Foresight Update 15
page 5
A publication of the Foresight Institute
 Recent
Progress: Steps Toward Nanotechnology
by Russell Mills
Proteins
Polymers (i.e., chains of molecular building blocks), while
not the most elegant or optimized of molecular structures, have
the advantage of being relatively easy to assemble. This ease of
assembly underlies both their attractiveness to industry and
their presence in living things. When cells produce the polymers
of life--proteins, nucleic acids, and carbohydrates--every atom
is accurately bonded in position. These molecules therefore fit
our definition of nanomaterials or nanodevices. While lower
levels of structural precision are acceptable in the industrial
production of bulk materials like plastics, only atomic-level
accuracy will suffice in the production of drugs, since drugs
must have precisely the correct structure in order to work
reliably and safely. Insulin and other biologically derived
polymers convinced pharmacologists decades ago of the potential
value of synthetic drugs based on these substances. Technological
production methods of the required precision are already
available for making proteins and nucleic acids, and rapid
progress is being made in carbohydrate chemistry as well.
Chemists are vigorously pursuing all three polymer types for drug
development. As they do so, they contribute willy-nilly to
progress toward nanotechnology.
Recent months have seen a surge of interest in combinatorial
chemistry (sometimes referred to as "irrational drug
design")--the selection of drug candidates from huge
libraries of randomly constructed polymers. A variety of
ingenious methods have already been devised for creating such
libraries and for identifying promising molecular variants, and
researchers continue to invent new ones. Most of these methods
could probably have been developed years ago had people realized
their potential value.
A combinatorial technique being developed by Richard Lerner and
Sydney Brenner is intended to provide an effective way to
determine the structure of molecules selected from a molecular
library according to their ability to bind a desired substrate. A
molecular library typically contains too small a quantity of each
variant to be structurally analyzed. Lerner's and Brenner's
method should enable them to construct a polymer library in which
each polymer is tagged with its own personalized DNA molecule;
the sequence of the DNA tag is a coded description of the
sequence of the polymer. Candidate polymer variants selected with
a binding assay can be identified by enzymatically replicating
the DNA tag, sequencing it, then decoding the sequence. [Science
257:330-331; 17July92]
Nucleic acids--molecular chains assembled from four different
subunits called "nucleotides"--are used in a variety of
ways in living things: for example, in chromosomes as recognition
sequences for regulator molecules; in RNA molecules as catalytic
elements and as structural elements; and in many genes as
descriptions of amino acid sequences. The term "genetic
code" refers to the relationship between sequences of
nucleotides and the sequences of amino acids they specify. In the
form it has evolved, the code relates each of 20 amino acids to a
certain set of nucleotide triplets. Since 64 different triplets
can be constructed from an alphabet of four nucleotides, some of
the amino acids are coded for by more than one triplet. This
redundancy is unfortunately necessary to compensate for the
otherwise low accuracy of biological protein synthesis.
Although evolution incorporated only 20 amino acids into the
genetic code, an unlimited number of different amino acids are
chemically possible. Of these there may be thousands that could
give useful properties to proteins. Just as a painter might be
unhappy with a fixed palette of 20 colors, some protein designers
are not satisfied with a repertoire of only 20 amino acids. While
chemical methods can be used to incorporate unusual amino acids
into synthetic proteins, large-scale production requires
biosynthesis. Efforts are therefore underway to expand the
genetic code by adding two more nucleotides. This would provide
216 triplets instead of 64, presumably making it possible to
encode several times as many kinds of amino acids. Researchers
would be free to choose the new amino acids to be included, and
the choices could be individualized for each application.
Proteins designed with an enlarged set of amino acids would be
manufactured in bacteria, yeast, and plants especially engineered
for the purpose, and might find uses as drugs, prosthetic
materials, coatings, and additives; declining costs should later
permit their use as fabrics and structural materials.
This feat would involve several technological tasks: (1) A new
pair of nucleotides must be designed that will pair with each
other but not with the four existing nucleotides. (2) They must
interact properly with ribosomes during protein synthesis. (3)
They must be correctly dealt with by the polymerase enzymes which
copy DNA or transcribe DNA to RNA (or else the enzymes must be
modified). (4) A set of new transfer RNA molecules must be
designed to interpret the new nucleotide triplets; genes must be
constructed to encode the structures of the new tRNAs. (5) A set
of tRNA synthetase enzymes must be engineered to couple the new
amino acids to the new transfer RNAs.
