productive nano systems darpa v4

8/8/2019 Productive Nano Systems DARPA V4

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Approaches to Productive Nanosystems

Approaches to Productive Approaches to ProductiveNanosystemsNanosystemsTihamer Toth-Fejel

[email protected]

March 28, 2008DARPA

3701 North Fairfax Drive , Arlington, Virginia

Richard Feynmans speech Theres Plenty of Room at the Bottom presented anencouraging vision of nanotechnology, as did Eric Drexlers Engines of Creation,with Drexlers Nanosystems providing a technical proof of concept.Unfortunately, none of these landmark publications provided a clear roadmap tothat achieve that vision.

Initiated by Scott Mize at the Foresight Nanotech Institute, with funding from TedWaitt, founder of Gateway Computer and of the Waitt Family Foundation, andleadership by Alex Kawczak from Battelle, the Technical Roadmap for ProductiveNanosystems was launched in late 2005 to map the technological achievementsnecessary to achieve Feynmans vision.Productive Nanosystems are those manufacturing systems which produceatomically precise products because they themselves are composed of nanoscaleparts that are atomically precise. This year, the main approaches to productivenanosystems were identified--including three biomimetic and two scanning probeapproaches:

Structural DNApioneered by Paul Rothemunds DNA Origami and supported byNanorexs softwareBis-amino nanostructuresChristian SchafmeisterDesigner EnzymesKendall Houk and David BakerTip-Based NanofabricationZyvexs Atomically Precise Manufacturing usespatterned Atomic Layer EpitaxyDiamondoid AssemblyRalph Merkle and Robert Freitas NanofactoryCollaboration


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ContentsContents

TopTop --Down vs. BottomDown vs. Bottom --UpUpProductive NanosystemsProductive NanosystemsNew ApplicationsNew ApplicationsApproachesApproachesModularization and TemplatingModularization and Templating

After a short introduction to nanotechnology in general, Ill specificallycover Productive Nanosystems and a few new applications that it willmake possible. Then I will discuss the most promising approaches toachieving Productive Nanosystems and some assembly techniquesthat may apply to many of them.

Im going to build some really grandiose castles in the sky, and thenIm going to show the ladders we need to build to get to them.


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DARPA QuestionsDARPA Questions

What are you trying to accomplish?What are you trying to accomplish?How is it done now, and with what limitations?How is it done now, and with what limitations?What is truly new in your approach which will removeWhat is truly new in your approach which will remove

current limitations and improve performance? Howcurrent limitations and improve performance? Howmuch will performance improve?much will performance improve?

If successful, what difference will it make?If successful, what difference will it make?What are the midWhat are the mid --term, final exams, or fullterm, final exams, or full --scalescale

applications required to prove your hypothesis? Whenapplications required to prove your hypothesis? Whenwill they be done?will they be done?

How could this transition to the end user (usually DoD)?How could this transition to the end user (usually DoD)?

How much will it cost?How much will it cost?

What are you trying to accomplish? Build the first (and best) productive nanosystem. Or at least takesome important steps towards it. Because once you have the first, the next billion or so suddenlycome within reach.

How is it done now, and with what limitations?Its not being done *at all*. Except biologically. But elephants arent reprogrammble to give birth to dump

trucks.

What is truly new in your approach which will remove current limitations and improve performance?Productive nanosystems offer a general manufacturing capability that has never existed before.Currently in manufacturing, we either we work at the nanoscale level (which determines material

properties) with deterministic orientation and precision one at a time (like stacking cans with abulldozer that has a pole tied to it),

OR we use thermodynamic probabilistic processes to get atomic precision in trillions of objects, but withno control over global orientation and very little long range control (like throwing things in a cementmixer and expecting to get Rolex watches out).

How much will performance improve? Depends on the application. Generally many, many magnitudes ofperformance increase in hierarchical complexity, tensile strength, and/or memory density.

If successful, what difference will it make? *Very* unfair advantage over adversaries. For example, it maybecome affordable to blanket an adversarial country in smart dust, or better yet--utility fog.

What are the mid-term, final exams, or full-scale applications required to prove your hypothesis? When

will they be done?Full scale killer apps: Printing appliance and Programmable Matter.Depends on the approach:1. Tip-based Nanofabrication: see Zyvex proposal for mid-term: One suggestion for an application:

30,000 perfect quantum dots, positioned as a quantum cellular automata NAND gates or triple-quantum dot rectifiers for other circuits.

2. Diamondoid: build a diamond NAND gate with perfectly positioned dopant atoms.3. Structural DNA: template a trillion NAND gates4. Bis-Peptides: template a trillion NAND gatesMeanwhile, develop1. Molecular actuators2. Assembling nanoNAND gates into CPUs and memories.

How could this transition to the end user (usually DoD)? Depends on application.The problem is that a general-purpose manufacturing technique (just like for 3D rapid manufacturing in

titanium pull out my printed titanium key fob) has tons of applications.


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Core CapabilitiesCore Capabilities

StructureStructure

ComputationComputation

SensingSensing

MotionMotion

The better we get at building structure, processing information,sensing changes in the environment, and moving at the nanoscale, thebetter well be able to do it at human scales.

To keep things in perspective, and to remind us to have some humility, weshould remember that people have been working on these core capabilitiesfor quite some time; the arch and the Antikythera computing device are bothmore than 2000 years old. The Lycurgus cup, which uses gold and silvernanoparticles to change color depending on the direction of the light, is 2500years old, and Herons steam engine is 1900 years old.

To achieve these core capacities, we need atomically precise control, andthis means mechanosynthesis.

