-
Systems Biology: Today and Tomorrow; the WTEC visit to The
NetherlandsThe Institute for Molecular Cell Biology, BioCentre
Amsterdam, Free University Amsterdam
-
The WTEC visit to The Netherlands:the program11:45 Welcome
address (Hans Westerhoff): 12:15 Marvin Cassman: Aims of the WTEC
study12:30 lunch 13:15 Welcoming remarks by Pier Vellinga (Dean
Faculty of Earth and Life Sciences)13:45-17:00 Examples of Dutch
Systems Biology 16:40 Teaching Systems Biology16:50 Drinks 17:05
General discussion (chair: Roel van Driel): Systems Biology and its
future 17:45 Departure for the restaurant (De Molen;
Amstelveen)
-
System Biology: Where it matters
International developmentsEuropean developments/potentialDutch
Systems Biology
-
What is/has been happening internationally?Institutes
(ISB-Seattle) [BCA/IMC here]Conference (ICSB)Electronic
cellsAlliances
-
BioCentre Amsterdam and its Institute for Molecular Cell
BiologyBCA: From Entering the living cell to Molecular Systems
BiologyIMC:
-
The 4th International Systems Biology Conference 2004 in
Heidelberg
-
Electronic cellsE-cellVirtual cellSilicon cell
-
www.siliconcell.net:Computer replica of parts of living cells
(NL, SA, USA)
-
Bottom up international alliancesIEcA (International E. coli
Alliance)
YSBN (Yeast Systems Biology Network)
EGF Signalling network
-
www.ieca2004.caRound Table discussion 2: Developing a White
Paper
-
IEcA status quoManifest being writtenGenome Canada supports
workshop funding organizations plus scientists to put together an
international prokaryotic SB programTo prepare concrete action
planGenome Canada looks for European partners (e.g. German SysMo)US
partner needed .
-
YSBN
-
YSBN
-
YSBN status quoWhite paper has been writtenCommittees have been
formedFunding unclear
-
GF signalling allianceIn preparation onlyKholodenko, Goryanin
(GSK)
-
System Biology: Where it matters
International developmentsEuropean developments/potentialDutch
Systems Biology
-
What is happening in Europe?National programsGermany
(BMBF):German Hepatocyte: Systeme des Lebens (20-50 ME); has
begunSysMo (Systems Biology of Microorganisms (10 ME); call in
2005Finland: System Biology and Bioinformatics (10.5 ME); has
begunThe Netherlands: SBNL; set of organism focused programs (L.
lactis, S. cerevisiae, E. coli, Silicon cell, Signal transduction,
Xomics, Cell Biophysics, ..); some funded (IOP) most still in
limboUK: BBSRC Integrative Biology 10 years program: > 6
national centres 5ME? each; bids (for first round) are now
in..Transnational programs:SysMO: Germany intends to have this as a
transnational program (Germany, Austria, Netherlands,
France?)ERANET: Brussels catalyzed transnational activity; inspired
by SysMO?Paris meeting August 26 (joint with EUSYSBIO
meeting)European programs:
-
Transnational initiatives; SysMoGerman BMBFPreparing for
microbial System Biology programWants to go transnationalAustrian,
Dutch ?partners2005: call for proposals
-
What is happening in Europe?National programsGermany
(BMBF):German Hepatocyte: Systeme des Lebens (20-50 ME); has
begunSysMo (Systems Biology of Microorganisms (10 ME); call in
2005Finland: System Biology and Bioinformatics (10.5 ME); has
begunThe Netherlands: SBNL; set of organism focused programs (L.
lactis, S. cerevisiae, E. coli, Silicon cell, Signal transduction,
Xomics, Cell Biophysics, ..); some funded (IOP) most still in
limboUK: BBSRC Integrative Biology 10 years program: > 6
national centres 5ME? each; bids (for first round) are now
in..Transnational programs:SysMO: Germany intends to have this as a
transnational program (Germany, Austria, Netherlands,
France?)ERANET: Brussels catalyzed transnational activity; inspired
by SysMO?Paris meeting August 26 (joint with EUSYSBIO
meeting)European programs:
-
What is happening in Europe?European programs:EU: FP6 (Specific
Support Action EUSYSBIO; Computational Systems Biology not in third
call; Synthetic Biology in April 2004 call)EUREKA: (New Safe
Medicines Faster) Virtual CellEMBO: SB in EMBL??ESF: Forward look,
towards EUROCORE and more?
-
FP6: Specific Support Action EUSYSBIOGet science policy makers
togetherHelp organize ICSB2004 (Heidelberg, October 9-13
2004)Organize SB course (FEBS): March 2005Set up ERANET:
transnational funding possibilitiesSet up European SB
organization/group
-
WP8 (Dutch WP) deliverablesD26: Platform of excellent Eur SB
groups:-at ICSB form network of excellence?D27: Workshop devoted to
standardsAt ICSB2004: October 10, Heidelberg (joint with ESF?)D28:
Strategy paper discussing scientific basis science policy
planningTo be written on request of WP6D29: Scientific journal A
book on Defining Systems Biology for now
-
BioSim ( NoE): MosekildeModels for pharmaceuticals
-
BioSim ( NoE): Models only
-
FP6: FutureComputational Systems Biology:Call for IP on
Computational Systems Biology with deadline November 2004 failed
(STREPS and Coordination Action remain)Promises for 4th call and
FP7Problem?: too dry ?..