Tasks 1 and 2 have now been accomplished. A paper by J.D. Bain, et
al at UC Irvine describes experiments in which an RNA message
written with an expanded genetic code was correctly translated
into a protein containing a 21st amino acid. [Nature
356:537-539; 9Apr92] (The researchers used nonenzymatic
methods to construct the messenger RNA and the new transfer RNA
with its attached amino acid.) The concept of an expanded genetic
code has therefore passed a major hurdle. The most iffy hurdle is
task 3 above, since existing polymerase enzymes may prove unable
to copy more than four nucleotides accurately; redesigning the
polymerases is beyond our current capabilities unless artificial
evolutionary methods can somehow be applied to the problem. Ditto
for task 5--designing the synthetase enzymes. Task 4, on the
other hand--designing new transfer RNAs and the genes for
them--should be easy.
How many kinds of proteins are there? The answer depends upon the
counting criteria--i.e., how different in sequence two
polypeptides have to be in order to be counted as separate
proteins. It also depends upon how one counts polypeptides whose
sequences appear as subsequences in other polypeptides. But such
matters can be quantified and dealt with statistically. Having
done so, Cyrus Chothia of the Cambridge Centre for Protein
Engineering states that "the large majority of proteins come
from no more than one thousand families." This number is far
smaller than the number of distinct protein molecules found in,
for example, the human organism, and explains why about a third
of the new sequences deciphered last year turned out to have
identifiable counterparts already in the sequence databases.
Chothia concludes from this that the basic structures for most
biological proteins will be known in time for completion of the
genome projects. [Nature 357:543-544;
18June92]
Surmounting a computational barrier, a group at the Swiss Federal
Institute of Technology in Zurich has exhaustively compared all
possible protein subsequences in the entire protein sequence
database. The result is a reorganized database that clarifies and
quantifies the similarities between proteins and reveals their
probable evolutionary interrelationships. This, in turn,
facilitates the reconstruction of ancestral proteins and
ancestral metabolisms of the organisms that must have possessed
them. The researchers have already reconstructed and prepared
samples of some of these ancient proteins for study. [Science
256:1443-1445; 5June92]
The relevance of this work to nanotechnology is indirect. The
indication is that in the near future biologists will have a
clear picture of the structures and relatedness of nearly all
biological proteins and their components. Protein technology
should benefit from this orderly presentation of its elements in
the same way that 19th-century chemistry benefited from the
formulation of the Periodic Table.
Molecular manipulators
Molecular manipulators like the scanning tunneling microscope
(STM) and the atomic force microscope (ATM) have been used to
perform a number of well-publicized tricks during the past two
years. With the STM, for example, individual atoms can be pulled
from surfaces, or picked up, moved, and positioned; single
molecules can be poked, pinned and broken. The AFM, however, has
provided poor resolution and control compared with the STM.
Yun Kim and Charles M. Lieber of Harvard have begun to correct
this deficiency by using a more rigid substrate. Applying an AFM
tip to a thin layer of molybdenum trioxide on a substrate of
molybdenum disulfide, they have successfully demonstrated the
ability of the AFM to perform elementary machining and cutting
operations. Into a layer of MoO3 they carved clean
accurate grooves about 2 nm deep, 10 nm wide at the surface and 5
nm at the bottom. Their most impressive feat, however, was to cut
a 60-nanometer triangular piece from an irregular region of MoO3,
and move it away from the parent body. An object of this shape
and size would be several atoms thick and several hundred atoms
across. Kim and Lieber suggest that nanostructures with novel
electrical and optical properties might be assembled from doped
MoO3 using these techniques. [Science 257:375-377;
17July92]
Electronics
At Argonne National Laboratory in Illinois researchers have
designed, built, and tested the optical properties of two
molecules they propose as molecular switches. One of these
substances (called HP-PBDCI-HP), has the potential ability to
modulate two light beams of different colors on a picosecond time
scale. When dissolved in pyridine and exposed to 160 femtosecond
pulses of light at 585 nm, HP-PBDCI-HP shows a strong absorbance
at either 713 nm or 546 nm, depending upon the light intensity.
(If a pulse delivers 20 photons or less per molecule then a
single photon will likely be absorbed. At slightly higher
intensities, a second photon may also be absorbed during the same
pulse.) If two different colors are used as inputs, the molecule
should be able to perform logic operations, as well.
