by K. Eric Drexler
March 20, 2007
Developing the ability to
design protein molecules will make it possible to construct
molecular machines. These can then build second-generation machines
that can perform extremely general synthesis of three-dimensional
molecular structures, thus permitting construction of devices and
materials to complex atomic specifications. This has important
implications for computation and for characterization, manipulation,
and repair of biological materials.
Originally published in Engines of Creation 2.0, WOWIO LLC, February
Development of the ability to design protein molecules will open a path to
the fabrication of devices to complex atomic specifications, thus
sidestepping obstacles facing conventional micro-technology.
This path will involve construction of molecular
machinery able to position reactive groups to atomic precision. It could
lead to great advances in computational devices and in the ability to
manipulate biological materials. The existence of this path has implications
for the present.
Feynman's 1959 talk entitled "There's
Plenty of Room at the Bottom" 1 discussed
micro-technology as a frontier to be pushed back, like the frontiers of high
pressure, low temperature, or high vacuum. He suggested that ordinary
machines could build smaller machines that could build still smaller
machines, working step by step down toward the molecular level; he also
suggested using particle beams to define two-dimensional patterns.
Present micro-technology (exemplified by
integrated circuits) has realized some of the potential outlined by Feynman
by following the same basic approach: working down from the macroscopic
level to the microscopic.
Present micro-technology 2 handles statistical populations of
atoms. As the devices shrink, the atomic graininess of matter creates
irregularities and imperfections, so long as atoms are handled in bulk,
rather than individually. Indeed, such miniaturization of bulk processes
seems unable to reach the ultimate level of micro-technology—the structuring
of matter to complex atomic specifications. In this paper, I will outline a
path to this goal, a general molecular engineering technology.
The existence of this path will be shown to have
implications for the present.
Although the capabilities described may not prove necessary to the
achievement of any particular objective, they will prove sufficient for the
achievement of an extraordinary range of objectives in which the structuring
and analysis of matter are concerned. The claim that devices can be built to
complex atomic specifications should not, however, be construed to deny the
inevitability of a finite error rate arising from thermodynamic effects (and
Such errors can be minimized through the use of
free energy in error-correcting procedures (including rejection of faulty
components before device assembly); the effects of errors can be minimized
through fault-tolerant design, as in macroscopic engineering.
The emphasis on devices that have general capabilities should be taken in
the spirit of early work on the theoretical capabilities of computers, which
did not attempt to predict such practical embodiments as specialized or
distributed computation systems. The present argument, however, will proceed
from step to step by close analogies between the proposed steps and past
developments in nature and technology, rather than by mathematical proof.
We commonly accept the feasibility of new
devices without formal proof, where analogies to existing systems are close
enough: consider the feasibility of making a clock from zirconium.
The detailed design of many specific devices to
render them describable by dynamical equations would be a task of another
order (consider designing a clock from scratch), and appears unnecessary to
the establishment of the feasibility of certain general capabilities.
Biochemical systems exhibit a "micro-technology" quite different from ours:
they are not built down from the macroscopic level but up from the atomic.
Biochemical micro-technology provides a beachhead at the molecular level
from which to develop new molecular systems by providing a variety of
"tools" and "devices" to use and to copy.
Building with these tools, themselves made to atomic specifications, we can
begin on the far side of the barrier facing conventional micro-technology.
What can be built with these tools?
Gene synthesis 3 and recombinant DNA
technology can direct the ribosomal machinery of bacteria to produce novel
proteins, which can serve as components of larger molecular structures. One
might think assembly of such components into complex systems would require a
preexisting technology able to handle molecules and assemble them;
fortunately, biochemistry demonstrates that intermolecular attraction
between complementary surfaces can assemble complex structures from
For example, the complex machinery of the
ribosome self-assembles from more than 50 different protein molecules and
can do so in vitro.4
At present, the design of protein systems as complex as a ribosome seems an
awesome task. Indeed, chemists cannot yet predict the three-dimensional
conformation of a natural protein from its amino acid sequence, an ability
that might seem requisite to the design of new proteins.
Two considerations suggest that this obstacle is
first, the continuing improvement in
second, the difference between natural
science and design engineering
Regarding the first, computer simulation of
protein molecules in solution 5 shows promise.
As computer technology and chemical knowledge
improve, simulations will increase in accuracy, speed, and size. Improvement
promises new insight into protein behavior and may permit the designer to
modify (simulated) molecules quickly and to observe their behavior directly.
