Approaches to Productive Nanosystems

Approaches to Productive
Nanosystems
Tihamer Toth-Fejel
Tihamer.Toth-Fejel@gd-ais.com

March 28, 2008

DARPA
3701 North Fairfax Drive , Arlington, Virginia

Richard Feynman’s speech “There’s Plenty of Room at the Bottom” presented an

encouraging vision of nanotechnology, as did Eric Drexler’s “Engines of Creation”,
with Drexler’s “Nanosystems” providing a technical “proof of concept”.
Unfortunately, none of these landmark publications provided a clear roadmap to
that achieve that vision.
Initiated by Scott Mize at the Foresight Nanotech Institute, with funding from Ted
Waitt, founder of Gateway Computer and of the Waitt Family Foundation, and
leadership by Alex Kawczak from Battelle, the Technical Roadmap for Productive
Nanosystems was launched in late 2005 to map the technological achievements
necessary to achieve Feynman’s vision.
Productive Nanosystems are those manufacturing systems which produce
atomically precise products because they themselves are composed of nanoscale
parts that are atomically precise. This year, the main approaches to productive
nanosystems were identified--including three biomimetic and two scanning probe
approaches:
Structural DNA—pioneered by Paul Rothemund’s DNA Origami and supported by
Nanorex’s software
Bis-amino nanostructures—Christian Schafmeister
Designer Enzymes—Kendall Houk and David Baker
Tip-Based Nanofabrication—Zyvex’s Atomically Precise Manufacturing uses
patterned Atomic Layer Epitaxy
Diamondoid Assembly—Ralph Merkle and Robert Freitas’ Nanofactory
Collaboration
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 Approaches to Productive Nanosystems

Contents

z Top-Down vs. Bottom-Up

z Productive Nanosystems
z New Applications
z Approaches
z Modularization and Templating

After a short introduction to nanotechnology in general, I’ll specifically

cover Productive Nanosystems and a few new applications that it will
make possible. Then I will discuss the most promising approaches to
achieving Productive Nanosystems and some assembly techniques
that may apply to many of them.

I’m going to build some really grandiose castles in the sky, and then
I’m going to show the ladders we need to build to get to them.

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 Approaches to Productive Nanosystems

DARPA Questions

What are you trying to accomplish?

How is it done now, and with what limitations?
What is truly new in your approach which will remove
current limitations and improve performance? How
much will performance improve?
If successful, what difference will it make?
What are the mid-
mid-term, final exams, or full-
full-scale
applications required to prove your hypothesis? When
will they be done?
How could this transition to the end user (usually DoD)?
How much will it cost?

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

How is it done now, and with what limitations?

It’s not being done *at all*. Except biologically. But elephants aren’t 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 a
bulldozer that has a pole tied to it),
OR we use thermodynamic probabilistic processes to get atomic precision in trillions of objects, but with
no control over global orientation and very little long range control (like throwing things in a cement
mixer and expecting to get Rolex watches out).

How much will performance improve? Depends on the application. Generally many, many magnitudes of
performance 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 may
become 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 gates
4. Bis-Peptides: template a trillion NAND gates
Meanwhile, develop
1. Molecular actuators
2. 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
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titanium – pull out my printed titanium key fob) has tons of applications.
 Approaches to Productive Nanosystems

Core Capabilities

Structure

Computation

Sensing

Motion

The better we get at building structure, processing information,

sensing changes in the environment, and moving at the nanoscale, the
better we’ll be able to do it at human scales.

To keep things in perspective, and to remind us to have some humility, we

should remember that people have been working on these core capabilities
for quite some time; the arch and the Antikythera computing device are both
more than 2000 years old. The Lycurgus cup, which uses gold and silver
nanoparticles to change color depending on the direction of the light, is 2500
years old, and Heron’s steam engine is 1900 years old.

To achieve these core capacities, we need atomically precise control, and

this means mechanosynthesis.

The Antikytheera is the most complex instrument of antiquity. Built around

87 B.C., it contained a differential turntable to calculate the phases of the
moon that repeats every 19 years.

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Mechanosynthesis

z Machine phase chemistry

z Chemical synthesis directed by
mechanical means (esp. position)
z Chemists are accustomed to adding
energy to random processes in
solution phase
z Biology controls orientation and
location of molecular parts

Mechanosynthesis is a method of chemical synthesis directed by

mechanical means, chiefly positional control
Chemists are accustomed to adding energy to random processes and
let thermodynamics overcome barriers- instead of precisely controlling
the orientation and trajectories of the parts to take advantage of energy
minimums.
Biology has many examples of low-energy reactions that work because
the enzymes control the orientation and location of molecular parts—
the ribosome is a perfect example—and it’s even programmable!
This is what we want.
But how do we get there from here?

