Foresight Update 24

Page 1

A publication of the Foresight Institute


Foresight Institute Offers $250,000 Feynman
Grand Prize For Major Advances
In Molecular Nanotechnology

Foresight Institute is offering a $250,000 cash prize to the first individual or group to achieve specific major advances in molecular nanotechnology.

To win the newly announced Feynman Grand Prize, entrants must design and construct a functional nanometer-scale robotic arm with specified performance characteristics, and also must design and construct a functional nanometer-scale computing device capable of adding two 8-bit binary numbers.

“Foresight Institute expects this large prize to attract the interest of talented people working in the many sciences and technologies bearing upon molecular nanotechnology,” said K. Eric Drexler, Ph.D., Chairman of Foresight Institute.

Prizes have long played a key role in technological advancement. For example, Charles Lindbergh flew the Atlantic Ocean to claim a $25,000 cash prize. More recently, the �50,000 ($95,000) Kremer prize led to the realization of humanity’s age-old dream of human-powered flight. “The Feynman Prize will recognize one of the most significant technological breakthroughs in human history,” Drexler said. “However, the rewards awaiting those who achieve significant nanotechnology breakthroughs will be far greater than the prize itself.”

Funds for the $250,000 Feynman Grand Prize have been donated to Foresight Institute by two Foresight Institute supporters – James R. Von Ehr II, formerly founder of Altsys Corporation, and currently vice president at Macromedia, a leading computer software company; and Marc Arnold, chief executive officer of Angel Technologies, a St. Louis-based wireless telecommunication company. Arnold suggested the concept at a Senior Associates meeting last November. Fund raising is continuing in an effort to increase the prize to $1 million, Drexler said.

Foresight Institute will continue to offer its biennial Feynman Prize for the most significant recent advance in nanotechnology. In recognition of pioneering work to synthesize complex three-dimensional structures built from DNA molecules, Foresight Institute awarded the 1995 Feynman Prize in Nanotechnology to Nadrian C. Seeman, Ph.D., chemistry professor at New York University.

Specifications for the Feynman Grand Prize require the winning entrant to:

  • design, construct, and demonstrate the performance of a robotic arm that initially fits into a cube no larger than 100 nanometers in any dimension, meeting certain performance specifications including means of input. The intent of this prize requirement is a device demonstrating the controlled motions needed to manipulate and assemble individual atoms or molecules into larger structures, with atomic precision; and
  • design, construct, and demonstrate the performance of a computing device that fits into a cube no larger than 50 nanometers in any dimension. It must be capable of correctly adding any pair of 8-bit binary numbers, discarding overflow. The device must meet specified input and output requirements.

The Feynman Grand Prize is named in honor of Nobel Prize winning physicist Dr. Richard P. Feynman, who in 1959 pointed in the direction of molecular nanotechnology in a talk at California Institute of Technology, “There’s Plenty of Room at the Bottom.” Carl Feynman, son of the late Nobel laureate, has participated in the definition of requirements for the Feynman Grand Prize and comments, “I’m delighted that Foresight Institute chose to name this prize after my father. It will be an important prize for an important accomplishment.”

Detailed technical specifications of the Feynman Grand Prize requirements will be posted on the Foresight Web site:



Naval Research Laboratory
Surveys European Nanotechnology

by Lew Phelps

Naval Research Laboratory‘s comprehensive survey of Nanoscience and Nanotechnology in Europe outlines the scope of significant nanotechnology research in Western Europe. Indirectly, it also points to the need for Foresight Institute to continue playing a strong role in public discussion of nanotechnology-related issues.

The 152-page report, written by NRL’s Associate Director of Research for Strategic Planning, William M. Tolles, covers a wide range of both “bottom up” and “top down” research efforts underway in Europe as of 1995.

“The nanoscience community is uncovering information that will make us see a world that we do not now even envision,” Tolles writes in his “Conclusions” section. “With an improved view of the forces, limitations and opportunities that may be controlled through intelligent application of the laws of physics, biology and chemistry, many opportunities can be foreseen for producing new materials. These materials are the basis for new products, enhanced performance, and capabilities that may now only be envisioned. A futuristic field such as robotics, as it unfolds, will inevitably make use of a great variety of new ideas emerging from this frontier.”

Tolles goes on to relay a concern expressed by many of the European scientists he interviewed for his study – that the subject of nanotechnology “could attract practitioners bent on hypothetical postulates or excessive ‘salesmanship’ without a realistic appraisal of the products of experimental research.”

Translation: much of the scientific community is restrained in its willingness to discuss the potential applications of nanotechnology. This reticence arises out of fear of over-promising results that scientists do not believe they can deliver soon.

While valid, such views create real concern for those who believe the economic, social and political consequences of nanotechnology are too significant to be limited to verbal discussion only. Indeed, one of Foresight Institute’s primary roles is to enhance awareness and discussion of nanotechnology-related issues. This role inevitably leads to discussion of technological advances that have not yet been achieved. Foresight Institute intends to continue to fulfill that role even if it sometimes appears at odds with the prevailing approach of the scientific community.

The NRL report itself covers a range of top-down research efforts in Europe, such as new means of lithography, that do not bear significantly on efforts to realize “bottom-up” molecular nanotechnology. However, it also describes significant work in Europe of interest to Foresight members, mostly in the self-assembly arena. European researchers appear “less far along in creative use of probe technology than their American counterparts,” the NRL report says. The most significant work described includes:

  • Research in the Chemistry Department at the University of Birmingham, UK, is largely focused upon catenanes and rotaxanes – molecular structures with switching properties which may provide piezoelectric or photochromic behavior of interest. “In many respects, the research undertaken in this laboratory represents an attempt to transfer knowledge and techniques involving self-assembly operating in life processes to more general molecular systems not found in life,” the report states. “From success in using supramolecular interactions to form unique product structures, there are thoughts of forming autocatalytic systems (or self-replicating molecular systems) in which the products would depend on the presence of a product already in the reactant mixture. In this case, the product would depend on the seed originally present. This then would resemble cell reproduction and life processes, areas of future research.” (Italics added by Update for emphasis.)
  • Research at the University of Groningen (The Netherlands) is reported to be investigating organic compounds with optically active properties. These appear to have potential for reversible optical data storage applications. Staffing and funding there for nanotechnology research were reported to be expanding.
  • A “novel approach” is reported under study at the University of Twente (The Netherlands) to make molecules that may switch between two stable forms. Such molecules are based on modified calixarene structures. The molecule forms a cage that can contain an introduced molecule with a dipole moment relative to that on the outside of the cage. Aligning or opposing configurations might be induced by an applied magnetic field, creating the molecular-scale equivalent of ferroelectric materials widely used today in computer data storage. Such molecules can be switched by devices such as a scanning tunneling probe. Organic chemistry Professor David Reinhoudt has been working for two decades on molecular recognition, the report says.
  • Also in The Netherlands, the research laboratory of Royal Dutch Shell is involved in some aspects of self-assembly. Given the nature of Shell’s business, it’s no surprise that their main motivation for the study of nanostructures relates to emulsification of oil (such as for oil spill cleanup) and catalysis, the basis for petroleum product manufacturing. The laboratory recently upgraded its computing capability with a new IBM SP-2, rated at 6 Gflops, used for molecular dynamic simulations.
  • Some scanning probe microscopy work at the Techniche University of Munich (Germany) involves modification of a passivated amorphous silicon surface that has been doped with phosphorous. A small exposure of this surface to electrons from an STM modifies the phosphorous from P3+ to P4+, which is an insulator. The effect can be reversed by heating the surface. The applications for thermally reversible multiple-read memory are obvious.
  • The Delft University of Technology (The Netherlands) is reported to be setting up a new nanofabrication facility with extensive proximal probe capabilities, including a chamber for manipulation of clusters and atoms with proximal probes. The initiative is funded by special government support (through the Dutch equivalent of the National Science Foundation) to introduce major hardware initiatives.
  • IBM in Switzerland is of course home to Dr. Heinrich Rohrer, a Nobel Laureate for his co-invention of scanning tunneling microscopy. Report author Tolles observes the irony that “The U.S. picked up on local probe techniques faster than did Europe or Japan… In Switzerland, people had many electron microscopes and were not interested in introducing a technique that was so different.”
  • Elsewhere in Switzerland, the Paul Scherrer Institute (the largest government-supported Swiss laboratory) established a nanotechnology group in 1993. The group has four main areas of emphasis, including molecular work. One program involves an immunosensor in which a ferrocene molecule is found to interact with an antibody to act as a transducer.
  • Perhaps the most exciting work in Switzerland comes at the Swiss Federal Institute of Technology, a technical university in Zurich. Francois Deidereich, an organic chemist formerly at UCLA, leads a group of 30 people (and growing) working on chemical fabrication of nanostructures. “Steve Benner is able to fabricate interesting geometric structures from proteins containing modified base pair sequences,” the report states. Efforts there include those that would fall generally into the category of supramolecular chemistry. One program under way seeks to design molecular systems to recognize cholesterol, in order to filter the substance from blood.

