Foresight Update 16
page 1
A publication of the Foresight Institute
 Nanotechnology in Medicine
The following paper was presented by Dr. Fahy of the
American Red Cross at the U.S. Pharmacopeial Convention in fall
1992. Our thanks to the Institute for
Alternative Futures for arranging the lecture.
Sometime in the next 30 years, mankind should acquire
unprecedented ability to grasp, manipulate and modify individual
molecules, and this ability may have profound implications for
the interests of the U.S. Pharmacopeia. The term "molecular
nanotechnology" has been coined to mean the technology of
highly versatile and inexpensive molecular fabrication, molecular
manipulation, and molecular-level manufacturing. It refers to the
nanometer size range, the scale of atoms and molecules, but could
be used to create macroscopic structures of precisely defined
composition. The key concepts of molecular nanotechnology are
that molecules can be machines and that molecular engineers can
work with molecules to build desired equipment just as
effectively as today's engineers now work with bulk materials.
The difference between nanotechnologists and biotech-nologists is
that the former do not restrict themselves to the biological
limitations of the latter, and they are much more ambitious about
the kinds of accomplishments that they want to achieve.
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Dr. Gregory Fahy discusses his presentation on
medical applications of nanotechnology with participants
at Foresight's First General Conference in November 1992.
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Organic chemists have long been able to synthesize complex
molecular structures, including drugs, by devising ingenious
reagents and by contriving reaction conditions in such a way as
to minimize undesired side reactions and maximize yield. The
results obtained depend on the statistics of uncontrolled
molecular collisions in solution involving all possible molecular
degrees of freedom. Statistically improbable reactions may be
slow. More important, solution-based reactions generally lead to
unwanted and potentially toxic byproducts. This imprecision of
present day chemical synthesis and manufacturing processes is one
reason that drug standards are needed. In contrast, molecular
nanotechnology would directly and rapidly produce the
desired chemical and only the desired chemical, giving yields of
100%. This would be achieved by precisely positioning and
bringing together the individual molecules involved in the
reaction in such a way as to catalyze the reaction desired and
only the reaction desired.
Pathways to Molecular Nanotechnology
Molecular nanotechnology has many precedents. Enzymes are
natural molecular machines that adsorb individual reactant
molecules from the surrounding solution and, as a result of
precisely orienting them with respect to each other in a
protected "nanoenvironment," catalyze reactions in a
highly specific manner at very high speeds and under mild
reaction conditions. This simple process in biological systems
ultimately allows synthesis of structures as diverse as carbon
dioxide and hair. In fact, living organisms are
naturally-existing, fabulously complex systems of molecular
nanotechnology. If nature can produce the biochemical
capabilities of living cells by accident, molecular engineers
should be able to accomplish comparable, but broader capabilities
by design, guided in part by the examples provided by living
systems.
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| Living organisms are
naturally-existing, fabulously complex systems of
molecular nanotechnology. |
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Many industries already make use of enzymes to catalyze
desired reactions one molecule at a time. Genetic engineers are
producing pharmaceuticals by using naturally occurring enzymes to
edit DNA, and the soft drink industry uses enzymes that have been
modified to allow them to produce sugar at high rates near 100
degrees C without denaturation. The real promise for the future,
however, lies in the development of fully artificial enzymes.
Enzymes have already been designed, synthesized, and found to
function as designed. Designed enzymes that are found not to
function as intended can be modified as many times as necessary
until they function as desired. Thus, whether from first
principles or from enlightened trial and error, industrially
useful artificial enzymes should be forthcoming. More than 10100
average-sized synthetic enzymes are possible with the use of
nature's 20 amino acids, whereas probably less than 1014
enzymes are presently responsible for maintaining the entire
biosphere.