-
What is happening in Europe?European programs:EU: FP6 (Specific
Support Action EUSYSBIO; Computational Systems Biology not in third
call; Synthetic Biology in April 2004 call)EUREKA: (New Safe
Medicines Faster) InSysBioEMBO: SB in EMBL??ESF: Forward look,
towards EUROCORE and more?
-
EUREKAs InSysBio: IMCs relevance for Biomed and Biotech
-
EUREKAs InSysBio: IMC connecting with European pharma & food
industry
-
InSysBio:Eurekas virtual cell initiativeEuropean, industry
driven researchAim: Making computer models of living organisms for
drug development etc. and(now also:) for food production
(biotech)BioinformaticsTool developmentModels for pharma and Models
for food
-
ESF forward lookStudy to see if System Biology could be ESF
themeThis would then make ESF catalyze common research programmes
betweenNational science foundations
-
What is needed?Wet SB, not just dry (FP6, EUREKA)Try to get the
national SFs to coordinate their SB programsConstruct mechanisms
for transnational fundingBecome partners for USA, Japan, Canada,
China, KoreaProvide funding anchors for the alliances
-
System Biology: Where it matters
International developmentsEuropean developments/potentialDutch
Systems Biology
-
Dutch/EU SB: Integrative Systems BiologyLook at all the leaves
individually2. The phenomena; top downDiagnosis; pattern
recognition3. Get to the roots; bottom up;Understanding of the
specialSystem properties/principles
-
Dutch Systems Biology:The AmbitionAmbition:Not just SB; aim is
to now understand living organisms from molecule to cell, organ,
and human organismPut a healthy man . on earthDutch Niche:
mechanistic (bottom up SB)wet plus dryindustry plus academia Bring
about common goal synergism between national programs (European
countries are too small for SB)Generate superfund from Europe
-
What is happening in NL?National programsNWO (Dutch NSF)
preludes (6 M$ each):BioinformaticsMolecule to CellComputational
BiologyNational Genomics Centres (200 M$): Centre Medical Systems
Biology (Leiden, VU, TNO; not really SB)Kluyver Centre (some
SB)Plant Systems (not SB)Cancer (not SB)IBIVU: Integrative
BioInformatics VU (3 M$)IOP-Genomics: Vertical Genomics (2
M$)Ecogenomics-BSIK (10 M$)
-
What is going to happen in NL?National programsSBNL; set of
focused program proposals:L. lactis (Kuipers, Teusink, Siezen,
Hugenholz. )S. cerevisiae (Bakker, Teixeira, Pronk, Heijnen)Silicon
cell Amsterdam (-Stellenbosch, Blacksburg; Snoep)SBNL: Industrial
platformPartner in Transnational SysMOPartner in EUREKAAttempt at
National Program integrating top down with bottom up
-
WTEC study: Systems Biology, Network Behavior in Biological
SystemsState of the art information on network behavior, also
internationallyResearch opportunitiesIdentify potential interagency
collaborationsIdentify potential international
collaborationsPublish results of study
-
The WTEC visit to The Netherlands:the program11:15 Coffee, tea,
cookies in G07611:45 Welcome address (Hans Westerhoff): Dutch and
European Systems Biology; where it might matter12:15 Marvin
Cassman: The aims of the WTEC study12:30 lunch 13:15 Welcoming
remarks by Pier Vellinga (Dean Faculty of Earth and Life
Sciences)13:20 Coffee + informal discussions
-
The WTEC visit to The Netherlands:the program11:15 Coffee, tea,
cookies in G07611:45 Welcome address (Hans Westerhoff): Dutch and
European Systems Biology; where it might matter12:15 Marvin
Cassman: The aims of the WTEC study12:30 lunch 13:15 Welcoming
remarks by Pier Vellinga (Dean Faculty of Earth and Life
Sciences)13:20 Coffee + informal discussions
-
The WTEC visit to The Netherlands:the program13:45-16:40
Examples of Dutch Systems Biology 13:45 Barbara Bakker; Vertical
genomics 14:00 Jurgen Haanstra: Network based drug design 14:15
Frank Bruggeman: Silicon cell as a tool for understanding
regulation14:30 Jan Lankelma: Treating cancer: fighting a
system14:45 Jorrit Hornberg: New principles of signal
transduction15:00:Tea
-
The WTEC visit to The Netherlands:the program15:30 Systems
Biology in Delft: Wouter van Winden16:30 Lactococcus lactis faster;
a Systems Biology endeavor; Bas Teusink16:40 Teaching Systems
Biology, Hans V. Westerhoff16:50 Drinks 17:05 General discussion
(chair: Roel van Driel): Systems Biology and its future 17:45
Departure for the restaurant (De Molen; Amstelveen) 18:00
Dinner.19:45 Departure for the airport20:00 Check in; KLM; Schiphol
airport21:05 flight to the UK......
-
The WTEC visit to The Netherlands:the program15:30 Systems
Biology in Delft: Wouter van Winden16:30 Lactococcus lactis faster;
a Systems Biology endeavor; Bas Teusink16:40 Teaching Systems
Biology, Hans V. Westerhoff16:50 Drinks 17:05 General discussion
(chair: Roel van Driel): Systems Biology and its future 17:45
Departure for the restaurant (De Molen; Amstelveen) 18:00
Dinner.19:45 Departure for the airport20:00 Check in; KLM; Schiphol
airport21:05 flight to the UK......
