Technology and the future
of medicine
The promise and perils
of nanotechnology
Michael T. Woodside
National Institute for Nanotechnology
and Department of Physics
Outline
1. Introduction, definitions, background
2. Promise and peril at the level of science fiction and hype/doom
3. Constraints on the vision imposed by scientific realities
4. Specific examples of promising, realistic, near-term
nanotechnology applications:
computation with quantum-dot cellular automata
DNA origami
synthetic biology
4. Specific examples of realistic, near-term concerns with
nanotechnology
What is “nanotechnology”?
Many possible definitions
“Nanoscience is the study of phenomena and manipulation of
materials at atomic, molecular and macromolecular scales, where
properties differ significantly from those at a larger scale.”
“Nanotechnologies are the design, characterisation,
production and application of structures, devices and systems
by controlling shape and size at nanometre scale.”
Royal Society (2004)
Nanoscience and nanotechnologies:
opportunities and uncertainties
http://www.nanotec.org.uk/finalReport.htm
Drexler-Merkle differential gear
(model), 1995
Richard Feynman: “There’s plenty of room
at the bottom”
Address to American Physical Society, 1959:
I would like to describe a field, in which little has been done, but in which an enormous amount can be done in
principle. This field is not quite the same as the others in that it will not tell us much of fundamental physics (in
the sense of, "What are the strange particles?") but it is more like solid-state physics in the sense that it might
tell us much of great interest about the strange phenomena that occur in complex situations. Furthermore, a
point that is most important is that it would have an enormous number of technical applications. What I want
to talk about is the problem of manipulating and controlling things on a small scale.
I will not now discuss how we are going to do it, but only what is possible in principle – in other words, what is
possible according to the laws of physics. I am not inventing anti-gravity, which is possible someday only if the
laws are not what we think. I am telling you what could be done if the laws are what we think; we are not doing
it simply because we haven't yet gotten around to it.
How do we write small?
Information on a small scale
The marvelous biological system
Problems of lubrication and waste heat
Rearranging atoms
…
Popularisation: Eric Drexler
Inspired by Feynman,
molecular biology
Influenced by ideas of
“limits to growth” in a
finite world
Controversial reception in
scientific community
Drexler-Smalley debates
2001-2003
Impact on public perception
1986
Nanotechnology: Promise
Many possibilities have been conceived:
• New materials with enhanced properties: strength, durability, functionality,…
invisibility cloak
diamandoid
coloured nanoparticles
carbon nanotube space elevator
Nanotechnology: Promise
Many possibilities have been conceived:
Quantum computers
Smartdust
Assemblers
wirelessly networked
nanosensors
Use “quantum wierdness”
to solve intractable
problems
Combination with AI:
swarm of intelligent
computation
Assemble anything from
atomic constituents
“molecular nanotechnology”
Nanotechnology: Promise
Many possibilities have been conceived:
Medical “nanobots”
• Drug delivery
• Distributed sensing and real-time monitoring
• Enhanced physical capabilities: strength,
endurance, …
• Enhanced immune system
• Cure diseases in real-time
• Interface with neurons: expand
mental capabilities
Combine with AI
and synthetic biology
• Cellular repair
• Longevity
The motivation for molecular nanotechnology
1. Biology provides proof of the feasibility of nanotechnology, supplies a
fully functional model
2. Structures that are able to self-replicate exist in Nature
3. Nanoscale machines do not violate any laws of physics, in principle
4. We can conceive of “bottom-up” fabrication, even starting from the
atomic level
5. Structures where atoms are arranged precisely exist in Nature
Hence we should be able to build nanoscale, self-replicating,
programmable “assemblers” capable of manufacturing
arbitrary objects from atomic constituents
The basic concept
Molecular nanotechnology:
“Thorough, inexpensive control of the structure of
matter based on molecule-by-molecule control of
products and byproducts of molecular
manufacturing.”
Unbounding the Future, Drexler et al., 1991
Based on:
The concept of the molecular “assembler”: pick up and manipulate
atoms, establish chemical bonds between arbitrary atoms
Incorporation of assemblers into self-replicating machines
Molecular-scale computation, programming, data storage,
and integration
The Promise of Molecular Nanotechnology
“Imagine a manufacturing technology capable of making trillions of
tiny machines — each the size of a bacteria. Each machine could
contain an onboard device programmed to control a set of molecular
scale tools and manipulators. An individual machine could be
designed to manufacture superior materials, convert solar energy to
electricity, or even, ultimately, enter the body to fight disease and
aging at the cellular and molecular level. Materials hundreds of times
better than today’s best materials, vastly more powerful computers,
precise machinery that doesn’t wear out, and a revolution in clean
manufacturing are but a few of the predicted benefits of applying
these new machines.”
source: Zyvex home page
www.zyvexlabs.com/Publications2010/WhitePapers/MolecularNanotech.html
…but many potential dangers lurk!
