Biology outmatches futurists' most elaborate fantasies for molecular robots
By George M. Whitesides
Among the promised fruits of nanotechnology, small machines have
always stood out. Their attraction is straightforward. Large
machines--airplanes, submarines, robotic welders, toaster ovens--are
unquestionably useful. If one could take the same ideas used to design
these devices and apply them to machines that were a tiny fraction of
their size, who knows what they might be able to do? Imagining two
types of small machines--one analogous to an existing machine, the
second entirely new--has captured broad attention. The first is a
nanoscale submarine, with dimensions of only a few billionths of a
meter--the length of a few tens or hundreds of atoms. This machine
might, so the argument goes, be useful in medicine by navigating
through the blood, seeking out diseased cells and destroying them.
The second--the so-called
assembler--is a more
radical idea, originally
proposed by futurist K.
Eric Drexler. This
machine has no
macroscopic analogue (a
fact that is important in
considering its ultimate
practicality). It would be a
new type of machine--a
universal fabricator. It
would make any structure,
including itself, by
atomic-scale "pick and
place": a set of nanoscale
pincers would pick
individual atoms from their
environment and place
them where they should
go. The Drexlerian vision
imagines society transformed forever by small machines that could
create a television set or a computer in a few hours at essentially no
cost. It also has a dark side. The potential for self-replication of the
assembler has raised the prospect of what has come to be called gray
goo: myriads of self-replicating nanoassemblers making uncountable
copies of themselves and ravaging the earth while doing so.
Does the idea of nanoscale machines make sense? Could they be
made? If so, would they be effectively downsized versions of their
familiar, large-scale cousins, or would they operate by different
principles? Might they, in fact, ravage the earth?
We can begin to answer these intriguing questions by asking a more
ordinary one: What is a machine? Of the many definitions, I choose to
take a machine to be "a device for performing a task." Going further, a
machine has a design; it is constructed following some process; it uses
power; it operates according to information built into it when it is
fabricated. Although machines are commonly considered to be the
products of human design and intention, why shouldn't a complex
molecular system that performs a function also be considered a
machine, even if it is the product of evolution rather than of design?
Issues of teleology aside, and accepting this
broad definition, nanoscale machines already
do exist, in the form of the functional molecular
components of living cells--such as molecules
of protein or RNA, aggregates of molecules,
and organelles ("little organs")--in enormous
variety and sophistication. The broad question
of whether nanoscale machines exist is thus
one that was answered in the affirmative by
biologists many years ago. The question now
is: What are the most interesting designs to use
for future nanomachines? And what, if any,
risks would they pose?
Cells include some molecular machines that
seem similar to familiar human-scale machines: a rotary motor fixed in
the membrane of a bacterium turns a shaft and superficially resembles
an electric motor. Others more loosely resemble the familiar: an
assembly of RNA and protein--the ribosome--makes proteins by an
assembly linelike process. And some molecular machines have no
obvious analogy in macroscopic machines: a
protein--topoisomerase--unwinds double-stranded DNA when it
becomes too tightly wound. The way in which these organelles are
fabricated in the cell--an efficient synthesis of long molecules, combined
with molecular self-assembly--is a model for economy and organization,
and entirely unlike the brute-force method suggested for the assembler.
And as for ravaging the earth: in a sense, collections of biological cells
already have ravaged the earth. Before life emerged, the planet was
very different from the way it is today. Its surface was made of inorganic
minerals; its atmosphere was rich in carbon dioxide. Life rapidly and
completely remodeled the planet: it contaminated the pristine surface
with microorganisms, plants and organic materials derived from them; it
largely removed the carbon dioxide from the atmosphere and injected
enormous quantities of oxygen. Overall, a radical change.
Cells--self-replicating collections of molecular nanomachines--completely
transformed the surface and the atmosphere of our planet. We do not
normally think of this transformation as "ravaging the planet," because
we thrive in the present conditions, but an outside observer might have
thought otherwise.
So the issue is not whether nanoscale machines can exist--they already
do--or whether they can be important--we often consider ourselves as
demonstrations that they are--but rather where we should look for new
ideas for design. Should we be thinking about the General Motors
assembly line or the interior of a cell of E. coli? Let's begin by
comparing biological nanomachines--especially the ultimate
self-replicating biological system, the cell--with nanoscale machines
modeled on the large machines that now surround us. How does the
biological strategy work, and how would it compare with a strategy
based on making nanoscale versions of existing machines, or a new
strategy of the type suggested by the assembler?