A good deal of the report deals with top-down research work, conducted in France, Belgium and Austria, where little bottom-up effort appears underway. The report does mention some work in Toulouse, France, to model images obtained by STM and AFM.

The 154-page report includes over 350 references to specific research.

The report is published by Naval Research Laboratory, Washington DC 20375-5320, publication NRL/FR/1003-94-9755.



European Nanotechnology Conference

Set for April 10-11 in Copenhagen

NanoTech�, a newly formed subsidiary of BioSoft (both Danish firms), is preparing to stage a major nanotechnology conference in Copenhagen – the Continent’s first, according to its sponsors. Just starting as we go to press, the planned dates are April 10-11 at Symbion, the Copenhagen Science Park. The conference will be conducted in English.

“Our intention will be to create a new European Nanotechnology Initiative (ENI) as a natural extension of our Conference,” says Bent Hundrup, BioSoft Group’s Research Coordination Manager, who is spearheading the conference. The ENI will be based in Copenhagen, but active from the Walther-Nernst Institute in Germany as well, he says. The goal is to “cover the European angle on future research in nanotechnology, making Europe very active, coordinated, determined and visionary.” Organizers also seek to promote cooperation between industry, universities, organizations, governments, and European Union commissions and institutes.

Topics for the planned conference include many areas that will be familiar to those attending Foresight’s Nanotechnology Conferences:

  • supramolecular chemistry
  • self-assembling mechanisms and technology
  • computational chemistry and molecular modeling
  • materials science
  • engineering
  • application areas (perspectives)

The list of possible attendees provided by conference organizers indicates a focus on both molecular nanotechnology and top-down approaches such as low voltage electron beam lithography. Many of the individuals cited for key research in the Naval Research Laboratory report on European nanotechnology (see related story) are on the roster of invited participants.

For further information contact:
Mr. Bent Hundrup
3 Fruebjergvej, DK-2100 0
Phone (+45) 39 17 98 28
Fax (+45) 39 27 90 11
He also lists an email address,
but at press time it was not yet operational:
[email protected]


Scientific American without the Science:

Lengthy Story Launches Ad Hominem Attack

[Editor’s Note: For an update and overview of this debate, now in its fourth round of discussion, see]

Scientific American staff writer Gary Stix attended last fall’s Foresight Conference in Palo Alto. He used that event as a springboard to launch a wholly unscientific attack on nanotechnology and Foresight Institute. Built around ad hominem attack and undefendable quotations lifted from World Wide Web sources, the news story concludes that nanotechnology involving a general purpose assembler is akin to “Cargo Cult Science,” a pathology described by the late Nobel Laureate Richard Feynman.

His son, Carl Feynman, has written a letter to Scientific American objecting to their misuse of his father’s essay (see As Carl points out, Richard Feynman saw great promise in nanotechnology, and considered it wholly achievable. We’re waiting to see if they will publish his and other pro-nanotechnology letters they have received from the science community.

Meanwhile, for those interested in a vigorous rebuttal to the Scientific American news story, visit on the World Wide Web. There, Ralph Merkle has done a splendid job of explaining the technological aspects of the field clearly and precisely, while dismantling the story. An email version can be requested from [email protected]

Foresight Chairman Eric Drexler commented, “Over the last twenty years, the intellectual quality of Scientific American has visibly declined, a circumstance that must demoralize the better members of its staff. This decline appears in the level of writing, in the displacement of informative diagrams by decorative illustrations, and in the dilution of science and technology coverage with business and politics.

“With the rise of the Web, however, the decay of general science publications matters less and less. The Web opens a fresh channel for publication on science and technology, one dominated not by organizations entrenched in their printing and distribution systems, pursuing sales down into the swamps, but rather by a free exchange of ideas and responses. On the Web, colorful pictures and biased reporting can’t push aside more serious explorations of the complex dangers and opportunities presented by the real world.”

Regarding some of the less technical matters raised in the Scientific American article, Eric confirms his view that “milk really does have merit as an additive to iced tea, but not with lemon,” and notes that, whatever the accuracy of the comparisons made by Mr. Stix, it is true that as a child he was fond of Mr. Peabody, and “still admires him for his thoughtfulness, responsibility, doggish loyalty, and time-spanning curiosity.”



“…One Very Large Step for Mankind”

by Lew Phelps

Economic and political constraints have diminished the scope and reach of America’s space exploration and development program. Many people seeking to increase long-term investment in space infrastructure, and make space travel more cost-effective, are looking toward nanotechnology as a means to achieve those goals.

Recent developments in this area include:

  • A major report to the board of the Space Studies Institute, summarized in SSI’s Update newsletter (Fourth Quarter 1995) by Dr. George Friedman, executive director of SSI.
  • A paper presented at SSI’s May 1995 Space Manufacturing Conference, on the topic Minimizing the Initial Space Manufacturing Base, by Steve Vetter, Senior Advisor, Space Studies Institute, and an active participant in Foresight Institute affairs.
  • A session at the Space Manufacturing Conference on the topic of Advanced Technologies, also chaired by Vetter.
  • Publication by Thomas L. McKendree, President of the Molecular Manufacturing Shortcut Group, of a paper entitled Planning Scenarios for Space Development, in which he applies scenario planning methods to key issues of space development.

The Space Studies Institute report provides recommendations for continuing research to the SSI Board. Removing weight (and also size) from things that must be sent off-planet is an obvious means to advance the prospects of space development, since the cost of lifting a pound to orbit hasn’t declined significantly in decades, the report says. “The ultimate leverage is achieved with a molecular nanotechnology-based self-replicating system,” the report says. It recognizes that getting there won’t be easy; it “will require at least two types of breakthrough to accomplish the actual synthesis of molecular nanotechnology devices useful for space and the achievement of real-world machine self-replication.

Based on the report, SSI’s board approved four research initiatives, including “Molecular Nanotechnology for Space” (MNTS), for which the principal investigator will be Tom McKendree. The initiative is a Ph.D. research project planned for completion in the spring of 1997. McKendree’s work will be supported by his employer, Hughes Electronics. He is addressing two major inter-related issues regarding the High Frontier- space manufacturing and space transportation.

He will begin with established “location theory” models which support decisions regarding the geographic placement of terrestrial factories as a function of the manufacturing investments and the locations and costs of all resource inputs as well as market outputs. This model will then be expanded to space with its analogous but complex costs and timing constraints for astrodynamic maneuvers. Finally, the impacts of molecular nanotechnology will be assessed.

The molecular nanotechnology impacts on space transportation to be examined include lower-cost conventional rockets, feasible skyhooks and momentum transfer tethers, and ultrathin solar sails. The MNT impacts on manufacturing to be examined include low cost, multiproduct manufacturing, minimal tooling, high-strength structures, synthesis of “vitamin parts,” and self-replication.

The other SSI research initiatives include Sub-Kilogram Intelligent Robots, Accelerated Near Earth Object Discovery, and Quest for Self-Replicating Systems.

Minimizing the Initial Space Manufacturing Base by Steve Vetter notes that the cost of opening the High Frontier is very dependent on the cost of transporting the initial mining and manufacturing facilities from the Earth. This cost is closely related to the mass of these facilities. His paper examines what limits are encountered as one tries to shrink the mass of the initial base. Solutions are proposed to break through or work around each limit as it is encountered. “Finally, we come to the conclusion that the only real limit is at the molecular level,” Vetter writes. “This leads to the realization that building things from the bottom up, with atomic precision, is not only possible, but highly advantageous to the goal of opening the high frontier. This work is based partly on research in minimizing the mass of a solar power satellite, lunar-material-insensitive SPS designs, robots, self-replicating systems, and other related areas of technology.” The heavily referenced paper assumes no new science, but is based on projections of scientifically-understood technological progress.

