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Vítor Martins dos Santos
Division of MicrobiologyNational Centre for Biotechnology Research (GBF), Germany
NEST Pathfinder project on Synthetic Biology
PROBACTYS:
Programmable Bacterial Catalysts
Research Organizations in Germany
Universities
Helmholtz-Association (HGF)
Max-Planck-Society (MPG)
Leibniz Association (WGL)
Fraunhofer-Society (FhG)
15 Research Centers25.000 Employees
600 Employees
200 Scientists
100 PhD students Yearly Budget: 40 Mill. € (plus 15 Mill. € External)
6 Divisions
The GBF
GBF Long-term Objectives and Goals
• Understand basic mechanisms of infection and immunity
• Develop new vaccines, anti-infectives and immunotherapies
How do we specifically capitalise on this wealth of
knowledge and how do we translate it into relevant
biotechnological & biomedical applications?
Engineering challenge:
Exponetial increase in
genome sequencing
and post-genomic research
Understanding Biology by Reverse Engineering Control: Aircraft Analogy
Sensor
Controller
Feed-Forward
Actuators
ElevatorAileronThrottle
Desired Altitude Aircraft Altitude
Functional Parts Plant
In biological systems, modular control features are hardly known.
Time
Infla
m. C
ytok
ines
healthy
variable disease states
variable response to treatment
E.g. Virtual experiment:
The experimental observation is that M. tubercolosis activates the glyoxylateshunt upon infection to switch to lipid metabolism
SPE IVIG
C OO-
Benzoa te 1-carboxy-1,2-cis-dihydroxy-cyclohexa-3,5 -diene
C OO-
OHOH
NA DH 2 NA D
O2+
Benzoate 1,2-dioxygenase
(CDCD)
- difficult to synthesize chemically
- precursor for many industrially relevant enantiopure derivatives
Example: Targeted Development of Biotransformation Processes
Attractive alternative: cofactor dependent biotransformation
Metabolic engineering
But, this reaction is part of a complex metabolic network and is under control of various interconnected regulatory loops
In biological systems, these modular control features are hardly known
and blueprints are basically nonexistent
Interplay circuits of interest and genome:
E4P
X5PGLC
G6P
F6P
FDP
T3P2
3PG
13PDG
T3P1
2PG
PEP
PYR
AcCoA
SuccCoA
SUCC
AKG
ICIT
CIT
FUM
MAL
OA
RL5P
R5P
S7P
D6PGL D6PGC
ACTP
ATP
NADPHNADH FADH
Qh2+
H
pgi1
fba
tpiAgapA
pgk
gpmA
eno
pykAppsAaceE
zwfpgl gnd
rpiA
talBtktA1tktA2
gltA
acnA icdA
sucA
sucCmdh
AC
purT1
pta
ppc
cyoA
pnt1A
sdhA2nuoA
atpA
O2
acspoxB
aceA
eda
2KD6PGedd
maeB
oad
sdhA1fumA
CO2
Pirpe
pckA
glk1
fbp
glcB
AMPATP
2 ADP
adk1
pflA
: unique to PAO1
: unique to KT2440
proteins
Xyl XYZLTEGFJQKIH
XylS
a
XylS
i
70
XylS
h
Xyl UWCMABN
PU
IHF
Pm
S
Ps1
54
HU
XylRa
xylene
Pr
XylRi
3MB
Genetic circuit
Logic circuit
Inputs Outputs P
r
NORAND OR
Aim is to have a bacterial
blueprint that allows precise
engineering
To construct a functioning, streamlined bacterial cell devoid of part (ideally
most) of its genome and endowed with a series of highly coordinated, newly
assembled genetic circuits for the biotransformation of a range of
chloroaromatics into high added value compounds that would include circuits for
synchronized behaviour, noise minimisation, low-temperature biocatalysis,
among others.
By achieving such constructs as a proof-of-principle, it aims at establishing
a solid, rational framework for the engineering of cells that can effectively
and efficiently perform specific functions of biotechnological,
environmental or medical interest
EU-NEST funded project:
PROBACTYS: Programmable Bacterial Catalysts
Our Goal is:
The global work strategy
1) Establishment, standardization and inventory of computational
and experimental strategies and platform;
2) Genome minimization (random ; directed),automation
3) Engineering the different genetic circuits of choice
(Biotransformation parts list etc.);
5) Assessment of the interplay of constructed circuits with the
template genome, intensive computational biology
6) Use of the model framework and constructed cells for the
production of high-added value products from halogenated
aromatics.
1% human genome
Rice genome
Chicken genome
Pig genome
Silk worm genome & various other
6th largest genome sequecing centre in the world
Many Prizes including Nikkei Asia Prize for Science in 2003
Dawning 4000, 3000...
Beijing Genomics Institutec & James Watson Hangzhou Genomics Institute of the Chinese Academy of Sciences
Setting up Strategic Collaborations with Beijing Genomics Institute and James Watson Hangzhou Genomics Institute of the Chinese Academy of Sciences
Collaborative activities with the BGI
Current and past:
BGI full partner in STREP project on Synthetic Biology (NEST-Pathfinder)
BGI full Partner in STREP project proposal in NEST ADVENTURE
Visit to the BJI Beijing & Hangzhou January 2006:
•Meeting with EU Minister Councellor for Research in Beijing•Meeting at Sino-German Science Foundation
Bilateral agreements, preparative collaborative work undergoing on Computational, Automation and Sequencing aspects
Planned:
Sino-German Workshop on Synthetic Biology in Hangzhou, October 2006Broader and more intensive joint work on these subjects beyond PROBACTYSExploration of joint funding possibilities for clearly defined projects (DFG, DAAD, Chinese Ministries??)