Molecular Copy Machines
The cell is a self-replicating structure. It takes in molecules from its
environment, processes some of them for fuel, and reworks others into
the pieces it uses to make, maintain, move and defend itself. DNA stores
the information needed for fabrication and operation from one generation
to the next. One kind of RNA (messenger RNA, or mRNA) serves as the
temporary transcript of this information, "telling" ribosomes which protein
to make. Membranes provide compartments that enclose the working
parts, house portals that control the flux of molecules into and out of the
cell, and hold molecules that sense the cell's environment. Proteins
(often cooperating with other molecules) build everything in the cell and
move its parts when they must be moved.
The strategy adopted by
the cell to make its
parts--and thus to
replicate and maintain
itself--is based on two
ideas. The first is to use a
single, conceptually
straightforward chemical
process--polymerization--to
create large, linear
molecules. The second is
to build molecules that
spontaneously fold
themselves into
functional,
three-dimensional
structures. This two-part
strategy does not require
a difficult and
sophisticated three-dimensional pick-and-place fabrication: it simply
strings beads (for example, amino acids) together into a necklace (a
polypeptide) and lets the necklace self-assemble into a machine (a
protein). Thus, the information for the final, functional, three-dimensional
structure is coded in the sequence of the beads. The three most
important classes of molecules in the cell--DNA, RNA and proteins--are
all made by this strategy; the proteins then make the other molecules in
the cell. In many instances proteins also spontaneously associate with
other molecules--proteins, nucleic acids, small molecules--to form larger
functional structures. As a strategy for building complex,
three-dimensional structures, this method of linear synthesis followed by
various levels of molecular self-assembly is probably unbeatable for its
efficiency.
The cell is, in essence, a collection of catalysts (molecules that cause
chemical reactions to occur without themselves being consumed) and
other functional species--sensors, structural elements, pumps, motors.
Most of the nanomachines in the cell are thus, ultimately, molecular
catalysts. These catalysts do most of the work of the cell: they form the
lipids (fats, for instance) that in turn self-assemble into the flexible sheet
that encloses the cell; they make the molecular components necessary
for self-replication; they produce the power for the cell and regulate its
power consumption; they build archival and working information storage;
and they maintain the interior environment within the proper operating
parameters.
Among the many marvelous molecular machines employed by the cell,
four are favorites of mine. The ribosome, made of ribosomal RNA
(rRNA) and protein, is a key: it stands at the junction between
information and action--between nucleic acids and proteins. It is an
extraordinarily sophisticated machine that takes the information present
in mRNA and uses it to build proteins.
The chloroplast, present in plant cells and
algae, is a large structure that contains arrays
of molecules that act as tuned optical antennas,
collect photons from sunlight and employ them
to generate chemical fuel that can be stored in
the cell to power its many operations. The
chloroplast, incidentally, also converts water to
the oxygen that so contaminated the
atmosphere when life first emerged: the stuff on
which our lives depend was originally a waste
product of cellular light-harvesting!
The mitochondrion is the power station: it
carries out controlled combustion of organic
molecules present in the cell--typically
glucose--and generates power for the system.
Instead of pumping electrons through wires to
run electric motors, it generates molecules of
ATP that move through the cell by diffusion and that are essential
contributors to many biological reactions.
The flagellar motor of bacteria is a specialized but particularly interesting
nanomachine, because it seems so similar to human-scale motors. The
flagellar motor is a highly structured aggregate of proteins anchored in
the membrane of many bacterial cells that provides the rotary motion
that turns the flagella--the long whiplike structures that act as the
propeller for these cells and allow them to propel themselves through
water. It has a shaft, like an electric motor, and a structure around the
shaft, like the armature of a motor. The similarity between flagellar and
electrical motors is, however, largely illusory. The flagellar motor does
not act by using electric current to generate moving magnetic fields;
instead it uses the decomposition of ATP to cause changes in the shape
of the molecules that, when combined with a sophisticated molecular
ratchet, make the protein shaft revolve.
Nanomachines That Mimic Human-Scale Machines
Can we ever approach the elegant efficiency of cellular nanomachines
by creating tiny cousins of the larger machines we have invented?
Microfabrication has developed as an extraordinarily successful
technology for manufacturing small, electronically functional
devices--transistors and the other components of chips. Application of
these techniques to simple types of machines with moving
parts--mechanical oscillators and movable mirrors--has been technically
successful. The development of these so-called microelectromechanical
systems (MEMS) is proceeding rapidly, but the functions of the
machines are still elementary, and they are micro, not nano, machines.
The first true nanoscale MEMS (NEMS, or nanoelectromechanical
systems) have been built only in the past few years and only
experimentally
.
Many interesting problems plague the fabrication of nanodevices with
moving parts. A crucial one is friction and sticking (sometimes combined
in talking about small devices in the term "stiction"). Because small
devices have very large ratios of surface to volume, surface effects--both
good and bad--become much more important for them than for large
devices. Some of these types of problems will eventually be resolved if it
is worthwhile to do so, but they provide difficult technical challenges
now. We will undoubtedly progress toward more complex
micromachines and nanomachines modeled on human-scale machines,
but we have a long path to travel before we can produce
nanomechanical devices in quantity for any practical purpose. Nor is
there any reason to assume that nanomachines must resemble
human-scale machines.