-
Orchestration of cellular processes in a simple cell: making
Systems Biology work for Lactococcus lactisBas TeusinkKluyver
Centre (Hugenholtz, Heijnen) RUG (Kuipers, Kok, Jansen, Poolman) VU
(Westerhoff, Bakker, Snoep) CMBI (Siezen,Teusink) WCFS
(Kleerebezem, Molenaar, de Vos) UvA (Brul, Hellingwerf, Breit)
TNO-Food (Van der Werf, Smilde)
-
Objective: use Systems Biology to understand the limits of
growth of Lactococcus lactisLimits of growth (at a given
condition): -biological and physico-chemical constraints
-
Reference state: the pH-auxostat- Possible to operate stably at
maximal growth rate- Study pH stress
-
Overview of work packages
-
Overview of consortium members1. Kluyver Centre (Hugenholtz,
Heijnen):metabolome, proteome, modelling, metabolic engineering,
fermentations
2. RUG (Kuipers, Kok, Jansen, Poolman):transcriptome, protein,
membrane proteome, protein interactions, bioinformatics,
statistics, model building
3. VU (Westerhoff, Bakker, Snoep):kinetic modelling, integrative
bioinformatics, metabolome, activity-proteome, transport,
hierarchical control analysis
4. CMBI (Siezen, Teusink):bioinformatics, comparative genomics,
genome mining, metabolic reconstruction
-
Overview of consortium members5. WCFS (Kleerebezem, Molenaar, de
Vos):regulation, mining, bioinformatics, metabolic engineering,
metabolomics
6. UvA (Brul, Hellingwerf, Breit):DNA-array technology, signal
transduction, experimental design
7. TNO-Food (Van der Werf, Smilde): metabolome, data analysis,
experimental design
-
The WTEC visit to The Netherlands:the program15:30 Systems
Biology in Delft: Wouter van Winden16:30 Lactococcus lactis faster;
a Systems Biology endeavor; Bas Teusink16:40 Teaching Systems
Biology, Hans V. Westerhoff16:50 Drinks 17:05 General discussion
(chair: Roel van Driel): Systems Biology and its future 17:45
Departure for the restaurant (De Molen; Amstelveen) 18:00
Dinner.19:45 Departure for the airport20:00 Check in; KLM; Schiphol
airport21:05 flight to the UK......
-
Teaching Systems BiologyMastersPh D students
-
TopMasterBiomolecular Integration/Systems BiologyEnquiries:Prof.
Dr. H.V. WesterhoffTelephone +31 20 444 7228E-mail:
[email protected]
A Masters of the CRbCSCentre for Research on bioComplex
SystemsUltrafast space- and time-resolved spectroscopy, single
molecule biophysics and biochemistry, chemistry of complex
molecules, molecular genetics in living cells, intracellular
networks, hierarchical control analysis, Integrative
bioinformatics, principles of Systems Biology, entering the living
cell, Silicon Cell, Integrative genomics, confocal microscopy,
tumor cell biology, medical Systems Biology, signal transduction,
nanotechnology, computational biology, ecological control
analysisTransnational student projectsCareer development
supportInternational peer groupConnected Ph D studentshipsNature
427, 568The real cellThe silicon cellExperimentsCalculations
-
TOP-BMI/SB : Aims continued:obtain expertise in advanced
conceptual and modeling methodologies for bioinformation and
computing technologies, such as medical Systems Biology, signal
transduction, computational biology, ecological control analysis,
intracellular networks, hierarchical control analysis, Integrative
bioinformatics, principles of Systems Biology, entering the living
cell, Silicon Cellobtain insight in the most important biological
and biomedical issues, and in how they might be addressed
scientificallyinsight into what systems biology and integrative
molecular biophysics may mean for societyunique and excellent
profile for advanced interdisciplinary research between the
physical sciences and the life sciences
-
TOP-BMI/SB : Curriculum structure (2 year, 120 ECTS credit
points)
Portal course14 ECTS6 obligatory (5 ECTS) courses with each of
the CRbCS professors30 ECTS1 international experts lecture course 6
ECTSorientation on future research project (including literature
thesis)12 ECTSrefereeing of research proposal 3 ECTS8 months
research project in Amsterdam and foreign laboratory40
ECTSscientific article about research project 5 ECTSfollowing and
discussing, reporting on scientific seminars 2 ECTSscientific
conference (co-organizing, participating, reporting) 3
ECTSpreparation for final comprehensive exam 5 ECTS
-
TOP-BMI/SB Obligatory courses:
Portal course: entry course of mathematics and physics for the
biologist and biology for the physics/chemistry/mathematics
bachelorBiomolecular dynamics (Van Grondelle)Single molecule
biophysics and biochemistry (nanobiology) (Schmidt)Chemistry of
complex biomolecules (Van der Vies)Looking at Integrating molecules
(Lill)Intracellular networks (Westerhoff)Integrative bioinformatics
(Heringa)Current topics in biomolecular integration and systems
biology (international lecturers, e.g. Heinrich)
-
TOP-BMI/SBResearch projects: One research exchange project in
two laboratories (partly in Amsterdam and partly in one of the
collaborating International Centers of Excellence), on Biomolecular
Integration / Systems Biology
-
SB teaching to Ph D studentsJoint graduate school with Humboldt
U (Berlin); Heinrich et alNow extended with Goteborgh Yeast Center
(Hohmann et al), EU fundedMany exchange projects alreadyAnnual
joint courses
-
SB teaching/human capital problemsVery difficult field because
of combination top experiments and top theoryLack of appreciation
peer groups (Biologists look down upon physicists and
mathematicians and vv)Lack of society appreciation (insufficient
job opportunities)Insufficient interest young students in
science
-
The WTEC visit to The Netherlands:the program15:30 Systems
Biology in Delft: Wouter van Winden16:30 Lactococcus lactis faster;
a Systems Biology endeavor; Bas Teusink16:40 Teaching Systems
Biology, Hans V. Westerhoff16:50 Drinks 17:05 General discussion
(chair: Roel van Driel): Systems Biology and its future 17:45
Departure for the restaurant (De Molen; Amstelveen) 18:00
Dinner.19:45 Departure for the airport20:00 Check in; KLM; Schiphol
airport21:05 flight to the UK......