The Antikytheera is the most complex instrument of antiquity. Built around87 B.C., it contained a differential turntable to calculate the phases of themoon that repeats every 19 years.


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MechanosynthesisMechanosynthesis

Machine phase chemistryMachine phase chemistryChemical synthesis directed byChemical synthesis directed bymechanical means (esp. position)mechanical means (esp. position)Chemists are accustomed to addingChemists are accustomed to addingenergy to random processes inenergy to random processes insolution phasesolution phaseBiology controls orientation andBiology controls orientation andlocation of molecular partslocation of molecular parts

Mechanosynthesis is a method of chemical synthesis directed bymechanical means, chiefly positional controlChemists are accustomed to adding energy to random processes andlet thermodynamics overcome barriers- instead of precisely controllingthe orientation and trajectories of the parts to take advantage of energyminimums.Biology has many examples of low-energy reactions that work becausethe enzymes control the orientation and location of molecular partsthe ribosome is a perfect exampleand its even programmable!This is what we want.But how do we get there from here?


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TopTop --Down and BottomDown and Bottom --UpUpBottom Up

Part Size

$ 100 mm

100 nm

100 m

100 pm

Product Complexity

$ 80 atoms

8 atoms

800 atoms

8,000 atoms

80,000 atoms

Top-Down

Top-down nanomanufacturing, like scanning probe microscopy and lithography, is likestacking cans with a pole tied to a bulldozer. Weve done some really amazing thingusing this approach, such as NISTs Autonomous Atom Assembler, which does in fiveminutes what it took Eigler all day. Were getting good science and good products outof the top-down approachmost notably the entire microelectronics industry--but itsnot revolutionary, mostly because as you get to the nanoscale level, building smallthings gets more and more difficult and expensive. In labor costs alone and this is atminimum wage-- Eiglers structures cost more than $10^23/lb. The InternationalTechnology Roadmap for Semiconductors (ITRS) and others are noticing that priceincrease, which is why theyre talking about bottom up approaches.Bottom-up nanomanufacturing, which is really chemistry and materials science, is likeassembling throwing stuff in a cement mixer and getting rolex watches out.Weve done some really amazing thing using this approach, such as the self-complementary rotaxane dimer pictured hereits a molecular actuator that iscontrolled by chemical signals. Again, were learning a lot and were making usefulproducts with it, but this approach is not very disruptive, mostly because building

more complex structures, such as complex machines-even those as simple as a 4-function calculator--it gets extremely difficult and prohibitively expensive. Lets faceitthe metal and semiconductor that make up a CPU is not a minimum energyarrangement. The way around that is to make each step a minimum energy process,but no such sequence of process steps is knownand is very difficult to imagine.But is there a better way?


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BottomBottom --toto--BottomBottomDeterministic nanoscale tools that build similar tools (machine Deterministic nanoscale tools that build similar tools (machine shop) shop)

AND/OR AND/OR Thermodynamic ratcheting and hierarchical design for guided Thermodynamic ratcheting and hierarchical design for guided assembly of huge numbers of complex tools ( assembly of huge numbers of complex tools ( biomemetic biomemetic ) )

The holy grail for nanotechnology is the ability to use nanoscale tools tomanipulate nanoscale parts, resulting in a factory with trillions ofprogrammable tools that can precisely position the location of each and everyatom in the final product (not necessarily robots as pictured here; most likelysomething simpler) .The important concept is closure; using the nanoscale capability of productivenanosystems to build others.This would make possible controlled exponential growth that might change theworld as fast as Mosaic transformed the Internet into the World Wide Web. Theonly thing we need to add is atoms. Adding atoms, OTOH, is not going to beeasy. Weve had replicating software for half a century, but only in the last fewyears did Greg Chirikjian build the first primitive autonomous programmablereplicating machines, while Matt Moses built a primitive replicating machinewith parts closure. (theyre working together now, so Im curious to see whatthey come up with).


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Productive Nanosystems Productive Nanosystems Nanosystems that make atomically precise structures underNanosystems that make atomically precise structures under

programmable controlprogrammable controlComposed of atomically precise structures and devicesComposed of atomically precise structures and devicesNot selfNot self --replicating; components not necessarily similar toreplicating; components not necessarily similar tooutput productsoutput products

http://www.foresight.org/roadmaps/

But parts closure willBut parts closure willoccuroccur somewhere somewhere

Atomic precision Atomic precision ,,notnot size size NanoscaleNanoscale machines machines ,,not novelnot novel properties properties

The important thing about the bottom-to-bottom approach, and the reasonexamples of it are more accurately called Productive Nanosystems, is becausethey *produce* atomically precise structures, components, and devices underprogrammable control.In order to do that, the productive nanosystem itself must be composed ofatomically precise nanostructures and nanodevices. These nanocomponentsare not necessarily included in the output envelope. If all of them weremanufactured in a closed loop with undifferentiated inputs, then the systemwould be self-replicating. This is very difficult to do in a microscale package,and undesirable. OTOH, some applications might benefit from some sort ofindirect replication. The figure illustrates how different productivenanosystems might supply parts to each other.Robert Freitas' example of a self-replicating machine shop from the 1980 NASAsummer study on self-replicating machines is a good example.We don't have any self-replicating machine shops today, yet we have a hugeindustrial output that is essentially based on what machine shops doand theentire industrial system is self-replicating.OTOH, the machine shop grew out of the blacksmith's shop, which *did* usemanual assistance to self-replicate.Also, the greatest examples of inspiration in the nanotech field (e.g. StructuralDNA) derive from biology, which self-replicates.How large and how closed this loop will be depends on economics, limitationsof chemistry and physics, and specific environments and applications (perhapsstarting with building machines that will refill expensive "inkjet" cartridges of