Regarding the second consideration, natural scientists seek a more general
understanding than design engineers require. Science seeks the ability to
predict the conformations of all natural polypeptides. In attempting this,
protein chemists can search for a minimum-energy chain conformation (in hope
that the protein assumes not a local but a global minimum-energy
conformation) 6 or can attempt to follow the chain-folding
mechanism to find the final conformation.7
Prediction will be easier if the natural
conformation has outstanding stability or if its folding mechanism proceeds
in a sequence of strongly preferred steps. Unfortunately, natural selection
accepts polypeptides that have natural conformations of low stability (in
terms of energy) so long as they exhibit long lifetimes on the cellular time
scale (or renature readily).
Similarly, natural selection accepts any folding
process so long as the chain reaches its natural conformation with
essentially 100% yield. Moreover, random mutations are unlikely to enhance
the stability of a particular conformation (or the predictability of its
Thus, natural proteins tend to accumulate
disruptive changes until they reach the threshold of poor stability or
reduced yield of the natural conformation; only then does natural selection
come into play. Thus, it is little wonder that chemists cannot yet predict
the conformations of natural proteins; they are not designed to fold
Engineers (in contrast to scientists) need not seek to understand all
proteins but only enough to produce useful systems in a reasonable number of
An engineer designing a protein that has 1000 amino acids may choose among
some 101300 different amino acid sequences. It might be that only one in 109
(or even 10700) randomly selected sequences would yield a predictable
conformation, yet this tiny fraction represents a vast number of proteins.
Through use of strategically placed charged
groups, polar groups, disulfide bonds, hydrogen bonds, and hydrophobic
groups, the engineer should be able to design proteins that not only fold
predictably to a stable structure (sometimes) but that serve a planned
function as well. Even a low success rate will lead to an accumulation of
Thus, the difficulties encountered in predicting
the conformations of natural proteins do not seem insurmountable obstacles
to protein engineering.
Computer modeling and chemical understanding of biological targets have
already found use in pharmaceutical design,8 and an artificial
34-residue polypeptide designed to interact with RNA has been synthesized
and found active.9 It has been proposed to give micro-circuitry
special sensitivities by adsorbing engineered proteins onto selected
The promise of enzyme design in chemical
engineering is evident. As protein science has great promise, and
difficulties in understanding natural proteins need not block engineering,
the substantial payoffs for improved capabilities should lead to development
of protein design technology.
It would be foolish to underestimate the time
and effort that will be required to develop basic design capabilities and
then a broad family of working molecular devices; still, the path seems
clear to achieving the capabilities exhibited by existing biochemical
systems, by copying their features if need be.
A comparison of biochemical to macroscopic components will show the
possibilities of the former by analogy to the latter (see Table 1 below).
With structural members, moving parts, bearings,
and motive power, versatile mechanical systems can be built. Molecular
assemblages of atoms can act as solid objects, occupying space and holding a
Thus, they can act as structural members and
moving parts. Sigma bonds that have low steric hindrance can serve as rotary
bearings able to support ~ 10-9 N. A line of sigma bonds can
serve as a hinge. Conformation-changing proteins (such as myosin) can serve
as sources of motive power for linear motion; the reversible motor of the
bacterial flagellum can serve as a source of motive power for rotary motion.
The existence of this range of components in
nature indicates that power-driven mechanical systems can be constructed on
a molecular scale.
Comparison of macroscopic and microscopic components
Struts, beams, casings
Transmit force, hold positions
Microtubules, cellulose, mineral
Support moving parts
Various tubular structures
Flagella, membrane proteins
RNA moved by fixed ribosome
Enzymatic binding sites
Metallic complexes, functional
Enzyme systems, ribosomes
Numerical control systems
Store and read programs
By analogy with macroscopic devices, feasible molecular machines presumably
include manipulators able to wield a variety of tools.
Thermal vibrations in typical structures are a
modest fraction of inter-atomic distances; thus, such tools can be
positioned with atomic precision. As present micro-technology 11
can lay down conductors on a molecular scale (10 nm) and molecular devices
can respond to electric potentials (through conformation changes, etc.),
such devices can be controlled by human operators or macroscopic machines.
Further, by analogy with biological sensors,
molecular scale instruments can evidently produce macroscopic signals,
indicating the feasibility of feedback control in molecular manipulations.