Advanced Technologies discussions at the SSI 1995 annual meeting included presentation of four papers, including Vetter’s topic discussed above. Another with nanotechnology implications was Bruce Mackenzie’s discussion of “Bootstrapping Space Communities with Micro Rovers and High-Tensile Boot Laces.” (The latter term refers to tethers and cable-like links between a planetary surface and an orbiting platform.) “The tethers make use of expected advances in material science,” Vetter commented. “The better material you have, the more efficient tether you can have.”

Mackenzie’s proposal looked at mass requirements, and determined that to keep the system running efficiently, you would have to send substantial weight into space to keep the angular momentum balanced with (mined and manufactured) products going to the surface, about as much mass would have to be lifted into orbit. “Basically, we can probably bootstrap up a space manufacturing facility, with just a few hundred kilograms of equipment, plus a few tons of tether and ballast and some ability to do some processing at some other point, like at a low Earth orbit space station.” The system requires not only efficient tethers (manufactured, no doubt, from atomically precise materials), but also self-replicating devices that could copy themselves a number of times, then convert to mining and manufacturing duties. The need for nanoscale computing devices is also clear.

Planning Scenarios for Space Development, Tom McKendree’s paper, published by the American Institute of Aeronautics and Astronautics, uses the scenario planning approach advanced by Foresight Institute Advisory Board member Peter Schwartz (President of Global Business Network). Scenarios are fictional representations of alternative futures, focused on particular issues. McKendree proposes a “Slow and Planned” scenario and a “Sooners” scenario.

In “Slow and Planned,” space development evolves gradually, with major institutional players (governments and aerospace corporations) gradually paying more attention to molecular nanotechnology’s development and capabilities. Private ownership of extraterrestrial real estate becomes a significant issue, and a market develops to allocate rights to carbonaceous solar system bodies that have been distributed to all adult citizens of the world. Large corporations accumulate development rights in space, paving the way for actual (gradual) exploration of the High Frontier. The scenario’s key features are relatively slow development of molecular nanotechnology capability, and a high level of planning. Its central feature is a well-conceived set of “rules of the road” for space development.

“Sooners” envisions an extraterrestrial land rush based on Internet distribution of information that allows small players to build rocket probes and self-replicating manufacturing capability very inexpensively. Before large institutions understand what’s happened, every developable asteroid in the solar system is claimed, developed, and colonized. It’s a disorganized, almost anarchic path to space development, but it occurs faster and more completely than the highly-planned path. The scenario’s key features are relatively fast development of molecular nanotechnology capability, and a low level of planning. It shows what might happen if the ability to go into space precedes creation of appropriate “rules of the road.”

Readers interested in using nanotechnology for space development should point their Web browser at:, the home page of the Molecular Manufacturing Shortcut Group, a chapter of the National Space Society.



Japanese “Atomcraft Project” Outlines Major Goals,
Publishes Interim Report

In its third interim activity report, the Aono Atomcraft Project of Japan outlined its goals and technical results. The Atomcraft Project is sponsored by the Exploratory Research for Advanced Technology (ERATO) program of the Research Development Corporation of Japan (JRDC). The project was begun in 1989.

The coined word used in the project name, “Atomcraft,” expresses “a new world of atomic-scale science and technology, including the creation of artificial micromaterials, quasi-molecules and other customized atomic arrangements which exhibit novel electronic, material and optical properties. Although only a dream a decade ago, this is now an actively pursued area of research, thanks to the invention of the scanning tunneling microscope (STM) by Binning and Rohrer,” says Atomcraft Project Director Masakazu Aono in the report’s introduction.

“Even though the STM was originally invented to observe individual atoms, it is also useful for manipulating individual atoms by carefully controlling the local interactions between the probe tip and the sample appropriately. In fact, several preliminary demonstrations suggest the power of this approach. Challenges remain, however, in clearly understanding the physical mechanisms involved and in many issues related to technological feasibility. Our project has been organized to perform systematic studies to overcome such scientific and technological hurdles and apply these results to the fields mentioned above,” Aono says.

The project consists of three groups:

Basic Analysis Group:

Atomcraft attaches importance to the close cooperation between experimentalists and theorists, so this group consists mainly of theorists, to balance the project’s large number of experimentalists. “The theorists are making various calculations to interpret experimental results and design promising experiments for atomcraft. In an experimental subgroup an apparatus for single-atom elemental analysis is also under construction,” the report says.

Structure Control Group:

Researchers in this group are studying various possible techniques for atomcraft, i.e., the manipulation of single atoms and the creation of nanometer-scale structure patterns. Specifically, these include the preparation of atomically sharp tips made of desirable materials, the compensation of thermal drift between tip and sample, the development of hardware and software that can control the movement and electric parameters of the tip in a sophisticated manner, and the preparation of sample surfaces with desirable composition and atomic arrangement. In addition, prototype experiments to control single electrons in nanometer-scale structures at room temperature are also in progress.

Surface Measurement Group:

This group is observing and analyzing various new phenomena related to atomcraft. “One of the most important research subjects is to clarify physical mechanisms involved in atom manipulation. New chemistry observed under the extreme conditions between tip and sample is also being studied. The key to these studies is to prepare tips with desirable shape and composition routinely with the use of an appropriate monitoring method in situ. Another important research subject is to directly measure the electronic properties of created novel micromaterials and nanometer-scale structure patterns in a wide temperature range,” the report says.

For more information, including copies of the group’s report (which contains technical papers in both English and Japanese), contact:

Aono Atomcraft Project
The Institute of Physical and Chemical Research (RIKEN)
Hirosawa 2-1, Wako-shi, Saitama, 351-01 Japan; Phone 81-484-62-1111; Fax 81-484-62-4656


Recent Progress: Steps Toward Nanotechnology

by Jeffrey Soreff

[Editor’s Note: This page has been optimized for Netscape 2 and later. If you are using a browser, such as Netscape 1.1, that does not support the html tag for superscripts, please be aware that an number like “2×109” is meant to be scientific notation for “2 times ten raised to the 9th power,” and that “e2” means “e squared,” etc.]

There were many important papers presented at the Fourth Annual Foresight Nanotechnology Conference. Since, however, the conference was summarized in the Foresight Update 23, this column will focus on information from other sources.



Protein and Peptide Design

Protein synthesis is one technology currently available for building nanometer scale systems. Its primary advantage is that it allows us to build macroscopic quantities of (potentially) atomically perfect nanometer scale structures. The primary disadvantage of protein synthesis is that we want to construct 3D structures, but we can only specify the sequence of amino acids directly. The next three papers advance the state of the art in allowing design of protein structures that fold into target 3D structures.

Helical Bundle Structures:

The current state of protein design is described by J. W. Bryson, S. F. Betz, H. S. Lu, D. J. Suich, H. X. Zhou, K. T O’Neil, and W. F. DeGrado, writing in [Science 270: 935-941 10Nov95]. They focus on the information that stability studies of synthetic proteins can yield about protein energetics. “Designed, helical peptides provide model systems for dissecting and quantifying the multiple interactions that stabilize secondary structure formation. De novo design is also useful for exploring the features that specify the stoichiometry and stability of alpha-helical coiled coils, and for defining the requirements for folding into structures that resemble native, functional proteins.”

The authors describe predictions of structures as rather well established in helical domains, with fairly good agreement (�0.3 kcal/mole out of a range of roughly 0.0-1.0 kcal/mole) on the helical propensities of the various amino acid residues, good understanding of “Specific hydrogen-bonded interactions that ‘cap’ the ends of helices,” and good information on the pairwise “hydrogen bonding and electrostatic interactions between amino acid side chains separated by a single alpha-helical turn.”

The associations between these helices can be harder to predict, with the authors citing one case where varying one pair of residues produced every state of aggregation from dimers to hexamers. In a number of four-bundle designs “the association of hydrophobic side chains provides a powerful driving force for the formation and association of helices…However, both lattice models as well as early design attempts lack the diversity of stabilizing interactions and specificity found in natural proteins, which we believe are essential for stabilizing native-like folds and function.”

They describe a variant of the four-helix bundle ROP, where the hydrophobic residues were packed “in layers consisting of two small and two large side chains per stack” with the resulting protein behaving “in all respects examined like a native protein.” In contrast to the helical peptides, beta sheets have had more experimental difficulties: “…the exposed amides at the edges of beta sheets can hydrogen bond to other sheets, leading to insoluble aggregates.” One of the first de novo designed proteins, Betabellin (which contains beta sheets), has had its solubility increased by introducing a special type of turn using D-amino acids. The authors write that “Recent progress in designing structural proteins has set the stage for the engineering of functional proteins.” They describe an example of a “four-helix bundle protein with four bound hemes,” with spectroscopic properties consistent with the design.

