical fields. This has been driven by the growing abundance and complexity of large biological data sets, the development of tools and techniques with which to perform comprehensive, genome-wide analyses, and the capacity to share these via high speed connections between disparate research groups and disciplines. Using a systems approach, life scientists are

now able, for the first time, to study the complex and dynamic interplay between the components RIChaRd KITnEY IS of a system (be it at the level of a cell, tissue, organ, organism or population). This can now go PROfESSOR Of BIOMEdICaL beyond understanding function, to enable intervention in the behaviour of the system in a predictive SYSTEMS EnGInEERInG, ChaIRMan Of ThE InSTITuTE and rational manner. The stories told in this publication illustrate the breadth of work going on in Of SYSTEMS and SYnThETIC this dynamic area. BIOLOGY and CO-dIRECTOR Of ThE EPSRC naTIOnaL Challenges remain, however: how to increase access to modelling, developing workable standards CEnTRE fOR SYnThETIC BIOLOGY and InnOvaTIOn aT that enable the effective reuse of data and models as well as training new generations of scientists IMPERIaL COLLEGE LOndOn. in this multidisciplinary approach. A number of the tools and resources featured in this collection have been developed to address individual bottlenecks but an integrated infrastructure for systems Kitney is a leading researcher in biology is needed if we are truly to exploit the potential of systems biology. From 2012-2015, the the field of synthetic biology and, with Professor Paul ISBE consortium of 23 partners from 11 EU member states has been working with the academic, Freemont, has been clinical and industrial research communities to develop plans for a systems biology infrastructure responsible for developing the that will address these challenges with services that support a range of users, from novices to UK National Centre for Synthetic Biology - which is experts, from SMEs to Big Pharma, from university labs to hospital clinics. Our proposals for the now recognised as one of the infrastructure’s development over the coming years have been published in a business plan (July leading international centres in 2015) and the roll out of preliminary services is due to commence in late 2015. the field. In June 2001, Professor Kitney I would like to thank my colleagues from academia and industry who gave up their time for this was awarded the Order of the collection. They have given a fascinating insight into the iterative research process that is the basis British Empire (OBE) in the Queen's Birthday Honours List of systems biology, the cycle of experimentation and computational modelling that harnesses the for services to Information potential of ‘big data’ and turns it into tangible outcomes for society. Technology in Healthcare.

Yours Prof. Richard I Kitney, OBE FREng Coordinator, Infrastructure for Systems Biology Europe Imperial College London

ISBE - www.isbe.eu 2 BIOGRAPHY

PROF. DENIS NOBLE DISCUSSES THE DEVELOPMENT OF HIS WORK IN CARDIAC CELL MODELLING FROM 1960 TO THE PRESENT

Your heart: without it, you wouldn’t survive formulae and spent late nights punching in very long. So medicine strives to keep it healthy machine code in his allotted time between 2 and fix it if something goes wrong. Yet the and 4am. heart’s central role in our bodies can also make it difficult to test out new clinical approaches in Soon his work paid off and the heart model humans. One way to get around this is to build began to work. “It didn’t take too long to get to DENIS NOBLE IS A BRITISH a mathematical model that predicts how the the point where rhythm was coming out of the BIOLOGIST WHO WAS THE heart will behave, and today the ‘virtual heart’ equations,” recalls Prof. Noble, who is today an FIRST TO MODEL CARDIAC CELLS, DETAILED IN TWO approach is helping to make drug discovery and Emeritus Professor at Oxford University and PAPERS IN NATURE IN 1960. HE testing safer. President of the International Union of WAS EDUCATED AT UNIVERSITY Physiological Sciences. Papers in the COLLEGE LONDON AND MOVED prestigious journal Nature followed swiftly, and TO OXFORD IN 1963 AS Middle out means that you since then the heart model and experimental FELLOW AND TUTOR IN data have closely intertwined, building up our PHYSIOLOGY AT BALLIOL start at one level - which might COLLEGE. FROM 1984 TO 2004, be in the middle, in our case it’s knowledge of how this key organ works. HE HELD THE BURDON the cell. Then you reach down SANDERSON CHAIR OF to individual molecules and you In some cases, the model has informed the CARDIOVASCULAR PHYSIOLOGY reach up to the organ. experiments - Noble recalls how in the early AT OXFORD UNIVERSITY. 1960s his model put paid to a method of using He is now Professor Emeritus double probes to stimulate heart tissue in the and co-Director of lab: the maths clearly showed that the Computational Physiology. His The heart model has its origins in 1960, and its experimental approach was disrupting heart research focuses on using growth since then exemplifies the systems cell function. In other cases, experimental computer models of biological biology approach of using modelling and findings enhanced the model. “By about 1967, organs and organ systems to interpret function from the experimental data to enable new insights. It the existence of calcium channels had been molecular level to the whole began when Denis Noble and his PhD demonstrated, and that was the first point at organism. supervisor Otto Hutter worked with heart which it was obvious that the model would tissue at University College London. They were have to be expanded,” says Prof. Noble. “That interested in a type of electrical ‘gate’ in heart process of expanding and taking more and cells called the potassium channel, and Noble more into account has gone on ever since.” wanted to develop a mathematical model of the heart to explore its actions. In the decades since he punched machine code into the Mercury, Prof. Noble has worked with He based his work on a 1952 mathematical collaborators around the world to build up the model that described the characteristics of heart model and shed new light on how ion excitable cells, and to build up the model Noble channels work. Meanwhile, computer managed to wrangle some time on the Ferranti technology grew too, enabling more Mercury Computer in London. He sat in on sophisticated modelling and the development maths lectures to get up to speed with the of a virtual organ. The growth of the heart

3 ISBE - www.isbe.eu model exemplifies the ‘middle-out’ approach He now sees potential for the virtual heart to that Prof. Noble has long supported. “Middle continue informing drug discovery and out means that you start at one level - which regulation, thereby reducing risks in drug CuRREnT might be in the middle, in our case it’s the cell,” development. “Many side effects of drugs hit dEvELOPMEnTS he explains. “Then you reach down to individual the heart and cause arrhythmia, that has in the In CaRdIaC CELL molecules and you reach up to the organ.” past been the cause of withdrawal of drugs,” MOdELLInG he says. “And many of the companies have got out of this kind of work, it’s too risky so we are Premature heartbeats explained We used computation to show looking to see if you can use the model to filter as a change in the stability at an early stage synergistic actions of properties of the dynamical why ranolazine’s combination system of the heart cell during potential drugs. Getting it right in the early of actions would be expected to the course of an action potential stages [of drug discovery and development] is be synergistic and that provided (Tran et al ., 2009). a good idea, and this is where the model can data about the drug as it went help.” Tissue electromechanics models through regulatory approval. show how infarctions can cause arrhythmia . Words: Claire O’Connell January 2014 Multiscale models of The mathematical approach can also offer a electrophysiology illustrate how safe and ethical support to look for new cellular action potentials give medications and anticipate side-effects, says rise to the electrocardiogram Prof. Noble, explaining how in one case the (ECG) measured macroscopically on the surface of the body heart model showed in the late 1970s that (Sundnes et al ., 2006). blocking a newly discovered ion channel would have interesting clinical effects. “We were able Multiscale, multiphysics models to show that a blocker of this mechanism can account for the effects of would not stop the heart, that it would slow it,” genetic mutations at levels from he says. “So a pharmaceutical company looked ion-channel structure, function, and macroscopic current; cell, for and found a compound that did that, and it tissue and organ function is now out there as an approved drug - ivabradine.”

In another case the heart model helped to explain the dual-action effects of a compound called ranolazine, explains Prof. Noble. “We used computation to show why its combination of actions would be expected to further Information be synergistic,” he says. “And that provided Denis Noble’s website data about the drug as it went through www.musicoflife.co.uk regulatory approval.”

ISBE - www.isbe.eu 4 BIOGRAPHY

WALTER KOLCH ON A EUROPEAN PROJECT THAT IS TACKLING PAEDIATRIC TUMOURS USING SYSTEMS BIOLOGY

Cancer is never welcome, but when it arises in Aggressive treatment for cancer is not only children it seems all the more unfair. The EU- harsh for the child, but it could potentially have funded ASSET (Analysing and Striking the longer term effects on their health. So if Sensitivities of Embryonal Tumours) project is clinicians can tell from the outset whether a taking a systems biology approach to figuring neuroblastoma is aggressive or likely to resolve out the most useful treatments for a range of on its own, the therapy could be targeted at the paediatric tumours (neuroblastoma, medul - children who would benefit from it, while those ASSET IS A 14 PARTNER loblastoma and Ewing’s sarcoma), and they are whose tumours who don’t need treatment will COLLABORATIVE EUROPEAN FP7-HEALTH-2010 PROJECT IN discovering new ways of investigating the be spared the need to go through it. THE THEME ‘TACKLING HUMAN diseases. DISEASES THROUGH SYSTEMS But how can you tell? Taking a systems biology BIOLOGY APPROACHES’. USING A A major focus within the consortium is approach, the 14-partner ASSET consortium COMBINATION OF STATE-OF- neuroblastoma, explains ASSET co-ordinator has found that molecular signals in the tumour THE-ART GENOMICS, Professor Walter Kolch, who is Director of cells can yield important information. Their PROTEOMICS AND MATHEMATICAL MODELLING, Systems Biology Ireland (SBI) at University work centres on a biochemical signalling ASSET’S MAJOR GOAL IS TO College Dublin. Contrary to what the tumour’s pathway called ‘JNK’, which is activated to IDENTIFIY MECHANISTICALLY name might suggest, “neuroblastoma does not differing levels in the tumour cells. UNDERSTOOD NETWORK VUL - arise in the brain but in the belly,” he explains. NERABILITIES THAT CAN BE “It is a tumour of the peripheral sympathetic EXPLOITED FOR NEW APPROACHES TO THE nervous system.” JNK can make the DIAGNOSIS AND TREATMENT OF neuroblastoma cells die or HIGHLY AGGRESSIVE AND Accounting for about 15% of all childhood live depending on the exact DEVASTATING PAEDIATRIC cancers, neuroblastoma strikes during infancy TUMOURS. or toddler years and presents in a variety of activation kinetics forms - some tumours are aggressive and Prof. Walter Kolch is director of Systems Biology Ireland and the potentially rapidly lethal, while other tumours Conway Institute of Biomolecular will eventually disappear even if they have “JNK can make the neuroblastoma cells die or and Biomedical Research in spread throughout the body (metastasised) live depending on the exact activation kinetics,” University College Dublin. In the and even if there is no treatment. “It can be explains Professor Kolch. “If the pathway is last ten years, Prof. Kolch has extremely aggressive and kill the child in a few activated very slowly then the cells survive and built an international reputation across three areas: MAPK months, or else it is the only tumour known grow, but if it is activated steeply like a switch, signalling, proteomics, and cancer which spontaneously regress even though it the tumour cells die - and that is a good thing.” research, especially in regard to has metastasised,” explains Professor Kolch. Using a mix of experimental measurements using systems biology “So in this case a metastatic tumour can go and computational modelling, the ASSET approaches. away without any treatment.” scientists have been able to assess the aggressiveness of the tumour cells. “By