Nanotechnology: Perils
Again, many possibilities have been conceived:
New toxic materials,
easily spread and hard
to contain
Tiny, invisible weapons
Self-replicating weapons
Weapons control impossible:
hard to embargo, hard to verify
“GI Joe” (2009)
Nanotechnology: Perils
More insidious dangers:
Undetectable and pervasive
surveillance: totalitarian
nightmare
Neural interfaces:
thought control/possession
Medical nanobots: remote
control of health
Consequences of system crashes in enhanced bodies and minds
Change in the economic basis of society
Nanotechnology: Perils
Higher-level dangers:
Societal fragility: consequences of network
crashes in complex systems run by
pervasive smartdust mesh
Emergent
complexity
2002
Swarm
intelligence
2000
Nanotechnology: Perils
Ultimate nightmare scenarios:
Self-replication of
assemblers, “grey goo”
Self-replicating disassemblers
(Un)Fortunately reality intrudes…
No obvious way forward for many of the dreams
Simple example: carbon nanotubes as ideal electrical nanowire
• 1 nm wide
• up to mm long
• very low electrical
resistance
• can be metal or
semiconductor
Carbon-based
electronics!
But: 15 years on, still can’t grow them to order—so how can they form the
basis of a technology to replace Si (purity of 99.9999999% is routine)?
(Un)Fortunately reality intrudes…
No obvious way forward for many of the dreams
Simple example: carbon nanotubes (CNT) as ideal electrical nanowire
Suppose we could make CNTs
to order…
…circuits would be 10,0001,000,000 denser!
• How do we connect to the
outside (“macro”) world?
• How do we check that it’s
built properly?
Practical problems that are “just
engineering”… but are very hard
and have no obvious solution!
(Un)Fortunately reality intrudes…
More basically: flawed philosophical premise for molecular nanotechnology
Is it always possible to build today anything that we can
conceive, provided it does not violate physical laws?
NO!
And it never has been…
Consider dream of human-powered flight:
Leonardo’s ornithopter, 1485
First human-powered flight, 1977
400 years later
The laws of physics must still be respected
Issues ranging from the mundane to the fundamental:
• Heat dissipation: as physical size decreases and density of components
increases, waste heat becomes a problem just as in computers today
• Friction: as parts scale down to near-atomic dimensions, what acts as
a lubricant? How do we control inter-atomic interactions so precisely
that some atoms stick together whereas others slide/move freely?
• Fluctuations become relatively more important as size decreases
• Quantum phenomena become
inescapable at atomic scales:
wave/particle duality, tunneling,
probabilistic vs deterministic
behaviour,…
Many pieces of basic science missing
Atomic-level control over manufacturing is chemistry!
Combinations of
atoms and geometries
are constrained by
properties of elements
and chemical bonding
We cannot make arbitrary
structures and compositions
—even relatively simple
structures can be very hard
to make!
cubane (explosive)
Biology as a template
Biological systems are most effective and efficient manufacturing systems
known:
DNA polymerase: reliable
replication, with error rate
~ 1 in 10,000,000,000
F1F0 ATP synthase: most
efficient motor known
(~90-100%)
Biology as a template
Based on simple processes (e.g. polymerisation)
Create one basic geometry (linear chains)
Rely on self-interactions to generate functional structures
automatically (“self-assembly”, “folding” in biology)
But we still can’t reliably predict folding for known structures
after decades of intensive research!
How do we design, de novo, both novel chemistries or functions,
and the folds protein folds to achieve them?
Yet another fundamental roadblock:
heterogeneity
How can one manufacture complex assemblies efficiently and reliably
without uniform, quality parts?
One can’t!
As in regular manufacturing, heterogeneity inhibits complexity—need
standardised, interchangeable parts
Self-assembly is statistical, not deterministic: will always yield mixtures
and distributions of products
Complex processes with multiple steps: need very reliable yield
1 step: 97% correct yield
20 steps: 50% worthless junk!
Comparisons of heterogeneity
Boltzmann entropy (disorder):
Shannon entropy (information):
SBoltzmann kB ln
Define generalised negentropy:
H Shannon i pi log2  pi 
S   lnerror, purity, precision,...
Taq polymerase
optimised PCR
nanoparticle
size dispersion
0
transcription
crystal purity
DNA replication
5
polymer
dispersion
human typing
10
precision
machining
15
book
typesetting
20
telescope
mirror
25
integrated
circuit components
30
digital
computing
(> 50)
Solutions
1. Do it right in the first place
Strong driving force
(thermodynamics)
2. Fix it up later
Error correction mechanism
(kinetics)
3. Ignore it
Fault-tolerant architectures
“Practical” nanotechnology
Very diverse, encompasses work at the intersection of physics, chemistry,
biology,and engineering
Specific examples of nanotechnology research in progress today:
1. Building structures by manipulating individual atoms:
“Quantum dots”, atomic corrals, new architectures
for computation
2. Biology as a template for nanotechnology:
Biomotors, DNA origami, synthetic biology
Manipulating atoms: STM
Scanning tunneling microscope: allows you to “see” individual atoms
electrons
“tunnel”
from sharp
tip into
sample
Nobel Prize 1986
Manipulating atoms: STM
Image atoms:
Si atoms
Push atoms around with tip
to build structures:
Manipulating atoms: STM
Build structures
to manipulate
electron waves:
ring of atoms
on metal
surface
“ripples”
from
electron
waves
Different atom-corral structures
Interesting interference effects
Electron at focal point: waves
interfere to generate “ghost”
Electron not at focal point: no
interference
Manoharan et al Nature (2000)
Powerful tool for science
but not technology yet!