11:00am-12:00am Keynote Address IIwww.siliconcell.net: Bringing
Bits and Chips to Life, Hans V. WesterhoffFree University,
Amsterdam, University of Amsterdam and Stellenbosch Institute for
Advanced StudyWith the rapid development of Systems Biology, it is
more and more emphasized that biological function stems more from
the nonlinear interactions between biomolecules than from those
molecules individually. With the completion of more and more genome
sequences it is becoming clear that the number of components is
vast. The new functional genomics data bring home the message that
life operates along many degrees of freedom, i.e. that expression
space is multidimensional. Some of this is bad news, as it
incapacitates the otherwise powerful traditional molecular biology
vis-a-vis the challenge of understanding even the simpler forms of
life, or at least understanding them with the existing methods. On
the other side, mathematical biology, able to deal with complicated
mathematics, has always shied away from true complexity, i.e. from
complexity comprising more than 4 degrees of freedom. Core models
would be used to understand the essence but not necessarily the
reality of biological phenomena.We shall discuss how a new
scientific community is now cutting the Gordian knot and combines
molecular and mathematical biology in an almost trivial way, i.e.
by making precise mathematical models as replica of substantial
parts of living cells. Such computer replica are called silicon
cells, and are collected and hopefully later connected on the
wwweb. They serve to store kinetic data in a dynamic sense, and
only those data matter for functioning living cells. They also
serve to do computer experimentation with living cells, or in
reality with their computer replica. We shall show how these can
serve to discover system behavior of living organisms tdeductively,
i.e. produce discoveries that do not always require experimental
testing.11:00am-12:00am Keynote Address IIwww.siliconcell.net:
Bringing Bits and Chips to Life, Hans V. WesterhoffFree University,
Amsterdam, University of Amsterdam and Stellenbosch Institute for
Advanced StudyWith the rapid development of Systems Biology, it is
more and more emphasized that biological function stems more from
the nonlinear interactions between biomolecules than from those
molecules individually. With the completion of more and more genome
sequences it is becoming clear that the number of components is
vast. The new functional genomics data bring home the message that
life operates along many degrees of freedom, i.e. that expression
space is multidimensional. Some of this is bad news, as it
incapacitates the otherwise powerful traditional molecular biology
vis-a-vis the challenge of understanding even the simpler forms of
life, or at least understanding them with the existing methods. On
the other side, mathematical biology, able to deal with complicated
mathematics, has always shied away from true complexity, i.e. from
complexity comprising more than 4 degrees of freedom. Core models
would be used to understand the essence but not necessarily the
reality of biological phenomena.We shall discuss how a new
scientific community is now cutting the Gordian knot and combines
molecular and mathematical biology in an almost trivial way, i.e.
by making precise mathematical models as replica of substantial
parts of living cells. Such computer replica are called silicon
cells, and are collected and hopefully later connected on the
wwweb. They serve to store kinetic data in a dynamic sense, and
only those data matter for functioning living cells. They also
serve to do computer experimentation with living cells, or in
reality with their computer replica. We shall show how these can
serve to discover system behavior of living organisms tdeductively,
i.e. produce discoveries that do not always require experimental
testing.Abstract: Metabolic signal transduction in space and time.
Facts, figures and principlesHans V. Westerhoff, Barbara M. Bakker,
Nathan Brady, Frank Bruggeman, Joke Blom, Christof Francke, Mark
Peletier, Boris N. Kholodenko, Karin A. Reijenga, and Jacky L.
