One approach to nanotechnology is to construct systems with scanning probe
techniques. This has the advantage of providing excellent control of the
locations of the molecules being assembled, but it has the disadvantage
of being an inherently serial process. It therefore requires techniques
to investigate very small numbers of molecules, ideally single molecules.
The following five items describe techniques applicable in this regime.
The first paper in this section extends a spectroscopic technique to single
molecules. Writing in [Science 275:1102-1105--MEDLINE
Abstract], S. Nie and S.R. Emory describe a type of Raman spectroscopy
that is sufficiently sensitive to detect individual molecules. In their
experiments, rhodamine 6G was bound to silver particles with average diameters
of 35 nm. Free rhodamine 6G absorbs light efficiently. Unfortunately, its
visible absorption (and fluorescence) spectra are fairly broad, carrying
little detailed information. In a normal dye's visible absorbtion spectrum
the incoming light is absorbed by a transition from one electronic state
to another and the effect of molecular vibrations on the energy difference
between the states spreads out the absorbtion. In Raman spectroscopy, on
the other hand, the energy of the visible photon is split into exciting
a well-defined molecular vibration and a reradiated visible photon. This
process yields much sharper spectra, with much more information about molecular
features. The spectra in the paper show 6-7 distinct peaks from separate
Normally, the "Raman process is an extremely inefficient process, and
its cross sections (~10-30 cm2 per molecule) are about
14 orders of magnitude smaller than those of fluorescent dyes (~10-16
cm2 per molecule." Raman scattering is, however, enhanced
at certain surfaces. These authors found that by binding a chromophore to
the surface of a nanoparticle they could enhance it by factors "as
high as 1014 to 1015," making it feasible to
measure the Raman spectrum of individual molecules. In addition to the enhancement,
another feature of the authors' system is that "photochemical decomposition
or photobleaching is significantly reduced for single molecules adsorbed
on metal nanoparticles because the metal surface rapidly quenches the excited
electronic state and thus prevents excited state reactions." This is
important since it increases the numbers of photons that can contribute
One odd feature of this paper is that the authors found that only certain
Ag particles were optically "hot" (perhaps 1% to 0.1% of the total),
and "only one out of 10,000 surface sites on a hot particle shows efficient
enhancement." The authors suggest a number of ways to better control
the fabrication of their nanoparticles, including some scanning probe methods.
This technique looks primarily attractive as a diagnostic technique for
determining whether an attempt to produce a chemical change to a single
molecule with an STM or AFM probe has been successful. Vibration spectroscopy
of organic molecules has been a powerful analytical technique for decades.
Making it feasible for individual molecules will add a valuable tool for
the development of nanotechnology.
The second paper in this section extends what might be considered a hydrodynamic
diagnostic to individual molecules. Writing in [Science 275:1106-1109
Abstract], X.-H. Xu and E.S. Yeung describe detecting the diffusion
of individual fluorescent rhodamine-6G molecules. In one mode, they imaged
the fluorescence in a 4-um thick layer of rhodamine solution confined between
a cover slip and a prism. In another mode, they imaged it in a 0.15 um thick
layer excited with the evanescent wave from a totally internally reflected
laser. In both modes, they used sufficiently low concentrations of rhodamine
(5 nM in the first case, 100 nM in the second) that molecules were isolated,
even accounting for diffusion in a 100-200 msec exposure window. The authors
measured the distribution of the fluorescence for each molecule and calculated
diffusion coefficients for them. In addition to the rhodamine-6G experiment,
the authors bound rhodamine to a 30-base strand of DNA. It had a reduced
diffusion rate, as expected. This technique may be useful as a diagnostic
for structures available in very small quantities, measuring the diffusion
rate of a handful of structures built with scanning probe techniques, for
example, perhaps to detect if an assembly step had succeeded.
The third item in this section describes the steady advances in application
of electron imaging to determination of the structure of small numbers of
particles. A trio of papers in Nature describe the determination of the
hepatitus B virus by electron cryomicroscopy. B. Böttcher et. al. [Nature
Abstract] and J.F. Conway et. al. [ibid. 91-94--MEDLINE
Abstract] wrote the detailed papers with D. J. De Rosier writing
a commentary on them [ibid. 26-27]. This technique involves solving a structure
by taking many electron micrographs (done at cryogenic temperatures, hence
the name) rather than by growing a crystal and diffracting X-rays with it.
