Foresight Update 10
page 4
A publication of the Foresight Institute
 Recent
Progress: Steps Toward Nanotechnology
by Russell Mills
Chymotrypsin-like enzyme synthesized
Chemists at the University of Colorado have designed and made
a modest-size peptide molecule called "CHZ-1" that
imitates the activity of chymotrypsin. (Chymotrypsin is an enzyme
that cleaves bonds on the acid side of the amino acids
phenylalanine, tyrosine, and tryptophan.) This is the first
report of a catalytically active peptide having gone all the way
from de novo design to functioning molecule.
While the activities of CHZ-1 and chymotrypsin are similar, their
structures have almost nothing in common except at the active
site where substrate molecules are bound and transformed. In
chymotrypsin the actual work of catalysis is carried out by a
particular configuration of three amino acids: histidine, serine,
and aspartate. One of the main tasks of the rest of the enzyme is
to maintain these amino acids in their relative positions. CHZ-1
was designed with the same three amino acids held in a similar
configuration.
CHZ-1 is much smaller than chymotrypsin: 73 amino acids versus
245. The two catalysts have many substrates in common; for these,
CHZ-1 cleaves bonds at about 1% the rate of chymotrypsin--a
100,000 times acceleration over the background rate. Heat
tolerance of CHZ-1 is greater than that of chymotrypsin, but this
difference may be attributable to the chemists' employment of a
non-standard amino acid and several non-peptide bonds to hold the
molecule together. These would not be found in an enzyme of
biological origin.
CHZ-1 was made in a protein synthesis machine; it could not have
been produced by recombinant DNA methods, since it contains
nonstandard parts. But having shown that the basic activity of an
enzyme can be transferred to a very different molecule simply by
copying the design of the active site, chemists will no doubt
soon develop active peptides consisting of single chains of amino
acids that can be produced in quantity by engineered
microorganisms. [See Science 249,1544-1547,22Jun90]
New mechanisms for chemistry at surfaces
In his book Engines of
Creation, Eric Drexler envisioned machines able to
assemble structures with atomic accuracy by thrusting each part
into an appropriate site on the workpiece, using an angle and
velocity likely to promote formation of the desired bond. The
reasonableness of this picture of an assembler, not so obvious
five years ago, is becoming more apparent as chemists explore the
mechanisms of chemical reactions. A good example is provided by
the work at MIT of Sylvia T. Ceyer and her colleagues who have
been using molecular beams to study the adsorption of small
molecules onto metal surfaces. Metal-catalyzed reactions
constitute a large class of chemical processes that have been
widely used but poorly understood--until now.
Ceyer's group investigated one such reaction in great detail: the
adsorption of methane onto nickel. The key factor is the velocity
of the molecular beam--specifically, the speed at which the
incident molecules approach the nickel surface. Since a methane
(CH4) molecule is a carbon atom surrounded by four
hydrogen atoms, the first atom to near the surface is always a
hydrogen. If the impact speed is great enough, this hydrogen will
be pushed aside, allowing the carbon atom to approach and bind to
a nickel atom; the hydrogen atom, now free, binds to a different
nickel atom. At lower speeds, the methane molecules remain
intact; some are trapped by forces near the metal surface, others
bounce off and escape.
The MIT researchers found they could control this and similar
reactions by varying the parameters of the molecular beam (e.g.,
the velocity and angle of incidence) and the temperature of the
nickel surface. They discovered that the reactions occur at lower
incident velocities when the methane molecules are given extra
vibrational energy before sending them to the nickel
surface--presumably because the vibrational distortions give
carbon and nickel atoms easier access to each other. And they
found that unreacted methane molecules trapped near a metal
surface can be forced to react with and bind to it simply by
"hammering" them with a beam of neutral atoms (such as
argon).
This work confirms the assembler concepts put forward in Engines
of Creation--atoms and molecules can indeed be added to a
workpiece by hammering them against it, and they can be
pre-processed to enhance their reactivity. [See Science
249:133-139,13Jul90]
Clusters
Small clusters of metal or semiconductor atoms give rise to
properties not seen composition. Adding or removing a few atoms
from an ordinary sample will not change its properties, but this
is not true of samples whose component particles each contain
only a few dozen atoms or less. For example, a cluster of nine
cobalt atoms is practically inert to hydrogen or nitrogen gas,
whereas a cluster of ten cobalt atoms is quite reactive.