Could these systems self-replicate? At
present, we do not know how to build
self-replicating machines of any size or
type. We know, from recent biological
studies, something about the minimum
level of complexity in a living cell that will
sustain self-replication: a system of
some 300 genes is sufficient for
self-replication. We have little sense for
how to translate this number into
mechanical machines of the types more
familiar to us, and no sense of how to
design a self-sustaining, self-replicating
system of machines. We have barely
taken the first steps toward
self-replication in nonbiological systems.
And other problems cast long shadows.
Where is the power to come from for an
autonomous nanomachine? There are
no electric sockets at the nanoscale.
The cell uses chemical reactions of
specific compounds to enable it to go
about its business; a corresponding
strategy for nanoscale machines
remains to be developed. How would a
self-replicating nanomachine store and
use information? Biology has demonstrated a strategy based on DNA,
so it can be done, but if one wanted a different strategy, it is not clear
where to start.
The assembler, with its pick-and-place pincers, eliminates the many
difficulties of fabricating nanomachines and of self-replication by ignoring
them: positing a machine that can make any composition and any
structure by simply placing atoms one at a time dismisses the most
vexing aspects of fabrication. The assembler seems, however, from the
vantage of a chemist, to be unworkable. Consider just two of the
constraints.
First is the pincers, or jaws, of the assembler. If they are to pick up
atoms with any dexterity, they should be smaller than the atoms. But the
jaws must be built of atoms and are thus larger than the atom they must
pick and place. (Imagine trying to build a fine watch with your fingers,
unaided by tools.) Second is the nature of atoms. Atoms, especially
carbon atoms, bond strongly to their neighbors. Substantial energy
would be needed to pull an atom from its place (a problem for the energy
supply) and substantial energy released when it is put in place (a
problem of cooling). More important, a carbon atom forms bonds with
almost everything. It is difficult to imagine how the jaws of the assembler
would be built so that, in pulling the atoms away from their starting
material, they would not stick. (Imagine trying to build your watch with
parts salvaged from another watch in which all the parts were coated
with a particularly sticky glue: if you could separate the pieces at all, they
would stick to your fingers.)
Would a nanosubmarine work if it could be built? A human-scale
submarine moves easily in water by a combination of a rotating
propeller--which, in spinning, forces the water backward and the
submarine forward--and movable planes that guide its direction. Bacteria
that swim actually use structures--flagella--that look more like flexible
spirals or whips but serve a function similar to a propeller. They typically
do not steer a very purposeful path but rather dash about, with motion
that, if all goes well, tends in the general direction of a source of food.
For nanoscale objects, even if one could fabricate a propeller, a new and
serious problem would emerge: random battering by water molecules.
These water molecules would be smaller than a nanosubmarine but not
much smaller, and their thermal motion is rapid on the nanoscale.
Collisions with them make a nanoscale object bounce about rapidly (a
process called Brownian motion) but in random directions: any effort to
steer a purposeful course would be frustrated by the relentless collisions
with rapidly moving water molecules. Navigators on the nanoscale would
have to accommodate to the Brownian storms that would crash against
their hulls. For ships of approximately 100 nanometers in scale, the
destination of most voyages would be left to chance, because the tiny
craft would probably be impossible to steer, at least in a sense familiar to
a submariner. Cells in the bloodstream--objects 10 or 100 times more
massive than a nanosubmarine--do not guide themselves in it: they
simply tumble along with it. At best, a nanosubmarine might hope to
select a general direction but not a specific destination. Regardless of
whether one could make or steer devices at the nanoscale, they would
not work for the sophisticated tasks required to detect disease if one
could make them.
Parts of the "little submarine" strategy for detecting and destroying
diseased cells in the body, such as cancer cells, would have to focus on
finding their prey. In doing so, they would probably have to mimic
aspects of the immune system now functioning in us. The recognition of
a cell as "normal" or "pathogen" or "cancer" is an extraordinarily complex
process--one that requires the full panoply of our immune system,
including the many billions of specialized cells that constitute it. No
simple markers on the outside of most cancer cells flag them as
dangerous. In many of their characteristics, they are not enormously
different from normal cells. A little submarine that was to be a
hunter-killer for cancer cells would have to carry on board a little
diagnostic laboratory, and because that laboratory would require
sampling devices and reagents and reaction chambers and analytical
devices, it would cease to be little. Operating this device would also
require energy. The cells of the immune system use the same nutrients
as do other cells; a little submarine would probably have to do the same.