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Top-Down and Bottom-Up

Top-Down Bottom Up

$ $
100 100 100 100 8 80 800 8,000 80,000
mm µm nm pm atoms atoms atoms atoms atoms

Part Size Product Complexity

Top-down nanomanufacturing, like scanning probe microscopy and lithography, is like

stacking cans with a pole tied to a bulldozer. We’ve done some really amazing thing
using this approach, such as NIST’s Autonomous Atom Assembler, which does in five
minutes what it took Eigler all day. We’re getting good science and good products out
of the top-down approach—most notably the entire microelectronics industry--but it’s
not revolutionary, mostly because as you get to the nanoscale level, building small
things gets more and more difficult and expensive. In labor costs alone – and this is at
minimum wage-- Eigler’s structures cost more than $10^23/lb. The International
Technology Roadmap for Semiconductors (ITRS) and others are noticing that price
increase, which is why they’re talking about bottom up approaches.
Bottom-up nanomanufacturing, which is really chemistry and materials science, is like
assembling throwing stuff in a cement mixer and getting rolex watches out.
We’ve done some really amazing thing using this approach, such as the self-
complementary rotaxane dimer pictured here—it’s a molecular actuator that is
controlled by chemical signals. Again, we’re learning a lot and we’re making useful
products 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. Let’s face
it—the metal and semiconductor that make up a CPU is not a minimum energy
arrangement. The way around that is to make each step a minimum energy process,
but no such sequence of process steps is known—and is very difficult to imagine.
But is there a better way?

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Bottom-to-Bottom
Deterministic nanoscale tools that build similar tools (machine shop)
AND/OR
Thermodynamic ratcheting and hierarchical design for guided
assembly of huge numbers of complex tools (biomemetic
(biomemetic))

The holy grail for nanotechnology is the ability to use nanoscale tools to
manipulate nanoscale parts, resulting in a factory with trillions of
programmable tools that can precisely position the location of each and every
atom in the final product (not necessarily robots as pictured here; most likely
something simpler) .
The important concept is closure; using the nanoscale capability of productive
nanosystems to build others.
This would make possible controlled exponential growth that might change the
world as fast as Mosaic transformed the Internet into the World Wide Web. The
only thing we need to add is atoms. Adding atoms, OTOH, is not going to be
easy. We’ve had replicating software for half a century, but only in the last few
years did Greg Chirikjian build the first primitive autonomous programmable
replicating machines, while Matt Moses built a primitive replicating machine
with parts closure. (they’re working together now, so I’m curious to see what
they come up with).

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 Approaches to Productive Nanosystems

Productive Nanosystems
z Nanosystems that make atomically precise structures under
programmable control
z Composed of atomically precise structures and devices
z Not self-
self-replicating; components not necessarily similar to
output products
z But parts closure will
occur somewhere

z Atomic precision,
precision,
not size
z Nanoscale machines,
machines,
not novel properties

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

The important thing about the bottom-to-bottom approach, and the reason
examples of it are more accurately called Productive Nanosystems, is because
they *produce* atomically precise structures, components, and devices under
programmable control.
In order to do that, the productive nanosystem itself must be composed of
atomically precise nanostructures and nanodevices. These nanocomponents
are not necessarily included in the output envelope. If all of them were
manufactured in a closed loop with undifferentiated inputs, then the system
would be self-replicating. This is very difficult to do in a microscale package,
and undesirable. OTOH, some applications might benefit from some sort of
indirect replication. The figure illustrates how different productive
nanosystems might supply parts to each other.
Robert Freitas' example of a self-replicating machine shop from the 1980 NASA
summer study on self-replicating machines is a good example.
We don't have any self-replicating machine shops today, yet we have a huge
industrial output that is essentially based on what machine shops do—and the
entire industrial system is self-replicating.
OTOH, the machine shop grew out of the blacksmith's shop, which *did* use
manual assistance to self-replicate.
Also, the greatest examples of inspiration in the nanotech field (e.g. Structural
DNA) derive from biology, which self-replicates.
How large and how closed this loop will be depends on economics, limitations
of chemistry and physics, and specific environments and applications (perhaps
starting with building machines that will refill expensive "inkjet" cartridges of 8
PNs). There will be some interesting lessons from the future success or
failure of Rep Rap (which is expecting to release Version 2 this year) and
 Approaches to Productive Nanosystems