5 ISBE - www.isbe.eu developing a computational model of the The ASSET consortium is making progress too activation network we could see which of the with a systems biology approach to the how do nodes control it,” says Professor Kolch. “Then paediatric brain tumour medulloblastoma and tumours form? in individual patients we can measure these to Ewing’s sarcoma, notes Professor Kolch. three or four protein concentrations and we “We have found better ways to stratify From an academic standpoint can adjust this model for each patient patients across the different types of cancer,” childhood tumours offer a individually. Using this approach we have he says. relatively ‘pure’ model to study shown we can assess each patient’s tumour how cancers arise, because the person has had less time to for likely aggressiveness.” And now the obvious route for translating develop non-cancerous DNA findings is through the clinical research groups mutations. in France, Germany and Switzerland who are By analysing molecular charac - involved in the project. We have found better teristics of a childhood cancer ways to stratify patients called neuroblastoma, Prof. “These clinical groups are doing clinical studies Walter Kolch and colleagues in across the different types all the time and can conduct trials to see how the ASSET project have found of cancer to most effectively implement the discoveries that there are many ways for that come through our systems biology such tumours to arise at the level of DNA, but that the effects approach,” notes Professor Kolch. “This is the on cell signalling are less varied. The project is also using computational best and most direct way to bring what we are “It tells you if you look at the modelling to look for new treatments, he adds, finding into the clinic.” effects of these mutations they by simulating the effects of drug combinations are rather similar so you need to on the key biochemical pathways. Words: Claire O'Connell target the effects rather than June 2015 the cause,” he says. “At the moment neuroblastoma is treated mainly with drugs that damage DNA and thereby cause JNK to be activated,” explains Professor Kolch. “But we are looking at how using combinations of existing drugs could activate JNK more specifically, without causing the problematic DNA damage. We have made very good progress in identifying potential Genetically modified further Information combinations, and some of these agents are zebrafish were used in the ASSET already in clinical use so there is the hope that project to evaluate potential www.ucd.ie/sbi/asset neuroblastoma drugs any new combinations we find could be Systems Biology Ireland translated into the clinic fairly quickly.” www.ucd.ie/sbi

Researchers from University College Dublin analysing results

ISBE - www.isbe.eu 6 BIOGRAPHY

YOU SEE THEM EVERY DAY, BUT HAVE YOU EVER STOPPED TO WONDER HOW YOUR FINGERS ‘KNEW’ TO BECOME FINGERS WHEN YOU WERE A DEVELOPING EMBRYO?

It’s a puzzle that has had scientists scratching “At that very early stage, when the hand is their heads for decades, but a recent study led forming, the individual cells within that plate of by Dr James Sharpe at the Centre for Genomic tissue have not yet decided whether they are Regulation in Barcelona has pointed out how a going to make a finger or an interdigit,” explains molecular system controls the process. Dr Sharpe, who co-ordinates the EMBL-CRG Systems Biology Unit. Dr Sharpe’s lab is interested in how cells and tissues interact to build organs and body parts, His lab examined the process underlying that JAMES SHARPE IS AN ICREA 4INSTITUCIÓ CATALANA DE and the limb has a strong track record in cellular decision using a mouse model where RECERCA I ESTUDIS AVANÇATS5 research on how it organises itself. “The reality cells have been transgenically engineered to RESEARCH PROFESSOR AND is that for any organ we probably know just the produce the fluorescently glowing protein GFP ALSO THE LEADER OF THE tip of the iceberg, but for the limb we have if they are choosing the digit fate (where the SYSTEMS ANALYSIS OF more of that tip of the iceberg than for the Sox9 gene is expressed) rather than the inter- DEVELOPMENT GROUP AT THE others,” he says. digital fate. CENTRE FOR GENOMIC REGULATION 4CRG5, BARCELONA. To dig deeper into the networks of cellular and molecular interactions that underpin limb We examine the The goal of his research group is development, Dr Sharpe uses a systems to focus on the development of approach, linking computer models with developing limb using a the vertebrate limb, both at the back-and-forth, iterative level of gene regulatory experimental results. “The developing limb networks, and of the physical involves hundreds of thousands of cells approach, where we use interactions between cells and communicating with each other, moving computer modelling tissues. To achieve this, the around and making decisions to become alongside experimental and group includes embryologists, muscle cells or bone cells,” he says. “So we computer scientists, imaging examine that using a back-and-forth, iterative molecular science. specialists and engineers. approach, where we use computer modelling alongside experimental and molecular science.” One of the lab’s most recent successes, This approach allowed them to sort the cells published in Science in 2014, has shed light on into two groups during the six-to-ten hour fingers. During embryonic development in window when the cells are making this critical animals with backbones and arms, fingers cell-fate choice: those about to make fingers, form when a flat plate of tissue grows out at and those about to become interdigital. the end of the miniature limb, and cells then die away in a pattern to form spaces and chisel out the digits.

7 ISBE - www.isbe.eu By examining the networks of genes that were “The most exciting thing was that we got the active in these distinct populations of cells, the same result in the computer simulation and in researchers identified two key signalling the real experiments. This interplay between Patterns in biology – pathways - BMP and WNT – that were most the modelling and experimentation is at the the Turing connection strongly involved in the decision about heart of the systems biology approach, and it ‘fingerness’ or ‘gapness’. “This analysis of gene is the strongest proof we have that these expression was complemented by examination molecules are part of a Turing system,” says Dr of the proposed pathways at the protein Sharpe. “For decades this idea was actively activity level, which also supported the resisted, but our results provide good evidence conclusions,” says Dr Sharpe. for it, and we think this Turing mechanism possibly goes back all the way into fish, even Once enough molecular data had been though the number of digit structures they gathered, the Barcelona lab began construction have is not the same.” of a computer model to explore a system of In August 1952, British development proposed by British computing Figuring out fingers is just one aspect of computing pioneer Alan Turing pioneer Alan Turing, where chemicals react understanding limb development, and Dr published a seminal paper entitled The Chemical Basis of with each other and diffuse over space to Sharpe’s lab is also using systems biology to Morphogenesis. create particular types of stripy or spotty examine how a limb as a whole organises itself It outlined how just two distinct patterns. to form a humerus, ulna and radius, wrist molecules (‘morphogens’) could bones and - finally - fingers. underpin the spontaneous development of spotted and The most exciting thing Understanding such aspects of limb stripy patterns by diffusing and was that we got the same development should also help to inform the interacting in specific ways to form repetitive motifs. result in the computer wider field of regenerative biology and tissue engineering. “To be able to heal and maybe one Turing died two years after the simulation and in the real paper was published in day to even build multi-cellular tissues, we experiments. Philosophical Transactions B , but ought really to understand how multicellular the reaction-diffusion model it tissues build themselves in the first place, and described has since been “The computer model was essential, because we still have a lot to learn about that,” says Dr proposed to underpin numerous repetitive patterns in nature, Turing systems are very non-intuitive,” says Dr Sharpe. including the stripes on a zebra, Sharpe. “But our initial step of screening for the and now the more subtle molecular components was also key: if the “Our view is that a systems biology approach patterns of digit formation. model had been abstract – not based on data will ultimately be the only way to explain, about real molecules involved – it would be understand and then engineer living unable to make predictions that we could multicellular tissues, either tissues in dish that experimentally test in the lab.” can then be put back into patients, or by stimulating patients’ own tissues to heal and The researchers turned the BMP and WNT regenerate.” signalling up and down – both in the computer model and in in-vitro experiments – and Words: Claire O’Connell watched what happened. When they switched May 2015 off the BMP pathway all the cells became gaps. If they repressed the WNT pathway instead, all of the cells became fingers. And repressing both the BMP and WNT pathways at the same time but to different degrees rearranged the pattern into fewer, fatter fingers.

further Information Centre for Genomic Regulation crg.es

ISBE - www.isbe.eu 8 BIOGRAPHY

STUART JOHN DUNBAR ON A COLLABORATION BETWEEN SYNGENTA AND IMPERIAL COLLEGE LONDON THAT IS PROVING FRUITFUL

When you choose tomatoes at the market, understanding of the biochemical and genetic what do you look for? Firm, crisp texture? A ripe ‘control points’ of key features such as texture product that will tantalise the tastebuds with and flavour. its strong flavour? Or what if you could have both firmness and that ripe taste? “We are interested in detecting molecular markers in the tomato ripening pathways that A project between Syngenta and Imperial grow flavour, and ultimately could we bring the College London is using systems biology to flavour components of ripening earlier into the SYNGENTA IS A WORLD- LEADING AGRI-BUSINESS examine the interplay of factors that ripening process,” explains Stuart, who is an COMMITTED TO SUSTAINABLE determine flavour during ripening of this major adjunct professor of cellular and molecular AGRICULTURE THROUGH fruit crop, and its findings are informing biology at Imperial. INNOVATIVE RESEARCH AND breeding programmes to develop new varieties TECHNOLOGY. THE COMPANY with a satisfying ripe flavour while the product EMPLOYS 28,000 PEOPLE IN is still crisp. OVER 90 COUNTRIES WITH A It would have been impossible PURPOSE OF BRINGING PLANT to analyse the datasets using POTENTIAL TO LIFE. Food producers and retailers want to sell as conventional biochemical much of their fare as possible, but consumers Prof. Stuart John Dunbar is Head have their preferences - and for many that approaches, so we took a of Bioscience at Syngenta and means turning up their noses at more ‘squidgy’ systems approach where we project leader of the University Innovation Centre on Systems tomatoes, explains Dr Stuart John Dunbar, tried to integrate complexity Biology at Imperial College Head of Bioscience at the global agribusiness and find the answers. London. Stuart is also an Adjunct company Syngenta. Professor of Cellular and Molecular Sciences at Imperial. “If you buy a tomato from supermarket, it tastes more tomatoey and nicer the riper it is and therefore the squidgier it is, but squidgy tomatoes are not good for supermarkets,” he says. “In northern Europe and in the United States in particular, shoppers want tasty tomatoes but they want a nice, crisp texture, they won’t tend to buy soft tomatoes.”

But how do you match those requirements? A project at the Syngenta Innovation Centre on Systems Biology at Imperial College London (the University Innovation Centre, or UIC) has been building a predictive model of tomato ripening and fruit quality to get a better Stuart at a public outreach event at Imperial College London, 2013

9 ISBE - www.isbe.eu The project focused on four isogenic lines from the data gaps that we can reliably bridge are the Ailsa Craig variety of tomato where the quite small, which was an interesting outcome, a systems approach lines have been bred to inhibit components of but the positive thing was that you need less to ecosystems the ripening process. “We have genomic and data than we thought,” says Stuart. biochemical information on these tomatoes, and the tomatoes fit a range of components on Molecular markers identified in the UIC project the ripening and flavour pathways - they are are now being brought forward and used in a representative of different types of outcomes,” breeding programme, but Stuart cautions there explains Stuart, citing the example of one, are no guarantees yet that retailers and Never Ripe. “It does what it says on the tin - it consumers will ultimately get the holy grail of never gets ripe.” a firm and ripe-tasting tomato. How does crop growth affect biodiversity and “The project furthered our understanding of food webs? Research at The project has successfully the complex pathways involved in fruit ripening the Syngenta Innovation and has allowed us to focus on specific aspects Centre on Systems modelled and integrated for further analysis and marker development,” Biology at Imperial data from the tomato lines explains Stuart. “It takes a long time to breed a College London using a about gene expression and new variety so we will see the fruits of our systems biology labour only after 6 years or so!” metabolism approach to model the potential impact of crops Words: Claire O’Connell May 2015 on biodiversity, and so far the project has been The work, led by Dr Charlie Baxter from Syngenta, used systems biology to model the extremely successful, biochemistry and the metabolic profile of these according to Dr Stuart four isogenic lines, and the enormity of that John Dunbar, Head of task meant a systems biology approach was Bioscience at Syngenta. needed, explains Stuart. “It would have been “It has showed that we impossible to analyse the datasets using conventional biochemical approaches, so we can predict food webs took a systems approach where we tried to and the impacts of integrate complexity and find the answers.” different types of cropping systems on The project used machine learning (where biodiversity,” he says. “It software carries out actions that have not been is helping us with our specifically pre-programmed) thanks to whole biodiversity Professor Stephen Muggleton’s team at agenda and Imperial, and this offered an unbiased understanding the approach to tackling the questions, according impacts on ecosystem to Stuart: “It is a way of addressing problems services.” without having to predefine what the problem was, so it is an unbiased way of addressing the complexity.”

