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Systems biologyComplexity explained Systems biology. A hot topic in contemporary science gaining ever-increasing attention. In order to address the role of systems biology in general and in microbiology, FEMS Focus interviewed two major personalities in the field – Professor Roel van Driel and Professor Víctor de Lorenzo. Dr. van Driel is the Director of the Netherlands Institute for Systems Biology (NISB) in Amsterdam, The Netherlands and a professor of Biochemistry. Dr. De Lorenzo is the Head of the Systems & Synthetics Biotechnology Program of the National Centre of Biotechnology in Madrid, Spain. Read on for their general views on systems biology, the interface between systems biology and microbiology and the challenges that these novel opportunities should address. What is “systems biology”? NISB Chief Roel van Driel defines systems biology as an approach based on integrative experimental data unified in a single quantitative and predictive mathematical model. This basis of information warrants a goal-oriented and cost-effective analysis, with

which the predictive model is used to identify the best experiments to reach specific goals. To understand complex systems, the iterative cycle of modeldriven experiments and experimental data-driven modeling allows systematic analysis of the underlying principles and logic of complex biomedical systems.

Prof. Dr. Roel van Driel, PhD, is a professor of Biochemistry, Head of the Nuclear Organisation Group (NOG) in the University of Amsterdam ( and the Director of the Netherlands Institute for Systems Biology (NISB) in Amsterdam, The Netherlands ( NISB includes two universities, one physics institute and one mathematics institute. It also has excellent national and international network and numerous collaborations. NISB aims to achieve a synergistic effect by combining and sharing knowledge, research efforts and facilities available at its partners. It practices as a group the same principle as underscores its science: components (i.e. partners) can only achieve their full potential when operating in the context of a network system (i.e. NISB). About 50 % of the x groups included in NISB work on systems biology in microbiology. However, Dr. Van Driel also claims that when one asks 3 persons to define systems biology, one gets 5 answers. Research in NISB is based on the synergism between experimental (‘wet’) and modeling (‘dry’) research, with the aim of developing generic tools in systems biology. Choices in ‘wet’ research are driven by quantitative and predictive bio-modPrinciple of systems biology

From the Editorial Team In this issue of FEMS Focus, we will closein on a topic which enables complicated matters to be addressed – Systems Biology. This field of science is rapidly emerging and gaining importance due to the limited knowledge on how to handle complex data. Systems biology is an interdisciplinary field that focuses on the systematic study of complex interactions in a large context, thus, using a holistic perspective rather than reductionism. With the use of systems biology, new emergent properties that may arise from the systemic view used in this discipline may be discovered and the entirety of processes that happen in a biological system may be better understood. This time, FEMS Focus will address the interface between microbiology and systems biology – “Complexity explained!” Tone Tønjum, Editor & Chared Verschuur, Communications Assistant

eling. At the same time, ‘dry’ research is devoted to develop generic and specific bio-modeling approaches and theories, based on experimental data sets. This approach allows full implementation of the systems biology paradigm, initiating and exploiting the iterative cycle of experiments that can be accumulated into predictive models. Quantitative and mathematical models can be employed to test the working hypothesis and the cycle of new quantitative prediction and experimental verification in a systematic manner (including many components in time and space) can generate an improved model. This approach demands large computational force and ensures a systematic and efficient tackling of key problems in life sciences. NISB concentrates on issues that are central in molecular and cellular life sciences, but has not been addressed systematically yet, namely, the integrated functioning of metabolic, signal transduction and genetic networks in combination with systems that drive the generation of

On the interface between systems biology and microbiology

shape and force in cells. The last topic is most complicated. However, it has the ultimate goal of generating causal relationships between questions in science and the explanatory power offered. Still, we are in the early days of the systems biology era, with a lot to expect on what this emerging field of science can contribute.

SSBP Head Victor de Lorenzo maintains that “what you cannot describe in numbers, you cannot understand”. He highly appreciates the systems biology approach of integrative description, deconstruction and reconstruction which has opened up for new levels of comprehension.


e thinks that systems biology has made a tremendous difference in moving descriptive ‘soft’ science to ‘hardcore’ biological science since it allows handling of multi-scale complexities in i.e. genomes, transcriptomes and all the ‘–omics’ to a new stage which introduced a new era in the comprehension of i.e. metabolism. Prof. De Lorenzo also believes that prior to systems biology, there was no way to understand this basic field of science. Prof. De Lorenzo highlights that systems biology has generated tremendous insight into the causality of complex processes, in microbial metabolism in particular and in deciphering environmental settings and mechanisms of disease development. In microbiology, systems biology can be integrated into most aspects of the discipline and can, for example, explain ‘multicellular behaviour’ and ‘what goes on in biofilm respiration’. Examples of the complexity of systems biology