PNs). There will be some interesting lessons from the future success or


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ApplicationsApplications

Product ResultsProduct ResultsLow costLow costHigh performanceHigh performanceHigh valueHigh value

Nanostructure Manufacturing CapabilitiesNanostructure Manufacturing CapabilitiesArbitrarily complexArbitrarily complexHeterogeneousHeterogeneousMolecular precisionMolecular precisionLongLong --range orderrange order

Bulk quantitiesBulk quantities

Lets just take a quick look at what kind of low-cost, high-performance,high value products would become possible if we could put moleculestogether into arbitrarily complex, heterogeneous, molecularly precisenanostructures with long-range order, in bulk quantities.Obviously, anything we can build now, well be able to build better atlower cost.But there are some new applications that productive nanosystems willmake possible for the first time. There are three that, in my view, willmake the industrial revolution look as trivial as the next release ofWindows.


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Nanocube Pores

Using the nanofactory/nanocube approach, such an improved filter can be built using two types ofinput nanocubes: solid structural nanocubes and nanocubes with .3 nanometer pores through them.Since a single layer is desirable, the pore nanocubes need to be supported by a fractal structure of thesolid nanocubes. This figure shows an interface between pore and solid nanocubes. Even withoutspecialized pore nanocubes, simply omitting blocks would produce a filter with nanocube-sized holes.Such a filter would pass larger molecules such as ethanol, benzene and other larger organics, butwould exclude all infectious organisms. On the other hand, if the specialized pore blocks could befunctionalized to repel other molecules (such as sodium ions, as is done by aquaporins), then the filtercould also be used to purify salt water and industrial pollution.

The same technique could be used to build air filters to screen out nanoscale particulates;functionalized pore nanocubes would be needed to reliably filter out carbon dioxide or carbonmonoxide.

If the pore nanocubes were biocompatible, with functionalized pores of different sizes, then simplychanging the blueprint file would enable the nanofactory could produce a double-filter device thatscreened blood for particular molecules such as ureai.e. an insertable dialysis machine.

In a weight-limited, long duration mission, NASA could not afford to pack a dialysis machine. But in anemergency, it would be very nice to have the capability to build one, or any of a vast array of equallycomplex machines. Just as a printer can print both novels and blueprints, the flexibility of the NIACdesktop nanofactory extends far beyond water filters, air filters, and kidney dialysis machines. 2]

[1] featured at http://www.filtomat.com/100-series/100-c-series.html and was modeled in 3dmax athttp://www.3dcafe.com/asp/industry.asp by Anthony Mcfadden[2] Under NSF/ANSI Standard 42 this is a Class VI filter (> 50 microns at 85% efficiency), where classI is 0.5 to < 1 micron and can generally be only be done by carbon/charcoal adsorption.


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PEM Fuel CellsPEM Fuel Cells

Proton Exchange Membrane Fuel Cells could improve performance by increasing surface area,electrode density, and by decreasing defect frequency.

Another class of products for which effectiveness depends on the precision of membranes is the PEM (forProton Exchange Membrane, also called Polymer Electrolyte Membrane) fuel cell. The power density of a fuelcell depends on the surface area of the electrolyte membrane, and the electrode contact area. The efficiency is

determined by membrane thickness, electrode density and placement, and defect frequency. If we can controlthese physical characteristics at molecular scales, that will improve performance.To build PEM fuel cells, two new nanocubes would need to be developed. First, a type of nanocube would needto replace perfluorocarbon sulfonic acid (PFSA), This is the insulator (in blue, here) that allows protons to passthrough it. Preliminary work with silsesquioxanes having this property has been started in this area.Second, another type of nanocube would need to maximize the steric exposure of platinum group metals tomaximize the catalytic effect. Work with specific platinum/silsesquioxane complexes has also been reported inthe literature, but I havent found any studies on how well they catalyze hydrogen.Currently, the best PEM fuel cell catalyst layers are typically 10-100 micrometers thick, made of 100 nm carbonparticles mixed with poorly defined 5 nm-sized platinum group nanoparticles. The entiremembrane/catalyst/electrode assembly is typically 0.2 millimeters thick.(I. Honma, H. Nakajima, O. Nishikawa, T. Sugimoto, and S. Nomura, Amphiphilic Organic/Inorganic Nanohybrid Macromolecules forIntermediate-Temperature Proton Conducting Electrolyte Membranes, Journal of the Electrochemical Society, Volume 149, Issue 10, pp.A1389-A1392, October 2002).(Rob Hanssen, On the formation and reactivity of multinuclear silsesquioxane metal complexes, Masters Thesis, Eindhoven :Technische Universiteit Eindhoven, 2003.http://www.catalysis.nl/silicon_catalysis/people/rob_hanssen.php?topic=research)


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Killer App #2:Killer App #2:Programmable MatterProgrammable Matter

Another interesting new machine that productive nanosystems could build isprogrammable matter.This is such a new thing that we have only imagined what we could do with it infiction.That being said, DARPA just awarded a contract for it, and Im very interested infinding out what they get.Dilbert cartoonist Scott Adams said,


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Killer App #3:Killer App #3:Human Medicine and EnhancementHuman Medicine and Enhancement

Im only going to mention this because it always comes up.People say, with nanotechnology you can do put atoms exactly where you wantthem, and youre made of atoms. So we will be able to cure all disease, end aging,and all become superhuman.The kicker is, assuming you can get to the 10^23 atoms you want to move one at atime, how do you know where to put the atom (or moleculelets be generous) onceyou got ahold of it?If we dont know, then all our nanoengineering is worthless.OTOH, it appears that respirocytes, which are about as complex as toasters, might bedoable if biocompatibility problems are worked out.And the printer appliance will lower the cost of microscale equipment that will helpyou discover scientific knowledge i.e. determine where the atoms in our bodies aresupposed to go.At any rate, engineering is fairly predictable, science is not.So I will not say anything about this topic.Lets get to work: understanding the four main approaches to productivenanosystems.


