Title: Synthetic Biology The Cell as a Nanosystem
1Synthetic Biology(The Cell as a Nanosystem)
- ARC Bioinformatics
- UC Davis Summer 2006
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3Synthetic Biology
- Nanotechnology is emulating biology
- Molecular assemblers, molecular sensors
- Bots that deliver medicine to specific cells
- Biotechnology is helping out
- Genetic reengineering of e-coli, phages
- Nano-Bio or Bio-Nano?
- Two very interesting approaches
- The answer might be synthetic biology
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5DNA 2.0
- DNA 2.0 Inc. is a leading provider for synthetic
biology. With our gene synthesis process you can
get synthetic DNA that conforms exactly to your
needs, quickly and cost effectively. Applications
of custom gene synthesis include codon
optimization for increased protein expression,
synthetic biology, gene variants, RNAi
trans-complementation and much more.
6Nano-Bio-Info-Tech (NBIT)
- Fusion or convergence of
- Nanotechnology
- Biotechnology
- Information technology
- Focus of regional development
- Nanobiotechnology (DNA microarrays)
- Bioinformatics and Informatics
- Add stem cell and genetic engineering
7Some Definitions
- Bionanotechnology
- Biology as seen through the eyes of nano
- How do molecules work in biology?
- How can we make biology work for us?
- Applications
- Self assembled protein metal complexes
- DNA scaffolding for arrayed assembly
- Phage injection of targeted viral DNA
8Bio-Nano Convergence
9Bio-Nano Machinery
- Using protein / viral complexes and DNA to
self-assemble devices, and novel function, into
biomechanical systems
Earths early nanostructures 2 billion years ago
10NanoBioConvergence
- Nanotechnology used in biotech
- DNA microarrays (GeneChip)
- SNP genotyping applications
- Silicon microtechnology for the lab
- Lab-On-A-Chip (LOC)
- System-On-A-Chip
- Biocompatible engineered surfaces
- Better performance / durability in humans
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12Affymetrix GeneChip
13Natures Toolkit
- Self Assembly
- Viral caspids
- Proteins
- Genetic Algorithms
- Information networks
- DNA gt miRNA gt mRNA gt Protein
- Protein gt miRNA DNA (intron) / DNA (exon)
- Energy networks (proteome / metabolome)
14Molecular Self Assembly
15Viral Self-Assembly
http//www.virology.net/Big_Virology/BVunassignpla
nt.html
16Self-Assembled Algorithms
17Bio-Nano-Info
- Looking at bio through the eyes of nano
- Physical properties of small / life systems
- Looking at nano through the eyes of bio
- Self-assembly of molecular nano structures
- Interaction of information and molecules
- Molecular assemblies as information and operating
systems - nano execution of IT
18Nano-Bio-Info-Tech
Nano
Quantum computing nanoelectronic devices
Self assembly Microarrays, BioMEMS
Bio
Info
Digital cells DNA computing insilico biology
Concept by Robert Cormia
19Bio-Informatics
- Looking at life as an information system
- DNA as a database
- RNA as a decision network
- Proteins and genes as runtime DLLs
- Modeling gene regulatory networks
- Simulating life as a computer program
- Using silicon to validate biological models
20Goal of Digital Cells
- Simulate a Gene Regulatory Network
- Goal of e-cell, CellML, and SBML projects
- Test microarray data for biological model
- Run expression data through GRN functions
- Create biological cells with new functions
- Splice in promoters to control expression
- Create oscillating networks using operons
21Digital Cell Components
- Bio-logic gates
- Inverters, oscillators
- Creating genomic circuitry
- Promoters, operons and genes
- Multigenic oscillating solutions
- Ron Weiss is the pioneer in the field
- http//www.princeton.edu/rweiss/
22Digital Cell Basics
http//www.ee.princeton.edu/people/Weiss.php
23Digital Cell Circuit (1)
INVERSE LOGIC. A digital inverter that consists
of a gene encoding the instructions for protein B
and containing a region (P) to which protein A
binds. When A is absent (left)a situation
representing the input bit 0the gene is active.
and B is formedcorresponding to an output bit 1.
When A is produced (right)making the input bit
1it binds to P and blocks the action of the
genepreventing B from being formed and making
the output bit 0. Weiss http//www.ee.princeton.ed
u/people/Weiss.php
24Digital Cell Circuit (2)
In this biological AND gate, the input proteins X
and Y bind to and deactivate different copies of
the gene that encodes protein R. This protein, in
turn, deactivates the gene for protein Z, the
output protein. If X and Y are both present,
making both input bits 1, then R is not built but
Z is, making the output bit 1. In the absence of
X or Y or both, at least one of the genes on the
left actively builds R, which goes on to block
the construction of Z, making the output bit 0.