The project successfully modelled and integrated data from the tomato lines about gene expression and metabolism, and several learnings emerged, including the value of systems biology and machine learning in this context. further Information Syngenta “It has told us how you can cross data gaps and www.syngenta.com how big those data gaps can be, and it told us Syngenta Centre on Systems Biology at Imperial College London about the nature of the data that you need - www3.imperial.ac.uk/syngenta-uic

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Daniel Vonder Müehll is Managing Director of SystemsX.ch and NATIONAL INITIATIVE IS PUTTING SWISS SYSTEMS BIOLOGY ON THE MAP leads the Management Office responsible for the Switzerland is an independent state used to generally assemble into higher order executive work of the systems striking out on its own path. In this vein, the structures such as membranes, rather than biology initiative. Previously he Swiss launched an initiative in 2008 to fund staying as individual entities. Therefore it was Head of Research and promote systems biology to fire makes little sense to study them in isolation," Management at University of Basel and Head of Permafrost Switzerland into the vanguard of an emerging says Gisou van der Goot of EPF Lausanne, lead Monitoring Switzerland. field. investigator for the project, now in its second phase. "There's been a paradigm shift from F. Gisou van der reductionist molecular biology to a holistic Goot is a professor at the systems biology approach, and Switzerland There's been a paradigm Ecole decided to support this new era by providing shift from a reductionist Polytechnique funding," explains Daniel Vonder Müehll, Fédérale de molecular biology to a Lausanne, Switzerland. From the Managing Director of the initiative, study of the interaction of SystemsX.ch. Encouragement also came from holistic systems biology bacterial pathogens with target big pharma firms like Roche and Novartis. approach, and Switzerland cells to her work on protein palmitoylation, van der Goot is The initiative now gels together 15 equal decided to support this new interested in how the organisation of cellular institutional partners from academia and era by providing funding membranes allows precise and industry which provide matching funds to the efficient communication. initiative, overseen by the Swiss National Science Foundation. Over 1,000 scientists are The consortium just published the first Cris Kuhlemeier is currently involved in SystemsX.ch projects. But database that provides knowledge on lipids. It head of the also remarkable is the multidisciplinary nature also took initial steps to getting to grips with Institute of Plant of the projects forged and advances achieved. how the nutrient state of cells and Sciences, environment affects lipid composition, and the University of Bern. The The aim of systems biology and, hence, of influence of lipids on cells. “Before this project Institute carries out research in SystemsX.ch concerns understanding none of us were actually doing lipidomics and plant development, molecular processes and the dynamics of biological thinking in a systems way about lipids. plant physiology, plant nutrition, systems and relies on extensive quantitative plant ecology, vegetation Ecology SystemsX made this possible and changed the and palaeoecology data and modelling. way we tackle the problem,” van der Goot explains. One of the earliest consortiums and at the same time the largest project within The entire initiative sped up the adoption of SystemsX.ch is LipidX, setting forth in 2008 to technologies and quantitative approaches in explore the world of lipids; though major experimental labs. Questions in systems building blocks of cells, lipids have been biology require a symphony of analyses in the neglected in the ‘-omics’ era. They are difficult lab and computer modelling, which itself to study and do not conform well to a demands input from biology, maths, physics, reductionist beat. "You can purify a protein. But chemistry, computer science, informatics, lipids are much smaller molecules and they engineering and medicine.

11 ISBE - www.isbe.eu It is not plain sailing. “It’s a real challenge. You picked up. A highpoint has been the creation of can talk but it doesn’t mean that other people new imaging technology called MorphoGraphX, SystemsX.ch listen,” observes van der Goot, speaking of the published in May 2015 in eLife , which makes it faCT fILE challenges of interdisciplinary communication. possible to segment cells and follow their “It took time, but was worth the effort.” Plant deformation over time in 3D. Uses include scientist Cris Kuhlemeier at the University of shape extraction, growth analysis, signal Bern says the first four years saw the quantification and protein localisation. consortium he leads “mostly trying to get to understand each other.” The SystemsX.ch Vonder Müehll recalls the first years of the project PlantGrowth2 is now “really an initiative, when projects were strong on data integrated group of people,” he says proudly. collection, but not accomplished in systems biology. “Scientists are human and most stay Crops in recent years have been scrutinised in their comfort zone if possible, so you need SystemsX.ch is the largest down the lens of genetics, but little is known clear incentives,” he says. In the second phase, ever public research initiative in Switzerland. It focuses about the mechanics of growth. “DNA is a which began in 2013, SystemsX.ch redirected specifically on a broad topical linear code, but how do you go from that to a more emphasis on theoretical work, area of basic research, 3D shape. Maybe 20 years ago people were simulations and modelling. systems biology. Initially, over totally focused on chemical signalling, but now 120 million Swiss francs were we are trying to explain morphogenesis also in The next big event is the ‘All SystemsX.ch Day’ committed to the initiative, to be held in Berne on September 15th 2015, with its first stage running terms of physics” says Kuhlemeier, who has from 2008 to 2012. studied a mysterious, truly quantitative a big meet and greet networking opportunity, accompanied by talks and panel discussions. problem for two decades: why leaves spiral A further 100 million francs predictably around stems according to the The Swiss initiative ends in 2018, with no was committed for Fibonacci sequence, with the next leaf always follow up: the Swiss are confident that they consolidation over the period displaced by 137 degrees. have opened a path that researchers will 2013 to 2016. A slight readjustment in the second willingly follow, assisted by multidisciplinary “This is a quantitative problem. You cannot stage saw promotion of more alliances and greater comfort in striking out on solve it only with genetics. There are no theory, simulations and a systems biology route. That’s one expected transcription factors that specify angles. We modelling projects. In addition, had to resort to modelling. I joined forces with return on investment. a special round invited for a computational scientist and we produced the Words: Anthony King applications of Medical May 2015 first mathematical model of a development Research and Development problem in plant biology,” Kuhlemeier recalls. projects, with medical and clinical parts. Projects covering But the PlantGrowth2 project is not solely topics such as prions, HIV, concerned with theory: it aims to tackle a real- metastasis, melanoma and world problem: hunger. The consortium inflammatory bowel disease investigates teff, the staple crop in the Horn of won funding. Africa, in an effort to improve yield and stop it falling over (lodging) in wind and rain – causing Today, SystemsX.ch supports losses of 35-50%. They have used quantitative around 220 projects , more methods and modelling to circle weak points than 1,000 scientists and and develop better varieties. almost 400 research groups .

SystemX changed the way we tackled the problem

Micro-machinery was devised to measure cell further Information wall strength at different places. Kuhlemeier’s SystemsX www.systemsx.ch biology postdoc Sarah Robinson has begun LipidX taking on hard core physics courses, while a www.systemsx.ch/projects/research-technology-and-development-projects/lipidx/ computational scientist colleague has PlantGrowth2 impressed him with how much biology he wiki.systemsx.ch/display/PGRTDproj/Plant+Growth+Home

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LUIS SERRANO FROM THE CENTRE FOR GENOMIC REGULATION IN BARCELONA EXPLAINS HOW HIS RESEARCH ON A SMALL BACTERIUM CAN HELP US TO UNDERSTAND OTHER LIVING SYSTEMS AND HOW IT CAUSES DISEASE

Given enough technology and know-how, been analysing the main biochemical could we completely understand how an entire components of the bacterial cell, how they living system works? It’s an ambitious respond under different conditions and how suggestion, but Dr Luis Serrano and colleagues the components fit together to form a at the Centre for Genomic Regulation in functioning system. Barcelona are in the process of finding out. THE CENTRE FOR GENOMIC Much like a car, a cell has various components REGULATION IN BARCELONA IS Living organisms vary hugely in size and that need to work both in their own right and AN INTERNATIONAL BIOMEDICAL RESEARCH complexity, so the researchers in Barcelona together for the system - or car - to work. In INSTITUTE OF EXCELLENCE have chosen their focus wisely: a small the car, an engine, gears and wheels function WHOSE MISSION IS TO bacterium called Mycoplasma pneumoniae , a individually and together to make the car go. In DISCOVER AND ADVANCE single cell organism that has a relatively simple a cell, molecular systems involving DNA, RNA, KNOWLEDGE FOR THE BENEFIT metabolism. proteins and sugars work in synchrony to run OF SOCIETY, PUBLIC HEALTH the living system, and Dr Serrano has been AND ECONOMIC PROSPERITY. looking at these systems. Dr Luis Serrano is Director of If you have enough results CRG and leads the Design of and enough money and ”We acquire the relevant data from the cell - Biological Systems research we are looking at its metabolism, its group. The group works toward enough know-how, would transcriptome [RNA], the proteome [proteins a quantitative understanding of you fully understand a biological systems to an extent in the cell],” he says. “But we are not looking at that one is able to predict living system? every protein individually, we try to get the systemic features, with the whole picture: so we are not looking at every hope to rationally design and screw in the car, we are looking at the main modify their behaviour. The microbe is of clinical relevance because it components.” can cause atypical pneumonia in humans, explains Dr Serrano, but the main reason for By perturbing the cells and seeing how each selecting it as a model organism is its system reacts, Dr Serrano and co-workers manageable size. have been bringing a larger picture into focus of how the system as a whole responds to ”It is one of the smallest bacteria you can grow changes in its environment. in the lab,” he says. “And the whole idea of the project has been to ask if you have enough ”We explore how it responds to factors like results and enough money and enough know- exposure to drugs, changes in temperature or how would you fully understand a living changes in nutrients,” he says. “Our approach system.” is a little like if you wanted to analyse the nervous system of the human you could apply To find out more about M. pneumoniae Dr something very hot and if the person jumps Serrano’s group and collaborators at the then the nervous system has responded.” European Molecular Biology Laboratory have

13 ISBE - www.isbe.eu One of the biggest findings to emerge is that doing something and which ones are just M. pneumoniae has sophisticated mechanisms passing by?” for controlling how its genes are expressed. COMPLICaTIOnS In the longer term, having such insights into aSSOCIaTEd WITh The microbe has two systems of ‘methylation’ the bacterium could help to understand how it MYCOPLASMA - a form of tagging on DNA that can determine causes disease, and it may also offer routes to PNEUMONIAE whether genes are switched on or silenced. engineer the microbe as a drug-delivery “We know the bacterium has very strong platform to bring medications to specific sites Lobar consolidation methylation and there are two systems, one is in the human body. Abscess Bronchiolitis obliterans general, and there is another more specific Necrotizing pneumonitis system that we don’t know what it is doing,” But for now Dr Serrano is driven by the Acute respiratory distress syndrome says Dr Serrano. ultimate goal of getting that complete picture Respiratory failure of a living organism. “When I give talks everyone is excited and amazed by the amount Having such insights … of information and what we are doing,” he says. may also offer routes to “And the impact will be that we come out with engineer the microbe as a a model that will explain the whole cell in detail. drug-delivery platform to Then we will say for the first time that we bring medications to specific understand the whole thing.” sites in the human body. Words: Claire O’Connell October 2013 In addition, the small bacterium contains a relatively large amount of ‘non-coding RNA’, an observation that has now also been made in Design of Biological Systems Group, 2013 more complex bacteria as well as in eukaryotic cells, which are the types of cells that make up plants and animals.

”It looks now like bacteria have as large a proportion of non-coding RNA as eukaryotes,” says Dr Serrano. ”I think this is something that is characteristic of all branches of life.”

The team also saw that the cell can read stretches of its DNA either classically or in a ‘staircase’ pattern - once more this was a surprise to see in the tiny cell, notes Dr Mycoplasma pneumoniae Serrano, and the phenomenon has since been observed in other species of bacteria too.