NISB thus starts from the notion that in this field, underlying principles are highly similar in all organisms, from ‘simple’ unicellular prokaryotes to multicellular higher eukaryotes, including animals and plants. Because the systems biology type of approach requires large and diverse experimental data sets, NISB will focus on two experimental systems in parallel, exploiting the benefits from each and combining the insights obtained: one microorganism and one higher eukaryotic cell system. Characteristics of the systems biology approach integrative experimental data sets from different projects and research groups are integrated in a single quantitative and predictive mathematical model goal-oriented and cost-effective the predictive model is used to identify the best experiments to reach specific goals understanding complex systems the iterative cycle of model-driven experiments and experimental data-driven modeling allows systematic analysis of the underlying principles Source:

What are the impacts of systems biology on environmental microbiology? According to Prof. De Lorenzo, this subject can be taken one step further. “Metabolomics can be extended to fluxomics, towards the understanding of global metabolism. Generally, what happens when pollution comes into soil and affects thousands of organisms? In the analysis of the fate of complex environments after external influence, model simulation of one component can, in the systems biology approach, be extended to monitoring a vast multiplicity of components,” he adds. What is the impact of systems biology in medicine? While deciphering the metabolic syndrome is a task keeping a number of systems biology scientists busy, in De Lorenzo’s view, major contributions of systems biology will also enlighten the understanding of microbe-host interactions, bacterial virulence and pathogenesis in infectious diseases. Systems biology in industry Systems biology has contributed mostly in bio-transformation and assessing responses to stress. In terms of new catalysis, this has resulted in new anti-malaria drugs. In patho-

Professor Dr. Victor de Lorenzo is the head of the Systems and Synthetic Biotechnology Program (SSBP) of the National Centre of Biotechnology in Madrid. His research focuses on the molecular biology and genetic engineering of microorganisms for environmental bioremediation. He belongs to the editorial boards of five international scientific journals of microbiology and microbial ecology and is a member of the European Molecular Biology Organisation and of the European Environmental Research Organisation. He has served in the OECD ad hoc Committee of Governmental Experts in Biotechnology for a Clean Environment and as a national delegate and core group member of the Standing Committee for Life and Environmental Sciences of the European Science Foundation. genesis, systems biology is most useful for assessing microbe-host interactions. Systems biology at the global level Systems biology is emerging worldwide. While Europe is setting the trend in the application of computational power in iterative modeling, the Far East, Singapore, Japan and China in particular, for the last decade, has lead the way in the generation of powerful computational systems and India has a front figure in bioinformatics. In the conceptual frame of developing new systems biology language and linguistics, the United States is taking the lead. At the same time, the United Kingdom has invested tremendous effort into the use of systems biology in the analysis of metabolomics. In supporting the urge to understand the multiscale complexity and interactions of matters, and not only single-scale descriptive science, the systems biology approach to assessment of the data generated by all the ‘–omics’ has made the former dream of holistic comprehension come true. Previously, in “older times”, the problem of complexity defined a barrier for certain questions to be raised. Now, in recent times, the possibilities of new technology from physics and biochemistry in combination with computational theory and power and the ‘— omics’ datasets defines a “new” era. “

Concepts and techniques associated with systems biology According to the interpretation of systems biology as the ability to obtain, integrate and analyze complex data from multiple experimental sources using interdisciplinary tools, some typical technology platforms are: Transcriptomics: whole cell or tissue gene expression measurements by DNA microarrays or serial analysis of gene expression Proteomics: complete identification of proteins and protein expression patterns of a cell or tissue through two-dimensional gel electrophoresis and mass spectrometry or multi-dimensional protein identification techniques Metabolomics: identification and measurement of all small-molecules metabolites within a cell or tissue Glycomics: identification of the entirety of all carbohydrates in a cell or tissue. Roel van Driel and Victor de Lorenzo

There are two main challenges that these vast datasets generate. One is the ever-emerging need to develop relevant nomenclature to define matters uniformly. The other is to develop relevant statistics to define, i.e., the number of experiments required to make the right conclusion. This combined data mining and text mining will ultimately have consequences for how papers are written, warranting “branch linguistics” and “baroque language” so that any topic studies can be dissolved into specifics.



Microbes as model organisms – an important tool for systems biologists

e are mindful of the total number of possible interactions among the parts in an organism, Leroy Hood at the Institute for Systems Biology (ISB) in Seattle, US, claims. Among a class of 20 students there can be 190 possible interactions, counting just the pairwise interactions. And among the approximately 25,000 genes that comprise each human being, there are more than 336 million possible pairwise interactions… since genes interact in more than pairs, the total number of possible interactions is staggering! Clearly, some simplification is necessary for us to approach understanding a system of such potential complexity. There can be thousands, even tens of thousands of genes and proteins interacting within an organism to trigger some function in an organism.


