physics of information technology mit – spring 2006 part ii avogadro scale engineering...
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Physics of Information Technology MIT – Spring 2006
PART II
Avogadro Scale Engineering‘COMPLEXITY’
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Homework• I] Nanotech Design:
Find an error function for which it is optimal to divide a logic area A into more than one redundant sub-Areas.
• II] Design Life: (a) Design a biological system which self replicates with
error correction (either genome copy redundancy with majority voting or error correcting coding). Assume the copying of each nucleotide is consumptive of one unit of energy. Show the tradeoff between energy consumption and copy fidelity.
(b) Comment on the choice biology has taken (64 -3 nucleotide) codons coding for 20 amino acids. Why has biology chosen this encoding? What metric does it optimize? Could one build a biological system with 256 – 4 bit codons?
Questions: [email protected]
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Area = A
Area = 2*A/2
Probability of correct functionality = p[A] ~ e A (small A)
Scaling Properties of Redundant Logic (to first order)
P1 = p[A] = e A
P
A
P2 = 2p[A/2](1-p[A/2])+p[A/2]2
= eA –(eA)2/4
Conclusion: P1 > P2
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Designing Life
Redundancy
Fault Tolerant
Error CorrectingOther Coding (e.g. Parity)
Fault Tolerant
Error Correcting
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Designing Life
Gene1 Gene2 Gene3 Gene1 Gene2 Gene3
I] Fault Tolerant Redundancy
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http://www.biochem.ucl.ac.uk/bsm/xtal/teach/repl/klenow.html
1. Beese et al. (1993), Science, 260, 352-355.
Replicate Linearly with Proofreading and Error Correction
Fold to 3D Functionality
template dependant 5'-3' primer extension
5'-3' error-correcting exonuclease
3'-5' proofreading exonuclease
Error Rate:1: 106
100 Steps per second
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MutS Repair System
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http://www.ornl.gov/hgmis/publicat/microbial/image3.html
[Nature Biotechnology 18, 85-90 (January 2000)]
Uniformed Services University of the Health
Deinococcus radiodurans (3.2 Mb, 4-10 Copies of Genome )
D. radiodurans: 1.7 Million Rads (17kGy) – 200 DS breaksE. coli: 25 Thousand Rads – 2 or 3 DS breaks
Approach 1b] Redundant Genomes
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Basic Idea:
M strands of N Bases
Result: By carrying out a consensus vote one requires only
To replicate with error below some epsilon such that the global replication error is:
EP
NM ln
Combining Error Correcting Polymerase and Error Correcting Codes One Can Replicate a
Genome of Arbitrary Complexity
M
N
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100 200 300 400 500
10
15
20
25
30
M (
# of
Cop
ies
o f G
enom
e)
N (Genome Length)
EPM
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Ribosome
mRNA
Amino Acid
II] Coding
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4 Base Parity Genetic CodeLet A=0, U,T=1, G=2, C=3 Use 3+1 base codeXYZ Sum(X+Y+Z, mod 4)
Leu: UUA -> UUAG
http://schultz.scripps.edu/Research/UnnaturalAAIncorporation/research.html
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Fault Tolerant Translation Codes (Hecht):NTN encodes 5 different nonpolar residues (Met, Leu, Ile, Val and Phe)NAN encodes 6 different polar residues (Lys, His, Glu, Gln, Asp and Asn)
Local Error Correction:Ribozyme: 1:103
Error Correcting Polymerase: 1:108 fidelity
DNA Repair Systems:MutS System
Recombination - retrieval - post replication repair Thymine Dimer bypass.Many others…
Error Correction in Biological Systems
E. Coli Retrieval system - Lewin
Biology Employs Error Correcting Fabrication + Error Correcting Codes
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Physics of Information Technology MIT – Spring 2006
4/101] Von Neumann / McCullough/Winograd/Cowan Threshold Theorem and Fault Tolerant Chips2] Simple Proofs in CMOS Scaling and Fault Tolerance3] Fault Tolerant Self Replicating Systems4] Fault Tolerant Codes in Biology
4/241]Introduction of the concept of Fabricational Complexity2]Examples, numbers and mechanisms from native biology: error correcting polymerase and comparison to best current chemical synthesis using protection group (~feedforward) chemistry.3]Examples from our error correcting de novo DNA synthesis (with hopefully a demo from our DNA synth simulator)4]Error correcting chip synthesis5]Saul's self replicating system with and without error correction
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Fabricational Complexity
Ffab = ln (W) / [ a3 fab Efab ]
Ffab = ln (M)-1 / [ a3 fab Efab ]
•Total Complexity•Complexity Per Unit Volume•Complexity Per Unit Time*Energy•Complexity Per unit Cost
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Fabricational Complexity
n
n
nFAB mpF ln
1
200 400 600 800 1000
10
20
30
40
50
60
70
A
A G
G T C
A T A C G T …
A G T A G C …
p2p3p
Total Complexity Accessible to a Fabrication Process withError p per step and m types of parts:
Complexity Per Unit Cost:For given complexity n*:
Cmpf nFAB /ln
*
Where C is cost per step
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Cmpf nFAB /ln
*
Fabricational Complexity
Non Error Correcting:
Triply Error Correcting:
Cmpppfn
FAB 3/ln)1(3*332
3
A G T C
A G T C
A G T C
A G T C
50 100 150 200 250 300
20
40
60
80
100
120
140
P = 0.9
n
FAB
FAB
f
f 3
p
0.86 0.88 0.92 0.94 0.96 0.98
500
1000
1500
2000
2500
3000
n = 300
50 100 150 200
0.05
0.1
0.15
0.2
0.25
0.3
FAB
FAB
f
f 3
n
P = 0.85
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1] Quantum Phase Space 2] Error Correcting Fabrication 3] Fault Tolerant Hardware Architectures 4] Fault Tolerant Software or Codes
Resources which increase the complexity of a system exponentially with a linear addition of
resources
Resources for Exponential Scaling
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…Can we use this map as a guide towards future
directions in fabrication?