Applications
z Product Results
z Low cost
z High performance
z High value
z Nanostructure Manufacturing Capabilities
z Arbitrarily complex
z Heterogeneous
z Molecular precision
z Long-
Long-range order
z Bulk quantities

Let’s just take a quick look at what kind of low-cost, high-performance,

high value products would become possible if we could put molecules
together into arbitrarily complex, heterogeneous, molecularly precise
nanostructures with long-range order, in bulk quantities.
Obviously, anything we can build now, we’ll be able to build better at
lower cost.
But there are some new applications that productive nanosystems will
make possible for the first time. There are three that, in my view, will
make the industrial revolution look as trivial as the next release of
Windows.

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Nanocube Pores

Using the nanofactory/nanocube approach, such an improved filter can be built using two types of
input 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 the
solid nanocubes. This figure shows an interface between pore and solid nanocubes. Even without
specialized 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, but
would exclude all infectious organisms. On the other hand, if the specialized pore blocks could be
functionalized to repel other molecules (such as sodium ions, as is done by aquaporins), then the filter
could 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 carbon
monoxide.

If the pore nanocubes were biocompatible, with functionalized pores of different sizes, then simply
changing the “blueprint file” would enable the nanofactory could produce a double-filter device that
screened blood for particular molecules such as urea—i.e. an insertable dialysis machine.

In a weight-limited, long duration mission, NASA could not afford to pack a dialysis machine. But in an
emergency, it would be very nice to have the capability to build one, or any of a vast array of equally
complex machines. Just as a printer can print both novels and blueprints, the flexibility of the NIAC
desktop 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 at

http://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 class
I is 0.5 to < 1 micron and can generally be only be done by carbon/charcoal adsorption.

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Silsesquioxane NAND Gate

With four types of nanocubes (conductor, insulator, electron donating

semiconductor, electron accepting semiconductor), we should be able
to build an NAND gate.
Because this circuit is not photolithographed, the 2nd “dopant” type
doesn’t need to be over-doped; this would be expected to increase
efficiencies.
Even more significantly, DNA-origami assembled electronics would no
longer be intrinsically limited to two dimensions, so circuit densities
per volume would increase significantly.
Cooling would get to be a very real problem, thought; but we’re out of time.

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PEM 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 (for
Proton Exchange Membrane, also called Polymer Electrolyte Membrane) fuel cell. The power density of a fuel
cell 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 control
these 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 need
to replace perfluorocarbon sulfonic acid (PFSA), This is the insulator (in blue, here) that allows protons to pass
through 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 to
maximize the catalytic effect. Work with specific platinum/silsesquioxane complexes has also been reported in
the literature, but I haven’t 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 carbon
particles mixed with poorly defined 5 nm-sized platinum group nanoparticles. The entire
membrane/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 for
Intermediate-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”, Master’s Thesis, Eindhoven :
Technische Universiteit Eindhoven, 2003.http://www.catalysis.nl/silicon_catalysis/people/rob_hanssen.php?topic=research)

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Killer App #1:

Printing Appliance

Productive nanosystems will make possible a 3D rapid prototyping printer—a nanofactory--

one that can fit on your desk and build a large variety of products with atomic precision.
The NASA Institute for Advanced Concepts funded a study on general purpose nanofactory
based on modules, and this concept is the result
The idea is to use chemistry to synthesize large molecules which would then be attached to
each other with top-down techniques. It turns out that all of the approaches to Productive
Nanosystems lead to this device. Depending on the size of the output envelope (and I don’t
mean length and width, but material/nanocomponent space) it may be a very big deal.
What is the first thing to build? Another nanofactory, of course-- perhaps a bigger one (as
illustrated on the right --the construction surface is optically flat, so it acts like a mirror). The
second thing to build is a machine that will refill your inkjet cartridges from cheap raw
materials. Then things could get interesting, because manufacturing costs go down as
capacity skyrockets, as build anything allowed in the machine’s output envelope.
For some applications, small and autotrophic nanofactories may be
necessary (e.g. space colonization). Unsupported special forces (like in the middle of
a desert) might also benefit from autotrophic nanofactories.