But there is nothing to restrict artificial enzymes to only 20
amino acids. There are many useful kinds of chemistry that are
not easily promoted by natural amino acids. One particularly
versatile method for transcending the biological limits of
proteinaceous catalysts has already been demonstrated (ref. 1). It is based on the fact that
the genetic code specifies amino acids by the sequence of any one
of four nucleic acid bases taken three at a time, with each
three-letter base sequence known as a codon. There are 64 codons
in all, but nature uses them to specify only 20 amino acids
rather than 64. Recently, it has become possible to create an
artificial transfer RNA that can add an unnatural amino acid to a
growing polypeptide chain in response to one of the
"unused" codons that exist naturally. This could be
expanded to an unlimited number of unnatural amino acids, and
these unnatural amino acids could contain totally nonbiological
catalytic groups or even pre-made machine parts, such as
structural support struts, molecular bearings, or the like. In a
fully artificial system, the 20 natural amino acids might even be
entirely dispensable. Furthermore, it is now possible to insert
artificial bases into DNA and RNA, drastically augmenting the
prospects for designing catalytically active RNA as well as
proteins with unnatural functional groups (ref. 2). The potential for programming
the creation of unprecedented chemical catalysts and other
molecular tools useful for molecular engineering is thus
virtually open-ended.
Yet a ribosomal pathway to molecular nanotechnology is far from
the only viable approach. Bulk techniques are now creating useful
building blocks for molecular nanotechnology, such as carbon
closed-end tubes with walls that are one atom thick (descendants
of buckminsterfullerene). Cryptands or cavitands are being
created that pack the catalytic punch of enzymes into
nonprotein-aceous structures far smaller than natural enzymes. At
the same time, the ability of the scanning tunneling microscope
not only to image, but also to manipulate individual atoms and
molecules is being combined with the biological specificity of
antibodies in an attempt to make all-purpose molecular
synthesizers similar in concept to industrial robots that now
make automobiles. These present-day efforts are being
supplemented by computational chemistry simulations of molecular
bearings, molecular planetary gears, and molecular robot arms
that would direct molecular factories.
Implications
An important premise of molecular nanotechnology is that the
products of this technology should ultimately be readily
affordable. This premise is based on the notion that an
all-purpose molecular assembler should be able to make copies of
itself. Thus, once the first programmable molecular assembler is
made, it will not be long before there are as many such
assemblers as the market needs.
Designs for computers with molecular data storage and processing
elements predict data storage capacities of 1,000 megabytes per
cubic micron and data-processing capabilities of 1010
operations per second for similar volumes. Translated into a
sugar-cube-sized personal computer, this molecular computer would
store 1020 bytes of information and process
information at a speed of 1020 operations per second.
This is 200 billion times the information storage capacity of
today's top level personal computer and well over 100 million
times the processing speed of today's fastest supercomputers.
Although it is difficult to project how many of the open-ended
possibilities suggested by molecular nanotechnology will be
realized by the year 2020, several innovations seem worth
considering.
Standards
Quality control in the pharmaceutical industry today is
necessary due to the imprecision of the manufacturing,
purification, and packaging processes and the inability to
monitor product quality on a continuous basis. When drugs are
made by programmable molecular fabricators and when molecular
sensing devices are available, continuous sensing of the
near-flawless production process should be possible, both for
internal use and for reporting purposes. Problems could be
corrected instantly by replacing defective chemical synthesizers
with backup copies and discarding the few molecules of
mis-synthesized material before any has a chance to leave the
factory.
Thus, the products reaching the public should conform to
standards with virtually exact fidelity. It is also possible that
multipurpose drug synthesizers could be on hand in most clinical
chemistry and toxicology laboratories and would make on-site de
novo synthesis an alternative to obtaining pre-synthesized
standards from bodies such as the USP. The barriers to this route
could be more political than technical, but the availability of
rapid local synthesis could make a life-or-death difference in
some cases, such as those involving acute poisoning, for example.
Alternatively, and more probably, instruments capable of
identifying and quantitating drugs without calibration standards
should be feasible.