Together, these arguments indicate the feasibility of devices able to move
molecular objects, position them with atomic precision, apply forces to them
to effect a change, and inspect them to verify that the change has indeed
been accomplished. It would be foolish to minimize the time and effort that
will be required to develop the needed components and assemble them into
such complex and versatile systems. Still, given the components, the path
Ordinary chemical synthesis relies on thermal agitation to bring reactant
molecules in solution together in the correct orientation and with
sufficient energy to cause the desired reaction. Enzyme-like molecular
machines can hold reactants in the best relative positions as bonds are
strained or polarized. Like some enzymes, they can do work on reactant
molecules to drive reactions not otherwise thermodynamically favored.
These are clearly techniques of great power, yet the synthetic capabilities
of systems based on polypeptide chains might seem limited by amino acid
properties. However, enzymes show that other molecular structures bound to
the polypeptide (such as metal ions and complex ring structures)11 can
extend protein capabilities. The range of such tools is large and greater
than found in nature.
Thus, the synthetic capabilities of enzymes set
only a lower bound on the capabilities of engineered protein systems.
Indeed, as tool-wielding protein systems can control the chemical
environment of a reaction site completely, they should be able, at a
minimum, to duplicate the full range of moderate-temperature synthetic steps
achieved by organic chemists.
Further, where chemists must resort to complex
strategies to make or break specific bonds in large molecules, molecular
machines can select individual bonds on the basis of position alone.
Conventional organic chemistry can synthesize not only one-, two-, and
three-dimensional covalent structures but also exotic strained and fused
With the addition of controlled site-specific
synthetic reactions, a broad range of large complex structures can doubtless
Still, the synthetic abilities of protein machines will be limited by their
need for a moderate temperature aqueous environment (although applied forces
can sometimes replace or exceed thermal agitation as a source of activation
energy and reaction sites and reactive groups can be protected from the
surrounding water, as in some enzymatic active sites).
These limits may be sidestepped by using the
broad synthetic capabilities outlined above to build a second generation of
molecular machinery whose components would not be coiled hydrated
polypeptide chains but compact structures having three-dimensional covalent
There is no reason why such machines cannot be
designed to operate at reduced pressure or extreme temperatures; synthesis
can then involve highly reactive or even free radical intermediates, as well
as the use of mechanical arms wielding molecular tools to strain and
polarize existing bonds while new molecular groups are positioned and forced
into place. This may be done at high or low temperature as desired.
The class of structures that can be synthesized
by such methods is clearly very large, and one may speculate that it
includes most structures that might be of technological interest.
Firmness of the
The development path described above should lead to advanced molecular
machinery capable of general synthesis operations. As the results of this
path can be shown to have consequences for the present, it is of interest to
discuss the degree of confidence that should be placed in its feasibility.
It might be argued that complex protein or non-protein machines are
impossible or useless, on the grounds that, if they were possible and
useful, organisms would be using them. A similar argument would, however,
conclude that bone is a better structural material than graphite composite,
that neurons can transmit signals faster than wires, and that technology
based on the wheel is impossible or useless.
Nature has been constrained less by what is
physically possible than by what could be evolved in small steps. Thus, the
absence of a proposed kind of molecular machinery in organisms in no way
suggests its infeasibility.
To deny the feasibility of advanced molecular machinery, one must apparently
either (i) that design of proteins will
remain infeasible indefinitely
or (ii) that complex machines cannot be
made of proteins
or (iii) that protein machines cannot
build second-generation machines
In light of the expected improvements in
computation, the simplified task of design engineers (compared with
scientists), the possibilities offered by sheer trial-and-error modification
of natural proteins, and the progress already made in protein design, the
first seems difficult to maintain.
Further, even if protein design were to prove
intractable (because of difficulties in predicting conformations), this
would in no way preclude developing an alternative polymer system with
predictable coiling and using it as a basis for further development.
In light of the presence of the needed components for mechanical devices in
the cell, the second seems difficult to maintain. Indeed, the cytoskeleton
provides a fair counterexample.
In light of the results of synthetic organic chemistry and the ability of
molecular machines to make reactions site specific, it seems difficult to
maintain that non-protein machine components cannot be built and assembled.
Each of the development steps outlined above seems closely analogous to past
steps taken by nature or by technology. Each of these steps can be
accomplished in many ways. To argue their infeasibility would seem to
require some general principle precluding success, and it is difficult to
see what such a principle might be like. Thus, the claim that advanced
molecular technology can be developed seems well founded.