This shortcut I’ve discussed today, to use synthetic chemistry to build some sort of molecularly precise building block, and then use scanning probe microscopy
or DNA origami to connect them, would result in a nanosystem that would take advantage of the intersection between bottom-up and top-down methods. What
kinds of realistic products might be built out of a limited number of types of simple, molecularly precise, connectible nanocubes?
This modular nanocube approach does have some disadvantages, as Ralph Merkle as pointed out: a greatly reduced strength-to-weight
ratio, slower speed, and a much smaller range of things can be synthesized with an atomic mechanosynthetic assembler. My response is, well, yes, we won’t
be able to get the nine magnitudes of improvement that atomic mechanosynthesis could get, but I’ll be satisfied with three magnitudes, as long as I can have it
now. Well, more realistically, 5-8 years from now, depending on how much money and smart people we throw at it.
The Filtomat M102C high performance self-cleaning water filter pictured on top can clean 410 liters/minute with a screen area of 580
square centimeters. The smallest particle size particle that it can screen is 50 microns, though the manufacturer also makes thread filters going down to 3
microns.
Building these filters, and all the different filters in their product line, requires a serious investment in equipment: about a hundred people
with a few acres of manufacturing plants. A small-scale manufacturing facility that could build water filters in non-terrestrial locations would require about 280
square meters and a few tons of heavy equipment. With an advanced nanofactory, however, such huge manufacturing plants would no longer necessary. The
only necessities will be the desktop nanofactory appliance, energy, and equipment to supply of a few different types of molecularly precise nanoscale cubes.
Not only will a desktop nanofactory make it possible to have a much lower overhead for manufacturing support, but the final products
will be superior. The screening ability of an M102C water filter, for example, could be improved from 3 microns to .3 nanometers: an improvement of four
magnitudes. Since water vapor has a kinetic diameter of .265 nanometers, nothing else would get through (except some light gasses and small ions). Also, the
pressure drop of 14 kPa across the current membrane could be lowered to about 3 kPa.
Filter at http://www.filtomat.com/100-series/100-c-series.html; modeled in 3dmax at http://www.3dcafe.com/asp/industry.asp by Anthony Mcfadden

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Killer App #2:

Programmable Matter

Another interesting new machine that productive nanosystems could build is

programmable matter.
This is such a new thing that we have only imagined what we could do with it in
fiction.
That being said, DARPA just awarded a contract for it, and I’m very interested in
finding out what they get.
Dilbert cartoonist Scott Adams said, “

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Killer App #3:

Human Medicine and Enhancement

I’m only going to mention this because it always comes up.

People say, “with nanotechnology you can do put atoms exactly where you want
them, and you’re 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 a
time, how do you know where to put the atom (or molecule—let’s be generous) once
you got ahold of it?
If we don’t know, then all our nanoengineering is worthless.
OTOH, it appears that respirocytes, which are about as complex as toasters, might be
doable if biocompatibility problems are worked out.
And the printer appliance will lower the cost of microscale equipment that will help
you discover scientific knowledge –i.e. determine where the atoms in our bodies are
supposed to go.
At any rate, engineering is fairly predictable, science is not.
So I will not say anything about this topic.
Let’s get to work: understanding the four main approaches to productive
nanosystems.

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Approaches

z Structural DNA
z Bis-amino nanostructures
z Tip-Based Nanofabrication
z Diamondoid

Structural DNA – making the fastest advances

Bis-amino nanostructures – least studied
Tip-Based Nanofabrication – most conservative (already funded)
Diamondoid– highest payoff

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DNA Origami: 50 billion Smiley

Faces

Paul W. K. Rothemund, Folding DNA to create nanoscale

Courtesy Paul Rothemund
shapes and patterns, Nature Vol 440,16 March 2006

The first, and currently most popular approach to Productive

Nanosystems is what Paul Rothemund called DNA Origami, but the
field, in general terms, is morphing into Structural DNA – OTOH,
Rothemund already has 95 citation references for his seminal paper
and a MacArthur fellowship too, so I don’t think he minds too much.
Unfortunately, half a million dollars is not enough to buy a high
resolution TEM to help him extend his process into 3D (even though
conceptually it’s quite easy).

The property that makes DNA very valuable is it’s phenomenal

molecular recognition. With such an information-rich molecule, we
can build nanostructures, as Rothemund has done when he built 50
billion of these smiley faces, by himself, in two hours, with very high
yield. This is a lot of fast, concentrated happiness.

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Easily reproducible

Qian Lulu, et al., Analogic China map

constructed by DNA. Chinese Science Bulletin.
Dec 2006. Vol. 51 No. 24

Lulu’s paper described the technical problems they had with “Taiwan Island”.
Given the political situation in Taiwan, I’d agree; Taiwan might be a big
problem.
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 I
brought up Paul’s claim. I said, “You’ve got a high school student. Why don’t
you see if Paul is right?”
Well, Paul was right. This logo on the right was done by Mark’s high school
daughter.