"Smart" Pharmaceuticals
Today's drug is essentially a single molecule with an often
sophisticated but always limited repertoire. Tomorrow's
"smart pharmaceuticals" could be essentially
programmable machines with a range of "sensory,"
"decision-making," and "effector"
capabilities. They might avoid side effects and allergic
reactions by coming in generic, biocompatible housings; becoming
active only upon reaching their ultimate destinations; and
attaining almost complete specificity of action. They might check
for overdosage before becoming active, thus preventing accidental
or intentional poisoning. They might have not one chemical action
but several, processing targeted invading organisms or malignant
cells through a series of chemical reactions that guarantee the
death of the target. They might work in concert with three or
four "sister" agents that together produce versatility
unattainable by one agent alone.
Despite the vast increase in complexity over present-day drugs,
such agents can be expected to be totally "pure" and
predictable in their behavior. Safety and efficacy may be
inherent in the designs of such "drugs," in which case
regulatory issues could be simplified rather than complicated.
Drug and Health-Related Information
When every intelligent person can have essentially unlimited
data storage and data-processing capability at his or her
fingertips, drug information will change dramatically.
Marked advances in diagnostic agents could have far-reaching
consequences. The year 2020 will occur approximately 15 years
after the complete human genome has been obtained. By 2020, great
advances in understanding biochemical individuality, which is so
important for side effects and proper dose adjustment, will have
been made. This may make it possible for the physician to read
critical aspects of a patient's phenotype from a noninvasively
obtained cell sample (e.g., cheek lining cells) and to inject
"smart" diagnostic agents that can be recovered in a
drop of saliva some time later and read out to reveal signs of
previously undetected, impending disease processes. The
opportunities for precise tailoring of individual treatment and
for preventive medicine, with all the cost savings implied by
both, would be revolutionary.
"Drug information" could come to include the complete
matrix of appropriate pharmacologic responses to the
newly-available individuality data. Eventually, this will become
so complex and extensive that the physician will be utterly
dependent on assistance provided by computer "expert
systems" in making decisions. In the long run, particularly
if ingestible diagnostic agents and home readout systems become
available, the need for physician participation in
pharmacological therapy may vanish altogether for those patients
with the right equipment available. A major incentive for this
decentralization of medical care will be ethical concerns over
patient privacy and the use of genotypic information for
unauthorized purposes: these are issues of "drug
information" that continue to redefine the term. Relevant
compendia should be available on line to any interested party,
particularly those whose software allows them to interface the
data with a medical "expert system."
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The line between
pharmaceuticals and medical devices
will become fuzzier and fuzzier. |
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Information about "drugs" per se will also change
dramatically. Drug documentation will come to resemble today's
protein structural databases because of the potentially great
complexity of "pharmaceutical agents" that differ from
medical devices only in that they are injectable, and/or
invisible to the naked eye. Indeed, the line between
pharmaceuticals and medical devices will become fuzzier and
fuzzier. On the other hand, the need to document contra-
indications, side effects, and complications of use should be
considerably reduced.
Conclusion
Clearly, the world of health care technology will be
substantially different in 2020 from that of today. The U.S.
Pharmacopeial Convention will likely be a much different
organization on the occasion of its bicentennial anniversary. The
need for pharmaceutical scrutiny by medical practitioners could
be even more intense, however, as all aspects of pharmaceutical
medicine and the pharmaceutical industry itself continue to
change dramatically and at great speed. It can be hoped that
molecular nanotechnology, in addition to helping to create these
dramatic changes, will also be one of the technologies that help
the practitioners of 2020 stay abreast of and manage these
developments.