Although the existence of molecular machinery in cells indicates the
feasibility of some sort of artificial molecular machinery, errors in
assembly might limit the synthesis of structures of great complexity. In the
cell, molecular machinery uses DNA to direct the assembly of DNA and other
molecules. In some eukaryotic cells, DNA directs DNA synthesis with an error
rate of ~10-11 per nucleotide added.12
As engineers commonly design systems to function
reliably with many more failed components than 1 in 1011, such an
error rate seems no barrier to the construction of quite complex devices.
The possibility of low error rates is not surprising. For synthesis systems
permitting error detection and correction (such as DNA synthesis), the net
error rate in assembly can be reduced to roughly the product of the raw
error rate in assembly and the rate at which errors are falsely identified
As no uncertainty principle prohibits accurate
discrimination between objects of different kinds (such as correctly and
incorrectly assembled molecular structures), no limits to the detection and
correction of errors are apparent.
Molecular technology has obvious application to the storage and processing
of information. A crude approach would involve literal "molecular machinery"
patterned on the Babbage machine. In a more subtle approach, bits could be
represented by protons, bound electrons, reactive groups, or conformation
changes and transferred by movement of protons or of well-localized
electrons,13 excitons, or phonons.
The range of plausible device speeds is
suggested by the 10-6-sec turnover time for a fast enzyme, by the
10-13 sec scale of collisional interactions, and by the 10-16
sec taken for an electron to cross an inter-atomic distance at a typical
It seems highly likely that a cubic cell 0.1 micrometers on a side
(containing some 108 optimally arranged atoms) can hold a bit or perform a
logic operation and, at the same time, transmit bits through itself to
provide communication from cell to cell in a lattice. If so, then computers
can be built with at least 1015 active elements per cubic
In a well-designed computer (with elements
closer to their true technological limit and not laid out in regular cubical
cells), this volume estimate should prove quite conservative. Elements so
small will be sensitive to radiation damage; to be reliable, systems will
require a large measure of redundancy.
Concern might be raised about the cost of such intricately patterned matter,
either because of labor or energy requirements. It seems clear, however,
that molecular-scale production systems can be completely automated (what
use is there for hands?). Thus, labor costs of production (including
production of additional production equipment) can approach zero.
The energy needed to produce molecularly
engineered material will generally be greater than the energy needed to
produce ordinary materials of similar bulk composition, but analogy suggests
that the energy cost need not be vastly greater than for the production of
In many cases (e.g., advanced computers or any
of a number of applications not discussed here), the unique value of the
products would make such energy costs unimportant, even if energy costs
Molecular devices can interact directly with the ultimate molecular
components of the cell and thus serve as probes of unique value in studying
processes within the cell. Further, molecular devices can characterize a
frozen cell in essentially arbitrary detail by removal and characterization
of successive layers of material (atomically thin layers, if desired).
Although the amount of data involved is large (a
typical cell contains billions of protein molecules), the physical bulk of a
device able to store and manipulate this amount of data will be quite small.
The change of temperature and water distribution during freezing modifies
cell structures in several ways, primarily by physical displacement of
structures by ice crystals and denaturation of proteins by concentration of
solutes in the residual liquid.14 With frozen tissue, knowledge
of normal structures (membrane geometries, natural protein structures) and
analysis of frozen structures (position of ice crystals, position of
denatured proteins) should permit quite accurate reconstruction of the
nature of the tissue before freezing.
Such procedures would have special utility in analyzing the structure of
tissue in the brain. Unlike, say, muscle or liver tissue, the function of
brain tissue depends on the detailed three-dimensional structure of
intertwined cells and their interfaces.
The freezing process is far too slow to stop
such dynamic processes as action potentials and synaptic transmission;
short-term memory, however, is suspected to involve chemical modification of
the neurons, and long-term memory is believed to involve the growth and
modification of neuronal structures, particularly synapses.15
At the modest freezing rates possible in
substantial pieces of tissue, ice crystals may be expected to nucleate and
grow in the intercellular fluid, displacing the cell membranes as they do
so.16 Electron micrographs, however, show that synapses (like
many intercellular junctions) involve complementary structures on both sides
of the intercellular gap, which should provide information enough to
reconstruct the pre-freezing configurations of the cells almost regardless
of ice crystal locations.