From a biological point of view this technique is notable primarily because
it permits the structural analysis of things such as membrane proteins and
ribosomes which are difficult or impossible to crystallize. From a nanotechnological
viewpoint, it is notable because it allows 3D structural analysis from a
small number of particles. In B. Böttcher et. al.'s paper 6,400 images
were used, and J.F. Conway et. al. used 600. If a structure is being built
by a scanning probe technique, these numbers of copies are substantial but
conceivable, while diffraction techniques requiring macroscopic quantities
of structures are not. Note that electron micrographs contain information
about the interior of objects, so, for example, they could provide valuable
confirmation of a successful alignment of two interior subsystems in a structure,
even if the structure's surface is being monitored with an AFM while it
is being assembled. The Böttcher team achieved 0.74 nm resolution while
the Conway team achieved 0.9 nm resolution. De Rosier writes that: "Structural
analysis by electron cryomicroscopy of two-dimensional crystals now extends
to essentially atomic resolution, of 3 to 4 Ä," even with only
thousands of units in the crystal.
The fourth item in this section describes imaging a single molecule's motion
during the course of a reaction. In [Science 275:1882
28Mar97], E. Stokstad describes a film made by P. Hansma et. al. of an enzyme
actually working its way down a DNA strand. The enzyme was an RNA polymerase.
The scene was imaged with a tapping mode AFM. A difficult part of the experiment
was to attach the DNA sufficiently firmly to the substrate that it would
not be pushed away by the AFM or diffuse away but sufficiently loosely that
the polymerase could still operate. Stokstad writes: "After several
attempts, the team found that zinc ions added to the water would loosely
attach the molecules to the sample dish." Hansma suggests that "an
AFM movie might reveal subtle changes in the shape of the RNA polymerase
as it passes over different letters of the genetic code on its way down
a DNA strand." As far I am aware, this would be a novel sensing architecture,
using a hybrid of a biochemically produced molecule acting as both an atomically
precise sensor and a mechanical sample feed mechanism, together with a AFM
used as a sensitive, but less precisely fabricated, readout mechanism.
The last item in this section describes a technique that can detect single
charges, and which places an amplifier in submicron proximity to the system
under study. Writing in [Science 276:579-582 25Apr97--MEDLINE
Abstract], M.J. Yoo et. al. describe a high resolution electrometer
that uses a single electron transistor (SET) as a sensing element on the
very tip of a scanning probe. They detected charge distributions on a surface
by scanning it with a tip terminated in a 100 nm patch of aluminum. Two
tunnel junctions were made to this patch, and the current through it measured.
The current varies approximately sinusoidally with the potential of the
patch, including the potential induced from charges on the sample surface.
It "passes through a full period each time the electric field lines
terminating on the island induce a charge of exactly one additional electron."
In this paper, this charge is primarily induced by the bias on the source
and drain electrodes coupled to the island. The effect of the sample charges
is to shift the phase of the variation. The phase shift can detect a signal
of as little as 1% of an electron's charge. The SET is biased with ~1mV,
switching currents of around ~1nA, so the signal power from the SET is ~1pW.
The SET island capacitance was ~0.1fF, so the input signal energy was only
around ~10-22 J and there is power gain for any scanning speed
below 1010 pixels/sec. This is useful because one limitation
in rapidly retrieving information stored in atomically precise structures
is the available signal power from these structures. In both STMs and AFMs
micron scale structures (FETs and cantilevers respectively) must be driven
by atomic structures, while this tiny SET avoids this requirement.
The fabrication of the SET is surprisingly simple. "Fabrication of
the SET involves the evaporation of three separate areas of a thin (10 to
20 nm) aluminum film onto a specially shaped glass fiber...The films for
source and drain leads spread out from the edges of the tip and extend up
the side of the fiber to electrical contacts...The three electrode shapes
are defined by natural shadowing." I would have expected a much more
complex process to be necessary to avoid shorting at such fine geometries.
The success of this instrument suggests the possibility of many other uses
for this technique. The authors have essentially gotten two voltage
sources to within 100 nm of a sample on a single tip, while conventional
STM tips only get one close to the sample. One might apply the same probe
fabrication technique to dual tunnelling instruments, lateral conduction
measurements on low conductivity samples, lateral electrostatic deflection
of surface molecules or a variety of other fabrication or sensing experiments.
This electrometer requires operation at 2K in order for the coulomb blockade
effect to make the SET operate. Scaling down the SET both improves resolution
(currently set to 100 nm by the SET size) and increases operating temperature.
The authors write: "Even room-temperature operation, although ambitious,
is conceivable, requiring the development of molecular- or even atomic-sized
An article by A. Hellemans in [Science275:920 14Feb97] covers
a new $3.7 million subproject in the EU's Esprit program. The project, "Fabrication
and Architecture of Single-Electron Memories", intends to store bits
with single electrons. Eight research labs are participating. The long term
goal of the project is to build large scale memory chips, 1012
bit devices by 2015. The short term goal for "the initial 3-year contract
is a 4 X 4 array of single-electron devices on a substrate of silicon."