In summary, the helical bundle proteins look like they may be ready for use as structural elements in nanotechnology, with careful attention to residue packing, while other structural motifs are being understood, but more slowly.

Self-Assembled Nanotubes:

A more successful use of beta sheets has been taking place in M. R. Ghadiri’s group at the Scripps Research Institute, as described by P. S. Zurer in [C&EN 18-20 15Jan96]. Ghadiri’s group has been synthesizing peptide rings with alternating D- and L-amino acids. The “rings adopt flat conformations with the amide carbonyls and NH groups pointing up and down, perpendicular to the plane of the ring. These rings self-assemble into nanotubes by stacking one on top of the other, linked by intermolecular hydrogen bonds in a beta-pleated sheet motif.”

The group has sufficiently fine control over the structures formed that they can add functions to their tubes. “For example, the chemists have engineered a system in which evenly spaced carboxylic acid side chains on the outside surface of the nanotube bind copper ions.” Ghadiri’s group has also been successful in freezing their self-assembled structures in place with covalent chemistry. “They incorporated two side chains bearing terminal olefins into a ring composed of eight amino acids. In nonpolar organic solvents, a Grubbs ruthenium catalyst initiates a ring closing reaction that couples two cyclic peptides together. The products are two 38-membered ring structures formed through a double metathesis [olefin exchange] reaction, with none of the smaller bridged rings that would result from intramolecular reaction.”

It would be interesting to see if the group could synthesize pairs of cyclic peptides which would assemble into nanotubes, since this could permit a Merrifield-style synthesis of distinct oligomers, as well as the nanotubes that they can currently build, which are impressively long (200-300 �m), but have uncontrolled length.

Redesigning hydrophobic cores:

J. R. Desjarlais and T. M. Handel, writing in [Protein Science 4: 2006-2018 1995] describe a novel computational and experimental approach to redesigning the hydrophobic cores of proteins. They “have designed and engineered several variants of the 434 cro protein, containing five, seven, or eight sequence changes to the hydrophobic core.” Prior to this work, “designed proteins generally lack a well-defined and uniquely structured folded state. These proteins usually display weak cooperativity in their unfolding transitions and poorly dispersed NMR spectra. Because of the poorly structured nature of these proteins, determination of high-resolution structures for these molecules has also been hampered.” The lack of high-resolution structural information is a particularly important hurdle to cross, because this information is crucial in providing detailed diagnostics for tuning the structures. We have to solidify the protein structures well enough to get enough information to really debug them.

The authors’ design methods start with the native protein. They build a “custom” rotamer library for the hydrophobic core by removing the core side chains from the protein, but retaining the backbone and the non-core side chains. They examined rotamers at 5� increments of torsion angles, retaining only 18 low energy configurations for each of the hydrophobic residues examined. The selection of well-packed structures using this rotamer library is a substantial computational task. “…for a small protein with 10 core positions, more than 1018 structural solutions exist with roughly 1010 sequence combinations.”

The authors dealt with this combinational explosion by optimizing their designs with a genetic algorithm. This step takes roughly 1 to 3 hours on a 150-MHz processor, examining 50,000 candidate structures. The primary result is that the authors were able to design two variations on 434 cro which “are of comparable thermal stability to the C-1 native control.” Not all of the designs were this stable. Another variant, designed by the same methods, was significantly destabilized relative to the native protein. In addition to the thermal stability evidence, 1D proton NMR spectra were examined for three of the proteins. “Designed proteins typically have very poorly dispersed NMR spectra due to a combination of exchange broadening and chemical shift averaging caused by a dynamic folded state.” In the spectra examined, the spectra are about as well dispersed as in the native protein. “This implies that for these representative variants, the folded state is well ordered.”



Catalytic Antibodies

One class of useful nanometer structures that can be constructed with protein technology is that of catalytic antibodies. These proteins help extend synthetic capabilities by controlling the orientation with which reactants encounter each other, reducing the number of side reactions that take place, increasing the purity of the products formed, and hence improving the synthetic utility of the reactions. This is both an application area for nanotechnology and potentially a mechanism for extending the variety of stiff, polycyclic building blocks available to the nanotechnologist. The next two papers extend the state of the art in this area.

Reactive Compound Immunogens:

Writing in [Science 270: 1775-1782 15Dec95], P. Wirsching, J. A. Ashley, C.-H. L. Lo, K. D. Janda, and R. A. Lerner describe an extension to the technology of antibody catalysis. Previous work has generated catalytic antibodies by inducing an immune response to an inert antigen that models the transition state of a desired reaction. The antibody produced then binds to the the transition state of the reaction, stabilizing this transition state, reducing the activation energy of the reaction, accelerating the reaction, and reducing the fraction of the substrates that undergo undesired side reactions.

The current work uses “reactive compounds as immunogens designed to promote specific chemistry in the antibody binding site, both in vivo during antibody induction and then later in catalysis. Thus, at the time of antibody-antigen encounter, a component of the binding energy results from complex chemical reactivity as well as from simpler forms of complementarity dependent on electrostatic and hydrophobic forces.” There is a trade-off required in using reactive immunogens, because “there must be sufficient reactivity to undergo chemical reactions in the binding site of the antibody, but not too [sic] much lability to be completely degraded by the many chemical entities encountered in vivo during immunization.”

The specific reactive system described in this paper was an organophosphonate diester, RP=O(OR’)2 and one of its hydrolysis products, RP=O(OR’)O-. The final antibody catalyzed the hydrolysis of an analogous carboxylic ester, as well as the hydrolysis of the organophosphonate diester. The number of turnovers of the phosphonate diester was limited (typically 1-3) because the antibody can itself be phosphonated by the diester, inactivating it. The net result of this work is to add a new option to catalytic antibody technology, broadening the range of immunogens that can be used to trigger formation of potentially useful antibodies.

Aldol Condensation with Catalytic Antibodies:

Writing in [Science 270: 1797-1800 15Dec95], J. Wagner, R. A. Lerner, and C. F. Barbas III describe catalytic antibodies that perform the aldol condensation. The aldol condensation is formally an addition of a ketone (or aldehyde) with an alpha hydrogen, R(C=O)CHR’R” (the aldol “donor”) across the carbonyl of another ketone (or aldehyde) R”'(C=O)R”” (the aldol “acceptor”) to give R(C=O)CR’R”C(OH)R”’R””. This reaction “is, arguably, the most basic C-C bond forming reaction in chemistry and biology.” There are natural enzymes that catalyze this reaction but “the most limiting aspect of the application of natural enzymes in synthesis is their rather poor acceptance of a range of substrates. Although natural enzymes display broad specificity with respect to the aldol acceptor, the aldol donor is usually limited to the natural substrate. For example, among the ketones studied for antibody catalysis only acetone is a substrate for a natural enzyme. In contrast, antibody aldolases can use various aldol donors and acceptors. The antibodies accept acetone, fluoroacetone, chloroacetone, 2-butanone, 3-pentanone, 2-pentanone, and dihydroxyacetone as aldol donor substrates.” This flexibility has advantages and disadvantages for applications of these antibodies to synthesis.

It is helpful to be able to catalyze a variety of reactions with one antibody, but it is also helpful to have the catalytic antibody be sufficiently selective to catalyze only one reaction amongst those reactions that can potentially occur within the reaction mixture. The potential reactions include possibilities due to various possible aldol condensations of the initial reactants (due to the variety of alpha hydrogens on the aldol donor and to the possible directions of attack of the aldol donor on the aldol acceptor) and due to possible further reactions of the products of the initial reactions.

In cases where the variety of alpha hydrogens on the aldol donor allow for a variety of possible products, for instance with “reactions with 2-butanone and 2-pentanone, the antibodies exhibit some control of the regioselectivity of the aldol addition by preferential formation of the most substituted enamine [the activated form of the aldol donor within the catalytic antibody].” These cases gave product ratios of 94:4 and 73:27, respectively, in favor of the products formed from the most substituted enamines.

In a test of the selectivity of the direction of attack of an aldol donor (acetone) on an unsymmetrical aldehyde acceptor, an 11:1 ratio of the two possible products was formed under antibody catalysis, demonstrating the stereoselectivity of the catalyzed reaction.