Cluster research is aimed partly at finding ways to make clusters
in quantity. Current methods produce a mixture of cluster sizes,
complicating the study of their structure and behavior.
The fact that the properties of these substances depend so
critically upon cluster size has mixed implications for
nanotechnology. On the positive side, it suggests that the range
of possible characteristics that materials may possess could be
much broader than we realize. But on the negative side, it means
that the characteristics of materials can be very sensitive to
small errors in design or construction. [See Science
248:1186-1188,8Jun90]
Chiral metal complexes as molecular catalysts
Nanotechnology uses assemblers; biochemistry uses enzymes;
chemistry uses catalysts; carpentry uses tools. Assemblers,
enzymes, catalysts, tools--four examples of objects that control
the processing of other objects.
We're all familiar with the evolution of tools, from crude
hammers and chisels capable of only the roughest sort of
production, to complex machine tools that control the shapes of
manufactured objects with micron accuracy. Enzymes underwent a
similar evolution more than a billion years ago, developing a
complexity and variety that enabled them to conduct the
biochemistry of life.
Analogous to these two traditional lines of development is the
current progress in chemical catalysis. Catalysts are substances
that direct the course of chemical reactions without themselves
being used up; catalysts participate in the reactions, but they
emerge intact and so are available for another round. Generally
speaking, simple catalysts are less specific than complex
catalysts. If a catalyst is to promote specific reactions and not
others, then it must contain sufficient structure to enable it to
distinguish between the reactants it is to use and those it is to
ignore.
In recent years a sophisticated class of catalysts has emerged
from research laboratories such as that of Ryoji Noyori at Nagoya
University. Noyori has been studying what are called "chiral
metal complexes" in which a metal atom is bound to an
asymmetric molecule to form a catalytic complex. Such catalysts
distinguish between reactants not only on the basis of their
chemical structure, but their chirality as well. (Chirality is
the symmetry property that causes certain structures to be mirror
images of each other but not identical--the same property that
prevents left-handed nuts from fitting on right-handed bolts.)
Ruthenium-BINAP catalysts are especially promising
examples--their superiority over conventional catalysts has been
demonstrated for the production of dozens of commercially
important chiral chemicals.
Noyori says, "In principle, any chiral structure can be
generated through rational modification of the catalyst's
molecular structure." From a traditional chemical viewpoint
it seems hard to believe that there would not be some chiral
structures for which no appropriate catalyst could be designed.
After all, traditional chemistry generally takes place in
solution where substrate molecules bump around randomly and often
prefer different reactions than the chemist does. On the other
hand, if chemistry is a stage in the development of
nanotechnology, then catalysts should be thought of as
rudimentary assemblers that are slightly "programmable"
through changes in the reaction milieu (i.e., changes in pH,
temperature, etc.). Plain metal catalysts, like platinum or
nickel, have played a major role in chemistry despite their
simplicity. In chiral metal catalysts the unique catalytic
features of metal atoms are combined with structures that aid in
the recognition and handling of desired substrates, and that can
be more readily "programmed" by the milieu.
As catalysts become more sophisticated, they will become more
complex, more varied, more programmable, and more selective;
their descendants sometime in the 21st Century may well turn out
to be the molecular assemblers we discuss in Update.
If they do, then Noyori's claim might evolve into this one:
"In principle, any physically realizable molecular structure
can be constructed by appropriately programmed assemblers."
[See Science 248:1194-1199,8Jun90]
Telomeres and aging
Rejuvenation buffs will be interested in the work of Calvin B.
Harley, et al. at McMaster University and Cold Spring
Harbor Laboratory. These researchers have shown that human
fibroblast cells undergo gradual losses at the ends of DNA
molecules.
In organisms having linear chromosomes (such as yeast and higher
organisms), the replication of DNA during cell division is often
incomplete--base pairs are lost at the ends of the DNA molecules.
To guard against the loss of important information, the end
segments of the DNA consist of repetitive sequences of base pairs
that contain no essential information; these are called
"telomeres."