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ApproachesApproaches

Structural DNAStructural DNABisBis --amino nanostructuresamino nanostructuresTipTip --Based NanofabricationBased NanofabricationDiamondoidDiamondoid

Structural DNA making the fastest advancesBis-amino nanostructures least studiedTip-Based Nanofabrication most conservative (already funded)Diamondoid highest payoff


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DNA Origami: 50 billion SmileyDNA Origami: 50 billion SmileyFacesFaces

Paul W. K. Rothemund, Folding DNA to create nanoscaleshapes and patterns, Nature Vol 440,16 March 2006 Courtesy Paul Rothemund

The first, and currently most popular approach to ProductiveNanosystems is what Paul Rothemund called DNA Origami, but thefield, in general terms, is morphing into Structural DNA OTOH,Rothemund already has 95 citation references for his seminal paperand a MacArthur fellowship too, so I dont think he minds too much.

Unfortunately, half a million dollars is not enough to buy a highresolution TEM to help him extend his process into 3D (even thoughconceptually its quite easy).

The property that makes DNA very valuable is its phenomenalmolecular recognition. With such an information-rich molecule, wecan build nanostructures, as Rothemund has done when he built 50billion of these smiley faces, by himself, in two hours, with very highyield. This is a lot of fast, concentrated happiness.


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Easily reproducibleEasily reproducible

Qian Lulu, et al., Analogic China mapconstructed by DNA. Chinese Science Bulletin .Dec 2006. Vol. 51 No. 24

Lulus paper described the technical problems they had with Taiwan Island.Given the political situation in Taiwan, Id agree; Taiwan might be a bigproblem.Rothemund claimed that his method was so simple that a high school student

could do it.I was talking about DNA origami to Mark Sims, the president of Nanorex, and Ibrought up Pauls claim. I said, Youve got a high school student. Why dontyou see if Paul is right?Well, Paul was right. This logo on the right was done by Marks high schooldaughter.


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The DNA Origami ProcessThe DNA Origami Process

c.

d.

b.a.

Figure a, b, and d from Paul Rothemund, Design of DNA origami, IEEE/ACMInternational Conference on Computer-Aided Design. Nov. 2005

Figure c by Toth-Fejel

a. Start with a ss DNA backbone (or scaffold) loop in this case from the M13mp18virus. It is a simple bacteriaphage which has been sequenced (it has 7249 bases) andis relatively cheap. You also need about 250 tiny helper strands, each of which isspecifically designed and synthesized so that half of it binds to one particular locationon the scaffold loop, and half of it binds to a different location.b. Five helper strands (the tiny u-shaped strings) have bonded with their uniquelycomplimentary sequences. This is because half of the helper strand matches asegment on one side of the backbone; the other side of the same helper strandmatches a different segment on the backbone.c. Many of the helper strands have finished most of the final backbone bending andhave completed many crossovers.d. Final productThe process works as follows: First, buy about three trillion copies of the genome of the M13mp18 virus. This isa circular, single stranded DNA, 7249 base pairs long, for about $30 from a biotech company such as NewEngland Biolabs. Then buy a similar number of 250 unique types of helper strands, each 32 base pairs long.This will cost from $800 (if you own a MerMade-384 Oligonucleotide synthesizer) to $2800 (if you buy it from ahigh-quality lab such Operan, Picoscript, Geneart, or DNA 2.0).Combine the circular single-stranded viral DNA in a test tube with the 250 helper strands, using a pipette tomeasure a 5 microliter drop of solution from each of 250 tubes (the order doesnt matter, since this is a one-

pot reaction). Once the scaffold and helper strands are combined, add a little buffer (to control pH; i.e. NaOH orTris EDTA) and magnesium salt (Magnesium Mg++ ions neutralize negative charges on the DNA and allow thesingle-stranded DNA to come together and form the double helix). Heat the mixture to near boiling (90C) andcool it slowly back to room temperature (20C) over the course of about 2 hours.This is so simple that a high school student can do it. The difficult part, of course, is specifying the uniquesequences of the 250 helper strands that you order from the lab before starting the experiment.


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Pixelated DNA and PositioningPixelated DNA and Positioning

courtesy Paul W. K. Rothemund Ke, et. al., Self-Assembled Water-Soluble Nucleic Acid Probe Tilesfor Label-Free RNA Hybridization Assays, Science, Jan 11, 2008

Of course, we can also write small letters. And patterns, remembering that thatcomputer electronics revolution is about writing small patterns. And keep inmind that Structural DNA is not limited intrinsically to 2D as photolithography is.We must note that the resolution is about five times bigger than what Eigler didwith individual atoms back in 1989.So why isnt this a big step backwards? DNA origami doesnt require hundredsof thousands of dollars worth of specialized equipment. More like $50 worth ofequipment and $2000 worth of input materials (though the AFM to see what youbuilt, the debugging equipment can get quite pricy).But even more important, there were 50 billion copies, not just one.Done by one mad scientist working alone in one lab.On the right, we see the first practical application of Rothemunds DNA Origami Arizona State researchers built a 100 trillion probes in one step that can detectspecific RNA sequences down to 200 picoMole levels. The two dots are the index,

and depending on which RNA sequence is in the sample, different bars becomevisible.