In a test of side reactions, monitoring the concentration of reactants and the expected product during antibody catalyzed addition of acetone to a branched 3-phenyl-propionaldehyde acceptor gave results where “the perfect mass balance (top line [from Fig. 6 in the paper]) indicates that no side reactions, such as elimination or polymerization, occurred over that period [a 35 hour reaction run converting 90% of the acceptor to the addition product]. Thus, the antibody-catalyzed aldol reaction is an exceptionally mild method of C-C bond formation.”

In summary, antibody catalyzed aldol condensations provide a promising technique for exploiting protein technology to extend synthetic capabilities, supplying both an application area for protein based nanostructures and possibly extending the range of building blocks available for nanotechnology.



A Protein/Polymer Actuator

The technologies described in the papers above are useful, but they all rely on diffusion of chemical species to a molecular machine such as a catalytic antibody in order for useful work to be initiated. The paper below describes a mechanism for thermal diffusion to trigger useful changes in a molecular machine, which is a much faster mechanism, and which brings us closer to being able to build molecular machines controlled by broadcast signals (as in Merkle’s replicator architecture) at a reasonable rate.

An advance in control of a protein’s ligand binding ability comes from P. S. Stayton, T. Shimoboji, C. Long, A. Chilkoti, G. Chen, J. M. Harris, and A. S. Hoffmann, writing in [Nature 378: 472-474 30Nov95]. They bound a temperature sensitive polymer (poly(N-isopropylacrylamide)) to a mutant streptavidin, a protein that normally binds biotin. “Normal binding of biotin to the modified protein occurs below 32�C, whereas above this temperature the polymer collapses and blocks binding. The collapse of the polymer, and thus the enabling and disabling of binding, is reversible.” Below the transition temperature the polymer “adopts a hydrated coil conformation” which spreads it out and keeps it from blocking the biotin binding pocket, while above the transition temperature the polymer “is a collapsed globule” which does block binding. Considered dynamically, the collapsing polymer acts as a thermomechanical actuator to shove the biotin molecule out of its binding pocket.

The authors suggest that this control of binding “could also be used to remove inhibitors, toxins, or fouling agents from the recognition sites of immobilized or free enzymes and affinity molecules, such as those used in biosensors, diagnostic assays or affinity separations. This could be used to ‘regenerate’ such recognition proteins for extended process use.” From a molecular manufacturing point of view, thermal control of affinity is notable since it permits an engineered protein to grasp or discard a feedstock molecule in response to a broadcast thermal signal. Unlike actuation via binding of some “signalling” molecule, this mechanism does not require movement of additional chemical species for each actuation cycle.



Diagnostic Techniques

The current state of the art of protein design and fabrication in particular – and the fabrication of nanometer scale structures in general – is still far from the point where it would be feasible to design structures in the absence of feedback on how successfully the target structure was actually fabricated. The papers below describe advances in diagnostic techniques which help provide this feedback.

Protein Crystal Growth:

Protein crystal growth is an important and difficult step in obtaining structural information on proteins from x-ray diffraction measurements performed on these crystals. A number of advances in protein crystal growth are described in an article by D. Normile in [Science 270: 1921-1922 22Dec95]. The article describes several different advances presented at the “Sixth International Conference on Crystallization of Biological Macromolecules.”

The first advance was a quantitative analysis of improved quality of protein crystals grown in space. The analysis found that the “mosaicity” of crystals grown in microgravity was reduced. Macroscopic protein crystals are really composed of many small blocks of crystal which are somewhat misaligned. Mosaicity is a measure of how severe this effect is. “Reduced mosaicity can improve the signal-to-noise ratio and should result in improved precision in determining crystal structures.” In experiments where lysozyme crystals were grown on Earth and in space under equivalent conditions, analysis of diffraction data showed “that the Earth-grown crystals had a mosaicity three times greater than the space-grown crystals.”

A second advance was made in microbatch techniques, “in which crystals are grown in 1 to 2 microliter drops of a mixture of a protein and a crystallizing agent…Using even smaller droplets of solution isn’t practical, because the drops dry up before the protein crystallizes. By covering each droplet with a layer of oil, Chayen and her colleagues found, they could prevent evaporation of the tiny microliter droplets and also protect the sample from contaminants in the air.” In addition, the remaining evaporation appears to go through the oil, allowing tuning of the rate by selecting the type of oil and the thickness of the oil layer.

NMR Probe Spectra:

Writing in [Science 270: 1967-1970 22Dec95], D.L. Olson, T. L. Peck, A. G. Webb, R. L. Magin, and J. V. Sweedler describe a new NMR probe that obtains spectra from samples which are a factor of 130 less massive than those usable in a conventional NMR probe. “The microcoil is 1 mm long and encloses a sample of 5 nl within the [fused silica] capillary.” A sustantial improvement in sensitivity came from immersing the microcoil in Fluorinert FC-43, which provides a match to the magnetic susceptibility of the copper coil, thereby improving the uniformity of the magnetic field, reducing the line widths of the signals, and improving sensitivity. “The ability to acquire high-resolution spectra on 5-nl samples with improved mass sensitivity enables a variety of uses for microscale NMR. Biological applications will greatly benefit from the ability to structurally identify molecules with submicrogram LODs [limits of detection]. As an example, a microcoil NMR spectrum of a seven-amino acid peptide is shown…” From the point of view of nanotechnology, this advance will assist in using NMR to confirm synthetic protein geometries (for sufficiently rigid proteins), or to screen synthetic proteins for rigidity based on the global dispersion of their NMR spectra, even when the synthetic difficulties limit sample sizes.



Larger Scale Components From Biological Systems

In addition to using individual protein molecules for nanotechnological applications, there are some larger scale components from biological systems that may also be useful components for nanotechnology.

Capping Microcubules:

One phase of research on microtubules has been capped as Y. Zheng, M. L Wong, B. Alberts, and T. Mitchison, writing in [Nature 378: 578-583 7Dec95], identify a gamma-tubulin complex which “acts as an active microtubule-nucleating unit which can cap the minus ends of microtubules in vitro.” The complex appears (via electron microscopy) to be a ring 25-28 nm in diameter (“similar to the outer diameter of a microtubule (25nm)”) with a thickness of about 10 nm. This is potentially useful since microtubules are important structural elements in cells. More precise knowledge of how to control their formation and orientation might allow us to exploit them as structural members in early nanomachinery. The control exerted by this complex may be quite precise. Microtubules which spontaneously assemble typically have 14 protofilaments (lines of protein molecules stretched out along the tubule) while those assembled in vivo (nucleated from the centrosome) have 13. Essentially the control of the nucleation acts like an initial circle of bricks in starting a spiral tower. It very precisely sets the pattern for the tower as a whole, even though the bricks themselves may permit several patterns.

DNA Sequence:

Writing in [Science 269: 496-512 28Jul95] J. C. Venter et. al. (40 authors in total) describe the full sequencing of Haemophilus Influenzae Rd. This genome of 1,830,137 base pairs is the first complete genome sequence for a free-living organism. The strategy followed by this group “eliminated the need for initial mapping efforts and is therefore applicable to the vast array of microbial species for which genome maps are unavailable.” Rather than preorganize the genome with a mapping approach, in this group’s strategy “a single random DNA fragment library may be prepared, and the ends of a sufficient number of randomly selected fragments may be sequenced and assembled to produce the complete genome.” A large part of the problem solved was computational, there had been a “lack of sufficient computational approaches that would enable the efficient assembly of a large number (tens of thousands) of independent, random sequences into a single assembly.” From the point of view of nanotechnologists, the main effect of this advance is to fully specify an existing system that can replicate itself using simple feedstocks. The analysis of the genome sequence has thus far yielded 1743 regions which appear to code for proteins. These regions were matched against “a database of nonredundant bacterial proteins (NRBP) created specifically for the annotation… NRBP is composed of 21,445 sequences extracted from 23,751 GenBank sequences and 11,183 Swiss-Prot sequences from 1099 different species.” Of the 1743 possible proteins, 1007 were identified with sufficient accuracy to allow assignment of their biological role. An additional 347 matched “hypothetical proteins” in the database, and 389 are unidentified. Ideally, it would be useful to know what function each of these proteins plays and to have tertiary structures for all of them, but this is clearly going to take some time. Other regions that have been identified in the genome include ribosomal RNA and transfer RNA.



Ab Initio Calculations

In the analysis of proposed nanometer scale structures, a variety of analysis methods are useful in evaluating the structures before attempts are made to fabricate them. The most expensive of these methods, but the ones which make the fewest approximations and are therefore potentially the most trustworthy, are the quantum mechanical ab initio methods. The papers described below extend these methods.