Genome (Natural)
Gene Chip (Chemical Parallel Synthesis)
Semi-conductor Chip
High Speed Offset Web TFT DVD-6
Liquid Embossing
Design Rule Smallest Dimension (microns) 0.0003 0.0003 0.1 10 2 0.25 0.2Number of Types of Elements 4 4 8 6 8 2 4Area of SOA Artifact (Sq. Microns) NA 7.E+08 7.E+10 2.E+12 1.E+12 1.E+10 8.E+09Volume of SOA Artifact (Cubic Microns) 6.E+01 5.E+06 7.E+09 2.E+12 1.E+11 7.E+12 8.E+08Number of Elements in SOA Artifact 3.E+09 7.E+04 7.E+12 2.E+10 3.E+11 2.E+11 2.E+11Volume Per Element(Cubic Microns) 2.E-08 8.E+01 1.E-03 1.E+02 4.E-01 4.E+01 4.E-03Fabrication Time(seconds) 4.E+03 2.E+04 9.E+04 1.E-01 7.E+02 3 6.E+01Time Per Element (Seconds) 1.E-06 3.E+02 1.E-08 7.E-12 2.E-09 2.E-11 3.E-10Fabrication Cost for SOA Artifact($) 1.E-07 1.E+02 1.E+02 1.E-01 2.E+03 3.E-02 2.E-01Cost Per Element 3.E-17 2.E-03 2.E-11 6.E-12 6.E-09 2.E-13 1.E-12Complexity 4.E+09 9.E+04 2.E+13 4.E+10 6.E+11 1.E+11 3.E+11Complexity Per Unit Volume of SOA(um 3̂) 7.E+07 2.E-02 2.E+03 2.E-02 5.E+00 2.E-02 3.E+02Complexity Per Unit Time 1.E+06 6.E+00 2.E+08 3.E+11 9.E+08 4.E+10 5.E+09Complexity Per Unit Cost 4.E+16 9.E+02 1.E+11 3.E+11 3.E+08 4.E+12 1.E+12Cost Per Area NA 2.E-07 2.E-09 6.E-14 2.E-09 3.E-12 3.E-11
Fabricational Complexity
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http://www.biochem.ucl.ac.uk/bsm/xtal/teach/repl/klenow.html
1. Beese et al. (1993), Science, 260, 352-355.
Replicate Linearly with Proofreading and Error Correction
Fold to 3D Functionality
template dependant 5'-3' primer extension
5'-3' error-correcting exonuclease
3'-5' proofreading exonuclease
Error Rate:1: 106
100 Steps per second
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Caruthers Synthesis
DNA Synthesis
http://www.med.upenn.edu/naf/services/catalog99.pdf
Error Rate:1: 102
300 SecondsPer step
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Molecular Machine (Jacobson) Group – MIT - May, 2005
Avogadro Scale Engineering
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Gene LevelError Removal
Error Rate 1:104Nucleic Acids Research 2004 32(20):e162
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In Vitro Error Correction Yields >10x Reduction in Errors
Nucleic Acids Research 2004 32(20):e162
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Error Reduction: GFP Gene synthesis
Nucleic Acids Research 2004 32(20):e162
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Autonomous self replicating machines from random building blocks
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1] Consider biological cells which are able to copy their genome using appropriate pieces of molecular machinery (e.g. polymerase). Assume that the total probability of correctly copying each nucleotide is p=.999 per nucleotide. Calculate the Total Fabrication Complexity accessible to this system assuming that there are 4 types of nucleotides (i.e. A,G,C,T). Now assume that we have created a new type of cell which has a genome possessing six different types of nucleotides (i.e. A,G,C,T,X,Y). If we assume that we wish to keep the total Fabricational Complexity the same what must the probability per nucleotide addition, p, now be?
2] Consider now the fabricational complexity per unit cost f. Calculate the threshold probability p for which it is advantageous to use a redundant error correction scheme (such as trible redundancy) and majority voting than no error correction. Into which regime does biology fall?
HOMEWORK – DUE 5/1/06