The big challenge is now to integrate the large volumes of data from the tiny Mycoplasma and to sift out the signal from the noise.

”We have been looking at proteomics, tran - scriptomics, chemogenomics, everything,” says Dr Serrano. “And now we want to put it together in a way that makes sense. So we are trying to integrate everything into a big model but this is not easy. You might find 100 proteins acetylated or 60 proteins phosphorylated - further Information how much of this is noise and how much is Centre for Genomic Regulation biologically significant? Which ones are really crg.es

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BAS TEUSINK FROM THE NETHERLANDS PLATFORM FOR SYSTEMS BIOLOGY DISCUSSES THE REMARKABLE DEVELOPMENTS IN HIS RESEARCH MADE POSSIBLE BY THE APPLICATION OF SYSTEMS BIOLOGY APPROACHES We must understand component parts to get deconstruct the metabolic network of the to grips with a complicated machine. Once you organism based on its genome,” Teusink build such a machine yourself, you can tweak explains. “In this case it was grown in a and adopt it. Industry understands how to do traditional production process where a this, but has not done so well in deconstructing historically defined medium was used.” A big the live machinery critical for the fermentations pharma company is involved, but cannot be at the core of so many food and named. pharmaceutical processes – the microbial cells. THE NETHERLANDS PLATFORM FOR SYSTEMS BIOLOGY Improving the medium would have meant trial FOSTERS SYSTEMS BIOLOGY Bas Teusink at the Netherlands Platform for and error, but Teusink’s team instead modelled APPROACHES IN THE RED, Systems Biology (SB@NL) is mapping out the around 1500 reactions underpinning the cell. GREEN, WHITE AND BLUE design of microbial cellular networks by asking They realized an ingredient in the growth SECTORS OF THE LIFE two straightforward but big questions: what medium impeded production. Teasing out the SCIENCES, CREATING makes the cell’s biochemical network tick and metabolic networks also showed them that SYNERGIES BETWEEN SYSTEMS BIOLOGY RESEARCH why did evolution choose that design? His the cells would be able to use alternative INSTITUTES/GROUPS AND group’s modelling of cells’ metabolic blueprints substrates to the ones that inhibited OTHER STAKEHOLDERS IN on a genome scale is yielding some dramatic production. They did the heavy lifting in silico, SYSTEMS AND SYNTHETIC successes relevant to industrial fermentation along with experimental test, successfully BIOLOGY, BIOTECHNOLOGY processes. predicting an improved formula. AND MEDICINE.

Prof. Dr. Bas Teusink developed His group worked in conjunction with the the Kluyver Centre Systems Kluyver Centre for Genomics of Industrial …it’s only now, because of Biology programme; he is Full Fermentation, now part of the BE-Basic our model, that we can Professor in Systems Foundation, an international public-private Bioinformatics at IBIVU, VU understand thirty years of Amsterdam. partnership that develops industrial bio-based solutions. This collaboration is putting pep into research… the R&D of industries that rely on innovation in industrial fermentation, optimising what is a critical step in many food, beverage and ”You can design all sorts of hypotheses this pharma processes. The aim is to boost way about the media. You can ask what are the performance and robustness of industrial minimal inputs I need to support growth or microbes by revealing how the genome and what are the cheapest materials,” Teusink environment interact. explains. The end result: higher productivity at lower costs. But Teusink’s systems biology Recently Teusink’s group doubled output of a approach has also yielded a fundamental certain toxin, a vaccine component essential breakthrough, solving a three decade long for a highly contagious but preventable disease mutant mystery, recently published in Science that kills thousands each year. “We could (van Heerden et al ., 2014).

15 ISBE - www.isbe.eu Researchers had struggled with a particular All sorts of processes could benefit from a mutant in yeast for years, but couldn’t figure greater understanding of why only some cells out this strange phenotype. It can’t grow on start to grow. Teusink says his yeast work BE-BaSIC faCT fILE glucose, something yeasts normally prefer shows that sometimes the average response above all else. Glucose is degraded in a seen in a population of cells is no such thing - Public-private partnership between: metabolic pathway called glycolysis – Greek for it is actually the sum of two completely breaking down sugar. It turns out there are two different behaviours caused by bistability. Such 27 Industrial partners solutions to the problem of degrading glucose noise in life is becoming clearer as 7 Research Institutes in these cells; with the mutant form you have technological advances improve single-cell 13 Universities a 99.9% chance of not growing on glucose, but measurements and the theory behind cellular this means that there is still a tiny network architecture advances; computers will subpopulation of the mutant that can thrive on need to run even faster to keep up with Since 2011: it. “This small subpopulation was 1 in 10,000, network models, Teusink predicts. 447 peer reviewed papers but we now realize that there are two states 8 patents filed these yeast can be in,” says Teusink. Teusink, from his base in Amsterdam, believes 8 start ups Europe must try harder when it comes to When this “bistability” phenomenon was training biology students. Today glycolysis is further investigated it turns out 7% of wild type taught as a pathway that goes from A to B, a cells by chance do not grown on yeast either static process; students are instructed that and normally just die off when fed it. certain genes are involved, but what does this Genetically the two yeast types in both groups really mean? “The way we should actually are the same, but chance gives rise to teach this is to make a model of this pathway heterogeneity in the system. “This now and let students play with it to see how it explains all these weird phenotypes in mutants actually behaves. It’s not so trivial, and stability that people have generated in this field. So it’s and steady state concepts today are not clear only now, because of our model, that we can to students,” says Teusink. “Biology is understand thirty years of research.” complicated and you need the maths.”

Words: Anthony King March 2014 Biology is complicated and you need the maths Lactobacillus bacteria

So far so basic, except that glycolysis is a central pathway in life and these subpopulations are everywhere and are particularly important during transitions – such as at the start of a fermentation process when microbes meet a large batch of sugar. “In these transitions we often see that only part of the population starts to grow and the other part dies or does nothing. Suppose that you inoculate a million cells in your milk or your fermentation vat, but only half these cells start doing something. This will lead to a delay in your production [a lag phase],” Teusink explains. Once you understand this split in your further Information population it is possible for you to add Netherlands Platform for Systems Biology (SB@NL) biosb.nl/sbnl something to the media as a pre-treatment to BE-Basic Foundation cut down on this delay. www.be-basic.org

ISBE - www.isbe.eu 16 BIOGRAPHY MERRIMACK PHARMACEUTI - CALS IS A BIOPHARMACEUTICAL US PHARMACEUTICAL COMPANY BASES ITS BUSINESS ON A SYSTEMS APPROACH AND IS COMPANY DISCOVERING, REAPING THE REWARDS DEVELOPING AND PREPARING TO COMMERCIALIZE INNOVATIVE MEDICINES PAIRED Merrimack Pharmaceuticals is a NASDAQ- therapeutics and identify biomarkers. Today, WITH COMPANION DIAGNOSTICS listed biopharma company that has confidently Merrimack has a market capitalization of over FOR THE TREATMENT OF placed its chips on a systems biology approach $900m, has around 270 people on staff and 6 CANCER. MERRIMACK APPLIES A to cancer drug discovery. The power of a drugs in clinical development. SYSTEMS BIOLOGY-BASED systems approach is to reveal not just APPROACH TO BIOMEDICAL RESEARCH, THROUGHOUT THE individual components of a system, but how Sorger believes firmly that systems biology RESEARCH AND DEVELOPMENT each part connects. offers a new path to drug discovery that will be PROCESS. far more efficient. “About 80% of the cost of Peter Sorger, Professor of Systems Biology at today drugs is in yesterday’s failures, so one Harvard Medical School, helped found the target for systems biology is to change that: so company while at MIT in partnership with serial to reduce the rate at which drugs fail and to entrepreneur Anthony Sinskey, Professor of incrementally improve the process by linking Microbiology, MIT. Cofounders Ulrik Nielsen the science back to critical decision making in and Gavin MacBeath are still with the company a company.” in senior positions. Peter Sorger PhD is a Professor Merrimack’s core values include drilling into the of Systems Biology at Harvard The very beginning of Merrimack came partly complex biology behind cancer. So far this has Medical School and holds a joint appointment in MIT’s Dept. of out of dissatisfaction with the myriad yielded the six molecules in clinical Biological Engineering and explanations in the literature of the induction development. In November, the company Center for Cancer Research. of apoptosis by anticancer drugs, Sorger reported news for Phase 2 studies in the Sorger was co-founder of the recalls. They decided it was necessary to treatment of women with ER/PR2, HER2 MIT systems biology program understand the key physiological pathways negative breast cancer with the inhibitor MM- CSBi, Merrimack Pharmaceuti - cals and Glencoe Software. involved in drug response and that that would 121. A positive signal was shown in a require a mix of computational modelling and subpopulation of patients that would dynamic modelling. potentially benefit from targeted therapy. The findings support ErbB3 signaling as an important pathway of resistance for breast, About 80% of the cost of ovarian and lung cancers. drugs today is in yesterday’s failures, so the number one ”MM-121 is a monoclonal antibody against target for systems biology is ErbB3 but is not as active in HER2 Birgit Schoeberl is Senior VP of to change that overexpressing or amplified tumours. Research with responsibility for Therefore we designed a second molecule, discovery and clinical stage projects. She is an internationally MM-111, which targets ErbB3 in HER2 recognised leader in Systems Merrimack remains rooted in the principles of overexpressing tumours,” says Birgit Schoeberl, Biology. She has been with grafting quantitative biology, computational Merrimack SVP of Discovery. “Based on our Merrimack since the very models and engineering to understand the preclinical research, we defined five different beginning and has been integral signalling pathways that are involved in biomarkers that would be predictive of ErbB3 to develop the Systems Biology disease in a holistic way and then using these activity in tumour samples and designed our platform. insights to identify drug targets, engineer novel clinical trials to test this hypothesis.” She added

17 ISBE - www.isbe.eu that, with the retrospective analysis of the five success rates across the industry,” adds biomarkers in Merrimack's clinical samples Schoeberl. they were able to identify a subgroup of MERRIMaCK patients with the same response biomarkers ”In the future a novel drug that comes out and faCT fILE across NSCLC, ovarian and metastatic breast costs US$180,000 per year per patient and is cancer who appear to benefit from the unknown if it will work in 50% of the people it 2000 Founded by treatment with MM-121. is prescribed to, it is not going to be tolerable,” scientists from Harvard adds Sorger. The systems biology route should and MIT This is the first time we've gone from an in silico mean a more quantitative and also more 2011 Announces $77M in preclinical biomarker hypothesis to the predictive approach; big pharma is unlikely to private financing ultimate translation into the clinic says turn, however. It is not structured to do so and 2012 Launch on NASDAQ Schoeberl, which is a "big moment for has no culture of systems biology. Chances are, Merrimack and I think for systems biology in agrees Sorger, new systems companies are 270+ Employees general. The predictive biomarkers will help likely to be spun out of universities and $900M Company value identify which patients may benefit from MM- research institutes, as was the case with 6 Cancer drugs in clinical 121, which completed six Phase 2 clinical trials Merrimack. development in collaboration with Sanofi.” Merrimack recently regained worldwide rights to develop Based on 2014 figures and commercialise MM-121 in June 2014 from This is the first time we've the cancer arm of French pharma giant Sanofi. gone from an in silico preclinical biomarker hypothesis to the Merrimack pairs up an experimentalist and a ultimate translation into modeller in a “discovery pod” and looks to the clinic understand the biology before setting off to develop certain drug candidates. “Early on we made some proof-of-concept antibodies Schoeberl herself is a chemical engineer by targeting ErbB3 and showed that the insights training, having started her career initially in derived from the model translated into the the oil industry. Her background exemplifies inhibition of cell proliferation, before starting an the cross-disciplinary nature and quantitative antibody campaign and selecting the lead underpinnings of a systems approach. molecule,” says Schoeberl. Schoeberl then did a PhD in systems biology in her native Germany because she was always The approach of going under the hood early on fascinated by biotechnology. “The concept of to get a good understanding of the biology is systems understanding and systems dynamics essential to Merrimack’s philosophy. It is about is what you do in chemical engineering. It was understanding how a drug targeting a specific a good background and the biology I basically disease gene will really work when it gets into learnt along the way.” a complex human patient, for example. The Words: Anthony King approach should allow for a better January 2014 understanding of which patients will respond to which drugs. It could also kill drugs off earlier, says Schoeberl, reducing resource loss through expensive late failures.