Theres also Lee, et. al., Site-Specific Control of Distances between Gold Nanoparticles. Angew. Chem. Int. Ed.2007, 46, 9006 9010 but its not very advanced. Neither is Park, et. al. DNA-programmable nanoparticlecrystallization, Nature January 31, 2008.


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BisBis --Amino Acids andAmino Acids and BisBis--PeptidesPeptides

Inverse of solving the protein folding problemInverse of solving the protein folding problemThe proposed approach is an integration of knownThe proposed approach is an integration of known

techniques and designed to produce a broadlytechniques and designed to produce a broadlyapplicable manufacturing process.applicable manufacturing process.

Molecular Lego Christian Schafmeister Scientific American , Feb 2007 , 64-71

Another biomemetic approach begins with Christian Schafmeisters bis-amino acids.The basic idea is that instead of trying to solve the protein folding problem,Schafmeister turns the problem on its head, greatly simplifying it. Instead oftrying to understand the weak Van der Wals and electrostatic forces topredict the self-bending of polypeptide, the idea is to design amino-acid-likemolecules that covalently bond to their neighbor in two places; therebymaking rigid and exactly predictable structures.One of the things that nice about this approach is that the basic chemicaltechniques have been around for decades.


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BisBis --Peptides Productive NanosystemPeptides Productive NanosystemIN: (NH4)2CO3,

H2O, CO2, traceelements

OUT:

MachineSolution

It takes 20 minutes just to explain this one slide, but the main idea is thatthese bis-peptide structures, together with a computer switchable customoxidation plates make up a machine solution, and with an artificial ribosome-like mechanism (made of bis-peptides of course), could manufacture a hugearray of arbitrarily complex, atomically precise structures. These productswould be limited only by the material properties of the fundamental bis-aminoacids (properties like conductivity, band-gap, and tensile strength).


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Protein Engineering:Protein Engineering:Designer EnzymesDesigner Enzymes

IN: (NH4)2CO3,

H2O, CO2, traceelements

OUT:

MachineSolution

Short term Design enzymes for reactions that naturally occurring enzymes don't do Understand how enzymes work

Houks UCLA chemists design the active site for the enzymes the area ofthe enzymes in which the chemical reactions take place and give ablueprint for the active site to their University of Washington colleagues.Baker and his group then use their computer programs to design a sequenceof amino acids that fold to produce an active site like the one designedby Houk's group; Baker's group produces the enzymes.

Houk, Science, March 7, 2008 (Retro-Aldol) - The aldol reaction is a keyprocess in living organisms associated with the processing and synthesis ofcarbohydrates. This reaction is also widely used in the large-scale productionof commodity chemicals and in the pharmaceutical industry.

Houk, March 19, 2008, (Kemp Elimination)1) Casey, M. L.; Kemp, D. S.; Paul, K. G.; Cox, D. D. J.Org.Chem. 1973 , 38, 2294-2301.(2) Kemp, D. S.; Casey, M. L. J.Am.Chem.Soc. 1973 , 95, 6670-6680.(3) Kemp, D. S.; Cox, D. D.; Paul, K. G. J.Am.Chem.Soc. 1975 , 97, 7312-7318.

The design of new enzymes for reactions not catalysed by naturally occurringbiocatalysts is a challenge for protein engineering and is a critical test of ourunderstanding of enzyme catalysis. Here we describe the computationaldesign of eight enzymes that use two different catalytic motifs to catalyse theKemp eliminationa model reaction for proton transfer from carbonwith

measured rate enhancements of up to 105 and multiple turnovers. Mutational


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TipTip--Based Nanofabrication:Based Nanofabrication:Atomically Precise ManufacturingAtomically Precise ManufacturingThe ability to produce 3D structuresThe ability to produce 3D structureswith topwith top --down control and atomicdown control and atomicprecision.precision.

The inevitable result of continuedThe inevitable result of continuedimprovements in ultraimprovements in ultra --precisionprecisionmanufacturing (IC manufacturingmanufacturing (IC manufacturingand others)and others)

The proposed approach is anThe proposed approach is anintegration of known techniquesintegration of known techniques

and designed to produce a broadlyand designed to produce a broadlyapplicable manufacturing process.applicable manufacturing process.

http://www.zyvexlabs.com/

The third approach, spearheaded by John Randall at Zyvex, was just fundedby DARPA, and involves using scanning tunneling microscopes to buildatomically precise components, starting with perfect quantum dots.This approach is actually the most conservative approach, based on smalladvances on equipment found in most semiconductor fabrication plants.


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Patterned Si ALEPatterned Si ALE

STM tip removesH atoms from theSi surface

A precursor gas isused to dose thesurface. Protected Siatoms are depositedonly where H hasbeen removed.

Completed depositionis verified and then thedeprotection/patterningis repeated.

The way it works is conceptually quite simple:First, in a high vacuum, the STM tip removes hydrogen atoms from thepassivated silicon surface.Second, standard atomic layer epitaxy is applied to the entire surface

(but of course, the silicon only binds to where there are danglingbonds left from where the hydrogen atoms were pulled off.Third, repeat as many times as necessary, perhaps with other types ofatoms (i.e. germanium).


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Demo of Patterned Si ALEDemo of Patterned Si ALE

Courtesy Joe Lyding UI Urbana-Champaign

Professor Joe Lyding of University of Illinois at Urbana-Champaign, amember of Zyvexs team, has achieved some success with thismethod, though as you can see, some work needs to be done inmaking sharper needles and controlling them more precisely.