The researchers expect to place charges on conducting islets a few nanometers
in size. While this project does not not directly attempt to control the
placement of atoms to atomic precision, a successful single electron memory
would allow routine contruction of precision electrostatic patterns that
might then drive assembly of large patterns of charged structures. In addition,
routine use of these memories would create incremental economic incentives
for precision fabrication from the low nanometer scale down to atomically
One approach to nanotechnology is to synthesize successively larger, more
complex structures by parallel techniques drawn from chemistry and biochemistry.
A key capability necessary for this approach is the use of very selective
catalysts to perform reactions on selected sites on substrates while avoiding
them on chemically similar sites in other locations. For a number of years,
researchers have been using catalytic antibodies, abzymes, as one of the
approaches towards building selective catalysts. The following two papers
describe some recent advances in this area.
Writing in [Science 275:945-948 14Feb97--MEDLINE
Abstract], K.D. Janda et. al. describe a novel selection mechanism
for catalytic antibodies which captures the genes for the antibody as a
result of the reaction itself rather as a result of binding to a transition
state analog. In the particular reaction that they studied, a hydrolysis
of a glycosidic bond, they synthesized a variation of the substrate which
reacted with the abzyme to form a covalent bond connecting it to a solid
support. More precisely, the substrate contained a phenol with an ortho
difluoromethyl substituent. They write: "On enzymatic clevage, the
difluoromethyl moiety generates a reactive quinone methide species at or
near the active site [of the abzyme], thereby alkylating any nucleophile
[in the enzyme, and capturing it]." The other end of the phenol was
connected to a solid substrate through a disulphide bond. Thus, the catalysis
itself bound the enzyme to the solid support. The authors also modified
the abzymes themselves to carry the information needed to make additional
copies of them. They used genetic engineering techniques to package the
antibody genes into a phage, and to bind the phage to the antibody. After
reaction with the substrate, phage, abzyme, and phenol are all left attached
to an insoluble support, while non-catalytic members of the library were
washed away. The authors then cleave the disulphide bond by reduction with
DTT, and the freed phages are "amplified through infection of E. coli."
This method can thus "detect catalysis in single phage particles",
allowing for the direct screening of a very large number of potential abzymes
in parallel. The authors write: "The advantage of purely chemical systems
[such as this one] is one of generality in that many desired reactions do
not yield intermediates or products that perturb cellular machinery, and
thus biologically based selection systems cannot be used." On the other
hand, this technique does require that the target reaction be modifiable
into a form that captures the abzyme with the irreversible formation of
a covalent bond, which may not be feasible for some reactions of interest.
J.-B. Charbonnier et. al., writing in [Science 275:1140-1142
Abstract] did an experiment that describes an improved procedure
for finding catalytic antibodies, but may also probe the limits of this
technology. The antibodies were generated in the usual way, by immunizing
a mouse with a transition state analog for the reaction to be catalyzed.
In this case, the reaction was an ester hydrolysis and the transition state
analog was a phosphonate. The usual process is to screen "the immune
response [library of antibodies] for binding to the hapten [transition state
analog] and then testing the best scoring clones for catalytic activity."
Instead, this group used a procedure called "catELISA, in which product-specific
antibodies are used to detect the appearance of product after immobilised
substrate is exposed to the supernatant of culture hybridoma cells."
They were able to screen all 1570 clones derived from a mouse, of which
9 scored positive for catalysis, "a figure to be compared to 970 hapten-binding
clones" which would otherwise have needed to be tested again
for catalytic ability. The authors purified and crystallized the three most
reactive antibodies complexed together with the transition state analog.
They found a great deal of structural convergence of these abzymes, to the
extent that "the conformations of the catalytic residues are similar."
They write that: "The central question now is whether the mechanism
we observe is a dead end or a point on the pathway which can be further
refined." They suggest that further cycles of mutation and selection
may improve it. It will be interesting to see if its catalytic efficiency
can indeed be increased.
Jeffrey Soreff is a researcher at IBM with an interest in nanotechnology.
its look toward the 21st Century by identifying nanotechnologist K.
Eric Drexler as one of "100 people to watch as America prepares
to pass through the gate to the next millennium." He was one of 15
selected by editors in the Science & Medicine category, and one of only
five of those not associated with medical research. "Drexler studies
the possibilities of molecule-size machines that might repair cells and
build microscopic computers. He chairs Palo Alto's Foresight Institute,"
the magazine said. Newsweek selected its roster not by identifying
"the great and powerful, or the beautiful and celebritous," but
rather "personalities whose creativity or talent or brains or leadership
will make a difference in the years ahead."
its gradual retraction of its April 1996 ad hominem critique of molecular
nanotechnology with a new posting on the magazine's
electronic version on the World Wide Web. The article by contributing
writer Alan Hall summarizes work by Al Globus and his colleagues at NASA.