”Making a drug should ideally be much more like designing a car or an airplane where it is not a trial and error process. There is a lot of design and modelling and simulation that happens even before a car is built,” she says. “We aspire to design and engineer our drugs based on clearly defined design criteria.” At the moment, the highest number of failures and most money gets spent before Phase I trials (Tollman et al ., 2012). “I believe that Systems further Information Biology applied to target identification and Merrimack Pharmaceuticals preclinical drug development could increase www.merrimackpharma.com

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BLANCA RODRIGUEz ON USING COMPUTER MODELS TO UNDERSTAND THE DIFFERENCES BETWEEN INDIVIDUALS IN THE SUBTLE BUT SOMETIMES CLINICALLY IMPORTANT WAYS THAT THEIR HEARTS BEHAVE What makes your heart miss a beat? How our identify key factors that determine ischemic hearts react to stresses such as disease, risk or an adverse response to a drug for exercise and even medicines can vary from example, then we can test those predictions person to person, and understanding those with additional experiments,” says Professor differences is key for developing more effective Rodriguez. “So the computation directs the diagnostics and safer therapies. next round of experiments, and the results of these experiments feed into the computational That’s why Professor Blanca Rodriguez at the model.” BLANCA RODRIGUEZ HOLDS A University of Oxford is developing WELLCOME TRUST SENIOR sophisticated computer models of how Such heart simulations offer the advantage of RESEARCH FELLOWSHIP AND populations of heart cells work, and her group’s high resolution data both in space and in time, IS PROFESSOR OF COMPUTATIONAL MEDICINE IN findings stand to have a wide impact on notes Professor Rodriguez: “That means we THE DEPARTMENT OF refining simulations of and experiments on can look at any viable property of the tissue COMPUTER SCIENCE AT THE living organs. that we want to and we can make calculations UNIVERSITY OF OXFORD. that are very difficult to do with experiments or Abstract models of the heart are not new - clinical methods.” Blanca and her team investigate more than 50 years ago Professor Denis Noble causes and modulators of created the first mathematical model based on variability in the electrophysio - the behaviour of cardiac cells, and the field has logical response of human grown since then, explains Professor The computation directs hearts to disease and therapies. the next round of experi- Understanding variability is Rodriguez, who is Professor of Computational crucial to ultimately determine Medicine and a Wellcome Trust Senior ments, and the results of these who, when and how patients Research Fellow in Basic Biomedical Sciences experiments feed into the may be at risk, and how to at Oxford. improve their diagnosis and computational model. treatment. The mechanisms are “Cardiac modelling a very mature area of complex, multiscale and non- computational medicine,” she says. “We now To improve the simulated heart model, she and linear, and Blanca’s team have multi-scale models of the human heart, exploits the power of her team have brought in an added real-life so they represent the activity of the heart from computational approaches complication - the differences between the sub-cellular to the whole organ level.” combined with experimental individuals in the subtle but sometimes and clinical research to unravel clinically important ways that their heart key mechanisms of cardiac Individual experiments provide snapshots of arrhythmias. particular aspects of the heart, then the model behave. can integrate and reassemble the experimental data to build a more complete picture. This “We are looking at how we can use computer computational model can act as a testbed for models to understand inter-subject variability simulations, and the responses can direct better,” explains Professor Rodriguez. “The further experiments, which in turn fine-tune current cardiac models are based on a generic the model. “With the simulations we can response of a particular cell, but that doesn’t

19 ISBE - www.isbe.eu allow us to investigate why certain people “We want this to have the widest impact react badly to a medicine or why people die of possible and we have been talking to them to virtual assay a certain disease and not other people. So we shape the research agenda in a way that can have developed a methodology that allows us be broadly exploitable.” We all respond to medicines in a to simulate populations of cells rather than a particular way. Knowing in single cell. This means we can consider a wide Another application of the model is to predict advance how a patient is likely range of possible cells, or possible responses risk for patients with genetic susceptibilities for to react to a drug is important to the same disease or medicine.” hereditary heart conditions such as Long QT for safety, and scientists at Oxford are developing user- syndrome, which can lead to sudden adult friendly software to research death. potential effects on populations We are looking at exploring of heart cells. pain research in neuro- “These genetic variations can be characterised science and developing at the ion channel level, so we can plug that models for diabetes using into our populations of models and determine whether it is a low or high risk mutation,” a similar approach explains Professor Rodriguez. “We are also using clinical data from partners at The Oxford Calibrating populations of cells in the model Heart Hospital - they have in vivo recordings with experimental data means a tighter of hearts that we are using to construct the coupling between the computer model and the populations and investigate the potential for ‘live’ results, thus building potentially more simulation there too.” realistic simulations with which to test various conditions. The Oxford researchers are also scaling up their populations-based model from cells to the Such simulations could ultimately help to whole heart to examine the impact of ion- reduce the levels of animal testing required for channel behaviour on ECG readings, she adds. medications to assess cardiac side-effects, and "My group is using the technology in different Called Virtual Assay, it generates Dr Oliver Britton - who completed his PhD with ways and we are quite keen in exploring how various models of responses Professor Rodriguez and Dr Alfonso Bueno- far it can take us both clinically, in industry and and calibrates them with data from experiments on Orovio in Oxford - recently won the ‘3Rs Prize’ of course in the science we do.” populations of cells. The now from The National Centre for the Replacement calibrated model can be tested Refinement and Reduction of Animals in Words: Claire O’Connell with drugs of interest to Research (NC3Rs). May 2015 simulate a response. The software has already flexed its computational muscles for in “Bringing in our calibration allows you really to silico case studies of specific tie computational models with a certain type drugs and their effects on of experiment,” explains Professor Rodriguez. populations of cardiac cells. “And we have created user-friendly software (called Virtual Assay, co-developed with Oxford Computing Consultants) that allows non- experts to run the simulations.”

The researchers are now working with various companies in the life sciences sector to test out the simulations and software, and being able to generate experimentally-calibrated populations in simulations could have applications that go even beyond the heart, notes Professor Rodriguez. further Information Department of Computer Science, University of Oxford “We are looking at exploring pain research in www.cs.ox.ac.uk neuroscience and developing models for Virtual Assay: Drug safety and efficacy prediction software diabetes using a similar approach,” she says. www.cs.ox.ac.uk/ccs/tools

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THIBAULT HELLEPUTTE FROM DNALYTICS EXPLAINS HOW SYSTEMS BIOLOGY IS HELPING TO DELIVER PERSONALISED MEDICINE PRODUCTS

A Belgian start-up has launched a unique test companies, especially in situations where to determine the type of arthritis a patient datasets are so expansive that specific suffers from. Patients may present with approaches to modelling of data analysis are inflammatory arthritis, but in a quarter of cases required. But it also develops personalised a clinician will not be able to diagnose which medicine products. type it is. With Rheumakit, Helleputte realised that DNALYTICS IS A BELGIAN The traditional approach is to wait until the traditional measures like inflammation COMPANY FOUNDED IN 2012 AS symptoms become clearer, but this can take markers in blood were not sufficient for A UNIVERSITY OF LOUVAIN SPIN one to three years. During this time the joint of diagnosis, but could be combined with other OFF THAT BASES ITS ACTIVITIES the patient can suffer irreversible damage. measures. They started with 50,000 ON A DATA MINING candidates of gene expression markers, more TECHNOLOGY PLATFORM. DNALYTICS COVERS THE Now DNAlytics in Belgium has developed than 10 clinical variables and about the same DEVELOPMENT OF DATA- Rheumakit, a biomarker-based tool to number of biological measurements from the DRIVEN PERSONALISED diagnose patients suffering from undifferenti - patients. “We applied feature selection MEDICINE SOLUTIONS, FROM ated arthritis. It predicts whether a patient algorithms in order to automatically select the R&D TO MARKET ACCESS. suffers from osteoarthritis – mechanical features (i.e. the variables) that are most damage to the joint – or something more relevant to differentiating the different Thibault Helleputte is co-founder and CEO of DNAlytics. He holds a complex like rheumatoid arthritis, an pathologies,” says Helleputte. M.S. in Computing Science autoimmune disease. Data analytics and Engineering and a PhD in predictive modeling, along with a systems Engineering Sciences from the biology mindset, are central to the firm’s Our solution combines some University of Louvain. His approach. research work during his PhD biological measurements in centered on Machine Learning blood, some clinical applied to the design of novel “The treatments are very different, so this is tools for automated prediction important,” says Thibault Helleputte, CEO and observation of the patient based on genomic technology. cofounder of DNAlytics. “Our solution and gene expression combines some biological measurements in signature, combined in blood, some clinical observation of the patient a predictive way. and gene expression signature, combined in a predictive way.” The current diagnostic solution combines three DNAlytics promises “data-driven personalized clinical markers and about 100 gene medicine from R&D to market access” in its expression measures, obtained by looking at tagline. It spun out of the UC Louvain’s RNA expression levels. DNA is fixed, but RNA computational and engineering department is a snapshot of metabolism and can vary and provides consultancy to pharma according to disease and medication.

21 ISBE - www.isbe.eu The DNAlytics team will take whatever are the treatment to be selected. Anti-TNFs, the most most relevant markers for making a predictive popular of which are disease-modifying Rheumakit diagnosis, whether that is clinical information, antirheumatic drugs (DMARDs), cost Belgium imaging data, psychological data or a range of around €100 million every year, yet only work genomic, epigenetic or proteomic data. Asked on 60% of rheumatoid arthritis patients. what gives the firm an edge, Helleputte says “That’s €40 million just wasted,” notes they focus not on the performance of their Helleputte. “If you could predict in advance model on already observed data, but rather its which patients will respond to treatment, you predictive performance for new samples, yet could use the right drug.” unseen. How does it work? DNAlytics is steeped in a systems biology Clinicians go online and mindset. It measures the activity of several If you could predict in order a kit. They take a metabolic pathways known to be involved in biopsy from the knee of the advance which patients will the disease or as targets of existing patient and put it in the kit respond to treatment, you treatments. “Really understanding all those within vials containing an pathways and the mechanics behind them, not RNA-preserving solution. could use the right drug just genes or proteins in isolation, but to see The box is shipped to the how those elements combine, so from DNA to company’s lab in Belgium, RNA to proteins to products of degradation, in which generate “Because when you work with data that have blood, in serum, in cells, that is key to the future transcriptomic data from more variables than observations, so more of our business.” the sample and uploads the features than patients say, you are guaranteed results onto the web application. The clinician to find a perfect model for your data, and this Helleputte is passionate about the projects he answers some clinical and is really bad news. You will find an infinity of and DNAlytics are wading into. “These are not biological questions on the models that look perfect, but these will then the kind of projects you can do in your office, or website, and a fail to make good predictions on new patients, on your own. You need to meet clinicians, meet mathematical algorithm because they are in fact too specific to the data regulatory authorities, meet the patients and kicks into gear and delivers that you have already observed.” perform the data analysis. These are really the diagnosis with a few complex projects and that's really stimulating seconds. “The process Consequently DNAlytics focuses on for me,” he enthuses. takes a matter of a few generalisation ability and on multivariate days, which is a solutions, meaning that a marker useful in Words: Anthony King tremendous gain,” says combination with others is preferred, as are June 2015 Helleputte. multiple data sources. “We select markers that will be more robust, and we developed algorithms to measure marker (in)stability,” says Helleputte.