SnoepCentre for Research on BioComplex Systems, BioCentrum
Amsterdam; Centre for Mathematics and Informatics, Amsterdam;
Stellenbosch Institute for Advanced Study; and Thomas Jefferson
University, PhiladelphiaGallia omnis divisa erat in partes
tres..... and so was cell biology. There was metabolism, there was
gene expression and there was signal transduction. The three parts
were examined as if in isolation from each other. In this era of
system biology, it is recognized that cells function by integrating
processes rather than by keeping them apart, and that processes
function differently when integrating with other processes. In this
presentation we shall discuss three examples where we are beginning
to understand the principles according to which the cellular
dimensions of signal transduction and time are integrated with the
physical dimensions of space and time. We shall also discuss a case
where we have no inkling of how the integration
proceeds.Estimations have suggested that signal transduction in
mammalian cells should be subject to spatial gradients. We examined
this point for the phosphotransferase system (PTS), which is a
hybrid between a signal transduction pathway, a metabolic pathway
and a transport system. Using the experiments based Silicon Cell
(www.silioncell.net) as a tool, we calculated that flux should not,
but signal transduction could well, be compromised in cells much
larger than Escherichia coli. Perhaps this is why mammalian cells
prefer kinase/phosphatase cascades.The control and regulation of
metabolism has not only been a complex but also a confusing issue
for a long time. How could several groups all claim to work on the
rate-limiting step of a metabolic pathway, whilst they worked on
different steps? Metabolic Control Analysis has clarified this
issue, but it is little known that a corresponding analysis method
exists for signal transduction pathways. One might be inclined to
extrapolate from metabolic pathways that also signal transduction
pathways tend to have a total control of 1 distributed over all
steps in the pathway. This then should allow at most 1, but usually
no step to be the rate limiting step. We shall demonstrate the
principle that signal transduction is at the same time devoid of
control and full of (absolute) control. The issue relates to the
relative importance of kinases and phosphatases. The dynamics of
signal transduction have been shown to be highly important, at
least for calcium signaling. We shall derive principles that should
govern the control of dynamics of the EGF response. Yeast cells can
communicate with each other through the metabolic signal
acetaldehyde. This signal appears to specialize in keeping the
individual cells coordinated, rather than in controlling their
oscillations per se. We shall show that a dynamic glucose signal
can address gene expression in yeast such that the metabolic
dynamics of the cells change.What we do not understand is how
mitochondria in isolated cardiomyocytes appear to communicate
energetically in a mitochondrial permeability-transition related
mechanism. Does this betray a subtle spatio-temporal mechanism that
ranges from total recovery through mitoptosis and apoptosis to
necrosis?
Abstract: Metabolic signal transduction in space and time.
Facts, figures and principlesHans V. Westerhoff, Barbara M. Bakker,
Nathan Brady, Frank Bruggeman, Joke Blom, Christof Francke, Mark
Peletier, Boris N. Kholodenko, Karin A. Reijenga, and Jacky L.
SnoepCentre for Research on BioComplex Systems, BioCentrum
Amsterdam; Centre for Mathematics and Informatics, Amsterdam;
Stellenbosch Institute for Advanced Study; and Thomas Jefferson
University, PhiladelphiaGallia omnis divisa erat in partes
tres..... and so was cell biology. There was metabolism, there was
gene expression and there was signal transduction. The three parts
were examined as if in isolation from each other. In this era of
system biology, it is recognized that cells function by integrating
processes rather than by keeping them apart, and that processes
function differently when integrating with other processes. In this
presentation we shall discuss three examples where we are beginning
to understand the principles according to which the cellular
dimensions of signal transduction and time are integrated with the
physical dimensions of space and time. We shall also discuss a case
where we have no inkling of how the integration
proceeds.Estimations have suggested that signal transduction in
mammalian cells should be subject to spatial gradients. We examined
this point for the phosphotransferase system (PTS), which is a
hybrid between a signal transduction pathway, a metabolic pathway
and a transport system. Using the experiments based Silicon Cell
(www.silioncell.net) as a tool, we calculated that flux should not,
but signal transduction could well, be compromised in cells much
larger than Escherichia coli. Perhaps this is why mammalian cells
prefer kinase/phosphatase cascades.The control and regulation of
metabolism has not only been a complex but also a confusing issue
for a long time. How could several groups all claim to work on the
rate-limiting step of a metabolic pathway, whilst they worked on
different steps? Metabolic Control Analysis has clarified this
issue, but it is little known that a corresponding analysis method
exists for signal transduction pathways. One might be inclined to
extrapolate from metabolic pathways that also signal transduction
pathways tend to have a total control of 1 distributed over all
steps in the pathway. This then should allow at most 1, but usually
no step to be the rate limiting step. We shall demonstrate the
principle that signal transduction is at the same time devoid of
control and full of (absolute) control. The issue relates to the
relative importance of kinases and phosphatases. The dynamics of
signal transduction have been shown to be highly important, at
least for calcium signaling. We shall derive principles that should
govern the control of dynamics of the EGF response. Yeast cells can
communicate with each other through the metabolic signal
acetaldehyde. This signal appears to specialize in keeping the
individual cells coordinated, rather than in controlling their
oscillations per se. We shall show that a dynamic glucose signal
can address gene expression in yeast such that the metabolic
dynamics of the cells change.What we do not understand is how
mitochondria in isolated cardiomyocytes appear to communicate
energetically in a mitochondrial permeability-transition related
mechanism. Does this betray a subtle spatio-temporal mechanism that
ranges from total recovery through mitoptosis and apoptosis to
necrosis?
Abstract: Metabolic signal transduction in space and time.
Facts, figures and principlesHans V. Westerhoff, Barbara M. Bakker,
Nathan Brady, Frank Bruggeman, Joke Blom, Christof Francke, Mark
Peletier, Boris N. Kholodenko, Karin A. Reijenga, and Jacky L.