Lego Assembler:

Writing in [C&EN 29 14Aug95], S. Borman describes an improved ab initio technique called MEDLA (molecular electron density Lego assembler) developed by P. G. Mezey and P. D. Walker of the University of Saskatchewan, Saskatoon. “To demonstrate the technique, Mezey has published ab initio electron density calculations for bovine insulin, which contains 773 atoms, and for a bacteriophage protein containing more than 1,000 atoms.” G. M. Maggiora, of Upjohn Research Laboratories, commented that “People have tried to divide molecules up in various ways…to estimate properties of larger molecules, but it’s been largely unsuccessful. At least to my knowledge, this is the first example where something of this accuracy has been accomplished.” Maggiora further commented that Mezey and Walker “calculate the smaller fragments that fit into large molecules in a very high level way…So for those molecules, they have information equivalent to the whole quantum mechanical wave function, the electron density, and any other properties (such as the molecular electrostatic potential) that can be derived from it.” From the point of view of nanotechnologists, this should permit tip reaction calculations to be extended to much larger neighborhoods of the reaction center than has previously been possible, extending our confidence in these analyses.

Flipping Dimers:

Writing in [Scanning Microscopy 9: 381-386 1995] K. Cho and J. D. Joannopoulos describe ab initio simulations of interactions between a tungsten tip and a silicon (100) surface. Their simulations used “a state-of-the-art density functional pseudopotential conjugate gradient scheme.” The simulation “results predict that the tip can be used to flip dimers on the surface, from one buckled configuration to the other, reversibly, and without inducing damage to either the intrinsic surface or the tip.” The top layer of a silicon (100) surface consists of a layer of silicon dimers, and authors’ simulations show that the dimers can reside on the surface with a tilt of about 20� in either direction with respect to the surface. In the absence of a tip, there is a barrier of about 0.1 eV between the two tilted geometries.

Calculations of the tip-surface system showed that the silicon atom underneath the apex of the tip is stabililized by about 0.2 eV in the configuration which tilts it up, closer to the tip atom. “Consequently, the tip always measures a dimer atom in the up-flip geometry, resulting in a symmetric STM image of the dimer.” The calculations indicate that gradually moving the tip up, while keeping it centered on one atom of the dimer, leaves the dimer with that atom elevated. At room temperature, thermal transitions would soon randomize the dimer between its two possible states. At low temperatures the authors suggest that “Since each dimer can be manipulated to exist in one of two equivalent states, it conceivably can be used to write and read one bit of information.” This work advances nanotechnology because the authors’ calculations, though fully quantum mechanical like Musgraves’ hydrogen abstraction tool work, extend those calculations towards a system which is currently experimentally accessible. In addition, the authors’ calculations uncovered a mode of operation which may be directly useful in information storage.



Nanotube Advances

Carbon nanotubes, also known as fullerine tubes or graphitic tubes, are potentially useful to nanotechnologists in a variety of ways. Nested nanotubes may prove useful as bearings; nanotubes have been proposed as pores in nanostructures; and nanotubes are strong and stiff enough to be useful in a variety of structural roles. In the nearer term, nanotubes with well-characterized terminations would be attractive probe tips for scanning microscopy. The papers below describe studies of electron emission from nanotubes, which is sensitive to the details of nanotube terminations, and may help to drive control of these terminations.

Nanotube Field Emitters:

Writing in [Science 270: 1179-1180 17Nov95], W. A. de Heer, A. Ch�telain, and D. Ugarte describe a carbon nanotube field emission electron source, with a current density of 100mA/cm2, that is potentially useful for flat screen display applications. The utility of the nanotubes comes directly from their sharp tips, which concentrate the effective field strength by a factor of as much as 1300 above the uniform field in which the tubes are immersed. By contrast, conventional field emitters typically concentrate the field by a factor of 10. This group has recently been able to align arrays of nanotubes, allowing this technique to be used for large area cathodes. “The large field amplification factors are related to the geometry of the tube terminations. As shown by Iijima et. al. [Nature 356: 776 1992], the terminations have a variety of structures and are often conical with 20� opening angles, with radii of curvature at the tips that may be <1 nm. The density of emitting tips is estimated to be on the order of 105 cm-2. Because this is only a small fraction of the nanotube density (approx. 108 cm-2), only those tubes with particularly sharp tips that are favorably situated on the film emit efficiently.” Since nanotubes with sharp, well-controlled terminations would be ideal for proximal probe work, it will be interesting to see if this group’s developments become applicable to that area.

Carbon Atomic Wire Emitters:

Writing in [Science 269: 1550-1553 15Sep95], A. G. Rinzler, J. H. Hafner, P. Nikolaev, L. Lou, S. G. Kim, D. Tom�nek, P. Nordlander, D. T. Colbert, and R. E. Smalley describe some electron emission experiments from individual nanotubes. They argue that the active field emitters are “individual linear carbon chains — Cn atomic wires — that have been pulled out from the open edges of the graphene sheets of the nanotube as shown in Fig. 4 and are held taut under the influence of the electric field.” At room temperature the field emission current was 0.4-0.8 microamp. Oddly enough, the emission goes down sharply on heating the nanotube with a laser to approx. 1500�C, an effect that the authors attribute to “thermally induced evaporation of C3 and other small carbon radicals from the tip of the chain until chain is so short that the electric field is no longer sufficient to produce efficient emission. We expect that there is a steep temperature dependence of the effective resistance of the carbon chain, with nearly ballistic transport when the chain is cool, but frequent scattering and consequent chain heating and further increase in resistance once the vibrations of the chain become excited.” The authors suggest that the chains “may turn out to be excellent coherent point sources of monochromatic electron beams and to have wide applications as probes, emitters, and connectors on the nanometer scale.”



Scanning Probe Techniques

Fabrication with scanning probes has the advantage of giving the experimenter direct control over the position where the modification occurs, at the cost of fabricating structures one at a time. Most of the atomically precise techniques using scanning probes, however, have used feedback from an STM current to determine if a selected atom has been moved. They are therefore limited to conducting substrates. The new technique described below relies on a novel feedback mechanism which avoids this limitation.

Writing in [Science 270: 1639-1641 8Dec95], E. S. Snow and P. M. Campbell described a novel nanometer scale fabrication method. The authors anodically oxidized a Ti film with an electrically biased (-10 volts with respect to the substrate) silicon AFM tip. The innovation in their technique was to monitor the electrical resistance of their structure during fabrication, automatically switching off the bias when the target resistance was reached. The current flow in the anodic oxidation itself is sufficiently low that it does not interfere with the resistance measurement. Thus far, the narrowest wire that the authors have fabricated “was obtained with a resistance increase that corresponds to a final wire width of 3 nm.” It will be interesting to see if the authors are able to extend this technique to produce atomic scale constrictions. Unlike most fabrication techniques, the introduction of feedback into this technique might allow atom-by-atom monitoring of the oxidation process as a target structure is approached.



Nanometer Scale Particles

There have been many articles over the last several years about nanometer scale particles. Typically, these articles have described particles with a fairly narrow distribution of diameters, but with curved surfaces that imply a fairly wide distribution of surface structures. These particles have interesting and potentially useful electronic properties, but consist of too broad a range of isomers to be attractive building blocks for atomically precise structures. The article below presents some experimental evidence for better control, which might make the new particles plausible components for atomically precise structures.

Writing in [MRS Bulletin 23-32 Aug95], A. P. Alivisatos describes some work on nanometer-scale (1nm-5nm, in various experiments) crystallites, mostly of CdSe, with some Si and some HgS examples. Most of the article was on spectroscopy, but what I found notable was that many of the micrographs of the nanocrystals showed not merely well ordered interiors but also well-defined facets. “The crystallite, at 350 �C, has been made in just the right way in that the temperature is high enough that it will become crystalline inside and that, even during the few seconds during which it is formed, there is enough time for it to arrange itself and to facet.” These crystallites may be potentially useful as building blocks for nanotechnology. The bonds in a crystal lattice can be considered to form a rigid, polycyclic molecule. The open question is whether a useful concentration of a single isomer of these molecules can be produced. The rounded crystallites that have appeared in many previous articles looked quite unpromising, considering the range of local structures that must be energetically or kinetically accessible to produce such a surface. Faceted crystallites, on the other hand, must include a much more limited range of surface structures, perhaps a range sufficiently small to make isolating a single species approachable.

Jeffrey Soreff is a researcher at IBM with an interest in nanotechnology.