Weiss http//www.ee.princeton.edu/people/Weiss.php
25Digital Cells Bio Informatics
Modeling life as an information system
http//www.ee.princeton.edu/people/Weiss.php
26Gene Regulatory Network
27Basic GRN Circuit Flow
Gross anatomy of a minimal gene regulatory
network (GRN) embedded in a regulatory network. A
regulatory network can be viewed as a cellular
input-output device. http//doegenomestolife.org/
28Gene regulatory networks interface with
cellular processes
http//doegenomestolife.org/
29Information vs. Processing
Just as in a computer, data bits and processing
bits are made from the same material, 0 or 1, or
A, T, C, G, or U in biology
30Nature as a Computer
- Biological systems like DNA and RNA especially
appear to be more than networks of information. - RNA itself can be seen as a molecular decision
network
31E-Cell
- E-Cell System is an object-oriented software
suite for modeling, simulation, and analysis of
large scale complex systems such as biological
cells. Version 3 allows many components driven by
multiple algorithms with different timescales to
coexist
32Computer Modeling Metabolic Pathways
- BioCyc collection of organism specific
metabolic pathway databases - cellML is an XML based format for exchanging
biological data from genes to proteins to
metabolism
33Digital Cells MeetSynthetic Biology
- Model the circuit
- Validate the circuit
- Tinker with the circuit
- Then
- Alter the gene to build a new protein
- SNPs will give you a first approach
- See if the new protein is well tolerated
34Gene Therapy
- Gene therapy using an Adenovirus vector. A new
gene is inserted into an adenovirus vector, which
is used to introduce the modified DNA into a
human cell. If the treatment is successful, the
new gene will make a functional protein.
http//en.wikipedia.org/wiki/Gene_therapy
35DNA Vaccines
- The ultimate method to train the immune system
against a multitude of threats - Inject a known sequence of DNA
- Trick the cell into expressing it, then seeing it
as an antigen to ward against. - Used to fight cancer.
36Animal Model Systems
- Mice make perfect models as they are
- Cheap (reasonably)
- Fast / easy growing
- Very inbred
- Mouse DNA arrays and the mouse genome are fairly
well known, characterized
37Stem Cell Technology
- Once you have an altered genome ready to test
beyond a simple one cell environment, you
leverage the ability of stem cells to mass
produce your synthetic biology solution
38Cell as a Nanosystem
- Bilayer outer lipid membrane
- Energy apparatus
- Diffuse metabolome
- Proteome with signaling network
- DNA / RNA operating system, nucleosome miRNA
control units
39Green Algae at Work Making H2
Algal cell suspension / cells
Thylakoid membrane ?
These little critters are very happy just to be
working!
40Proposed Engineered H2 Bacterium
http//gcep.stanford.edu/pdfs/tr_hydrogen_prod_uti
lization.pdf
41In Vitro Photo-Production of H2
Yellow arrow marks insertion of hydrogenase
promoter. Right side data cell optimized for
continuous H2 production.
42Synthetic Biology Roadmap
- Understanding of gene elements and
transcriptional control at miRNA level - Ability to model protein structure, and surface
potential / folding / function - Ability to create functional operons and
regulated / feedback transcriptional control - Stem cell and gene therapy synergism
43Role of Bioinformatics
- Where are genes?
- What are the regulatory inputs?
- What are the proteins?
- Where are post translational modifications?
- What are the pathways?
- What are the protein RNA interactions?
- Can we modulate the operon networks to include
precision feedback control?
44Global Gene Expression
Gene expression tells you how the machine is
working Bioinformatics shows you where the
control points are
45Reprogramming the Cell
- The cell is a molecular system where all parts
also participate in an information system. - We model that system, and then attempt to alter
the internal influences to create different
functional outputs.
46Synthetic Proteins
All proteins are synthetic peptides gt
polymers
47Synthetic Proteins
- Synthesis
- New polymers
- Biochemistry
- Structural studies
- Structure / function
- Functional studies
- New properties
- New applications
- Cell structure adapts well to environments
48Nature as a NanoToolbox
http//www.cse.ucsc.edu/hongwang/ATP_synthase.htm
l
49Summary
- Nano-Bio-Info Technology
- Builds on nanotech and biotech
- Adds information tech to model systems
- Synthetic biology
- Building informatics into modified genomes
- Integrating biology and nanotechnology, working
with life as an information system - Stem cell work will be the next frontier
- Bringing innovation to life in higher organisms
50References
- http//www.ee.princeton.edu/people/Weiss.php
- http//www.dbi.udel.edu/
- http//biospice.lbl.gov/
- http//www.systems-biology.org/
- http//www.e-cell.org/
- http//sbml.org/
- http//biocyc.org/
- http//www.sbi.uni-rostock.de/teaching/research/
- http//www.ipt.arc.nasa.gov/