SnoepCentre for Research on BioComplex Systems, BioCentrum
Amsterdam; Centre for Mathematics and Informatics, Amsterdam;
Stellenbosch Institute for Advanced Study; and Thomas Jefferson
University, PhiladelphiaGallia omnis divisa erat in partes
tres..... and so was cell biology. There was metabolism, there was
gene expression and there was signal transduction. The three parts
were examined as if in isolation from each other. In this era of
system biology, it is recognized that cells function by integrating
processes rather than by keeping them apart, and that processes
function differently when integrating with other processes. In this
presentation we shall discuss three examples where we are beginning
to understand the principles according to which the cellular
dimensions of signal transduction and time are integrated with the
physical dimensions of space and time. We shall also discuss a case
where we have no inkling of how the integration
proceeds.Estimations have suggested that signal transduction in
mammalian cells should be subject to spatial gradients. We examined
this point for the phosphotransferase system (PTS), which is a
hybrid between a signal transduction pathway, a metabolic pathway
and a transport system. Using the experiments based Silicon Cell
(www.silioncell.net) as a tool, we calculated that flux should not,
but signal transduction could well, be compromised in cells much
larger than Escherichia coli. Perhaps this is why mammalian cells
prefer kinase/phosphatase cascades.The control and regulation of
metabolism has not only been a complex but also a confusing issue
for a long time. How could several groups all claim to work on the
rate-limiting step of a metabolic pathway, whilst they worked on
different steps? Metabolic Control Analysis has clarified this
issue, but it is little known that a corresponding analysis method
exists for signal transduction pathways. One might be inclined to
extrapolate from metabolic pathways that also signal transduction
pathways tend to have a total control of 1 distributed over all
steps in the pathway. This then should allow at most 1, but usually
no step to be the rate limiting step. We shall demonstrate the
principle that signal transduction is at the same time devoid of
control and full of (absolute) control. The issue relates to the
relative importance of kinases and phosphatases. The dynamics of
signal transduction have been shown to be highly important, at
least for calcium signaling. We shall derive principles that should
govern the control of dynamics of the EGF response. Yeast cells can
communicate with each other through the metabolic signal
acetaldehyde. This signal appears to specialize in keeping the
individual cells coordinated, rather than in controlling their
oscillations per se. We shall show that a dynamic glucose signal
can address gene expression in yeast such that the metabolic
dynamics of the cells change.What we do not understand is how
mitochondria in isolated cardiomyocytes appear to communicate
energetically in a mitochondrial permeability-transition related
mechanism. Does this betray a subtle spatio-temporal mechanism that
ranges from total recovery through mitoptosis and apoptosis to
necrosis?
Abstract: Metabolic signal transduction in space and time.
Facts, figures and principlesHans V. Westerhoff, Barbara M. Bakker,
Nathan Brady, Frank Bruggeman, Joke Blom, Christof Francke, Mark
Peletier, Boris N. Kholodenko, Karin A. Reijenga, and Jacky L.
SnoepCentre for Research on BioComplex Systems, BioCentrum
Amsterdam; Centre for Mathematics and Informatics, Amsterdam;
Stellenbosch Institute for Advanced Study; and Thomas Jefferson
University, PhiladelphiaGallia omnis divisa erat in partes
tres..... and so was cell biology. There was metabolism, there was
gene expression and there was signal transduction. The three parts
were examined as if in isolation from each other. In this era of
system biology, it is recognized that cells function by integrating
processes rather than by keeping them apart, and that processes
function differently when integrating with other processes. In this
presentation we shall discuss three examples where we are beginning
to understand the principles according to which the cellular
dimensions of signal transduction and time are integrated with the
physical dimensions of space and time. We shall also discuss a case
where we have no inkling of how the integration
proceeds.Estimations have suggested that signal transduction in
mammalian cells should be subject to spatial gradients. We examined
this point for the phosphotransferase system (PTS), which is a
hybrid between a signal transduction pathway, a metabolic pathway
and a transport system. Using the experiments based Silicon Cell
(www.silioncell.net) as a tool, we calculated that flux should not,
but signal transduction could well, be compromised in cells much
larger than Escherichia coli. Perhaps this is why mammalian cells
prefer kinase/phosphatase cascades.The control and regulation of
metabolism has not only been a complex but also a confusing issue
for a long time. How could several groups all claim to work on the
rate-limiting step of a metabolic pathway, whilst they worked on
different steps? Metabolic Control Analysis has clarified this
issue, but it is little known that a corresponding analysis method
exists for signal transduction pathways. One might be inclined to
extrapolate from metabolic pathways that also signal transduction
pathways tend to have a total control of 1 distributed over all
steps in the pathway. This then should allow at most 1, but usually
no step to be the rate limiting step. We shall demonstrate the
principle that signal transduction is at the same time devoid of
control and full of (absolute) control. The issue relates to the
relative importance of kinases and phosphatases. The dynamics of
signal transduction have been shown to be highly important, at
least for calcium signaling. We shall derive principles that should
govern the control of dynamics of the EGF response. Yeast cells can
communicate with each other through the metabolic signal
acetaldehyde. This signal appears to specialize in keeping the
individual cells coordinated, rather than in controlling their
oscillations per se. We shall show that a dynamic glucose signal
can address gene expression in yeast such that the metabolic
dynamics of the cells change.What we do not understand is how
mitochondria in isolated cardiomyocytes appear to communicate
energetically in a mitochondrial permeability-transition related
mechanism. Does this betray a subtle spatio-temporal mechanism that
ranges from total recovery through mitoptosis and apoptosis to
necrosis?11:00am-12:00am Keynote Address IIwww.siliconcell.net:
Bringing Bits and Chips to Life, Hans V. WesterhoffFree University,
Amsterdam, University of Amsterdam and Stellenbosch Institute for
Advanced StudyWith the rapid development of Systems Biology, it is
more and more emphasized that biological function stems more from
the nonlinear interactions between biomolecules than from those
molecules individually. With the completion of more and more genome
sequences it is becoming clear that the number of components is
vast. The new functional genomics data bring home the message that
life operates along many degrees of freedom, i.e. that expression
space is multidimensional. Some of this is bad news, as it
incapacitates the otherwise powerful traditional molecular biology
vis-a-vis the challenge of understanding even the simpler forms of
life, or at least understanding them with the existing methods. On
the other side, mathematical biology, able to deal with complicated
mathematics, has always shied away from true complexity, i.e. from
complexity comprising more than 4 degrees of freedom. Core models
would be used to understand the essence but not necessarily the
reality of biological phenomena.We shall discuss how a new
scientific community is now cutting the Gordian knot and combines
molecular and mathematical biology in an almost trivial way, i.e.