Personalised medicine is increasingly entering oncology practice, with a patient’s tumour genotyped to see which drugs will work best against it. This is not the case in rheumatology, but DNAlytics is working with rheumatologists and clinicians to reverse this situation. There are around 10 treatments for rheumatoid arthritis, but they are only effective in 60% of patients (and each is effective on a different subpopulation).

“Right now it is impossible to tell which treatment will be beneficial to which patient, further Information so it's trial and error,” says Helleputte. He is DNAlytics dnalytics.com working on genetic profiling and other RheumaKit measures to allow the most relevant www.rheumakit.com

ISBE - www.isbe.eu 22 BIOGRAPHY

PUBLICLY-FUNDED GERMAN FLAGSHIP INITIATIVE IS LEADING THE WAY IN LIVER RESEARCH

Systems biology has now reached a new stage sub-cellular levels to the whole organ. of maturity. No better proof is the existence of Ultimately, better treatments for the many an audacious research project called the Virtual liver-related diseases are expected to be Liver Network (VLN). It provides an excellent produced. example of how systems biology is now yielding a level of detail and quantitative data This €50M flagship initiative is supported by SINCE ITS BEGINNING IN APRIL in biology at a scale not previously attained. the German Federal Ministry of Research and 2010, THE VIRTUAL LIVER “We need to do research in biology at the scale Education, BMBF. Research teams that were NETWORK HAS ENGAGED GROUND BREAKING AREAS OF of what astrophysics has done,” explains previously in competition are gathered under SYSTEMS BIOLOGY IN A Adriano Henney, Programme Director of the the VLN umbrella for five years, until 2015. COORDINATED AND FOCUSED VLN. “This is the first example of an investment in ATTEMPT TO SHOW THAT systems biology of this size in a single country MODELLING AND SIMULATION The aim of the VLN is to design a dynamic that focuses on delivering solutions to CAN HELP TACKLE THE mathematical model of the human liver. This clinicians, and aiming to do so using simple to CHALLENGES OF UNDERSTANDING THE model will represent, rather than fully replicate, use formats,” Adriano Henney points out. DYNAMICS OF BIOLOGICAL the liver’s physiology and morphology. More COMPLEXITY. importantly, it will also integrate the wealth of The VLN involves a distributed network of data we have acquired post-genome through research teams spread over Germany, in 70 Dr Adriano Henney is multiple models. Its ultimate goal is to laboratories. This approach is unique in Programme Director of the VLN. Dr Henney has a PhD in represent the multiple liver functions, including international research in the biosciences. No Medicine and many years detoxification, the fight against inflammation team in the USA, Japan or any other country academic research experience in and the production of biochemicals necessary has managed to perform such an intricate cardiovascular disease in for digestion. geographically distributed research laboratories in London, collaboration. Nor has any other research effort Cambridge and Oxford, and integrated the most fundamental biological worked with AstraZeneca €50M flagship initiative is exploring strategic supported by the German research directly through to clinical studies in improvements to the company’s patients. Federal Ministry of Research approaches to pharmaceutical and Education target identification, and the An organ as seemingly anodyne as the liver reduction of attrition in early harbours surprising complexity. Using development. This so-called multi-scale modelling is a modelling and simulation to tackle this challenge. “The ability to model across scales complexity, VLN scientists have been able to of time and space is not easily done in biology,” show, according to Dr Henney, “that we can explains Dr Henney. What makes this project use it to highlight inaccuracies in our current possible is the data crunching capabilities of knowledge of physiological processes within bioinformatics and the power of new computer this vital organ”. Specifically, the results of the modelling. This combined approach enables team lead by Prof. Rolf Gebhardt, Deputy the integration of quantitative data from the Director of the Institute of Biochemistry at the

23 ISBE - www.isbe.eu University of Leipzig, point to inaccuracies in identify patients more likely to benefit from our knowledge of liver steatosis, or fatty liver treatment. Previously, liver toxicity has been disease. The team found that challenging liver the reason for the failure of a significant vLn faCT fILE cells, called hepatocytes, by external fatty proportion of novel medicines. Now, systems acids, results in accumulation of triglycerides in biology is opening new avenues for drug German government- fat droplets. However, it only results in minor discovery. funded initiative changes in the central metabolism of the liver, €50M investment against all expectations. The team also found For now, the team hopes to extend the funding over 5 years that the influence of insulin on fatty acid by another five years, to create the prototype 70 research groups biosynthesis in liver was previously strongly of a true multi-scale model within a single 41 Institutions overestimated, while that on the conversion of organ and link it to human physiology. 250 Scientists carbohydrates into fatty acids was rather underestimated. These findings led to a patent To meet the challenges of 21st Century likely to have a high impact on future therapies medicine to deliver more effective therapies, of steatosis and related diseases. we need a deeper understanding of the complexity of common disease and the Integrating the most dynamic interplay of genes and environment that underpins it. Systems biology offers fundamental biological research potential solutions, examples of which are directly through to clinical being pioneered in the Virtual Liver Network. studies in patients Words: Sabine Louet Crucially, the project aims to translate the basic January 2014 research into clinically-relevant applications for doctors. A team working on a showcase of the inflammatory process in the liver has developed a user-friendly interface for doctors, available on a tablet. This team is led by Prof. Steven Dooley, a specialist of molecular hepatology at the Mannheim Medical Faculty, and Jens Timmer, an expert in dynamic process modelling at the University of Freiburg. These inflammation models are available to professionals without the need for extensive training and can be used to help patients understand their illness.

Further concrete results of the VLN project have potential applications in medicine. They include two patents on potential biomarkers for steatosis, which are pending. These disease indicators could ultimately be used as a diagnostic test predicating the onset of fatty liver disease.

The network’s research efforts also draw on expertise from industrial collaborators, including German pharmaceutical company Bayer Technology Services. Industry partners have studied some genetic variants connected to the way individuals metabolise drugs. This further Information team is led by VLN leadership team member, Virtual Liver Network Lars Küpfer. The team’s findings will help virtual-liver.de

ISBE - www.isbe.eu 24 BIOGRAPHY

MICHAEL HUCKA FROM CALIFORNIA INSTITUTE OF TECHNOLOGY ON AN OPEN FORMAT FOR CREATING MODELS THAT HAS STIMULATED THE CREATION OF AN INTERNATIONAL COLLABORATIVE COMMUNITY OF SOFTWARE DEVELOPERS The emergence of web-based technologies hypertext mark-up language (HTML), says has catalysed the emergence of systems Mike Hucka, of the California Institute of biology, in which dynamic biological structures Technology, a key figure in the creation and and processes can be recast as software code ongoing development of SBML. “Just as HTML and computational models. This promises to lets a person or software express some provide a powerful new interpretative lens for content using text formatted in a certain SYSTEMS BIOLOGY MARKUP LANGUAGE 4SBML5 IS A FREE molecular biologists struggling to cope with the way—with the formatting mark-up normally AND OPEN INTERCHANGE increasingly large datasets generated by large- hidden from view by software—so too SBML FORMAT FOR COMPUTER scale investments in modern ‘omics’ lets a person or software express certain kinds MODELS OF BIOLOGICAL disciplines—such as genomics, transcrip - of data using text formatted in a certain way,” PROCESSES. SBML IS USEFUL tomics, proteomics, kinomics and he says. The “certain kinds of data” are usually FOR MODELS OF METABOLISM, CELL SIGNALLING, AND MORE. metabolomics. But if systems biology is to but not necessarily mathematical models of IT CONTINUES TO BE EVOLVED become a fully networked discipline—with all some biological phenomena, and the AND EXPANDED BY AN of the synergies that that implies—it requires “formatting” is actually descriptions of data INTERNATIONAL COMMUNITY. an underlying information infrastructure akin fields and relationships between parts of a to that which underpins information and mathematical model, instead of items such as Michael Hucka is a member of communications technology. It needs agreed section headings and bold or italic text that you the professional staff of the Department of data standards and formats for the automated find in HTML. Computing and Mathematical creation, publication and exchange of complex Sciences, California Institute of biological information. Technology. His work focuses on SBML provides a common the development of software The emergence during the past fifteen years of standards and infrastructure for format for describing the systems biology mark-up language (SBML) as scientific computing and he has structure and components been instrumental in the a free and open format for creating models, is development of SBML. an important part of this effort. SBML is an of biological models application of Extensible Mark-up Language (XML), the Worldwide Web Consortium (W3C) standard for formatting documents that now The significance of SBML goes beyond its underpins data exchange across the public immediate role as an information tool. The internet and private networks. SBML provides emergence of SBML has itself acted as a a common format for describing the structure positive feedback loop in terms of the and components of biological models. development of systems biology. It has stimulated the creation of an international The role of SBML as the lingua franca of collaborative community of software systems biology is loosely analogous to that of developers, theoretical biologists and

25 ISBE - www.isbe.eu computational modellers. The reproducibility of changes to existing features in a standard. All SBML-based models allows for their scrutiny of these activities corrections, updates and SBML In uSE and evaluation by other scientists. Previously, evolutionary chan―ges need to be done in a models were typically represented in the form fair and systematic fas―hion. SBML Level 3, the Total number of known of printed equations, which limited their utility. most recent version of SBML, has been SBML-compatible SBML has enabled the development of curated structured in such a way as to enable new software packages databases of biological models—such as the extensions to be added with ease. It has a each year BioModels Database and JWS Online—which modular structure, with a defined set of core users can access and interrogate dynamically. features and additional packages that extend It also underpinned the automated generation its functionality into specific topic areas. of 140,000 biological models from represen - tations of biochemical pathways, in the Notwithstanding its importance, SBML relies, Path2Models project, which will greatly in large part, on voluntary efforts from the accelerate the development of the entire field. developer community to support its ongoing maintenance and development. Direct funding is limited to Mike Hucka’s four-strong team The specification is subject to who support its underlying infrastructure, ongoing revision and including the extensive SBML.org website, development, to take account libSBML, a free, open-source programming library, which enables users to read, write and of changes in the external manipulate SBML files, and JSBML, a Java- technological environment based alternative to libSBML. US National and changes driven by Institutes of Health funding for this work ends developments within the in mid-2016. At the very least, follow-on systems biology field. funding is needed to maintain the ongoing effort, but a wider level of support for SBML’s broader development is crucial for the further In setting out the importance of SBML, Hucka maturation of systems biology. frequently invokes a passage written by Nicolas Le Novère, of the Babraham Institute Words: Cormac Sheridan in Cambridge, UK: “One of the biggest problems June 2015 of ‘Theoretical Biology’ was the failure of two of Popper's criteria for science: reproducibility and falsification. I have reviewed papers in the field for quite a few years now, and there is one commonality. You can't really evaluate them. You have to completely trust what is written by the authors. SBML could change that. It could permit better evaluation of modelling, and raise the whole field to a new level of confidence and consideration by other scientists in life science.”