Fortunately for research scientists, biological processes have been found to operate exactly the same in many different organisms. The “Krebs cycle” (the process cells use to extract energy from sugars) is the same across most species. Because of this, scientists can use simpler organisms for their initial studies of biological systems. In this context, microbes represent most useful “model organisms”. The simplicity of a model organism allows a scientist to more easily focus on the properties and functions of interest, without having to sort out the complexity arising from additional systems embodied in more complex organisms. For instance, scientists can study yeast cells to understand how sugars are metabolized in many species (including

On the impact of systems biology ahead

ccording to Leroy Hood, the systems biologists’ understanding of the interplays of different hierarchies of biological information DNA, RNA, proteins, macromolecular complexes, signaling networks, cells, organs, organisms, species within their environmental contexts will promote conceptual insights and practical innovations that in turn will profoundly transform peoples’ daily lives. Predictive, preventive, personalized and participatory medicine will be the most ob-

vious impact. But other transformations will also occur, for example, in the development of alternative sources of food and energy. Likewise, a much deeper understanding of the biological basis of human behavior may, in the future, lead to efforts to predict and control it. The ethical, social, legal and political implications of systems biology and its applications, are significant and ought not be ignored or underappreciated by the research community.

in humans), without having to deal with the additional complexity from other systems in complex organisms (such as contracting muscles). Moreover, small organisms (such as yeast cells) reproduce quickly, allowing biologists to study multiple strains and generations of an organism in a short time. “Systems biology is the science of discovering, modeling, understanding and ultimately engineering at the molecular level the dynamic relationships between the biological molecules that define living organisms.” Leroy Hood, PhD, MD Source:

Model organisms must be carefully selected to provide simple cases for studies of biological systems. They simplify initial research, yet still provide data-rich and flexible experimental “systems” to be examined. Research findings from model organisms must be confirmed by also studying humans. But studies on model organisms are crucial to eventually answering the central biological questions regarding human life. Due to the complexity of biological systems, we rely on the expertise of scientists from multiple disciplines to probe and fully understand the properties of biological systems. In fact, it is the collaborative efforts of scientists cooperating in an interdisciplinary environment which is critical to advances in systems biology.

News from the European Commission

FEMS 2009

An EU strategy for systems biology

3rd Congress of European Microbiologists Göteborg, Sweden, June 28 - July 2, 2009

The EU is supporting systems biology with the aim of transforming the complexity of information generated into explanatory power. Relevant findings can be found on: http://

See you at GÖTEBORG, SWEDEN, JUNE 28 - JULY 2, 2009

Systems biology events Workshop: Systems Biology for Plant Design 8-11 July 2009, Wageningen, The Netherlands 7th Conference on Computational Methods in Systems Biology 30 August—01 September 2009, Bologna, Italy International Workshop on High Performance Computational Systems Biology (HiBi 2009), 14-16 October 2009, Trento, Italy

Register as a FEMS Affiliate! Systems biology links and resources

Systems biology @ FEMS n

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The Federation of European Microbiological Societies aims at promoting microbiology activities including its development in new directions. Systems biology @ FEMS is an emerging field with many prominent scientists engaged, engendering good promise for the shortand long-term future of this field. Several

SysMO2 – Systems Biology of Microorganisms 2 ERASysBio is a systems biology funding initiative for the European Research Area. The most recent major EC call for research activities with a long-term perspective of systems biology was open in May 2009 (SysMo2): SysMO2 is operating under the umbrella

of ERASysBio; it provides funding for research on “Systems Biology in Micro-organisms”. It is so far financed by funding agencies in Gemany, Spain, Netherlands, Norway and the United Kingdom. A total amount of € 17M has been committed by the five partner organisations.

Thematic issue now available

sessions at the FEMS third congress in Göteborg, Sweden, in 2009 will address various aspects of Systems Biology. Recently, a FEMS Microbiology Reviews thematic issue with Victor de Lorenzo and Michael Galperin as editors was dedicated to systems biology in microbiology as an umbrella concept that includes a range of efforts to transform the complexity of live organisms into a level of quantitative comprehension. Front page of FEMS Microbiology Reviews thematic issue on Microbial Systems Biology, Volume 33 Issue 1 - January 2009 (1-255)

Online subscription to the full set of

FEMS journals for only 175 Euro The FEMS Focus is published by the FEMS Central Office. Whom to contact? Prof. Dr. Tone Tønjum ( Design: FEMS is a registered charity (no. 1072117) and also a company limited by guarantee (no. 3565643). © 2008 Federation of European Microbiological Societies FEMS Central Office Keverling Buismanweg 4 2628 CL Delft The Netherlands Tel: +31-15-269 3920 Fax: +31-15-269 3921 E-mail:


June 2009 No. 4 which the predictive model is used to identify the best experiments to reach specific goals. To understand complex systems,...

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