Law in Technology

by Elizabeth Enayati

Elizabeth Enayati, an attorney with Venture Law Group, answers Foresight members questions on intellectual property issues in nanotechnology.

This column will discuss the significant changes in U.S. intellectual property law in 1995 that potentially impact the molecular manufacturing industry.

The Legislature was busy this past year catching up on changes required by the implementation of GATT (the General Agreement on Tariffs and Trade). The impact of the change in patent laws resuslting from implementation of GATT has a disproportionate impact on leading technology, such as nanotechnology. (Those issues were discussed in detail in the previous “Law in Technology” column, Update 23.)

Relevant bills which were introduced in Congress over the past year included:

  • HR8O, to establish a government corporation to oversee the transfer of government-funded technologies (Rep. Paul Kanjorski, D-Pa);
  • HR989, to extend the copyright term by 20 years to be consistent with a similar amendment made in Europe (Rep. Carlos Moorhead, R-Calif);
  • HR1659, to create a PTO government corporation (Rep. Carlos Moorhead);
  • HR1733, to provide for the publication of patent applications at 18 months, consistent with the patent system of the rest of the developed world (Rep. Carlos Moorhead);
  • HR 8909, to provide for the protection of inventors contracting for invention development services (Sen. Joseph Lieberman, D-Conn);
  • HR2233, to provide a limited defense to patent infringement for good faith prior use of a patented invention by a third party (Rep. Carlos Moorhead);
  • S81122, to reinforce criminal copyright infringement provisions for infringement of works worth $5,000.00 or more by including infringement by distribution on an Internet bulletin board (Sen. Patrick Leahy, D-Vt);
  • S81284 and HR244l, to set forth the “rules of the road” for the protection and use of copyrighted works on the “information superhighway” (Sen. Orrin Hatch, R-Utah, and Rep. Carlos Moorhead, respectively).

None of these bills passed by the end of 1995.

The judiciary were equally busy in 1995 deciding important cases impacting intellectual property rights. The Supreme Court held that color alone could properly be the subject of trademark protection. The impact of this decision is not direct for the nanotechnology industry, but it does indicate a more expansive interpretation of the trademark laws. As the law continues to expand it may provide protection for certain aspects of nanomachines and inventions arising out of nanotechnology and molecular manufacturing, including packaging, marketing, and even the use of trade dress protection (which provides legal protection for the nonfunctional shape of items, such as molecular machines).

Also in the courts this past year, two of Lemelson’s patents were declared unenforceable because over the 13 years of prosecution for the patents, Lemelson failed to cite a material reference. As you may recall, the patent activities of Lemelson have been cited as a basis for much foreign pressure on the US to change its patent laws. Lemelson was dealt another blow later in the year by a magistrate who recommended to the District Court for the District of Nevada that eleven patents asserted against Mitsubishi Electric Corp., Motorola, and Ford, be held unenforceable for unreasonable and prejudicial delays during prosecution of the patents. Although both Mitsubishi and Motorola had settled the suit with Lemelson, Ford continued to defend against the assertion of infringement, and apparently convinced the magistrate that its defense was valid.

Early in 1995, a district court held that the menu hierarchy of the Lotus 1-2-3 spreadsheet program was an unprotectable “method of operation,” in the case of Lotus v. Borland International. Lotus was granted Supreme Court review of the decision. Oral arguments at the Supreme Court were held on January 8, 1996, on the day of the big blizzard which shut down most of the east coast. One week after the oral arguments, the Supreme Court issued an order, without an accompanying written opinion, affirming the lower court’s decision denying copyright protection for Lotus’ spreadsheet. The Supreme Court was evenly divided, 4 to 4 (Justice Stevens abstained from the decision). Because of the nature of the case, the decision is only binding precedent upon the First Circuit. Nevertheless, copyright protection for GUIs, and some say for software in general, remains restricted. This is in contrast to increased recognition of copyright protection for software in Europe.

In a case worth noting, the Court of Appeals for the Ninth Circuit held that intermediate copying of software is infringing activity. That court held that infringement occurred when the defendant used the plaintiff’s computers at a customer’s site to service the customer’s computers, which then caused the plaintiff’s software to be copied to the customer’s computer RAM. By contrast, in the northern district of Texas, a court held that intermediate copying of software is fair use, to the extent that it is a necessary step in disassembling the software to discover its unprotectable elements, and thus not copyright infringement. Both of these decisions are consistent with previous decisions on these points, and affirm that courts are becoming increasingly sophisticated about copyrights conveyed to software products.

In a final noteworthy case, the District Court for the Northern District of California decided, at the end of 1993, that an operator of a computer bulletin board service and an Internet access provider may be contributorily liable for copyright infringement. The court held that both such parties were liable for infringement if they knew or should have known that the infringing works were uploaded and refused to remove the works from the bulletin board.

The US Patent Office was not idle in 1995. In fact, it was quite busy with implementing and clarifying the changes in US patent law. The PTO held public hearings on the proposed 18 month publication of patent applications and on newly proposed software examination guidelines. To date, the PTO does not publish US patent applications, and has not officially implemented any guidelines for examining computer-related inventions.

In 1995 the PTO announced that it would consider software embodied in a tangible medium, such as a diskette, patentable subject matter. This opened up the type of patent protection available to software. Again, in a trend that is counter to the current trend in Europe, the US is strengthening the patent protection available for software products and weakening the scope of copyright protection available for software.

Perhaps in response to the diminishing copyright protection in software, and perhaps in response to the strengthening of copyright protection in other sectors, the Copyright Office created a Board of Appeals in June 1995 for applicants whose applications for copyright registration are refused. The Copyright Office has taken an increasingly proactive role in the examination of copyright registration applications.

All of these changes, and proposed changes, to the intellectual property laws will have an impact on the type of legal protection available for nanotechnology inventions. The leading-edge nature of the emerging nanotechnology is a disadvantage in the face of the changes made to US patent law under GATT. However, the courts and the PTO are taking increasingly expansive views of protection for software inventions, either under patent laws or copyright laws. To the extent that much of nanotechnology and molecular manufacturing currently reside in software, the increased protection clearly benefits the software developer. However, the terrain to effective protection became more complex last year. The requirement for careful maneuvering around various obstacles (such as the new patent term) is required.

Elizabeth Enayati is an attorney with Venture Law Group, 2800 Sand Hill Road, Menlo Park, CA. 94025 She can be reached at tel (415) 233-8459, fax (415) 233-8459, or by email at [email protected].

The information in this column is not to be construed as legal advice and is not necessarily the view of Venture Law Group.



Media Watch

BBC Carries Major Program on Nanotechnology


BBC’s Horizon program last November 13 carried a major program on nanotechnology that provides an excellent video introduction to the topic. Featuring interviews with Foresight Institute Chairman Eric Drexler, nanotechnologist Ralph Merkle at Xerox, computer scientist Carl Feynman, and others, the program “Nanotopia” provides an excellent layman’s introduction to the technical aspects of nanotechnology (showing, for example, how a scanning tunneling microscope can precisely move individual atoms) and a thoughtful discussion of the potential real-world outcomes when nanotechnology is realized.

The End of Moore’s Law?

Economic considerations may repeal – at least temporarily – Moore’s Law, describing the exponential density increase of semiconductor chips. Gordon Moore, an Intel founder, observed that since the early 1970s chip density has doubled every 18 months. Forbes Magazine (March 25 issue) reports on the newly formulated Moore’s Second Law, the exponential growth in the cost of building a new chip fabricating plant. In coming years, Forbes says, technology will continue to expand the number of transistors per chip, but companies won’t be able to afford plants to take advantage of the new technology. “The price per transistor will bottom out between 2003 and 2005,” Forbes says. “From that point on there will be no economic point to making transistors smaller. So Moore’s Law ends in seven years.”

Comment: probably true, but only as an extension of existing lithographic technology. That’s why many firms in the semiconductor industry are watching bottom-up nanotechnology technology very closely.

New Scientist Magazine Reports on Work Toward “Molecular Construction Kit” at Univ. of Colorado

[Editor’s Note: This page has been optimized for Netscape 2 and later. If you are using a browser, such as Netscape 1.1, that does not support the html tag for superscripts, please be aware that an number like “2×109” is meant to be scientific notation for “2 times ten raised to the 9th power,” and that “e2” means “e squared,” etc.]

Prague-born chemist Josef Michl, now on the faculty at the University of Colorado, is working to build a “molecular construction kit” using rods and connectors the size of molecules, reports the English publication New Scientist in its June 1995 issue.