A major advantage this substance has over other recently studied
molecular switches is its reliance on intramolecular electron
movements rather than changes in the molecule's shape. The latter
result in slower switching speeds. [Science 257:63-65;
3July92]
Single-atom transistors may be a step closer to reality thanks to
experiments by M.W. Dellow at the Universities of Nottingham and
Glasgow, and S. Gregory of Bellcore, both of whom have
demonstrated the ability to control currents tunneling through
single atoms. In both experiments the placement of the atoms in
question was left to chance; the goal was to study conduction and
control rather than to build precision nanodevices. [Nature
357:199-200; 21May92]
Materials
Crystallume in Menlo Park, California, has a new process for
bonding diamond to cobalt/tungsten carbide composites, the stuff
of which drill bits and the like are made. [The Economist
25July92, pp. 81-82]. Diamond films are expected to improve many
wear-limited products, from machine tools to razor blades. Since
nanotechnology may make heavy use of diamond as a structural
material, the current high interest in diamond technology could
not have come at a better time.
One can't help but wonder, though, about the ultimate fate of
these diamond films. Will they eventually chip off and blow
around in the wind? If so, do they quickly become dull or do they
remain a razor sharp hazard of increasing magnitude as more and
more products are coated with diamond? What happens if a sliver
of diamond film blows into your eye, or if you step on some at
the beach? I don't know the answers to these questions, but I
hope someone has looked into the matter.
Recent progress on the fullerene front also includes the
preparation of several bromine derivatives of C60 and
the determination of their exact structure. C60 is the
famous soccer-ball shaped molecule, the most stable and
symmetrical of the fullerenes. This first complete
characterization of a chemically modified fullerene marks the
beginning of a systematic chemistry of these materials. [Nature
357:443-444; 11June92]
We should note that fullerene chemistry is being pursued as a
bulk technology, not as a nanotechnology. The reactions take
place between molecules floating randomly in solution and not
between molecules held and moved by manipulators. Nevertheless,
fullerenes could turn out to be useful structural elements for
building nanodevices, particularly if their springiness can be
selectively controlled. For example, one can imagine using an STM
to build a complex structure out of fullerene components prepared
by ordinary chemistry. An appropriately shaped fullerene molecule
studded with several reactive atoms (like bromine) would be
picked up on the STM tip, moved into position on the workpiece,
and held there while a suitably tuned laser zaps the entire
workpiece for a few picoseconds. The laser light would excite
particular chemical bonds, causing the new part to be
"welded" into place. (How can one use the STM both to
view the workpiece and to manipulate a molecule at the same time?
It's a problem that cries out for a solution, but I haven't a
clue. Why should laser chemistry be effective on fullerenes when
it hasn't worked well in general? Perhaps it will work better on
molecules that are being held in place.)
Russell Mills is research director at a company in California.
Report
from Japan
by Dr. Charles Sweet, a social scientist who also writes for
Nikkei Sangyo Shimbun in Japan.
Last July I went to Japan to interview several leaders of that
country's rapidly growing nanotechnology research effort. I
talked with them about their own programs and others that are
operating or being planned; and I asked their advice concerning a
research project of my own, which will survey and compare
attitudes toward nanotechnology development among Japanese and
U.S. researchers and policy makers.
In Japan, public-sector scientific research programs are
implemented through three different ministries: Trade and
Industry (MITI), Education, and the Science and Technology Agency
(STA) within the Prime Minister's Office. All three are overseen
by the Cabinet and receive their funds through the Ministry of
Finance, but it should not be presumed that this structure
results in tight coordination and cooperation among them. Quite
the contrary: they are intensely competitive, to the point of
headhunting one another's scientific personnel. The Japanese
business world has always been extremely competitive, and it has
been been appreciated that the virtues of competition should
apply in the public sector as well. Not only do parallel programs
quicken the pace of research, they also provide redundancy. And,
though the walls between ministries are as formidable as those
that separate Japanese corporations (or at least, groups of
corporations), there is plenty of formal and informal cooperation
at the researcher level, to mitigate against excessive
duplicative effort and experimental dead ending.
The three ministries appear equally serious about getting a leg
up in the nanotechnology race. MITI, through its Agency of
Industrial Science and Technology (AIST) is launching a ten-year,
$185 million "Ultimate Manipulation of Atoms or
Molecules" project this year, as part of the ongoing
National Research and Development Program (also called the
"Large-Scale Project"). The project will be carried out
at the new interdisciplinary research center that MITI is
erecting in Tsukuba. The purpose of the project is stated as
"the development of techniques [for] probing and
manipulating atoms and molecules on solid surfaces or in 3D space
with extreme precision." Potential applications in materials
science and human genetic analysis are identified.
The Science and Technology Agency (STA), through its Research
Development Corporation of Japan (JRDC), has operated the ERATO
(Exploratory Research for Advanced Technology) program since
1981. It is comprised of 15 projects at any one time, with three
five-year component projects starting and ending each year.