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The DNA Origami Process

a. b.

d.
c. Figure a, b, and d from Paul Rothemund, Design of DNA origami, IEEE/ACM
International 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 M13mp18
virus. It is a simple bacteriaphage which has been sequenced (it has 7249 bases) and
is relatively cheap. You also need about 250 tiny helper strands, each of which is
specifically designed and synthesized so that half of it binds to one particular location
on 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 uniquely
complimentary sequences. This is because half of the helper strand matches a
segment on one side of the backbone; the other side of the same helper strand
matches a different segment on the backbone.
c. Many of the helper strands have finished most of the final backbone bending and
have completed many crossovers.
d. Final product
The process works as follows: First, buy about three trillion copies of the genome of the M13mp18 virus. This is
a circular, single stranded DNA, 7249 base pairs long, for about $30 from a biotech company such as New
England 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 a
high-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 to
measure a 5 microliter drop of solution from each of 250 tubes (the order doesn’t 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 or
Tris EDTA) and magnesium salt (Magnesium Mg++ ions neutralize negative charges on the DNA and allow the
single-stranded DNA to come together and form the double helix). Heat the mixture to near boiling (90° C) and
cool it slowly back to room temperature (20° C) 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 unique
sequences of the 250 helper strands that you order from the lab before starting the experiment.

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Pixelated DNA and Positioning

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

Of course, we can also write small letters. And patterns, remembering that that
computer electronics revolution is about writing small patterns. And keep in
mind 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 did
with individual atoms back in 1989.
So why isn’t this a big step backwards? DNA origami doesn’t require hundreds
of thousands of dollars worth of specialized equipment. More like $50 worth of
equipment and $2000 worth of input materials (though the AFM to see what you
built, 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 Rothemund’s DNA Origami –
Arizona State researchers built a 100 trillion probes in one step that can detect
specific 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 become
visible.

There’s also Lee, et. al., Site-Specific Control of Distances between Gold Nanoparticles. Angew. Chem. Int. Ed.
2007, 46, 9006 –9010 but it’s not very advanced. Neither is Park, et. al. DNA-programmable nanoparticle
crystallization, Nature January 31, 2008.

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Design-ahead: NanoEngineer-1

One important requirement for building productive nanosystems is is

to have CAD tools such as Nanorex’s free, open source software,
NanoEngineer. Version 1 will be released in April.
Note the “Order DNA” button in the middle.
There will be a Structural DNA Workshop at the Nanoscale Science &
Engineering Conference on August 18-19, 2008 at Oakland University
in Rochester, MI
http://www2.oakland.edu/research/nanotech/pages/index.cfm, where
attendees will be able to design structures, download the sequence to
a on-site oligomer synthesizer, mix up the resulting products in a PCR
machine, and then look at them with a AFM.

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Bis-Amino Acids and Bis-Peptides

z Inverse of solving the protein folding problem

z The proposed approach is an integration of known
techniques and designed to produce a broadly
applicable manufacturing process.
“Molecular Lego” Christian Schafmeister Scientific American, Feb 2007, 64-71

Another biomemetic approach begins with Christian Schafmeister’s bis-

amino acids.
The basic idea is that instead of trying to solve the protein folding problem,
Schafmeister turns the problem on it’s head, greatly simplifying it. Instead of
trying to understand the weak Van der Wals and electrostatic forces to
predict the self-bending of polypeptide, the idea is to design amino-acid-like
molecules that covalently bond to their neighbor in two places; thereby
making rigid and exactly predictable structures.
One of the things that nice about this approach is that the basic chemical
techniques have been around for decades.

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Bis-Amino Acids and Bis-Peptides

Schafmeister has synthesized many of these bis-amino acids, and

using solid-phase oligomer synthesis, has connected them into
several dozen small bis-peptides. The three bis-peptides on the right,
for example, have all been synthesized.