Ten years on from that observation, it is clear that SBML, the de facto standard for biological modelling, has delivered on its promise, by providing a common format that many software systems and users could agree to use. SBML is itself not a static entity. The specification is subject to ongoing revision and further Information development, to take account of changes in the SBML sbml.org external technological environment and California Institute of Technology changes driven by developments within the www.caltech.edu systems biology field. Over time, people also European Systems Biology Community find new needs and desire additions or community.isbe.eu

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DEVELOPMENTS IN STANDARDS-BASED INFORMATION INFRASTRUCTURES ARE HELPING BIOLOGISTS TO INTERROGATE ‘BIG DATA’

One of the big challenges for biological to run individual models remotely, eliminating research is its full maturation into a ‘big the need for painstaking recoding work that science’ discipline, capable of tackling big, would be otherwise necessary. “It’s a lot of (L-R) Dawie van Niekerk, Johann complex questions in a coordinated fashion. work to code mathematical models from the Eicher, Danie Palm and Jacky The inherent complexity and diversity in literature, and it’s error-prone,” says Jacky Snoep (JWS Online team, biology makes the maturation harder for the Snoep, Professor of Biochemistry at University of Stellenbosch) life sciences than it was for physics, but a Stellenbosch University. “Every researcher who JWS ONLINE IS A SYSTEMS growing adoption of standardisation, data- wanted to use these models would have had BIOLOGY TOOL FOR sharing strategies and attempts to address big to do the same work.” SIMULATION OF KINETIC questions in truly collaborative efforts are MODELS FROM A CURATED speeding up the process. MODEL DATABASE. JACKY the ‘digitisation’ of biology SNOEP IS PROFESSOR OF BIOCHEMISTRY AT The ongoing development of systems biology, STELLENBOSCH UNIVERSITY, which integrates computer-based SOUTH AFRICA. mathematical modelling of living systems with JWS Online now contains some 200 curated experimental observation, represents an models, which have been rendered into a important strand of this process of maturation. standard format using Systems Biology An essential element of this is the Markup Language (SBML), the de facto development of robust, standards-based standard for creating computational models of information infrastructures capable of biological processes. The system is also managing large quantities of data and employed by the FEBS Journal, to test models software code in readily accessible formats. that are submitted for review along with JWS Online and BioModels represent two papers. Reviewers have access to the JWS significant and complementary model toolset, via a secure site, and can run the management initiatives, which are contributing models, to ensure that the data contained in to the ‘digitisation’ of biology by enabling the paper can be reproduced by the model. researchers to explore previously developed models of diverse biological processes. JWS Online has been incorporated into the SEEK collaboration environment (PubMed: JWS Online, originally developed in 2000 at 21943917), originally developed for the SysMo Stellenbosch University (SU; Stellenbosch, project on the systems biology of South Africa), is now co-developed at the microorganisms. The SEEK is a mature data University of Manchester (UM; Manchester, and model management platform for large- United Kingdom) and the Vrije Universiteit (VU; scale systems biology projects. “The data and Amsterdam, Netherlands). It played a model management structure we set up for prominent role in pioneering the concept of the SysMo project is currently the best system providing researchers with online, centralised available, and its approach is likely to evolve access to biological models. It includes a into a standard,” says Snoep. simulation environment that enables scientists

27 ISBE - www.isbe.eu BioModels Database, developed at the models cover domains such as metabolism, European Bioinformatics Institute (EBI; signal transduction, electrophysiology, CURRENT DEVELOPMENTS Hinxton, UK) since 2005, was created in population and ecosystem dynamics, pharma - IN CARDIAC CELL response to the needs of the community for a cokinetics and pharmacodynamics, and MODELLING model repository. It reflects the growing mechanisms of disease. “We are fulfilling the number of models published in the literature classical library function in this domain—we and provides them in a computationally have the record of the developed models,” says reusable form. These models originate from a Henning Hermjakob, head of the EBI’s plethora of domains representing work that proteomics services team. spans decades of refinement. Notable examples include: BioModels is not just a passive repository—it • Synthetic biology (BIOMD0000000012) is a true database, which can be interrogated BioModels Database serves as a • Neurobiology (BIOMD0000000020) dynamically. Models can be readily reliable repository of computational • Oncology (BIOMD0000000234) downloaded or can be run remotely using models of biological processes, and • Virology (BIOMD0000000463) several different tools, including the JWS Online hosts models described in peer- • Immunology (BIOMD0000000243) simulation environment. A ‘Model of the reviewed scientific literature. • PK/PD – Systems Pharmacology Month’ feature enables new users to learn Recently it has also begun to incorporate models that can be (BIOMD0000000490) about important individual models in a largely automatically generated from 'big jargon-free way; BioModels provides a variety data' pathway resources. Henning of teaching materials and resources, and can Hermjakob is team leader of a true database, which be regarded, says Hermjakob, as a portal to the Proteomics Services at the European can be interrogated world of modelling. Bioinformatics Institute, based in dynamically Hinxton, Cambridge. Modelling biological systems continues to a Growing database evolve from being an early-stage endeavour. 2005 2013 BioModels Database is now by far the field’s The field has taken major steps in recent years, largest repository of biological models, having culminating in the publication of the first Models 20 1000+ amassed more than 1,000 manually curated whole-cell computational model, which Species 300 400,000+ biological models. Each of these models are predicts a cell’s phenotype (or visible charac - Cross- described in peer-reviewed publications, teristics) from its genotype (or genetic make- References 1000 1,000,000+ manually curated to verify that the model in up) (Karr et al ., 2012). JWS Online and the database is capable of reproducing the BioModels are both vital components of the published results, and is extensively annotated information infrastructure supporting these to specify the biological entities that are efforts. represented within the model. Additional Words: Cormac Sheridan annotations are also provided that link the January 2014 model itself to further information such as mathematical concepts, ontological terms (including those that reference biological processes), and to other models (allowing hierarchical analysis on model lineages). Over 300 journals recommend deposition of models directly to the database in their submission guidance notes to authors.

With the ever-growing means by which 'big data' is generated, there is an ever-evolving further Information need to deal with it. The BioModels team has JWS Online recently introduced a means to automatically jjj.biochem.sun.ac.za manage models from large data sets; Besides BioModels Database the 1,000+ curated models, BioModels also www.ebi.ac.uk/biomodels The SEEK now contains an additional 140,000 models www.seek4science.org which were generated automatically from rep - SysMo resentations of biochemical pathways taken www.sysmo.net from multiple sources. Collectively, these Path2Models code.google.com/p/path2models

ISBE - www.isbe.eu 28 BIOGRAPHY

UK ONLINE COURSE IS CREATING NEW GENERATION OF SYSTEMS BIOLOGISTS

A UK initiative is delivering a thriving and They will emerge with skills suited to modelling expanding online course in systems biology, biological systems, be it ecological systems or Systems training in Maths, Informatics and the growth of organisms or cell signalling SYSMIC IS A COMPREHENSIVE Computational Biology (SysMIC). The course, pathways. Plus, they will no longer be baffled ONLINE COURSE IN SYSTEMS BIOLOGY AIMED AT which is now looking to spread beyond the UK, by other people’s simulations of the biological RESEARCHERS IN THE serves up introductory and advanced training world. BIOLOGICAL SCIENCES. THE in maths and computing, but always with “The immediate aim is that they can read a COURSE PROVIDES biological examples. INTRODUCTORY AND paper, recognise the assumptions made, look ADVANCED TRAINING IN SysMIC sprang from a desire by a UK research at the code and check it if they want,” says MATHS AND COMPUTING council to ensure its workforce had the Thomas. There are three modules, each last BASED AROUND BIOLOGICAL mathematical and computational horsepower six months and requiring five hours work per EXAMPLES. to engage with systems biology and the inter - week – progressing from basic skills to Geraint Thomas is the lead on disciplinary science agenda. Funded by the advanced topics and then project work. the SysMIC project and is based Biotechnology and Biological Sciences in the Department of Cell and Research Council in the UK and run by a Developmental Biology at consortium of University College London, SysMIC is for anyone University College London. Birbeck College, the University of Edinburgh interested in biosciences, from He is a core member of the UCL/Birckbeck Institute of and Open University, SysMIC has immersed molecules to ecosystems, and Structural Molecular Biology participants in programming MATLAB to model for all levels of seniority and the admissions tutor and and simulate biological systems and and using PhD liaison for the R statistical software. The core team at UCL Understanding Biological comprises Geraint Thomas, Gerold Baier, web Course organisers say undergrad and postgrad Complexity PhD programme at CoMPLEX. technologist Philip Lewis and administrator students too often see their maths skills Hannah Lawrence, and the course has already atrophy as biology courses pack in core Gerold Baier leads the served up skills and confidence to over one subjects and squeeze maths out. SysMIC will development of the SysMIC thousand biologists. instil linear algebra, dynamical systems, and course and is based in the differential equations, but turn maths teaching Department of Cell and Twelve of the 14 University Doctoral Training on its head. Traditionally teaching starts with Developmental Biology at Partnerships funded by the UK’s Biotechnology maths and seeks applications. University College London. With and Biological Science Research Council have a background in biochemistry adopted the course as core training for their “We start with a biological example and ask and nonlinear dynamics, his research work is on developing PhD students, but it caters too for established what kind of mathematics is needed,” says computational models of researchers wishing to brush up their skills. “It Gerold Baier at UCL. Computationally the epileptic seizure dynamics. is for anyone interested in biosciences, from programming language of MATLAB and R molecules to ecosystems, and for all levels of statistical package are taught, giving the basics seniority,” explains Geraint Thomas, the cellular to set up code, analyse data and write a script biologist at University College London, UK, who to run a model. Real papers are chosen, but leads SysMIC. nothing too advanced for beginners.

29 ISBE - www.isbe.eu Trainees see gains in being able to SysMIC adds new papers, examples and communicate with mathematicians, datasets continuously, along with multimedia statisticians and computer scientists. “It is the resources. There are online tutors and an communication skills that people value most. expanding FAQs pile. Course quizzes serve to They learn how to think in a structured, reassure people that they are making progress, quantitative way, and are able to talk to while supervisors, line managers or a training specialists in a way that allows them gain team can determine whether sufficient high much more profound advice,” Baier explains. standard is being achieved. Course sponsors The SysMIC course comprises of typically expect 70% of course questions to be three modules, each taking completed by students, with the remainder approximately 6 months to Now that things are devoted to a mini-project, but that can be complete: adjusted. Modules 1 and 2 consist of a working out, we want to series of units based around expand into Europe The course never sits still. It’s expanding to biological examples which are take on a parallel version with the Python supported with mathematical background reading. programming language. As new languages The biological examples shows The course is woven to fit time-poor people, establish themselves, organisers will build new how the maths techniques can be used to model biological engaged full time in biological research. There versions of the course, which will stand as a perpetual resource. “If you do it in MATLAB and systems, with code examples of is strong demand from pharma. “The pharma computer programming. 3 years later you realise you need some Python industry have employed people with a Students are taught using bioscience or pharmacological degree, but training, then you can go back and see familiar hands-on code examples in often little mathematical or programming material and take on all the examples in a MATLAB (used for mathematical analysis and modelling) and the training, yet the nature of data today means completely different language,” Thomas says. Another major objective he has is to move R package (used for data that you must use quantitative and analysis). computational means to deal with them beyond the UK and embrace European scientists. “Now that things are working out, Module 3 consists of support for properly,” says Baier. students undertaking an we want to expand into Europe.” extended project to apply inter - Bespoke parts for bioscience industries are disciplinary skills to their own Anja Korencic at the University of Ljubljana area of interest. being created, which focus on experimental began the course to assist her with modelling design, statistical analysis and how to optimise in her research project on circadian clocks. “I those in drug discovery programme. The core had some MATLAB, but I was looking for a material is akin to a solid trunk of taught systematic introduction to modelling and to be modules, but with branches now beginning to able to communicate with modellers.” She is grow out to cater for individuals or particular impressed by how the course begins at a basic groups. level, taking you through step by step, and how it is really designed for biologists. “I thought I That the future of biology is going to be more might skip over some of the early sessions, but mathematical is hardly a revelation. This was even the first and second sessions had some clear 15 years ago, says Thomas, “but it has really nice tricks or details that proved really taken a while to turn around the training super useful for me.” tanker.” Thomas set out as a biochemist, Words: Anthony King tacked to a more multidisciplinary line, before June 2015 devoting six years to a maths degree at the Open University, UK.