Outdesigning Evolution
Small machines will eventually be made, but the strategy used to make
them, and the purposes they will serve, remain to be devised. Biology
provides one brilliantly developed set of examples: in living systems,
nanomachines do exist, and they do perform extraordinarily
sophisticated functions. What is striking is how different the strategies
used in these nanometer-scale machines are from those used in
human-scale machines.
In thinking about how best to make
nanomachines, we come up against two
limiting strategies. The first is to take existing
nanomachines--those present in the cell--and
learn from them. We will undoubtedly be able to
extract from these systems concepts and
principles that will enable us to make variants
of them that will serve our purposes, and others
that will have entirely new functions. Genetic
engineering is already proceeding down this
path, and the development of new types of
chemistry may enable us to use biological
principles in molecular systems that are not
proteins and nucleic acids.
The second is to start from scratch and independently to develop
fundamental new types of nanosystems. Biology has produced one
practical means for fabrication and synthesis of functional
nanomachines, and there is no reason to believe that there cannot be
others. But this path will be arduous. Looking at the machines that
surround us and expecting to be able to build nanoscale versions of
them using processes analogous to those employed on a large scale will
usually not be practical and in many cases impossible. Machining and
welding do not have counterparts at nanometer sizes. Nor do processes
such as moving in a straight line through a fluid or generating magnetic
fields with electromagnets. Techniques devised to manufacture
electronic devices will certainly be able to make some simple types of
mechanical nanodevices, but they will be limited in what they can do.
The dream of the assembler holds seductive charm in that it appears to
circumvent these myriad difficulties. This charm is illusory: it is more
appealing as metaphor than as reality, and less the solution of a problem
than the hope for a miracle. Considering the many constraints on the
construction and operation of nanomachines, it seems that new systems
for building them might ultimately look much like the ancient systems of
biology. It will be a marvelous challenge to see if we can outdesign
evolution. It would be a staggering accomplishment to mimic the
simplest living cell.
Are biological nanomachines, then, the end of the line? Are they the
most highly optimized structures that can exist, and has evolution sorted
through all possibilities to arrive at the best one? We have no general
answer to this question. Jeremy R. Knowles of Harvard University has
established that one enzyme--triose phosphate isomerase, or TIM--is
"perfect": that is, no catalyst for the particular reaction catalyzed by this
enzyme could be better. For most enzymes, and all structures more
complicated than enzymes, we have made no effort to discover the
alternatives.
Biological structures work in water, and most work only in a narrow
range of temperatures and concentrations of salts. They do not, in
general, conduct electricity well (although some, such as the chloroplast
and the mitochondrion, move electrons around with great sophistication).
They do not carry out binary computation and communications. They are
not particularly robust mechanically. Thus, a great many types of
function must be invented if nanomachines are to succeed in
nonbiological environments.
And what have we learned from all this about the doomsday scenario of
gray goo? If a hazard were to arise from nanomachines, it would lie in a
capability for self-replication. To be self-replicating, a system must
contain all the information it needs to make itself and must be able to
collect from its environment all the materials necessary both for energy
and for fabrication. It must also be able to manufacture and assemble (or
allow to assemble) all the pieces needed to make a copy of itself.
Biology has solved all these problems, and self-replicating biological
systems--from pathogenic bacteria to cancer cells--are a danger to us. In
computer systems, self-replicating strings of bits (computer viruses),
although not material objects, are also at least a great nuisance, but only
indirectly a danger, to us.
If a new system--any system--were able to replicate itself using materials
present in the environment, it would be cause for concern. But we now
know enough to realize how far we are from reproducing self-replication
in a nonbiological system. Fabrication based on the assembler is not, in
my opinion, a workable strategy and thus not a concern. For the
foreseeable future, we have nothing to fear from gray goo. If robust
self-replicating micro (or perhaps nano) structures were ultimately to
emerge, they would probably be chemical systems as complex as
primitive bacteria. Any such system would be both an incredible
accomplishment and a cause for careful assessment. Any threat will not
be from assemblers gone amok but from currently unimaginable systems
of self-catalyzing reactions.
So biology and chemistry, not a mechanical engineering textbook, point
in the direction we should look for answers--and it is also where our
fears about organisms or devices that multiply uncontrollably are most
justified. In thinking about self-replication, and about the characteristics
of systems that make them "alive," one should start with biology, which
offers a cornucopia of designs and strategies that have been successful
at the highest levels of sophistication. In tackling a difficult subject, it is
sensible to start by studying at the feet of an accomplished master. Even
if they are flagella, not feet.
The Author
George M. Whitesides is a professor in the chemistry department of
Harvard University. This is his third article for Scientific American. He is
grateful to graduate students Kateri Paul and Abraham Stroock, who
made many helpful suggestions on this essay.
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