References
1. Noren, C.J., Anthony-Cahil, S.J., Griffith, M.C., and
Schultz, P.G. A general method for site-specific incorporation of
unnatural amino acids into proteins. Science 244:
182-188, 1989. [MEDLINE
Abstract]
2. Piccirilli, J.A., Krauch, T.,
Moroney, S.E., and Benner, S.A. Enzymatic incorporation of a new
base pair into DNA and RNA extends the genetic alphabet. Nature
343: 33-43, 1990. [MEDLINE
Abstract]
First
Meeting: Computer Scientists for Nanotechnology
by Jane Nikkel
Support for nanotechnology has always been strong -- perhaps
strongest -- within the computer community. The first
nanotechnology course was taught in a computer science
department, the first
conference was sponsored by the same (along with Foresight
Institute), the first PhD was granted by a computer-oriented
department (MIT's Media Lab), and the first text won the
publishing industry's "best computer science book"
award.
A high proportion of the Foresight Institute's members are
computer professionals of one flavor or another, and for years
they have asked with increasing vigor "What can I do,
technically, to further nanotechnology?" In response to
these demands, Foresight's third research conference is
especially designed to enable members of the computer
community--programmers, software engineers, hardware designers,
and computer scientists in general -- to move their knowledge
base and, ideally, their careers toward nanotechnology. All those
with any computer background are urged to attend.
The Third Foresight Conference on Molecular
Nanotechnology: Computer-Aided Design of Molecular Systems
will be held in Palo Alto on October 14-16, 1993. The meeting
includes speakers who have made or are making the transition from
computer science to nano-technology. According to conference
co-chair Ralph Merkle,
"The main emphasis of this conference will be on
computational approaches to the development of molecular
manufacturing, in particular the use of molecular modeling and
the development of molecular computer-aided design (CAD) tools to
speed the process of of developing molecular manufacturing
systems. The conference will be valuable both for people who work
professionally in computational chemistry and for people who have
a background in computer science and are interested in finding
out what they can do to contribute to the development of
molecular manufacturing.
"There will also be a tutorial the day before the
conference, so that people who have a background in computer
science, and who wish to come up to speed with what is going on
in the computational chemistry world, can attend the tutorial and
get their feet wet in the methodologies and techniques that are
commonly used."
The conference will feature fifteen or more speakers giving
presentations on topics relevant to the pursuit of molecular
control. We can only sketch a few of these here:
CAD for Nanotechnology
Joel Orr, Autodesk
Fellow, past president of the National Computer Graphics
Association, and president of the Virtual Worlds Society, will
address CAD industry professionals, would-be nanotech designers,
and others interested in hearing about the peculiar needs of
nanotechnology with respect to CAD. In the macro and micro
worlds, computer-aided design is optional: design can be done by
hand. But in the nano world, CAD is essential. He will discuss:
- Is standard CAD good enough for nanotech?
- What are the characteristics of the ideal system?
- Who is working on such systems?
- When will results be available?
- Nano a mano: What can be done by hand, without CAD?
Virtual Reality for Nanotechnology
Russell Taylor,
a researcher at the University of North Carolina at Chapel Hill,
will be speaking on a subject of particular interest to two
groups of people: (1) surface scientists who are interested in
better interfaces to their instruments, and (2) builders of
virtual worlds, since the system is an example of a virtual world
applied to a scientific problem.
The system under discussion, the Nanomanipulator,
is an immersive virtual-environment interface to a Scanning
Tunneling Microscope (STM). A head-mounted display presents a
scaled image of the surface being scanned by the STM in front of
the user while a force-feedback Argone-III Remote Manipulator
(ARM) allows the user to feel contours on the surface.
Computer-controlled instrumentation allows the user to make bias
pulses at specified locations, thus modifying the surface.
What Can a Programmer Do to Help Create Nanotechnology?
Ted Kaehler, a
computer scientist at Apple Computer, points out that we do not
know how the first assembler will be built or what exact research
is needed to get there. A person who is not a professional
chemist or materials scientist, and yet wants to be involved in
this effort, has to think about how his/her skills match the
problem. In this talk, entitled "What Can a Programmer Do to
Help Create Nanotechnology?", he discusses three efforts he
has been involved in.