(Globus is cochair of the upcoming Fifth
Foresight Conference on Molecular Nanotechnology ) "Globus and
his colleagues at Ames's Numerical Aerospace Simulation Systems Division
are among a growing number of investigators who now believe that atom-scale
factories will one day produce new structural materials and advanced computer
components, and may even act as tiny repairmen," Hall wrote. He reported
on the NASA team's designs for molecular gears, their thoughts about "matter
compilers" and the possibilities of "smart materials" that
could heal themselves if torn or broken. "There is no question that
real nanomachines are probably decades away. But more and more, research
is demonstrating that such things are possiblepossibly sooner than
most of us think," Hall concluded.
Shortly after the article appeared, NASA issued a substantial press
release from its Washington headquarters describing the team's work.
Sky(the monthly in-flight
publication of Delta Airlines with 500,000 copies in print and a total readership
exceeding 1 million) devoted part of its March 1997 issue to "The Future
Of The Future: Peering Into The Nanofuture." Author Robert Ebisch surveyed
current micromachines created using lithographic techniques, and dismissed
them as "crude monkey tricks compared with what is to come, if the
core concepts of future nanotechnology are on target." He extensively
quoted Ralph Merkle (computational nanotechnologist at Xerox Corp. and cochair
of the upcoming Fifth Foresight Conference
on Molecular Nanotechnology), cited Eric Drexler's Engines
of Creation, and discussed resistance in the old line science community
to its concepts. "A complete scandal," MIT professor Marvin
Minsky is quoted as saying of the April 1996 Scientific American
article on nanotechnology. Ebisch surveyed recently reported advances in
the field, both in protein engineering and mechanical construction, and
quoted Minsky that "it shows there's no technical reason why the stuff
can't be done."
Popular Mechanicscarried a brief item in the Tech Update column of its July 1997 issue
about recent fullerene tube developments at Rice University and in Switzerland,
and reported that "Nanotube cable...between 10 and 12 times stronger
than steel" would make feasible a "space elevator" using
a cable suspended from a geosynchronous satellite. "Even if a space
elevator is never built, researchers say nanotubes will find their way into
a variety of aerospace applications. They could also be used in bulletproof
vests, sports equipment and automotive parts. Electrically conductive nanotubes
could wire computer chips," the article said.
Knight-Ridder Newspapers science
correspondent Robert Boyd authored a solid basic survey of nanotechnology
carried by member newspapers in late March. The chain owns major dailies
including the San Jose Mercury, Miami Herald,
Detroit Free Press and Philadelphia Inquirer,
and dozens of smaller papers. Boyd quoted Merkle, Nobel Laureate Richard
Smalley of Rice University, Paul Green of Nanothinc, and Foresight executive
director Chris Peterson. Nanotechnology is "a very broad field, and
it is, in many ways, the ultimate playground" of science, Smalley is
quoted as saying. The story also referred to research by Al Globus and his
NASA colleagues. It echoed may of the themes in a February 20 story in the
Inquirer by Reid Kanaley, which was discussed in MediaWatch.28.
The electronic computer is now 50 years old.
Noting the anniversary both of its invention and of the formation of the
Association for Computing Machinery, (ACM) Electronic Engineering
Timesused a review of the first half century
to look forward to the next. At ACM's
anniversary meeting in San Jose, plenary speakers discussed advancing
the state of silicon chip architecture, the physical limits imposed on Moore's
Law as circuit dimensions continue to shrink, and even the continued viability
of the basic von Neumann computing architecture (in which a sequence of
operations retrieves data from a central memory, processes it and then returns
the result). Caltech electrical engineering professor Carver Mead discussed
analog approaches to computing "inspired by biology's mode of information
processing: neural networks. Departing once again from the conventional
wisdom, Mead...now predicts that analog/neural systems represent the future
of computing," the magazine wrote.
Editor Matt Crenson wrote in February about a laboratory demonstration of
the Casimir Effectvirtual photons that "spontaneously burst into
existence like kernels of popping corn and then disappear almost instantly,
(which) ought to push two narrowly separated metal plates together."
Dutch physicist Hendrik Casimir postulated the effect in 1948, based on
quantum electrodynamics, but nobody had set out to verify it until a University
of Washington physicist did so last summer. Although too weak to be significant
at macro scales, the Casimir force may need to be taken into account in
nanomachines, Crenson wrote. "Right now the possibilities of nanotechnology
are as endless as the imagination of the field's most enthusiastic proponents.
But in the future, nanotechnology will rely on understanding the Casimir
force and similar effects," he said.