Remarkable achievement of a fundamental step: direct mechanical
manipulation of individual atoms
Very technically challenging:
• ultra-stable instrument
• low temperature (a few degrees above absolute zero!)
• very constrained in choices of materials
• highly error prone
Not “routine” even after 20 years of research
Patterning electronic states with STM
2.25 Å
3.84 Å
7.68 Å
Generate “dangling bond”
by removing H atom
Silicon surface with H atoms
Patterning electronic states with STM
10 nm
single
dangling
bonds
Wolkow lab, UofA
React to add metals or molecules
But these bonds will also interact between each other
Interacting dangling bonds
Four dangling bonds next to each other:
Interacting dangling bonds
Nearby bonds “tilt” the occupancy of the quartet:
Quantum-Dot Cellular Automata
Cellular automaton: grid of
cells with discrete states (eg
on/off). The state is set by the
state of neighboring cells
following an algorithm
Conway’s Game of Life
wire
fanout
inverter
High density, low power
consumption computation
Lent et al Nanotechnology (1993)
QCA computation
Biology as a template for nanotechnology
Hijack the self-assembly properties of biological molecules:
“DNA origami”
uses predictable
basepairing
interactions to
form geometric
structures
DNA origami: self-assembled shapes
Rothemund Nature (2006)
DNA origami: self-assembled shapes
DNA origami: lockable box
Andersen et al
Nature (2009)
DNA origami: larger structures
Douglas et al
Nature (2009)
DNA origami: larger structures
Powerful method:
• Complex structures
• Simple ingredients
• Self-assembly: high
throughput
But…
• Limited repertoire
of materials
• Limited range of
environments
• No error correction?
Motor proteins: linear motors
Motor proteins move cargo around cell
kinesin
Langford lab
microtubule
vesicle
microtubule
Yildiz et al., Science 2003
Myosin V walks
along actin
filaments
hand-overhand motion
Motion of a single kinesin molecule
Discrete 8 nm steps seen in optical trap:
350
300
Position (nm)
250
200
Native
squid
kinesin
(LpK)
150
100
8 nm
50
stochastic dwell times
0
-50
0
1
2
3
4
5
6
Time (s)
7
8
9
10
11
Asbury et al.,
Science (2003)
Motor proteins: rotary motor
Enzyme ATP synthase: makes ATP, the energy currency of the cell
Functions as a rotary motor:
H+ gradient drives rotation of
axle (γ) and hence enzymatic
activity of α, β subunits
Wang & Oster
Nature (1998)
Track dye-labelled molecules:
fluorescent actin
Boyer and Walker
Nobel Prize 1997
discrete
steps
Yasuda et al., Cell 1998
Noji et al., Nature (1997)
Synthetic biology
Fusion of biology and engineering: engineering entirely new biological
functions and systems
Goes beyond standard genetic engineering: improved designability
Sprinzak & Elowitz Nature (2005)
Synthetic biology
Standardized process for bioengineering:
Synthetic biology examples
E. coli engineered to take pictures
Levskaya et al Nature (2005)
Bacterium with artificial chemicallysynthesised genome:
Gibson et al Science (2010)
“Genome: bought the book. Hard to read.”
“Synthesis: can write DNA. Little to say.”
Nanotechnology and safety
“Grey goo” is not what we should be worrying about!
Self-replicating organisms a potential worry from synthetic biology
More prosaically: nanotoxicology
Not just a question of materials: properties and
effects may also depend on size and shape, as
seen for metal oxide nanoparticles (e.g. used
in sunscreens)
ZnO NPs of different size
Certain forms of carbon nanotubes
can have asbestos-like toxicity
asbestos fibres
CNTs
Nanotoxicology
Nanoparticles can partially
denature proteins
Lacerda et al
ACS Nano (2010)
Nanoparticles can modulate
lipid membrane structure
Dawson et al
Nature Nanotech (2009)
Nanotoxicology
Many uncertainties
Many questions unclear:
What is important: Dose by mass? By surface area? How do we evaluate
toxicity?
How do the properties changes with time (e.g. aggregation)?
Where do the substances end up (life cycle analysis)?
What is the level of exposure from different environments?
Is any aspect of toxicology predictable from bulk material? Shape?
Size? Can it be modeled?
Risks must be framed appropriately