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Bis-Peptides Productive Nanosystem

IN: (NH4)2CO3, OUT:
H2O, CO2, trace Machine
elements Solution

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

24
 Approaches to Productive Nanosystems

Protein Engineering:
Designer Enzymes
IN: (NH4)2CO3, OUT:
H2O, CO2, trace Machine
elements Solution

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

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

Houk, Science, March 7, 2008 (Retro-Aldol) - The aldol reaction is a key

process in living organisms associated with the processing and synthesis of
carbohydrates. This reaction is also widely used in the large-scale production
of 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 occurring
biocatalysts is a challenge for protein engineering and is a critical test of our
understanding of enzyme catalysis. Here we describe the computational
design of eight enzymes that use two different catalytic motifs to catalyse the
Kemp elimination—a model reaction for proton transfer from carbon—with 25
measured rate enhancements of up to 105 and multiple turnovers. Mutational
analysis confirms that catalysis depends on the computationally designed
 Approaches to Productive Nanosystems

Tip-Based Nanofabrication:
Atomically Precise Manufacturing
z The ability to produce 3D structures
with top-
top-down control and atomic
precision.

z The inevitable result of continued

improvements in ultra-
ultra-precision
manufacturing (IC manufacturing
and others)

z The proposed approach is an

integration of known techniques
and designed to produce a broadly
applicable manufacturing process.

http://www.zyvexlabs.com/

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

26
 Approaches to Productive Nanosystems

Patterned Si ALE

STM tip removes A precursor gas is Completed deposition

H atoms from the used to dose the is verified and then the
Si surface surface. Protected Si deprotection/patterning
atoms are deposited is repeated.
only where H has
been removed.

The way it works is conceptually quite simple:

First, in a high vacuum, the STM tip removes hydrogen atoms from the
passivated silicon surface.
Second, standard atomic layer epitaxy is applied to the entire surface
(but of course, the silicon only binds to where there are dangling
bonds left from where the hydrogen atoms were pulled off.
Third, repeat as many times as necessary, perhaps with other types of
atoms (i.e. germanium).

27
 Approaches to Productive Nanosystems

Demo of Patterned Si ALE

Courtesy Joe Lyding UI Urbana-Champaign

Professor Joe Lyding of University of Illinois at Urbana-Champaign, a

member of Zyvex’s team, has achieved some success with this
method, though as you can see, some work needs to be done in
making sharper needles and controlling them more precisely.

28
 Approaches to Productive Nanosystems

Tip Arrays
z Dip Pen
z 55,000 tips
z Thermally actuated
z Multiple inks
z 15 nm resolution
z Fast

The big problem, of course, is throughput.

Zyvex plans to imitate Chad Mirkin’s work on multiple tips, which is
illustrated here.

55 000 miniature images of a US nickel reproduced by dip-pen

lithography are shown in the background. It took 30 minutes. (Each
circle is only twice the diameter of a red blood cell.) Each image (in
foreground), showing Thomas Jefferson's profile, is made from a
series of 80 nm dots.

Salaita, Chad A. Mirkin, et al., Angew. Chem. Int. Ed. November 6 issue
Salaita, 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&vie
w=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=4fe038c67c68e5df
6e206ecb317cfc59

29
 Approaches to Productive Nanosystems

Diamondoid

DCB6-Si dimer
placement 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 we
need to be able to build individual carbon bonds.
Wilson Ho already proved this for individual silicon atoms, and the carbon binding
reaction has been thoroughly explored with DFT algorithms. On the right we have an
example tooltip from the DFT work, on the left we have a snapshot from the Burch video
of 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 break
covalent bonds.
[1] Wilson Ho, “Single Molecule Chemistry”, Journal of Physical Chemistry, 117 (2002): 11033-11061, L.J. Lauhon and W. Ho, “The
Initiation 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", Annual 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 two
group 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 are
part of two substituted adamantane (C10H16) frameworks that position and orient them. The two substituted adamantane frameworks are
rotated and fused together to make a biadamantane structure (Figure. 1), creating very high-angle strain in the bonds between the two
supporting atoms and the dimer. This molecule, a bi-silaadamantane dicarbon, is only the tip of a complete tool. In a complete
mechanosynthetic apparatus, a somewhat larger version of this molecule would likely be required, so that the active tip could be held and
positioned 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 time
have simulated two important things about this structure:
The successful interaction of the DCB6-Ge tool at room temperature (and the DCB6-Si tool at 80ºK) with the C(110) dehydrogenated
diamond 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.htm
Jingping 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. 62–70, 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
30
Theoretical Nanoscience, Vol. 1. 71–80, 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
C(110) Surface Using Si/Ge/Sn Based Dimer Placement Tools" Journal of Computational and Theoretical Nanoscience Vol 3 1 14 2006
 Approaches to Productive Nanosystems

Diamondoid

• Rigid, well-characterized nanomachinery is good

(made of diamond, CNTs, oxides, and other
crystalline and/or regular structures)
• Deterministic processes may be more difficult
than thermodynamically-driven ones, but have
better 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, and
A deterministic process with error correction

The good news is that the Robert Freitas, Ralph Merkle and their cohorts
expect to run the first experiments this year to prove the conservative DFT
predictions.