“I enjoyed it straight away. I got a buzz out of solving things. ” says Thomas. “But at every stage of my degree I was thinking, I can apply this to my research, or my colleague could use this mathematical approach.” Those taking the course often say they spend so long dealing with complexity that it is satisfying to have further Information clear answers to problems. SysMIC www.sysmic.ac.uk

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PEDRO MENDES FROM THE UNIVERSITY OF MANCHESTER EXPLAINS HOW BIOLOGISTS ARE BEING GIVEN A HELPING HAND TO INTRODUCE MODELLING INTO THEIR RESEARCH

The best front-of-house greetings are friendly The software began its journey in 2000 as and do not require you to know what’s going collaborations between Mendes and Ursula on behind the scenes. This trend is seen in Kummer, biological modeller at the University technology with intuitive digital user interfaces of Heidelberg, Germany. The first version developed for simplicity and ease of use, hiding launched four year later in 2004. the heavy duty lifting. But there is an Under the hood it had two major types of analogous option for biologists. simulations. One for simulating biochemical COPASI IS A SOFTWARE COPASI is an open source software package networks with differential equations, which is APPLICATION FOR SIMULATION that offers biologists a guiding hand in the most traditional approach and probably the AND ANALYSIS OF modelling and simulation. This is a welcome most widely used. “Essentially users describe BIOCHEMICAL NETWORKS AND THEIR DYNAMICS. COPASI IS A service given how modelling and simulation is a network and the software builds differential STAND-ALONE PROGRAM increasingly needed to aid the understanding equations for them, based on the network and THAT SUPPORTS MODELS IN of cellular behavior and to facilitate a some mathematical details they may need to THE SYSTEMS BIOLOGY quantitative reading of experiments. add,” Mendes explains. MARKUP LANGUAGE 4SBML5 STANDARD AND CAN “The software was made to target those SIMULATE THEIR BEHAVIOR biologists who want to do modelling, but don’t USING ORDINARY COPASI allows necessarily have all the mathematical DIFFERENTIAL EQUATIONS researchers to create 4ODES5 OR GILLESPIE'S background. The software tries to hide some STOCHASTIC SIMULATION of the mathematics behind the user interface, models of biochemical ALGORITHM. so the user doesn’t need to know all the networks and then using algorithms being used,” says Pedro Mendes, different algorithms to Pedro Mendes is Professor of Professor of Computational Systems Biology Computational Systems Biology simulate them and at the University of Manchester at the University of Manchester, UK, and a and Professor in Residence at leader in its development. analyse the results the University of Connecticut Health Center. His research is in “It allows researchers to create models of the area of computational biochemical networks and then using different The other type – stochastic simulations – systems biology, which aims to algorithms to simulate them and analyse the considers each molecule as a single entity, better understand biological results.” systems through the use of takes on more of the physical details of the computer models. Cells are composed of many organelles; so this whole network and offers more accurate, more software allows the reactions to be distributed mechanistic simulations. But COPASI makes it across several compartments. It is used in straightforward for researchers to switch systems biology to develop reaction kinetic between the two. “You can tell the software to models for biochemical networks, to simulate do it this way or that, and it tries to do their behavior and to analyse their properties. everything automatically,” says Mendes. Models can be based on ordinary differential equations or stochastic kinetics.

31 ISBE - www.isbe.eu COPASI is not standing still. Different MATLAB requires researchers to learn some algorithms are added all the time, with MATLAB programming language. “Learning parameter estimation now an option: this our software should be easy and the language essentially links experimental data with the used is often specific to biochemistry,” Mendes model, building a bridge between the model explains. COPaSI faCT fILE and what is observed. He compares it to the difference between Being open source, COPASI’s success can be Windows and DOS – where you had to type in Copasi is an difficult to precisely quantify. But with 10,000 and remember commands. For windows, you international downloads last year and a registered use macros and icons and don’t need to collaboration community of 2,000 users, it is obviously a remember everything. That is how COPASI between: popular computational tool. works. It essentially has menus and dialogue boxes and icons and people click on these Right now, the Mendes and Kummer labs are things and build the model up. Still, SBML responding to user demand by introducing means researchers can test models out on delay differential equations, which are types of either or both packages. models that have explicit delays built in; it is important in fields like circadian biology but has Putting his perfectionist hat on, Mendes says uses in other areas too. they are striving to improve the software and learning tools for users. “If a pathogen invades a person, the immune system takes a while to respond. Sometimes It is open source, so others can contribute. “We you don’t need to account for that delay,” says have an API (an application programming Mendes. “But sometimes researchers want to interface) which is essentially a way of allowing make a higher level model where they add a other people to write programmes and use specific delay in the model. If the system part of COPASI in their programmes,” says responds five hours later, this must be Mendes. 10,000 downloads represented in a specific algorithm.” They have posted instructive clips on YouTube, in 2014 introducing COPASI and giving tutorials on Community of Learning our software what you can do with it. The Mendes and Kummer labs often give workshops at 2,000 users should be easy conferences with the lessons learnt from watching users helping them to continually improve this vital software package.

COPASI is able to import and export in Systems Words: Anthony King Biology Markup Language (SBML), which is a June 2015 free file format useful for exchanging models of metabolism and cell signaling and more.

What other options are open to researchers? People can write their own specific software in languages like C or python says Mendes, which is how he started out when doing his PhD. This led him to develop GEPASI in the early 1990s, the precursor of COPASI. “The number of people writing their own programmes is smaller now,” he says. “The majority of people who don’t use COPASI use MATLAB, a commercial package designed originally for further Information engineers.” COPASI www.copasi.org

ISBE - www.isbe.eu 32 BIOGRAPHY KATY WOLSTENCROFT FROM THE UNIVERSITY OF LEIDEN DISCUSSES HOW THE WEB- BASED SEEK PLATFORM IS ENABLING SCIENTISTS GREATER ACCESS TO AND MORE INTELLIGENT USE OF THE VAST REPOSITORIES OF BIOLOGICAL DATA BEING AMASSED

The increasing data intensity of biological environment, in order to maximise the use and research, which is closely linked to the reuse of the data that are generated. The increasing complexity of scientific platform extends into the systems biology collaboration, has created an urgent need for domain concepts and standards developed new tools to allow researchers to navigate the under the semantic web initiative of the World ever-expanding information universe. Systems Wide Web Consortium (W3C), an ongoing effort THE SEEK PLATFORM IS A WEB- BASED RESOURCE FOR biology, the emerging discipline that seeks to to present disparate forms of information in SHARING HETEROGENEOUS map precisely all of the dynamic processes machine-readable formats, to enable more SCIENTIFIC RESEARCH within living cells and organisms, has created sophisticated forms of data searching and DATASETS, MODELS OR very particular data management analysis across distributed systems. SIMULATIONS, PROCESSES AND requirements. At its core is a tight coupling RESEARCH OUTCOMES. IT between experimental data and data SEEK was developed by researchers based at PRESERVES ASSOCIATIONS BETWEEN THEM, ALONG WITH modelling, as predictions and hypotheses the University of Manchester (UK), the INFORMATION ABOUT THE based on computer models are tested Heidelberg Institute for Theoretical Studies PEOPLE AND ORGANISATIONS experimentally, which can lead to further (Germany) and the University of Stellenbosch INVOLVED. refinements in the model or to revisions in (South Africa) in response to a requirement on certain parameters. The scale and complexity the part of SysMO’s funders that its grantees, Dr Katy Wolstencroft is an Assistant Professor at the of the data that are generated require who are distributed across more than 100 Leiden Institute of Advanced standards of data stewardship that represent institutions located in six countries, share data Computer Science (LIACS), significant challenges to biologists and data and data models. Before SEEK there was no teaching courses in management specialists alike. obvious way to do this in any kind of bioinformatics and computer comprehensive or controlled fashion. science. Dr Wolstencroft previously was a Research Researchers shared data by exchanging very Fellow in the School of an ambitious attempt to basic forms of documentation, such as Computer Science, University of capture the complexities of spreadsheets, by setting up project-specific Manchester working on systems biology research … to wikis or by using generic web-based or cloud- scientific workflows with the maximise the use and reuse of based collaboration environments, which are Taverna workbench, and not adapted to the specific methodologies or Systems Biology data and the data that are generated model management with the information architectures of systems biology. SEEK platform. The SEEK platform is a commons interface The SEEK system acts both as a repository, which has grown out of a large-scale European which allows users to publish and share data project on the systems biology of and models, and as a registry, which provides microorganisms (SysMO). It represents an links to relevant data sources and models ambitious attempt to capture the complexities hosted elsewhere. Its main components of systems biology research within a web- include an assets catalogue, which holds data based data management and collaboration files, protocols, workflows, models and

33 ISBE - www.isbe.eu publications; a ‘yellow pages’ feature, which established under the European Commission’s contains information on SysMO participants 7th Framework Programme (FP7), which has and their host institutions; and an access deployed SEEK to develop a comprehensive SEEK In uSE control feature, which enables user to control picture of research activity within the network. German government-funded third party access to their data. The Virtual Liver Network, which comprises 70 initiative research groups distributed across Germany, €50M investment One of the main challenges inherent in its has implemented SEEK to enable its members over 5 years design was to create a system that was to find and share data, models and processes sufficiently powerful and robust to be useful, that relate to liver function—at multiple levels 70 research groups while not placing an excessive burden on its of organisation, from the individual cell up to 41 Institutions users. Biological information is inherently the complete organism. Other users include: 250 Scientists heterogeneous and complex. Systems biology Unicellsys, another FP7 project, which is generates multiple types of data, including developing a quantitative understanding of the various species of ‘omics data (genomics, tran - control of and coordination of cell growth in scriptomics, proteomics, metabolomics, etc.), response to internal and external triggers; imaging data and enzyme kinetics data. To JenAge, a German research initiative on the enable all of this to be managed coherently in systems biology of ageing; and ROSage, a web environment, data and accompanying another German project, which is exploring the models and experimental protocols need to be role of reactive oxygen species in the aging ‘annotated’ or described in a precisely defined process. manner, and the relationships between the various elements must also be specified. SEEK is part of a wider ecosystem of standards-compliant, open-source systems that will, ultimately, facilitate greater access to The SEEK … eliminates what and more intelligent use of the vast would otherwise represent a repositories of biological data that are being significant overhead for users amassed globally. Words: Cormac Sheridan December 2013 The SEEK system can generate this ‘metadata’—or data about data—on the fly, as users deposit data held in commonly used file formats, such as spreadsheets, using predefined templates. This eliminates what would otherwise represent a significant overhead for users. “There are not that many incentives for people to spend time curating and annotating their data and their models,” says Katy Wolstencroft , a member of the SEEK development team at Manchester (now at the University of Leiden, in the Netherlands.).

The system also draws on the ISA framework (Investigation, Studies, Assays), an emerging software standard for managing biosciences data.

SEEK can be readily adapted for any systems further Information biology project. Its user base has, in fact, grown The SEEK platform to more than a dozen other implementations www.seek4science.org since it became available via an open source ISA framework (Investigation, Studies, Assays) licence in 2010. These include the European www.isacommons.org Virtual Institute of Malaria Research SysMO (EVIMalaR), a Network of Excellence www.sysmo.eu

ISBE - www.isbe.eu 34 acknowledgements

This publication was produced by Systems Biology Ireland, University College Dublin, as part of the Infrastructure for Systems Biology Europe (ISBE) programme, supported by an EU FP7 Infrastructure award (Grant agreement no: 312455).

We would like to thank the interviewees for generously giving up their time to talk about their work, as well as their support teams for providing additional information.

Editor: Will Fitzmaurice, Systems Biology Ireland Writers: Anthony King, Sabine Louet, Claire O’Connell, Cormac Sheridan Design: Resonate Design

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