Several projects have already focused on topics of
nanotechnological interest. These include the Yoshida
Nano-Mechanism Project (1985-90), the Kuroda Solid Surface
Project (1985-90), the Hotani Molecular Dynamic Assembly Project
(1986-91), and the Kunitake Molecular Architecture Project
(1987-92). (ERATO projects are named after the researchers who
organize and run them.) ERATO's current major nanotechnological
thrust is the Aono Atomcraft Project (1989-94), which is aimed at
studying the behavior of atoms and molecules on surfaces and
techniques for precision deposition, centering on use of the
scanning tunneling microscope (STM). An effort is also being made
to develop rapid surface-analysis techniques capable of providing
feedback to deposition devices.
STA also runs the Institute of Physical and Chemical Research
(RIKEN), whose "Frontier Research Program," headed by
Dr. Hiroyuki Sasabe, is working in the areas of molecular
electronics, bioelectronics, and quantum electronics. One aim is
said to be the development of an "artificial brain."
The Ministry of Education provides research funding to
universities, several of which are already strongly involved in
nanotechnology. The leader appears to be the Tokyo University
Research Center for Advanced Science and Technology (RCAST), an
innovative, interdisciplinary program in the physical,
biological, and social sciences. According to Dr. Setsuo Osuga,
the Center's director, in the four years since RCAST was founded,
"every effort has been made to break through the stale
situation of the old university and make RCAST a center of
excellence. . ." He adds, "If necessary, we will make
organizational changes in order to facilitate and continue
creative scholarship." This sort of language, coming from a
highly placed Japanese academic, is quite remarkable.
I visited Prof. Iwao Fujimasa, a medical doctor who heads up the
Biomedical Devices Laboratory within RCAST's Advanced Devices
Department. He made clear the importance with which he regards
nanotechnology research, and emphasized his intention to bring
foreign researchers to RCAST in order to pursue it in as
effective and cooperative a manner as possible. (It should be
added that RCAST was one of the principal sponsors of the Second
Foresight Conference on Molecular Nanotechnology in November
1991, at which Dr. Fujimasa was a speaker.)
Other universities prominently involved in nanotechnology include
the Tokyo Institute of Technology ("the Japanese MIT"),
Tohoku University, Kyushu University, Osaka University, and Kyoto
University.
Both MITI and STA invite corporate researchers to participate in
their projects (and STA involves academicians as well), and both
strive to transfer R&D results to the private sector. I saw
an example of their success in doing so when I visited Mr. Ichiro
Yamashita, who is organizing the new International Institute for
Advanced Research (IIAR) of the Matsushita Electric Co. Until
early this year, Mr. Yamashita and his colleagues Dr. Toshio
Akiba and Dr. Keiichi Namba had participated for several years in
STA's (ERATO) Hotani Molecular Dynamic Assembly Project. They
brought their research in flagellar motor structure and dynamics
back to Matsushita, and have laid the groundwork for a strong
program that is already conceptualizing first-generation
nanotechnology applications that could eventually be developed by
Matsushita's Panasonic division. The IIAR will move next spring
to permanent facilities in the new Keihanna "science
city" being built at the intersection of Osaka, Kyoto, and
Nara prefectures.
Another impressive corporate effort in nanotechnology is being
mounted by the Mitsubishi Research Institute (MRI). MRI is a
think tank but, unlike others in Japan, it integrates physical
science R&D with research in the social and information
sciences. In Tokyo I met Dr. Shin-ichi Kamei, a researcher in the
Material Science Laboratory of MRI's Frontier Science Institute.
Dr. Kamei's research is focused on the application of laser
technology to the determination and control of atomic bonding
energy levels in solids, which may have applications in molecular
assembly and the development of molecular computers. I was
surprised, however, to find Dr. Kamei working hand in hand with
colleagues in MRI's Techno-Economics Dept., who are looking
closely at nanotechnology's potential economic and social
impacts.
It would be exaggerating to say that molecular nanotechnology has
already become a central and clearly defined feature in the
Japanese vision of next-generation technological and social
development: nanotechnologists are still in a minority in Japan,
as elsewhere. Yet, I recently mailed my survey questionnaire to
235 Japanese researchers who are doing nanotechnology-like
research; and I think we can expect to see a rapidly converging
focus on nanotechnology in Japan in the next few years.
From Foresight Update 15, originally
published 15 February 1993.
Foresight thanks Dave Kilbridge for converting Update 15 to
html for this web page.
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