Frequency and Amplitude Response for Frequency and Amplitude Response for Model Reconstruction in Systems BiologyModel Reconstruction in Systems Biology

Will Zimmerman

Leader

Biophysicochemical Hydrodynamics Research Team

Reader in Chemical and Process Engineering

University of Sheffield

OutlineOutline

Who are we?__________________________________________ What do we do?

Helical micromixing and reactionTransport-limited heterogeneous catalysisInterfacial dynamics and transportMetabolic pathways modelling and engineering

__________________________________________ Four current projects on biotechnology

Development of a microfluidics shotgun for proteomics (PCW+)Metabolic / statistical modelling for energy from biomass (PCW)Optimizing grain processing for bioproduction (UMIST+PCW)Kidney modelling / remodelling (RS, Sheffield Kidney Institute)

__________________________________________

BPCH teamBPCH team 4 PDRAs

– Dr W Zimmerman, ARF: helical mixing and reaction (microfluidics)– Prof Vaclav Tesar, Colloidal electricity generator / swirl burners– Dr B Hewakandamby, Acoustic tomography / swirl burners– Dr L Jeanmeure, Metabolic pathways modelling / inverse problems

6 PhD (+ 4 MSc + 1 intern)– D Hassell, Helical micromixing/microfluidics– K Deshpande, Mass transfer limited liquid-liquid reaction engineering– J Lozano-Parada, Microchannel plasma reactors– D Garner, Metabolic pathways modelling – J Mohal, Neural network modelling of speech and behaviour– G Regunath, Control by helical dynamics of swirl burners

Internal collaborations (PFG, PPG, CIG, BESG, App Maths, HCS) Alex Routh (latex films/complex fluids), Julia Rees (solitary waves and acoustic

rheometry), Jordan MacInnes/Ray Allen (microfluidics), Nigel Russell (combustion), Phil Wright (metabolic engineering, protein separation), Patty Cowell (speech and behaviour), Rile Ristic (protein crystalliser).

External (TC Dublin, Neuchatel, Madrid, Dunkirk, Kharkov, UMIST)

Transport-Limited Heterogeneous Transport-Limited Heterogeneous ChemistryChemistry

New universal theory for treating heterogeneous reaction based on a dynamical systems approach. A generalization of the Thiele modulus concept that applies to different contacting patterns, unit operations, multiple components and multiple reaction networks.

Predictions of optimum batch time and reactor length, controlled by turbulence structure or physicochemical mobilities.

Applications:– microfluidic shotgun for protein separations (EPSRC £1.3m)– microfluidic foam protein separator (EU €1.8m NEST shortlist)– cell free protein synthesis (Basic Technology bid ~£2.5m)

Metabolic Pathways Metabolic Pathways Modelling/Engineering (with PCW)Modelling/Engineering (with PCW)

Dynamical systems approach with computational inverse techniques

Hydrogen production with cyanobacteria. 1Post-doc + 1PhD student.– Using a battery of monitoring systems under oscillatory light

conditions to infer internal metabolic fluxes leading to a kinetics model.

– Recombinant DNA technology to optimize hydrogen production

Epitheliome project led by Rod Smallwood (£1m awarded). Renal Medicine of the Northern General (Prof M El-Nahas)

kidney pathologies that are cancer-like --polycystic kidney disease, fibroblast tissue scarring, aberrent cell differentiaion.

Kinetics modelsKinetics models

Glycolytic pathway in yeast (Pritchard & Kell, 2002)

535

54 55 54 55 56 52

53

52

57 5 58 5

54 55 59 60 55 54 55

58

55 59 60 54 55 61

13 12

73

5

2, , 1

, , 1

kn NAD AcAld NADH PYRk k k k k k

kPYRk

k n k AcAld n NADNADk k k k k k k

k AcAld NAD n AcAld NAD NADHk k k k k k k

v vAcAld k AcAld

f AcAld NAD NADH

f AcAld NAD NADH

57 5 5

59 54 55 59 59 60 59 60 62

k n NADH n AcAld NADHAcAld NADHk k k k k k k k

• 17 Equation kinetics model for 17 metabolites and co-metabolites• 87 kinetics parameters including fourteen sets of Michaelis-Menten flux laws

;d

dtcN c k;μ

SMBL transient modelSMBL transient model

Oscillatory input fluctuationsOscillatory input fluctuations

Glucose“boundary condition”

Fourier analysisFourier analysisAcetalaldehyde time series and power spectrum

Stability analysisStability analysis

EigenvectorsEigenvectors

Parameter estimation (inversion)Parameter estimation (inversion)

ConclusionsConclusions