Programming Computers

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Programming Computers Cells, Computer-Aided
Design (CAD)
Harris WangBiophysics 101Sept 15, 2009
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How are cells computers similar?

• programmable
• computation
• modular components? (maybe)

How are cells computers different?

• spatial freedom/mobility
• information relay
• self-correcting hardware
• evolvable

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Cell as a Computing Machine
DNA/mRNA ? Executable programs (in
long-term/short-term memory) Polymerase/Ribosome ?
Processor Signaling molecules ?
Transistors Sensor molecules ? Input
interface Reporter molecules ? Output interface
function make_green() print green
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Complex Biological Networks
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Complexity of Metabolism
Central Components http//www.genome.jp/kegg/
Modular Components
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Digital computers vs. Organic Life
tools, tools, tools!
cheap rapid prototyping industry
standardization modularity of components scalable
manufacturing automation
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Synthetic Biology Bioenergy
SYNTHETIC
BIOLOGY
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in silico Modeling and Predictions

• OptKnock (B. Palsson, C. Maranas)
• Linear programming bilevel optimization
• Flux-balance analysis

SimPheny (Genomatica Inc. )
Pharkya, Biotech Bioeng, 2003

• RBS calculator (H. Salis)
• protein translation level

• Mfold (M. Zucker)
• DNA/RNA folding

http//mfold.bioinfo.rpi.edu/
http//voigtlab.ucsf.edu/software/
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DNA Sequencing Technologies
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DNA Gene Synthesis
6.4K per 10bp ? 500 per 15Mbp
Agilent 244K feature Ink-jet
oligo synthesizer
Febit photolabile
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Next Generation Cellular Programming
27 E.coli genomic changes in 7 yrs 400M RD
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Multiplex Automated Genome Engineering (MAGE)

• Screen or selection to isolate desired mutants

fast efficient automatable high-throughput
Wang HH, Nature 2009
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Biological Parts Wet-Ware
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Tools to Engineering Biology
Computation/Simulation Tools
Tinkercell (UW)
SynBioSS (Minn)
BioJADE (UCB)
Viz-a-Brick (Davidson-Missouri Western)
Clotho (UCB/JBEI)
BioMortar (Waterloo)
Gene Designer (DNA 2.0)
BB Studio (Stanford)
APE (Utah)
BioStudio (Johns Hopkins)
BrickIt (Grunberg)
Parts Registry (MIT)
GenoCAD (VTech)
Design/Analysis Tools
Data Management Tools
More info http//clothocad.sourceforge.net/wiki/i
ndex.php/RelatedWorkOverview
Courtesy of Doug Densmore, UCB
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Data Management - BrickIt
Pros Easy to set up, extend, distribute
Portable web based registry Download and use!
Cons BioBrick centric
Based on PoBoL
Database-backed Django web server (python)
Created by Raik Grunberg
Filters/Search
Name
Nickname
Status
Type
Cells
DNA
http//brickit.wiki.sourceforge.net/
Courtesy of Doug Densmore, UCB
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Data Management Viz-a-Brick
Pros Web based, very visual
Cons Reliant on MIT API
Created by Max Win at Davidson University
Visual browsing of the MIT parts registry
Connections based on subparts and super-part
relations
Ranking system
Offline support by storing data locally Google
gears
http//gcat.davidson.edu/VizABrick/
Courtesy of Doug Densmore, UCB
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Design Gene Designer
Pros Free, multiple views, codon optimization
Cons No database support, removed from larger
community efforts
Created by DNA 2.0 in Menlo Park
Two views Sequence view DNA sequence and
codons Icon view Icons associated with
sequence info
Local connectivity only
https//www.dna20.com/tools.php
Courtesy of Doug Densmore, UCB
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Analysis - GenoCAD
Cons abstract structural constructs, rules limit
expressiveness, rigid lexer
Pros Formal, well defined, extensible
Developed at Virginia Tech
Organizes parts into 4 categories with 26 total
variable assignments (e.g terminator, RBS, start
codon)
Defines production rules to generate various
constructs
S SOS S AMG S HNB S PMR

• Uses
• Create generic constructs (GUI driven)
• 2. Verify sequences by parsing (rules have
  precedence, successive rule application)

S- start, A- promoter, M transcript,
G-terminator, H-terminator rev, N- transcript
rev, B promoter rev, P-T7 promoter, R T7
terminator
http//www.genocad.org/genocad/
Courtesy of Doug Densmore, UCB
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Simulation - Tinkercell
Cons Unclear how useful simulations are at this
point
Pros Customizable (parts and simulation),
complete environment, part of community efforts
Developed at UW by Deepak Chandran
Build models in a visual manner and analyze them
with custom C/python code
http//www.tinkercell.com/
Courtesy of Doug Densmore, UCB
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Clotho Data Management/Design
Clotho Parts Manager
Clotho Sequence View
Clotho Binding Manager
Clotho Algorithm Manager
Spectacles
Clotho Plate Manager
Kepler
Pros PlugIn Based Tools, Flexible Data
Retrieval, Automatic Assembly, Part/Device Design
Eugene
Cons Still in development, requires data source
and internet connection, most powerful with
Part/Device methodology
http//www.clothocad.org
Courtesy of Doug Densmore, UCB
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Databases of Biological Information

• GenBank http//www.ncbi.nlm.nih.gov/sites/gquery
• BioCyc http//www.biocyc.org/
• Human Genetics
• dbSNP
• http//www.ncbi.nlm.nih.gov/SNP/National Center
  for Biotechnology Information (NCBI) short
  nucleotide substitution, deletion, and insertion
  polymorphisms. 
• OMIM, Online Mendelian Inheritance in
  Manhttp//www.ncbi.nlm.nih.gov/sites/entrez?dbOM
  IMCurated catalog of human genes and genetic
  disorders. 18,000 entries in prose. Mutations and
  phenotypes textually described.
• SNPediahttp//www.snpedia.comWikipedia-style
  uncurated, describe functional consequences of
  SNPs. 
• HGMD, Human Gene Mutation Databasehttp//www.hgm
  d.cf.ac.uk/ac/index.phpCollates published gene
  mutations and variations thought to be
  responsible for human inherited disease. 73411
  total mutation entries in gt2000 genes.

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Databases of Biological Information

• GenBank http//www.ncbi.nlm.nih.gov/sites/gquery

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Databases of Biological Information

• BioCyc http//www.biocyc.org/
• 500 pathway/genome databases

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Personal Genomics (public)

• PGP http//www.personalgenomes.org

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Personal Genomics (private)

• Navigeneics http//www.navigenics.com

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Personal Genomics (private)

• 23andme http//www.23andme.com

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Personal Genomics (private)

• Knome http//www.knome.com/