Michl is working with simple molecular structures that form stiff, flexible rods. Michl has assembled rods from a mixture of carbon-hydrogen molecules and carbon-boron molecules, providing fine control over the total rod length. The rods are built up from such molecules as propellane, a “strained” form of C5H6, and cubane, a strained form of C8H8. “Strained” molecules are constructed with bonds that are forced out of their normal angles – 90� in cubane, for example, compared with carbon’s normal orientation of 109.5�. So far, Michl has made rods whose lengths vary from 5 to 25 angstrom (10-10 meters), with precision within 1 angstrom.

Michl envisions that “his construction kit of such rod-like molecules could be used to make an inert scaffolding on which could be hung more reactive molecules with useful electronic or mechanical properties,” New Scientist reported. While there are other ways of making rod-like molecules, Michl’s are highly inert. They do not absorb visible or ultraviolet light, and they are stable at temperatures of at least 200� C and often much higher.

Related work is underway on connectors to join the rods together, the story reports. Metal atoms would be the simplest solution, offering the useful quality of strong joints that can be easily disassembled. Different metals give different binding geometries – square, octrahedral, and so on.

One application Michl proposes is a nano-scale “wind farm,” with turbine propellors made from fused aromatic rings. It could also be run backwards, using microwaves to spin the rotors and propel helium atoms, creating nano-scale turbopumps.

Michl’s real agenda, New Scientist reports, is “to get chemists thinking about the possibility of mechanically conceived molecular structures. When he presented simulations of his turbine concepts at a meeting in Paris in 1995, he encountered significant scepticism, the magazine reports. It quotes English chemist Fraser Stoddart, from the University of Birmingham, that, “‘I don’t think chemists’ contributions will be to make mini-mini-mini computers or mini-mini-mini cars.'”

“But Michl holds to his belief in molecular machines-if not the turbines he is working on now, then perhaps molecular waterwheels or something completely different,” New Scientist concludes. He says that many ingenious molecular devices, including a molecular shuttle devised by Stoddart himself, for instance, have been invented, but as yet they simply float freely in solution. “Michl’s construction kit could be the ‘bricks and mortar’, coupling such devices together to make microscopic machines that are now just pipe dreams. And if he has set his sights high, he has an answer: ‘I have always taught my children that a hiker who is lost in the woods and comes to a fork in the trail should always take the branch that goes more steeply uphill. I should live up to my own admonitions, right?'”

A PAL at USC – The Programmable Automation Laboratory Newsletter Discusses Molecular Robotics Efforts Underway There

USC Professor Aristides A.G. Requicha directs the Programmable Automation Laboratory, part of the Institute for Robotics and Intelligent Systems at the University of Southern California.

In his December 1995 newsletter he writes, “I gave an invited talk at the 4th Nanotechnology Conference in Palo Alto, which was probably the most interesting conference I have attended in the last few years. There is really a lot of excitement in the nanotech area! People at the conference reacted very positively to my talk, and thought that putting together robotics folks with chemists and materials scientists was ‘obviously’ a great idea. That means we had better hurry up, before others follow us into the area.”

Those interested in nanotechnology-relevant work at USC can visit their Web site at

Byte Magazine Looks at Molecular-Based Computer Alternatives

Byte Magazine, one of the oldest and most respected publications in the computer world, devotes its April cover to the question, “When Silicon Hits its Limits, What’s Next?” It answers with a look at three “new directions for the future of computing: Quantum computers, protein memory, and holographic storage.” The story cites Moore’s Law (see above), discusses the rapidly approaching limits of photolithography, and concludes that for computer memory storage, both holographic devices and protein molecules as bit storage devices offer hope. The latter approach is described by Robert R. Birge at the W.M. Keck Center for Molecular Electronics at Syracuse University, who has been working with bacteriohodopsin, a photosensitive protein obtained from nature. His work is also extensively discussed in the BBC television program “Nanotopia,” discussed above.



Web Watch

Weird is the name of the Web site where Foresight Director Chris Peterson has posted a breezy, but informative, article for teenagers about nanotechnology. It’s located at, a site to help enlist younger minds in the cause of science. “Learn more about the technical side of things,” Chris writes. “The book Engines of Creation-the first and still classic vision of a world with nanotechnology-is going up on the Web, complete and free for all, as you read this. Watch the Foresight page for the publication announcement. Once you’re up to speed, geek out on sci.nanotech. To become a nano-whiz, try grinding through Nanosystems.”

Club Wired hosted nanotechnologist Ralph Merkle late last year. The interactive online “chat” forum provided by Wired Magazine invited Ralph to discuss nanotechnology in the context of a Wired Magazine scenario, The Museum of Nanotechnology. This was part of Club Wired’s Future of the Future series. He describes the experience as “like trying to carry on a dozen simultaneous conversations by typewriter.”

Earthshaking news sometimes appears on the site, but that’s where Stephen L. Gillett, Department of Geological Sciences, has placed the poster and manuscript of his talk at last November’s Nanotechnology Conference. They’re available by anonymous ftp in the directory /pub/gillett. Look for nearterm.wrd, the Microsoft Word file for his poster presentation “Near-term Nanotechnology: the molecular fabrication of nanostructured materials,” and extract.wrd, his talk on “Nanotechnology, Resources, and Pollution Control.” Both are in MS Word for Windows format and must be downloaded as binary files.

Do you know of an Internet site related to nanotechnology you’d like to bring to the attention of the Foresight community? Send the URL and a brief description to Foresight Update Editor Lew Phelps at [email protected]. Please do not duplicate site references already posted on Foresight and other key nanotechnology sites.



Foresight Upgrades Web Site

Update Expands in Digital Format

Foresight Institute is greatly expanding its presence on the Web. Check out the ever-growing content on the site by pointing your Web browser to

Among other things, the site now houses an expanded (and more timely) version of Foresight Update, the quarterly newsletter of Foresight Institute.

The site also has become a primary means of response by Foresight Institute to an extended, and highly inaccurate, story in Scientific American about nanotechnology. (See article above.)

Foresight has expanded its staff to further the growth of its Web site. “We view the Web as the single most valuable means of expanding awareness of nanotechnology developments and discussion of relevant issues,” said Chris Peterson, Director of Foresight Institute.

The “webmaster” for the Foresight Web site is Robert Armas, who joins the staff part-time. He is a Senior Associate of Foresight Institute. He previously has served Foresight as a speaker, conference volunteer and active member since 1991. He recently left a nanotechnology information service to teach classes about Web Authoring and the Internet. As a freelance writer, Robert examines how future technologies may impact human cultures and the planet.



Our World Wide Web activity is ramping up, thanks to Robert Armas and Marcia Seidler, with major assistance from volunteers Russell Whitaker (internal webmaster at Silicon Graphics) and Jim Lewis. Jim did the work to get the 1981 PNAS paper up, and Russell is putting the entire Engines of Creation into Web format. Meanwhile, thanks to Ralph Merkle and Josh Hall for maintaining Foresight materials on their sites until we’re fully up to speed.

Thanks also to Ralph Merkle for providing an excellent rebuttal to the Scientific American news story on nanotechnology (see elsewhere in this issue). Thanks also to Lew Phelps and Niehaus Ryan Group for timely media assistance on this. Additional thanks go to all of those who wrote letters to the editor of SciAm, especially Carl Feynman. Please keep these coming, and remember to cc Foresight.

Thanks go to Richard Terra for starting implementation of a major new Foresight project, the annual technical report.

For sending information, we thank John Burke, Jeff Cavener, Gino Coviello, Chuck Estes, Keith Farrar, Dave Forrest, Robert Freitas, Eric Geislinger, Frank Glover, Norm Hardy, Mark Haviland, Tad Hogg, Graham Houston, Marie-Louise Kagan, Rick Lewis, Joy Martin, Hugh McLarty, Anthony Napier, Chris Portman, Brian Reed, Mark Reiners, Tanya Sienko, Alvin Steinberg, John Walker, John Wynkoop.

Finally, ongoing thanks to Josh Hall of Rutgers, who moderates the sci.nanotech newsgroup, and our two hard-working staffers, Judy Hill and Elaine Tschorn. These three routinely do massive amounts of work benefiting Foresight and IMM.

With nanotechnology-relevant activity ramping up, it’s getting harder to thank everyone who’s helping. Your assistance, ideas, and contributions are greatly appreciated.

-Chris Peterson, Director