Biosensors and Bioelectronics 20 (2005) 2404–2407

Review

Systems Biology—an interdisciplinary approach

Alain Friboulet, Daniel Thomas∗

UMR CNRS 6022 – G´enie Enzymatique et Cellulaire, Universit´e de Technologie de Compi`egne, B.P. 20529 – 60205 Compi`egne Cedex, France

Received 26 August 2004; received in revised form 2 November 2004; accepted 19 November 2004Available online 23 February 2005

Abstract

System-level approaches in biology are not new but foundations of “Systems Biology” are achieved only now at the beginning of the 21stcentury [Kitano, H., 2001. Foundations of Systems Biology. MIT Press, Cambridge, MA]. The renewed interest for a system-level approachis linked to the progress in collecting experimental data and to the limits of the “reductionist” approach. System-level understanding of nativebiological and pathological systems is needed to provide potential therapeutic targets. Examples of interdisciplinary approach in SystemsBiology are described in U.S., Japan and Europe. Robustness in biology, metabolic engineering and idiotypic networks are discussed in theframework of Systems Biology.©

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eywords: Interdisciplinarity approach; Robustness in biology; Systems Biology

ontents

1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2404

2. Systems Biology has three possible impacts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2405

3. Examples on interdisciplinarity in Systems Biology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2405

4. Examples of Systems Biology approaches. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24054.1. Robustness and Systems Biology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24054.2. Metabolic engineering a part of Systems Biology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24064.3. Idiotypic network and Systems Biology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2406

5. Summary and conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2406

Acknowledgement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2407

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2407

. Introduction

System-level approaches in biology are not new.Vonertalanffy (1933, 1968)applied general systems theory to

different scientific fields, including biology: “problems of oganization of various orders are not understandable by itigation of their respective parts in isolation”.Weiner (1948developed “Cybernetics or control and communication in

∗ Corresponding author. Tel.: +33 3 4423 4408; fax: +33 3 4420 3910.E-mail address:daniel.thomas@utc.fr (D. Thomas).

animal and the machine” in the frame of a system-level ap-proach.Turing (1952)was not only a pioneer in computerscience and technology with his famous machine but also a

956-5663/$ – see front matter © 2004 Elsevier B.V. All rights reserved.oi:10.1016/j.bios.2004.11.014

A. Friboulet, D. Thomas / Biosensors and Bioelectronics 20 (2005) 2404–2407 2405

pioneer in a system-level approach of the chemical basis ofmorphogenesis in biology. The Prigogine’s school was ac-tive in the field since 1960 (Prigogine et al., 1969; Goldbeter,1996) with the concept of “dissipative structures” to explainbiochemical oscillations, cellular rhythms and morphogene-sis. Numerical analysis and control of distributed biochemicalsystems were developed by Kernevez since 1970 (Kernevezand Thomas, 1975).

System approaches are not new but foundations of “Sys-tems Biology” are only achieved now at the beginning ofthe 21st century (Kitano, 2001) with the support of the twomain international journals “Science” (Kitano, 2002a) and“Nature” (Kitano, 2002b). The content of Kitano papers isnot new by itself, but they were written at the right time.First of all, the renewed interest today for a system-level ap-proach is linked to the progress in molecular biology (genomesequencing), high-throughput measurements, biosensors andnanobiotechnology. This progress enables scientists to collectcomprehensive data sets on system performance and to gaininformation on the structures and functions of biomolecules(Laval et al., 2000). A second major reason for a renewedinterest for a system-level understanding is the failure of theclassical philosophy of molecular biology: the “reduction-ist” approach. Now it is obvious that everything in physiol-ogy and pathology will not be explain by one, two or a fewgenes.

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tems Biology is a focus of our interdisciplinary activities.The scientific strategy focuses on Biocatalysis, Biomath-ematics and Biocomputing, Biomolecular and CellularAnalysis, Biophotonics and Bioelectronics, Biomolecu-lar Structure and Dynamics, Bionanotechnology and Sys-tems Biology”. The above text is a good definition of thewide spectrum of Systems Biology, an interdisciplinary ap-proach by nature.

- The Massachusetts Institute of Technology (MIT) has cre-ated a “Computational and Systems Biology Initiative”(CSBi). CSBi is a campus-wide education and researchprogram that links biologists, computer scientists and en-gineers in a multi-disciplinary approach to the system-atic analysis of complex biological phenomena (http://csbi.mit.edu/whatis). CSBi places equal emphasis on com-putational and experimental methods and on molecular andsystems views of biological function. Multi-investigatorresearch in CSBi is supported through a sophisticated re-search infrastructure, the CSBi Technology Platform. CSBiincludes over 10 academic units across MIT’s Schools ofScience and Engineering, the Sloan School of Managementand the Whitehead Institute for Biomedical Research.

