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]
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]
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]
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
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
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
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
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
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]
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,
[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.