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Tip ArraysTip Arrays

Dip PenDip Pen55,000 tips55,000 tipsThermally actuatedThermally actuatedMultiple inksMultiple inks15 nm resolution15 nm resolutionFastFast

The big problem, of course, is throughput.Zyvex plans to imitate Chad Mirkins work on multiple tips, which isillustrated here.

55 000 miniature images of a US nickel reproduced by dip-penlithography are shown in the background. It took 30 minutes. (Eachcircle is only twice the diameter of a red blood cell.) Each image (inforeground), showing Thomas Jefferson's profile, is made from aseries of 80 nm dots.

Salaita, Chad A. Mirkin, et al., Angew. Chem. Int. Ed. November 6 issueSalaita, K. S.; Wang, Y.; Mirkin, C. A. "Applications of Dip-Pen Nanolithography," Nature Nanotech. 2007, 3 , 145-155.http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B82X8-4M97WHX-5&_user=10&_coverDate=11%2F30%2F2006&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=4fe038c67c68e5df6e206ecb317cfc59


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DiamondoidDiamondoid

DCB6-Si dimerplacement tool tip.

http://www.MolecularAssembler.com/Nanofactory/Challenges.htm

The 4th approach is technically the most difficult, but also the most rewarding.If we want to build the most valuable engineering material; i.e. the one with the

highest strength, highest electrical conductivity, and highest thermal conductivity, i.e.diamond, carbon nanotubes, graphene, and other diamondoid nanostructures, then weneed to be able to build individual carbon bonds.

Wilson Ho already proved this for individual silicon atoms, and the carbon bindingreaction has been thoroughly explored with DFT algorithms. On the right we have anexample tooltip from the DFT work, on the left we have a snapshot from the Burch videoof how it might be used.

Wilson Ho [1] at UC Irvine and Saw Hla [2] at Ohio University have manipulated individual atoms and molecules to make and breakcovalent bonds.

[1] Wilson Ho, Single Molecule Chemistry, Journal of Physical Chemistry , 117 (2002): 11033-11061, L.J. Lauhon and W. Ho, TheInitiation and Characterization of Single Bimolecular Reactions with a STM, Faraday Discussion 117 , 249-255 (2000), and H.J. Lee and W.Ho, Single Bond Formation and Characterization with a Scanning Tunneling Microscope, Science 286, 1719-1722 (1999), and Wilson Ho,Hyojune Lee, "Single bond formation and characterization with a scanning tunneling microscope," Science 286(26 November 1999):1719-1722; http://www.physics.uci.edu/~wilsonho/stm-iets.html

[2] Saw-Wai Hla and Karl-Heinz Rieder, "STM control of chemical reactions: single-molecule synthesis", A nnual Review of Physical Chemistry , 54(2003):307-330.

There are many possible tool tips that might satisfy both requirements, but the problem can be simplified by bonding the dimer to twogroup IV supporting atoms: carbon, silicon, germanium, tin, or lead. This series of elements forms progressively weaker bonds with carbon,so the proposed tools will likewise be progressively more weakly bound to the carbon-carbon (CC) dimer. The supporting group IV atoms arepart of two substituted adamantane (C10H16) frameworks that position and orient them. The two substituted adamantane frameworks arerotated and fused together to make a biadamantane structure (Figure. 1), creating very high-angle strain in the bonds between the twosupporting atoms and the dimer. This molecule, a bi-silaadamantane dicarbon, is only the tip of a complete tool. In a completemechanosynthetic apparatus, a somewhat larger version of this molecule would likely be required, so that the active tip could be held andpositioned via a rigid handle structure. [1]

Using the Zyvex Beowulf cluster of computers and Density Functional Theory (DFT) software, over 100,000 CPU-hours of computer timehave simulated two important things about this structure:

The successful interaction of the DCB6-Ge tool at room temperature (and the DCB6-Si tool at 80K) with the C(110) dehydrogenateddiamond surface, and

The behavior of isolated 1-, 2-, and 3-dimer clusters on the C(110) surface. [2][1] Ralph C. Merkle, Robert A. Freitas Jr., Theoretical analysis of a carbon-carbon dimer placement tool for diamond mechanosynthesis,

Journal of Nanoscience and Nanotechnology , 3(August 2003):319-324. http://www.rfreitas.com/Nano/DimerTool.htm[2] Robert A. Freitas Jr., Pathway to Diamond-Based Molecular Manufacturing, First Foresight Conference on Advanced

Nanotechnology, 22 October 2004, Washington, DC, http://www.molecularassembler.com/Papers/PathDiamMolMfg.htmJingping Peng, Robert A. Freitas Jr., and Ralph C. Merkle, Theoretical Analysis of Diamond Mechanosynthesis. Part I. Stability of C2

Mediated Growth of Nanocrystalline Diamond C(110) Surface, Journal of Computational and Theoretical Nanoscience , Vol. 1. 6270, 2004.See also David J. Mann, Jingping Peng, Robert A. Freitas Jr., and Ralph C. Merkle, Theoretical Analysis of Diamond Mechanosynthesis.Part II. C2 Mediated Growth of Diamond C(110) Surface via Si/Ge-Triadamantane Dimer Placement Tools, Journal of Computational and Theoretical Nanoscience , Vol. 1. 7180, 2004, and Jingping Peng, Robert A. Freitas, Jr., Ralph C. Merkle, James R. Von Ehr, John N.Randall, and George D. Skidmore, "Theoretical Analysis of Diamond Mechanosynthesis. Part III. Positional C2 Deposition on Diamond

"


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DiamondoidDiamondoid

Rigid, well-characterized nanomachinery is good(made of diamond, CNTs, oxides, and othercrystalline and/or regular structures)

Deterministic processes may be more difficultthan thermodynamically-driven ones, but havebetter error detection and correction

Diamondoid has highest performance Experimental work necessary to prove concept Longest development time

The advantages of diamondoid is that we would have:Nanocomponents with very high performance, andA deterministic process with error correction

The good news is that the Robert Freitas, Ralph Merkle and their cohortsexpect to run the first experiments this year to prove the conservative DFTpredictions.


