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.
Table of Contents - Foresight
Update 15
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]
Table of Contents - Foresight
Update 15
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]
Table of Contents - Foresight
Update 15
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.
Table of Contents - Foresight
Update 15
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.
Table of Contents - Foresight
Update 15
Foresight thanks Dave Kilbridge for converting Update 15 to html for
this web page.
From Foresight Update 15, originally published 15
February 1993.
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