31
 Approaches to Productive Nanosystems

Other 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 don’t seem as likely or as
rewarding.
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 I’ve talked about involve
assembly techniques for structures.
It turns out that these structures might act as templates to larger modules.

32
 Approaches to Productive Nanosystems

Modularization and Templating:

DNA-mediated Nanocube Assembly

For example, here a G1 silsesquioxane nanocube is linked to short

helper strand and a section of the scaffold of structural DNA.
Currently, DNA origami is only two dimensional, and as any electrical
engineer knows, for electronic circuits we need many layers; for
interconnects, insulated crossovers, and gates. But conceptually, that
problem is solvable in ways that are not possible for micro
photolithography, though one problem is connecting nanocubes to
each other once they are held in close proximity to each other.

33
 Approaches to Productive Nanosystems

Connecting Nanocubes

Photochemical bonding

Zinc fingers

Pyrimidine photodimerization Diels-Alder cycloaddition

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 controllable
means; e.g. triggering by light, electric fields or currents, mechanical pressure, or
simply by holding reactive molecules near each other until thermal energy overcomes
the reaction barrier.
Keep in mind that this connection method must be considered when designing the
nanocube in the first place. You can’t just glue arbitrary atoms to gray blocks, as
deceptively shown in these four schemes.
The ones on the left are activated by photons of different wavelengths; the one on the
upper right has a connection scheme based on amino acids that is activated by zinc
ions. The one on the lower right, which uses the cycloaddition process, works
spontaneously at room temperature, so the nanocubes would need to be kept from
the 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 Advanced
Concepts, 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 (2π + 2π)
cycloaddition reactions on exposure to UV light at 254 nm. Photodimerization in pyrimidine-substituted dipeptides, BRIAN LOHSE, P. S.
RAMANUJAM, SØREN HVILSTED and ROLF H. BERG, J. Peptide Sci. 11: 499–505 (2005) DOI: 10.1002/psc.645
http://www.polymers.dk/publikation/pdf/101%20J%20Peptide%20Sci%2005.pdf
Markus Krummenacker proposed using Diels-Alder cycloaddition to connect Molecular Building Blocks in “Steps Towards Molecular
Manufacturing”, Chemical Design Automation News, 9, (1994) p. 1 and 29-39, http://www.n-a-n-o.com/nano/cda-news/cda-news.html. It’s
called Diels-Alder cycloaddition reaction, and it is the concerted bonding together of two independent pi-electron systems to form a new
ring of atoms. http://www.cem.msu.edu/~reusch/VirtualText/addene2.htm Unfortunately, I haven’t yet figured out how to hang an open
diene 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

34
 Approaches to Productive Nanosystems

Silsesquioxane NAND Gate

So with four types of nanocubes (conductor, insulator, electron

donating semiconductor, electron accepting semiconductor), we
should be able to build an NAND gate.
Because this circuit is not photolithographed, the 2nd “dopant” type
doesn’t need to be over-doped; this would be expected to increase
efficiencies.
Even more significantly, DNA-origami assembled electronics would no
longer be intrinsically limited to two dimensions, so circuit densities
per volume would increase significantly.
Cooling would get to be a very real problem, thought; but we’re out of time.

35
 Approaches to Productive Nanosystems

CNT/DNA NAND Gate

Mark Sims may have discovered an easier to make DNA-assembled

nanoNAND gates.

36
 Approaches to Productive Nanosystems

Functional Pattern

37
 Approaches to Productive Nanosystems

Functional pattern extended:

nano-breadboard

38
 Approaches to Productive Nanosystems

Preferential bonding of 3 DNA Templates

Q Q

S R

This illustrates one way of using hierarchies to build circuits.

39
 Approaches to Productive Nanosystems

Hierarchical, Direct, and 3D Self-Assembly

of Nanotile Polyominoes

Hierarchical

3D Di
re
ct

And hierarchical patterns can be continued in other ways, some of

which can be three dimensional.