by making precise mathematical models as replica of substantial
parts of living cells. Such computer replica are called silicon
cells, and are collected and hopefully later connected on the
wwweb. They serve to store kinetic data in a dynamic sense, and
only those data matter for functioning living cells. They also
serve to do computer experimentation with living cells, or in
reality with their computer replica. We shall show how these can
serve to discover system behavior of living organisms tdeductively,
i.e. produce discoveries that do not always require experimental
testing.11:00am-12:00am Keynote Address IIwww.siliconcell.net:
Bringing Bits and Chips to Life, Hans V. WesterhoffFree University,
Amsterdam, University of Amsterdam and Stellenbosch Institute for
Advanced StudyWith the rapid development of Systems Biology, it is
more and more emphasized that biological function stems more from
the nonlinear interactions between biomolecules than from those
molecules individually. With the completion of more and more genome
sequences it is becoming clear that the number of components is
vast. The new functional genomics data bring home the message that
life operates along many degrees of freedom, i.e. that expression
space is multidimensional. Some of this is bad news, as it
incapacitates the otherwise powerful traditional molecular biology
vis-a-vis the challenge of understanding even the simpler forms of
life, or at least understanding them with the existing methods. On
the other side, mathematical biology, able to deal with complicated
mathematics, has always shied away from true complexity, i.e. from
complexity comprising more than 4 degrees of freedom. Core models
would be used to understand the essence but not necessarily the
reality of biological phenomena.We shall discuss how a new
scientific community is now cutting the Gordian knot and combines
molecular and mathematical biology in an almost trivial way, i.e.
by making precise mathematical models as replica of substantial
parts of living cells. Such computer replica are called silicon
cells, and are collected and hopefully later connected on the
wwweb. They serve to store kinetic data in a dynamic sense, and
only those data matter for functioning living cells. They also
serve to do computer experimentation with living cells, or in
reality with their computer replica. We shall show how these can
serve to discover system behavior of living organisms tdeductively,
i.e. produce discoveries that do not always require experimental
testing.11:00am-12:00am Keynote Address IIwww.siliconcell.net:
Bringing Bits and Chips to Life, Hans V. WesterhoffFree University,
Amsterdam, University of Amsterdam and Stellenbosch Institute for
Advanced StudyWith the rapid development of Systems Biology, it is
more and more emphasized that biological function stems more from
the nonlinear interactions between biomolecules than from those
molecules individually. With the completion of more and more genome
sequences it is becoming clear that the number of components is
vast. The new functional genomics data bring home the message that
life operates along many degrees of freedom, i.e. that expression
space is multidimensional. Some of this is bad news, as it
incapacitates the otherwise powerful traditional molecular biology
vis-a-vis the challenge of understanding even the simpler forms of
life, or at least understanding them with the existing methods. On
the other side, mathematical biology, able to deal with complicated
mathematics, has always shied away from true complexity, i.e. from
complexity comprising more than 4 degrees of freedom. Core models
would be used to understand the essence but not necessarily the
reality of biological phenomena.We shall discuss how a new
scientific community is now cutting the Gordian knot and combines
molecular and mathematical biology in an almost trivial way, i.e.
by making precise mathematical models as replica of substantial
parts of living cells. Such computer replica are called silicon
cells, and are collected and hopefully later connected on the
wwweb. They serve to store kinetic data in a dynamic sense, and
only those data matter for functioning living cells. They also
serve to do computer experimentation with living cells, or in
reality with their computer replica. We shall show how these can
serve to discover system behavior of living organisms tdeductively,
i.e. produce discoveries that do not always require experimental
testing.11:00am-12:00am Keynote Address IIwww.siliconcell.net:
Bringing Bits and Chips to Life, Hans V. WesterhoffFree University,
Amsterdam, University of Amsterdam and Stellenbosch Institute for
Advanced StudyWith the rapid development of Systems Biology, it is
more and more emphasized that biological function stems more from
the nonlinear interactions between biomolecules than from those
molecules individually. With the completion of more and more genome
sequences it is becoming clear that the number of components is
vast. The new functional genomics data bring home the message that
life operates along many degrees of freedom, i.e. that expression
space is multidimensional. Some of this is bad news, as it
incapacitates the otherwise powerful traditional molecular biology
vis-a-vis the challenge of understanding even the simpler forms of
life, or at least understanding them with the existing methods. On
the other side, mathematical biology, able to deal with complicated
mathematics, has always shied away from true complexity, i.e. from
complexity comprising more than 4 degrees of freedom. Core models
would be used to understand the essence but not necessarily the
reality of biological phenomena.We shall discuss how a new
scientific community is now cutting the Gordian knot and combines
molecular and mathematical biology in an almost trivial way, i.e.