The ability to reconstruct the pre-freezing structure of tissue, when
combined with the general synthetic capabilities outlined above, will make
feasible the physical restoration of tissue damaged by ordinary freezing
through characterization, reconstruction, and restoration of successive
segments of frozen material. Although restored to a frozen condition, such
tissue would lack the characteristic damage caused by the freezing process.
As many tissues can survive the gross insult of ordinary freezing 17,
it seems likely that most could survive freezing followed by repair.
The remaining mode of damage would seem to be
denaturation of proteins sensitive to cold alone during the thawing process.
Should cell components of some species prove
sensitive to short periods of cold, they could presumably be modified to
resemble those of hardier species (hamsters can survive freezing of half
their body water)17 without changing either cell function or DNA.
Implications for the
The existence of a path to an advanced molecular technology has implications
for the present. As with all technologies, long-range promise should tend to
increase interest in undertaking the early steps, even beyond the interest
springing from more immediate benefits. The longer the expected wait,
however, the less the interest.
On the other hand, molecular engineering of materials and devices can extend
the capabilities of technology many fold in many areas. The implications of
the feasibility of molecular technology are important to present day
speculations concerning the probable behavior (and likelihood of existence)
of extraterrestrial technological civilizations.
Similarly, those concerned with the long-range
future of humanity must concern themselves with the opportunities and
dangers arising from this technology.
Finally, the eventual development of the ability
to repair freezing damage (and to circumvent cold damage during thawing) has
consequences for the preservation of biological materials today, provided a
sufficiently long-range perspective is taken.
Development of the ability to design protein molecules will, by analogy
between features of natural macromolecules and components of existing
machines, make possible the construction of molecular machines.
These machines can build second-generation
machines able to perform extremely general synthesis of three-dimensional
molecular structures, thus permitting construction of devices and materials
to complex atomic specifications. This capability has implications for
technology in general and in particular for computation and
characterization, manipulation, and repair of biological materials.
I thank C. Peterson, P. Morrison, J. Lettvin, A. Kantrowitz, and C. Walsh
for their comments and criticism.
1 Feynman, R. (1961) in "Miniaturization",
ed. Gilbert, H. D. (Reinhold, New York), pp. 282-296.
2 Krumhansl, J. A. & Pao, Y. H. (1979) "Physics Today" 32 (11), 25-32.
3 Itakura, K. & Riggs, A. D. (1980) "Science" 209, 1401-1405.
4 Nomura, M. & Held, W. (1974) in "Ribosomes", eds. Nomura, M., Tissiers,
A. & Lengyel, P. (Cold Spring Harbor Laboratory, Cold Spring Harbor,
NY), pp. 193-203.
5 McCammon, J. A., Gelin, B. R. & Karplus, M. (1977) "Nature" (London)
6 Scheraga, H. A. (1978) in "Versatilty of Proteins", ed. Li, C. H.
(Academic, New York), pp. 119-132.
7 Karplus, M. & Weaver, D. L. (1976) "Nature" (London) 260, 404-406.
8 Gund, P., Andose, J. D., Rhodes, J. B. & Smith, G. M. (1980) "Science"
9 Gutte, B., Dannigen, M. & Wittschieber, E. (1979) "Nature" (London)
10 Anonymous (1980) "Semiconductor International" 3 (5), 10.
11 Walsh, C. (1979) "Enzymatic Reaction Mechanisms" (Freeman, San
Francisco), pp. 33, 38.
12 Drake, J. (1969) "Nature" (London) 221, 1132.
13 Chance, B., Mueller, P., DeVault, D. & Powers, L. (1980) "Physics
Today" 33 (10), 32-38.
14 Fennema, O. R. (1973) in "Low-Temperature Preservation of Foods and
Living Matter", eds. Fennema, O. R., Powrie, W. D. & Marth, E. H.
(Dekker, New York), pp. 476-503.
15 Entingh, D., Dunn, A., Glassman, E., Wilson, J. E., Hogan, E. &
Damstra, T. (1975) in "Handbook of Psychobiology", eds. Gazzinga, M. S.
& Blakemore, C. (Academic, New York), pp. 201-238.
16 Fennema, O. R. (1973) in "Low-Temperature Preservation of Foods and
Living Matter", eds. Fennema, O. R., Powrie, W. D. & Marth, E. H.
(Dekker, New York), pp. 150-239.
17 Fennema, O. R. (1973) in "Low-Temperature Preservation of Foods and
Living Matter", eds. Fennema, O. R., Powrie, W. D. & Marth, E. H.
(Dekker, New York), pp. 436-475.