Organisms that do not age (like yeast) have
"telomerase" enzymes that maintain the length of
telomeres by adding repetitive sequences when necessary. Higher
organisms also have telomerases, but these appear to be active
only in the production of reproductive cells (e.g., sperm) and in
tumors. Consequently--and this is what Harley et al. have
shown--human somatic cells lose about 50 base pairs per DNA
terminus per cell division, on the average. Since sperm DNA has
about 9000 base pairs of repetitive DNA at each terminus, the
process of incomplete replication would have eaten into critical
parts of the DNA at a given terminus after about 180 cell
divisions. There are, however, 92 different telomeres in each
human cell (23 pairs of chromosomes x 2 telomeres per
chromosome). A cell may die or become impaired if even one of
these 92 telomeres begins losing critical information--an event
that would generally occur sooner than the average.
If telomere shortening proves to be a major mechanism of aging,
then gene therapy offers a possible way to deal with it. We can
envision a day when genes can be introduced into the human genome
to provide a telomerase system that has been redesigned to be
active in somatic cells. [See Nature 345:458-460,31May90]
Nano-Mechanism Project
Shoichiro Yoshida and his research team with the Research
Development Corporation of Japan have completed a five-year
project aimed at developing instruments and techniques for
measuring and processing at nanometer scales. Among the fruits of
this effort are:
- Systems for measuring and positioning samples with
subnanometer accuracy.
- A combination scanning electron microscope/scanning
tunneling microscope to provide a wide range of
magnifications;
- An STM in an ultra-high-vacuum chamber to enable
ion-etched surfaces to be studied before they get
contaminated;
- Techniques for producing x-ray multilayer mirrors by
sputter deposition. The mirrors will be used in x-ray
microscopes, x-ray lithographic steppers, and other
instruments.
- Improved zone plates for x-ray microscopy;
- Compilation of data on optical constants of various
materials for use in making multilayer mirrors and zone
plates;
- Methods for making atomically smooth surfaces by
low-energy ion/atom beam sputter etching.
This is just one of 21 projects in Japan's national ERATO
program. With efforts like these taking place, progress toward
nanotechnology should be rapid. [See Nanotechnology 1:13-18,1990]
New design for AFM probes
Atomic force microscopes construct images by scanning a sharp
tip over a sample at sub-nanometer distances and measuring the
force between tip and sample. The tip is fastened to a cantilever
arm; samples lie on an atomically-flat surface (or
"stage").
Lacking techniques for making atomically perfect tips,
researchers have had problems with resolution, interpretation and
reproducibility. Earlier this year Eric Drexler at Stanford and
John Foster of IBM suggested that these problems could be
alleviated if AFMs were equipped with engineered molecular tips
[See Nature 343:600, 15Feb90]. A variety of
different molecules could be designed to have desired
characteristics and then synthesized with atomic precision by
chemical methods.
This earlier work left unanswered the important question of how
such molecular tips could be installed and placed on the AFM's
cantilever. In a paper presented in July at the Fifth
International Conference on Scanning Tunneling
Microscopy/Spectroscopy and First International Conference on
Nanometer Scale Science and Technology, Drexler suggests an
answer to this question: the tips need not be installed on the
cantilever at all. In the new arrangement, the sample is to be
held on a round bead fastened to the cantilever; a variety of
tips are bound to the stage, not necessarily in an organized
pattern. To image a sample, the operator must first find an
appropriate molecular tip on the stage by broadly scanning the
stage with the bead--in this mode of operation, the stage with
its array of tips serves as the sample, and the bead acts as a
probe. When a molecular tip is found, a confined scan is carried
out so that the molecular tip can image a sample bound to the
bead; in this scan, the bead and stage have exchanged roles.
An even more interesting application of this new design would be
in molecular construction. The array of molecular tips could be
designed so that each tip binds a reactive atom or molecule. As
these "parts" are added to a workpiece located on the
bead, they would be replenished from the surrounding solution.
[See Journal of Vacuum Science and Technology B, in
press]
[Editor's note: The publication reference for the JVST-B
article is: Drexler, K.E. (1991) Molecular tip arrays for
molecular imaging and nanofabrication. JVST-B 9:1394-1397.
See also section 15.4 of Nanosystems.]
Russell Mills is research director at Group 9 Research
Associates in Palo Alto, California.
From Foresight Update 10, originally
published 30 October 1990.
Foresight thanks Dave Kilbridge for converting Update 10 to
html for this web page.
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