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Other Approaches to PNOther Approaches to PN

Other Biomemetics Solid Phase DNA and Protein Synthesis Viraculture and Bacteraculture

Organic and Inorganic Supramolecular Chemistry MEMS Hybrids

There are numerous other possbilities, but they dont seem as likely or asrewarding.

Except for the last one.I suspect hybrids between the four I discussed, and maybe one of these long

shots, may reach the low-hanging fruit first.

As you may have noticed, all the approaches Ive talked about involveassembly techniques for structures.

It turns out that these structures might act as templates to larger modules.


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Modularization and Templating:Modularization and Templating:DNADNA--mediated Nanocube Assemblymediated Nanocube Assembly

For example, here a G1 silsesquioxane nanocube is linked to shorthelper strand and a section of the scaffold of structural DNA.Currently, DNA origami is only two dimensional, and as any electricalengineer knows, for electronic circuits we need many layers; forinterconnects, insulated crossovers, and gates. But conceptually, that

problem is solvable in ways that are not possible for microphotolithography, though one problem is connecting nanocubes toeach other once they are held in close proximity to each other.


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Connecting NanocubesConnecting Nanocubes

Pyrimidine photodimerization Diels-Alder cycloaddition

Zinc fingers

Photochemical bonding

In order to build any product at all, it is necessary to connect nanocubes.There are a number of methods that might be used with externally controllablemeans; e.g. triggering by light, electric fields or currents, mechanical pressure, orsimply by holding reactive molecules near each other until thermal energy overcomesthe reaction barrier.Keep in mind that this connection method must be considered when designing thenanocube in the first place. You cant just glue arbitrary atoms to gray blocks, asdeceptively shown in these four schemes.The ones on the left are activated by photons of different wavelengths; the one on theupper right has a connection scheme based on amino acids that is activated by zincions. The one on the lower right, which uses the cycloaddition process, worksspontaneously at room temperature, so the nanocubes would need to be kept fromthe product until the instant of assembly.

Upper left suggested by Eric Drexler; Upper right suggested by Chris Phoenix. Both from Chris Phoenix and Tihamer Toth-Fejel, Large-Product General -Purpose Design and Manufacturing Using Nanoscale Modules: Final Report, CP-04-01, NASA Institute for AdvancedConcepts, May 2005, http://www.niac.usra.edu/files/studies/final_report/1030Phoenix.pdf

Lower left: pyrimidine photodimerization -- chromophores of various pyrimidine analogues which can undergo photoinduced (2 + 2 )

cycloaddition reactions on exposure to UV light at 254 nm. Photodimerization in pyrimidine-substituted dipeptides, BRIAN LOHSE, P. S.RAMANUJAM, SREN HVILSTED and ROLF H. BERG, J. Peptide Sci. 11: 499505 (2005) DOI: 10.1002/psc.645http://www.polymers.dk/publikation/pdf/101%20J%20Peptide%20Sci%2005.pdfMarkus Krummenacker proposed using Diels-Alder cycloaddition to connect Molecular Building Blocks in Steps Towards MolecularManufacturing, Chemical Design Automation News, 9, (1994) p. 1 and 29-39, http://www.n-a-n-o.com/nano/cda-news/cda-news.html. Itscalled Diels-Alder cycloaddition reaction, and it is the concerted bonding together of two independent pi-electron systems to form a newring of atoms. http://www.cem.msu.edu/~reusch/VirtualText/addene2.htm Unfortunately, I havent yet figured out how to hang an opendiene at each free corner of a silsesquioxane cube, and I would need to keep the nanocubes in solution from bumping into the product.See also http://orgchem.chem.uconn.edu/namereact/dielsalder.html


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Silsesquioxane NAND GateSilsesquioxane NAND Gate

So with four types of nanocubes (conductor, insulator, electrondonating semiconductor, electron accepting semiconductor), weshould be able to build an NAND gate.Because this circuit is not photolithographed, the 2 nd dopant typedoesnt need to be over-doped; this would be expected to increaseefficiencies.Even more significantly, DNA-origami assembled electronics would nolonger be intrinsically limited to two dimensions, so circuit densitiesper volume would increase significantly.Cooling would get to be a very real problem, thought; but were out of time.


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CNT/DNA NAND GateCNT/DNA NAND Gate

Mark Sims may have discovered an easier to make DNA-assemblednanoNAND gates.


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Functional PatternFunctional Pattern


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Functional pattern extended:Functional pattern extended:nanonano --breadboardbreadboard


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Preferential bonding of 3 DNA TemplatesPreferential bonding of 3 DNA Templates

Q Q

S R

This illustrates one way of using hierarchies to build circuits.


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Hierarchical, Direct, and 3D SelfHierarchical, Direct, and 3D Self --AssemblyAssemblyofof NanotileNanotile PolyominoesPolyominoes

3D

Hierarchical

D i r e c t

And hierarchical patterns can be continued in other ways, some ofwhich can be three dimensional.


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Individual bis-roteins

N

N-1

N-2

N-3

1

Stage

. ..