by making precise mathematical models as replica of substantial
parts of living cells. Such computer replica are called silicon
cells, and are collected and hopefully later connected on the
wwweb. They serve to store kinetic data in a dynamic sense, and
only those data matter for functioning living cells. They also
serve to do computer experimentation with living cells, or in
reality with their computer replica. We shall show how these can
serve to discover system behavior of living organisms tdeductively,
i.e. produce discoveries that do not always require experimental
testing.11:00am-12:00am Keynote Address IIwww.siliconcell.net:
Bringing Bits and Chips to Life, Hans V. WesterhoffFree University,
Amsterdam, University of Amsterdam and Stellenbosch Institute for
Advanced StudyWith the rapid development of Systems Biology, it is
more and more emphasized that biological function stems more from
the nonlinear interactions between biomolecules than from those
molecules individually. With the completion of more and more genome
sequences it is becoming clear that the number of components is
vast. The new functional genomics data bring home the message that
life operates along many degrees of freedom, i.e. that expression
space is multidimensional. Some of this is bad news, as it
incapacitates the otherwise powerful traditional molecular biology
vis-a-vis the challenge of understanding even the simpler forms of
life, or at least understanding them with the existing methods. On
the other side, mathematical biology, able to deal with complicated
mathematics, has always shied away from true complexity, i.e. from
complexity comprising more than 4 degrees of freedom. Core models
would be used to understand the essence but not necessarily the
reality of biological phenomena.We shall discuss how a new
scientific community is now cutting the Gordian knot and combines
molecular and mathematical biology in an almost trivial way, i.e.
by making precise mathematical models as replica of substantial
parts of living cells. Such computer replica are called silicon
cells, and are collected and hopefully later connected on the
wwweb. They serve to store kinetic data in a dynamic sense, and
only those data matter for functioning living cells. They also
serve to do computer experimentation with living cells, or in
reality with their computer replica. We shall show how these can
serve to discover system behavior of living organisms tdeductively,
i.e. produce discoveries that do not always require experimental
testing.11:00am-12:00am Keynote Address IIwww.siliconcell.net:
Bringing Bits and Chips to Life, Hans V. WesterhoffFree University,
Amsterdam, University of Amsterdam and Stellenbosch Institute for
Advanced StudyWith the rapid development of Systems Biology, it is
more and more emphasized that biological function stems more from
the nonlinear interactions between biomolecules than from those
molecules individually. With the completion of more and more genome
sequences it is becoming clear that the number of components is
vast. The new functional genomics data bring home the message that
life operates along many degrees of freedom, i.e. that expression
space is multidimensional. Some of this is bad news, as it
incapacitates the otherwise powerful traditional molecular biology
vis-a-vis the challenge of understanding even the simpler forms of
life, or at least understanding them with the existing methods. On
the other side, mathematical biology, able to deal with complicated
mathematics, has always shied away from true complexity, i.e. from
complexity comprising more than 4 degrees of freedom. Core models
would be used to understand the essence but not necessarily the
reality of biological phenomena.We shall discuss how a new
scientific community is now cutting the Gordian knot and combines
molecular and mathematical biology in an almost trivial way, i.e.
by making precise mathematical models as replica of substantial
parts of living cells. Such computer replica are called silicon
cells, and are collected and hopefully later connected on the
wwweb. They serve to store kinetic data in a dynamic sense, and
only those data matter for functioning living cells. They also
serve to do computer experimentation with living cells, or in
reality with their computer replica. We shall show how these can
serve to discover system behavior of living organisms tdeductively,
i.e. produce discoveries that do not always require experimental
testing.11:00am-12:00am Keynote Address IIwww.siliconcell.net:
Bringing Bits and Chips to Life, Hans V. WesterhoffFree University,
Amsterdam, University of Amsterdam and Stellenbosch Institute for
Advanced StudyWith the rapid development of Systems Biology, it is
more and more emphasized that biological function stems more from
the nonlinear interactions between biomolecules than from those
molecules individually. With the completion of more and more genome
sequences it is becoming clear that the number of components is
vast. The new functional genomics data bring home the message that
life operates along many degrees of freedom, i.e. that expression
space is multidimensional. Some of this is bad news, as it
incapacitates the otherwise powerful traditional molecular biology
vis-a-vis the challenge of understanding even the simpler forms of
life, or at least understanding them with the existing methods. On
the other side, mathematical biology, able to deal with complicated
mathematics, has always shied away from true complexity, i.e. from
complexity comprising more than 4 degrees of freedom. Core models
would be used to understand the essence but not necessarily the
reality of biological phenomena.We shall discuss how a new
scientific community is now cutting the Gordian knot and combines
molecular and mathematical biology in an almost trivial way, i.e.
by making precise mathematical models as replica of substantial
parts of living cells. Such computer replica are called silicon
cells, and are collected and hopefully later connected on the
wwweb. They serve to store kinetic data in a dynamic sense, and
only those data matter for functioning living cells. They also
serve to do computer experimentation with living cells, or in
reality with their computer replica. We shall show how these can
serve to discover system behavior of living organisms tdeductively,
i.e. produce discoveries that do not always require experimental
testing.