The first is an efficient program to discover voids inside large
molecules. Programs that search for the proper design of a large
molecule need to know where the empty spaces are. The second is a
project to build the "relaxation server" on the
Internet. This server accepts proposed molecules (via email
messages) and computes the coordinates of the atoms. The results
are sent back by email. The third project is a
"program" of a different sort -- a meeting group. The
"Assembler Multitude," a subgroup of the local Computer
Professionals for Social Responsibility chapter -- meets every
other Monday night in Palo Alto and covers a wide variety of
nanotechnology-related topics.
Ab Initio Calculations for Mechanosynthesis
Charles
Musgrave, a doctoral candidate at the California Institute of
Technology, will talk about ab initio calculations for
mechanochemical construction of diamondoid structures. Accurate
transition state barriers for a positionally controlled reaction
are necessary to both the design of the tool and the design of
the synthetic process. If either of these designs is not
practical, then an alternate structure is required. High level ab
initio calculations are required to obtain accurate transition
state structures and thus reliable mechanochemical modeling.
Reversibility in Nanocomputer Architectures
J. Storrs Hall,
a researcher at Rutgers University, will be speaking on
nanocomputing; particularly the expected developments in computer
architecture that make use of reversibility to reduce heat
dissipation. The techniques will be critical for nanocomputers,
but are on the verge of becoming useful in VLSI, so the talk will
be of interest to anyone in computer architecture as well as
those studying molecular computers per se.
Macromolecule Design
Markus Krummenacker,
an Institute for Molecular
Manufacturing researcher, will be presenting a "cavity
stuffer" program which should enable the design of
macromolecules the size of proteins. These macromolecules should
then be easily synthesizable and should also have specifiable
interface surfaces so that they can self assemble.
Additional talks include:
- Introduction to the Design of Molecular Systems, by Eric Drexler, IMM
- Computational
Nanotechnology, by Ralph
Merkle, Xerox PARC
- Design of Macromolecular Objects, by Manfred
Mutter, Institut de Chimie Organique [Related
Paper]
- Molecular Modeling, by William
Goddard, Caltech
- Crystal-Based
Molecular CAD, by Geoff Leach,
Royal Melbourne Institute of Technology
- Visualization with Molecular Graphics, by Michael Pique, Scripps Research Institute
- Modeling Diamond CVD with Density Functional Theory, by Warren Pickett,
NRL
- Ab Initio Methods and Software, by Charles Bauschlicher, NASA Ames
- Atom Manipulation by Proximal Probes: Experiment and
Theory, by Makoto Sawamura, Aono
Atomcraft Project
As at past conferences, vendors are expected to demonstrate
both hardware and software useful in nanotechnology development.
The meeting includes a reception and two luncheons to promote
interaction and the formation of new collaborations.
Submissions of abstracts for presentation at the meeting are
being accepted through July 31. Papers from the meeting will be
reviewed for publication in the Institute
of Physics journal Nano-technology.
We at the Foresight Institute urge all computer professionals
interested in nanotechnology to attend this unique meeting.
Information regarding registration, proceedings, and the call for
papers is available from the Foresight Institute, telephone
415-324-2490, fax 415-324-2497, email foresight@cup.portal.com.
Books
of Note
Nanotechnology Playhouse. Christopher Lampton,
1993, Waite Group Press, Corte Madera, CA, 131 pages, softcover
with disk, $23.95. An easy introduction to nanotechnology,
written by a longtime Foresight member. Heavily illustrated.
Includes an IBM-PC disk with "multimedia nanomachine
simulation." Technical accuracy: reasonably high in the
book, poor on the disk.
Unbounding the
Future: the Nanotechnology Revolution. Eric Drexler,
Chris Peterson, Gayle Pergamit, 1991, Quill, New York, 304 pages,
softcover, $10.00. New trade paperback edition of the Morrow
hardcover; available from Foresight.
To order these books
from Foresight
From Foresight Update16,
originally published 1 July 1993.
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