- The School of Fundamental Science and Technology atKeio University (Tokyo) has created “The Systems BiologyInstitute” (SBI) (http://www.systems-biology.org/000). Ittakes a cross-disciplinary faculty – biologists, computer

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The goal of the article is to show to the journal readersiosensor actors the importance of the new field of “Sysiology” for sensors and bioanalysis as far as the stra

s concerned. The “Systems Biology” approach will reqore biosensors and more bioanalysis.

. Systems Biology has three possible impacts

(i) A system-level understanding of native biological stems (animals, plants, microorganisms) with not osystem structures but also system dynamics. Thicludes metabolic analysis, sensitivity analysis andfurcation analysis (Kernevez et al., 1983).

(ii) A system-level understanding of pathology and mfunction in order to control the state from the celthe whole body and to provide potential therapeuticgets for treatment of diseases (Bailey, 1999; Fribouleet al., 2002).

iii) The development of a system-level approach in Biotenology to design biological systems having desproperties not existing in nature (Bailey, 1991).

. Examples on interdisciplinarity in Systems Biology

Progress in any of the above areas requires an inteciplinary approach. Recently (Science, 2004, 305, 2the University of Manchester has published in a classadvertisement to recruit a Chair in Systems Biology: “S

scientists, chemists, engineers, mathematicians and pcists – who speak and understand the languages ofdifferent disciplines to facilitate the development of nglobal technologies.The University of Technology of Compiegne is setting upfederation between Laboratories belonging at least todifferent scientific departments in the CNRS: Informaand Communication Sciences and Technology, Engining Sciences and Life Sciences. The strategy of the Fetion is to focus on Systems Biology (“Systemes et vivant”to address the challenges previously described.

. Examples of Systems Biology approaches

.1. Robustness and Systems Biology

Among various interdisciplinary scientific questions,ustness is receiving considerable attention even if amiologists the interest is a recent one. Robust systems

ain their state and functions against external and inteerturbations and robustness is an essential feature o

ogical systems even if the use of the word is rare amiologists. Biological systems have been found to be rot a variety of levels from genetic switches to physiologeactions.

Robust systems are both relatively insensitive to alteraf their internal parameters and able to adapt to chang

heir environment. Such properties are achieved throughack, modularity, redundancy and structural stability.

2406 A. Friboulet, D. Thomas / Biosensors and Bioelectronics 20 (2005) 2404–2407

The robustness of a biological system is not always an ad-vantage, for instance in therapy and biotechnology. As far aspathology is concerned cancer cells are extremely robust fortheir own growth and survival against various perturbations.They continue to proliferate, driven by the cell cycle, elimi-nating communication with their external environment, thusmaking it insensitive against external perturbations. To estab-lish treatments that move patients from a stable but diseasedstate to a healthy one will require an in-depth, system-levelunderstanding of biological robustness (Kitano, 2002b).

In biotechnology, metabolic engineering of cells or or-ganisms is facing the “biological robustness”; circuits existto compensate the effects of the molecular modification. Thisis also true for gene therapy. The phenomenon is especiallyimportant in plant with the “co-suppression”. Not only theexpression of the transgene is suppressed but also the equiva-lent native gene (Vaucheret and Fagard, 2001). This exampleshows that a Systems Biology approach is needed to developthe use of metabolic engineering (Sweetlove et al., 2003).

4.2. Metabolic engineering a part of Systems Biology

Metabolic engineering has emerged as the scientific fieldaiming at the directed modification of enzymatic, regulatoryor transport activities of the cell to improve cellular prop-erties (Bailey, 1991; Stephanopoulos and Sinskey, 1993).T useo anu ofp olice s,1 thea atedn theo tiona y beo riousp

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types of living systems – from microorganisms to plant, ani-mal and human cells. The in situ NMR measurement acts as anon-invasive pH, ion and concentration-meter, with31P and13C as the two main isotopes of study. In situ NMR can pro-vide many of the state variables needed for modeling pathwayfunctions.

An important part is metabolic flux analysis, which com-bines data on uptake and secretion rates, biosynthetic require-ments and quasi steady-state mass balance on intracellularmetabolites. The concept of network is a prerequisite to un-derstand metabolic pathways and is fundamental to studyimmunology.