Guided HierarchicalGuided Hierarchical AssemblyAssembly


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Molecular ActuatorsAnnulenesAnnulenes

Interlocking Rotaxane Dimers

Poly calix[4]arene-bithiophene

Azobenzene

Jimenez-Molero, Dietrich-Buchecker, and Sauvage, Chemically Induced Contraction andStretching of a Linear Rotaxane Dimer, Chem. Eur. J. 2002, 8, No. 6

Note that Ive been concentrating on structure thats because it is the easiest. But structureis primary because none of the other three core capabilities (computation, sensing, andmotion) are possible without structure. For productive nanosystems, we also need the othercore capabilities. Fortunately, there are many possibilities, and here are some for molecularactuators.The nice thing about these is that they are normally produced billions at a time.One challenge is make them as dependable as an electric motor that we can pick up at ahardware store.And it will be another challenge to integrate these standardized motors into standardizednanostructures to do useful work.Biology has quite a few molecular motors, but they all depend on ATP for energy, so they are all proton-motive or ion-motiveprocesses. What we want are molecular motors that work using electrons, move much faster than ions, require no material input,and produce no waste.Unfortunately, the molecules pictured here, like the biologically-based protein motors, all depend on oxidation and reductionreactions that require the addition or subtraction of a proton or larger ion. However, some researchers have been able to buildphoton-induced movement.T.R.Kelly, X. Cai, F. Damkaci, S.B. Panicker, B.Tu, S.M. Bushell, I. Cornella, M.J. Piggott, R. Salives, M. Cavero, Y. Zhao, S.Jasmin, Progress toward a Rationally Designed, Chemically Powered Rotary Molecular Motor. J. Am. Chem. Soc , 2007, 129,376-386 .T.R.Kelly (Editor) Molecular Machines, Topics in Current Chemistry, Springer Verlag, Heidelberg, 2005, Vol. 262.There are quite a few from biology: The F0-F1 ATPase, the kinesin, myosin, and dynein types of protein molecular machines, andbacteria flagellar motors all depend on ATP for energy, so they are all proton-motive or ion-motive processes. Biological processesthat use ion gradients, DNA, or ATP are inferior to electromechanical actuators because, among other things, electrons movefaster than protons, because purely electrical processes will require less material input, and because moving and constrainingelectrons is much easier.

The F0-F1 ATPase, the kinesin, myosin, and dynein types of protein molecular machines, and bacteria flagellarmotors all depend on ATP for energy, so they are all proton-motive or ion-motive processes. Biological processesthat use ion gradients, DNA, or ATP are inferior to electromechanical actuators because, among other things,electrons move faster than protons, and because purely electrical processes will require less material input, andbecause moving and constraining electrons is much easier.The problem is that, like the biologically-based protein motors, the molecules pictured above are all redox-controlled. You have to add or subtract a proton or larger ion. However, batteries are a well-understoodtechnology that connect electric currents to redox reactions. Since nanobatteries have already been built, wemight somehow protonate actuators with battery-type reactions that are driven by varying electric currents fromnearby nano-wires.Some of these actuators are very difficult to build: the yield for these actuators is very low (the yield for theinterlocking rotaxane dimers is < 1%).The unidirectional rotary motion of trypticiene involves 5 steps:Phosgene-fueled isocyanate formation ,Slight rotation,Urethane formation,Rotation involving an energy barrier in an irreversible mannerHydrolysis of the urethane bondkelly 2001, 1999

Manfred Schliwa, Molecular Motors, Wiley-VCH, 2003 ISBN 3527605657


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Nanocube MotorsNanocube Motors

On the other hand, a nanocube-compatible motor like this might beavailable by 2020, if not earlier.With motors like this in stock, we might be able to build deterministic,molecularly precise robots like the ones Drexler and others havedreamed of.But what can we do today?


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PN 1

PN 2

PN 3PN 4

PN 2 Out

P N

3 I n

P N 1 I n

PN 4 Out

PN 1 Out

PN 2 In

CHEM 1

PN 4 In

P N

3 O u t

BIO 1

BIO 2

Let me clarify first: Self-replication is not really necessary (and is very difficult to pack it into a smallpackage; plus nanoscale self-replication is probably undesirable, at least on this planet); But some sortof indirect replication *is* necessary to reap the benefits of exponential manufacturing.The example of a self-replicating machine shop from the NASA summer study on machine replication isa good example. We don't have any self-replicating machine shops today, yet we have a huge industrialoutput that is essentially based on what machine shops do. And the entire industrial complex can (anddoes) build copies of itself in undeveloped countries.The machine shop grew out of the blacksmith's shop, which used manual assistance to self-replicate.Also, the greatest examples of inspiration in the nanotech field (e.g. Structural DNA) derive frombiology, which self-replicates.Here we have a replication loop of four simple productive nanosystems; none of which can build thecomponents out of which it is made of; yet the system of four nanosystems, when augmented withsimple biological and chemical building blocks, does replicate.How large and how closed this replication loop will be depends on economics, limitations of chemistryand physics, and specific environments and applications (e.g. when we return to the Moon, a self-replicating machine shop/foundary would be *very* useful; so will building a machine that will refillexpensive "inkjet" cartridges). There may be some interesting lessons from the future success orfailure of macroscale Rep-Rap (which is expecting to release Version 2 this year and *is* thinkingabout how to make a preprocessor that will make feedstock out of plastic bottles). When we return tothe Moon, a self-replicating machine shop/foundry would be useful.Note that at the nanoscale, the difference between biology and chemistry starts disappearing. Thething that is interesting is that molecular biologists look at cellular mechanisms like mechanicalengineers look at cars as machines.Biology got there first, but its machines are evolved; not necessarily easy to analyze. But us engineersneed to have some humility so that we can learn from Mother Nature (even if she is a heartlesspsychopath).

productive nano systems darpa v4

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