40
 Approaches to Productive Nanosystems

Guided Hierarchical Assembly

Stage
N

N-1

N-2

N-3
..
.
Individual bis-
1 proteins

41
 Approaches to Productive Nanosystems

Molecular Actuators
Annulenes Poly calix[4]arene-bithiophene

Interlocking Rotaxane Dimers

Azobenzene

Jimenez-Molero, Dietrich-Buchecker, and Sauvage, Chemically Induced Contraction and

Stretching of a Linear Rotaxane Dimer, Chem. Eur. J. 2002, 8, No. 6

Note that I’ve been concentrating on structure – that’s because it is the easiest. But structure
is primary because none of the other three core capabilities (computation, sensing, and
motion) are possible without structure. For productive nanosystems, we also need the other
core capabilities. Fortunately, there are many possibilities, and here are some for molecular
actuators.
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 a
hardware store.
And it will be another challenge to integrate these standardized motors into standardized
nanostructures 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-motive
processes. 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 reduction
reactions that require the addition or subtraction of a proton or larger ion. However, some researchers have been able to build
photon-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, and
bacteria flagellar motors all depend on ATP for energy, so they are all proton-motive or ion-motive processes. Biological processes
that use ion gradients, DNA, or ATP are inferior to electromechanical actuators because, among other things, electrons move
faster than protons, because purely electrical processes will require less material input, and because moving and constraining
electrons is much easier.

The F0-F1 ATPase, the kinesin, myosin, and dynein types of protein molecular machines, and bacteria flagellar
motors all depend on ATP for energy, so they are all proton-motive or ion-motive processes. Biological processes
that 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, and
because 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-understood
technology that connect electric currents to redox reactions. Since nanobatteries have already been built, we
might somehow protonate actuators with battery-type reactions that are driven by varying electric currents from
nearby nano-wires.
Some of these actuators are very difficult to build: the yield for these actuators is very low (the yield for the
interlocking 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 manner
Hydrolysis of the urethane bond
kelly 2001, 1999
42
Manfred Schliwa, Molecular Motors, Wiley-VCH, 2003 ISBN 3527605657
 Approaches to Productive Nanosystems

Nanocube Motors

On the other hand, a nanocube-compatible motor like this might be

available 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 have
dreamed of.
But what can we do today?

43
 Approaches to Productive Nanosystems

Conclusion
z Atomic Precision, not size
z Conservative machines, not novel properties
z Nanosystems that produce nanocomponents
and assemble them into nanosystems
z Focus on approaches:
z Mutually different from each other
z Have huge world-
world-changing potential
z Not currently receiving funding
z At or close to experimentally verified

A DARPA workshop would sharpen focus

Nanomanufacturing depends on atomically precise systems made up

of conservatively-designed nanodevices & nanomachinery, not novel
nanoparticles & nanomaterials with novel properties.
The ultimate goal of Nanomanufacturing is Productive Nanosystems—
this is what will bring about a disruptive industrial revolution that will
give us affordable tools in the quantity necessary to discover more
novel scientific properties at the nanoscale.
To meet these challenges, we should cover all our bases, especially
the unfunded, realistic, high payoff approaches.
Thank you.

44
 Approaches to Productive Nanosystems

PN 2 In PN 2 Out
BIO 1

PN 3 In
PN 1 Out PN 2

PN 1 PN 3

PN 3 Out
PN 4
PN 1 In

PN 4 Out PN 4 In

BIO 2 CHEM 1

Let me clarify first: Self-replication is not really necessary (and is very difficult to pack it into a small
package; plus nanoscale self-replication is probably undesirable, at least on this planet); But some sort
of 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 is
a good example. We don't have any self-replicating machine shops today, yet we have a huge industrial
output that is essentially based on what machine shops do. And the entire industrial complex can (and
does) 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 from
biology, which self-replicates.
Here we have a replication loop of four simple productive nanosystems; none of which can build the
components out of which it is made of; yet the system of four nanosystems, when augmented with
simple biological and chemical building blocks, does replicate.
How large and how closed this replication loop will be depends on economics, limitations of chemistry
and 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 refill
expensive "inkjet" cartridges). There may be some interesting lessons from the future success or
failure of macroscale Rep-Rap (which is expecting to release Version 2 this year – and *is* thinking
about how to make a preprocessor that will make feedstock out of plastic bottles). When we return to
the Moon, a self-replicating machine shop/foundry would be useful.
Note that at the nanoscale, the difference between biology and chemistry starts disappearing. The
thing that is interesting is that molecular biologists look at cellular mechanisms like mechanical
engineers look at cars – as machines.
Biology got there first, but its machines are evolved; not necessarily easy to analyze. But us engineers
need to have some humility so that we can learn from Mother Nature (even if she is a heartless
psychopath).
Both mechanical and biological paradigms can work at the nanoscale; mechanical approaches may be
easier to analyze and therefore provide more design options—when Mother Nature gets herself into an
evolutionary dead end, she’s too stupid to get out (though sometimes our being smarter doesn’t
always help).

45