4.3. Idiotypic network and Systems Biology

The immune system is not only devoted to defense butit is also the best “machine” to produce protein diversity,by generating and screening tremendous numbers of anti-bodies that bind virtually any natural or synthetic moleculewith high affinity and exquisite selectivity. In immunol-ogy, the main system-level approach was developed byJerne (1973)with both an important contribution support-ing selection in the frame of the selection versus instruc-tion controversy and a new idea, the idiotypic theory (Jerne,1974).

The thrust of the idiotypic theory is that an antigen gener-a alleda an-t edAi es nti-g zymea nti-b et an-t

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his entails modifications at the genetic level makingf recombinant DNA technology, in combination withnderstanding of cellular function through evaluationhysiological states. A major contribution of metabngineering is its emphasis on integration (Stephanopoulo998). As in Systems Biology the focus is no longer onnalysis of individual, isolated reactions, but on integretworks of metabolic pathways. The concern is withverall metabolic system, in the sense that informabout the intracellular regulatory mechanisms can onlbtained through studying the interaction among the vaarts of a network.

In the traditional reductionistic approach, complex cear systems were dissected into their components anlyzed individually, presuming that once sufficient detere known the whole system could be understood. How

here is now ample experimental and theoretical evidencxtensive knowledge about many cellular components is

nsufficient to describe many aspects of cell operation.Recent advances in global mRNA and protein ana

rovide access to certain aspects of biological complexityhere is currently no direct link between such compositiata and the dynamic metabolic and physiological aspeellular systems. Nuclear magnetic resonance (NMR) sroscopy is expected to play a major role in global invesions of metabolism (Barbotin and Portais, 2000). The firsteport on the application of NMR to microorganisms it tf Eakin et al. (1972)on the yeastCandida utilis. In the las

hree decades, NMR spectroscopy has been applied fonvasive characterization of metabolic function in differ

tes antibodies whose serologically unique structure, cn idiotype, results in the production of anti-idiotypic

ibodies (Jerne, 1974). The original antibody is designatb1, and the anti-idiotypic antibody Ab2. The Ab2 antibod-

es recognize the antigen-binding site of Ab1, and thereforhare a motif or structural similarities with the original aen. This approach was used with the active site of an ens original antigen to produce catalytic anti-idiotypic aodies as Ab2 (Izadyar et al., 1993). After Ab2, the cascad

hen perpetuates with the generation of anti-anti-idiotypicibodies (Ab3) that recognize Ab2, and so on.

Any serious study dealing with the idiotypic network isonging to Systems Biology. Strong hypothesis are assuhat anti-antibodies in the 80 autoimmune diseases knre resulting from the idiotypic network (Shoenfeld, 2004).nti-idiotypic catalytic antibodies have also a possible lge with autoimmune diseases (Debat et al., 2001). Autoim-une diseases will be understood and cured only throuystems Biology approach.

. Summary and conclusions

The input of a system approach to biology is hugeas already discussed but the fertilization in the reverse

s also important. A better knowledge of system structuystem dynamics, control, regulation, robustness in bioill be useful for system approaches in general, roboutomatics, computer, technology, synthetic receptorsBiosensors and Bioelectronics”, the synthetic receptors se

A. Friboulet, D. Thomas / Biosensors and Bioelectronics 20 (2005) 2404–2407 2407

tion is dedicated “to contributions focusing on the comple-mentary intersection between synthetic receptors, nanotech-nology, molecular recognition, molecular imprinting andsupramolecular chemistry”. Synthetic receptor systems couldbe a crossroad between different components of Systems Bi-ology through a “biomimicking approach” (Haupt, 2003).

As far as the field of biosensors is concerned the devel-opment of “Systems Biology” is of a key importance. Theefficiency of a system-level approach is linked to the progressin collecting experimental data, often on line. System-levelunderstanding of native biological and pathological systemswill provide new ways for therapeutics and diagnostics. Cur-ing a disease will not be any more based only on the discoveryof a new drug but on the control and regulation of parame-ters. The main founder of Systems Biology (Kitano, 2001) islinked to an electronics company and not to a pharmaceuticalcompany.

In conclusion, the aims and scope of “Biosensors and Bio-electronics” are fully relevant for the development of the newfield of “Systems Biology”.

Acknowledgement

We thank Bernard Dubuisson, Research director of theUniversity of Compiegne, for fruitful discussions and stimu-l

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