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Foresight Update 14 (page 2)

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Table of Contents - Foresight Update 14

Open Conference on Nanotechnology

Although Foresight has sponsored two conferences for nanotechnology researchers, we have yet to hold a major meeting at which all Foresight participants can learn more about the subject, meet each other, and share perspectives. This meeting--the First General Conference on Nanotechnology: Development, Applications, and Opportunities--will be held this fall in Palo Alto, California, on November 11-14, and will cover technical, business, and policy issues.

Speakers will be drawn from the extended Foresight community. We plan to ask representatives of the following groups to address the meeting: From our experience with the scientific meetings, we've learned that conference participants like to have plenty of time to interact informally, and we'll try to include that as well as scheduled presentations.

We will be contacting selected organizations regarding financial sponsorship of the meeting. If your organization would like to be considered for such participation, call the Foresight Institute office.

The Foresight leadership look forward to meeting as many of you as possible at this first conference for the interested layperson, and we cannot urge you too strongly to attend. We believe that years from now, this meeting will be regarded as a seminal event in both the industrial development and policy planning for nanotechnology.

[Editor's note: See Update 15 for a brief review and for selected photos from this conference. The proceedings of this conference have been published in book form.]

Table of Contents - Foresight Update 14

Gerald Feinberg

We regret to report the recent loss of Prof. Gerald Feinberg, a member of the Foresight Board of Advisors, to cancer. Formerly Chairman of the Columbia University Department of Physics, Prof. Feinberg brought both scientific expertise and a profound concern for humanity to the Foresight effort (see his interview in Update No. 9). He will be greatly missed.

Table of Contents - Foresight Update 14

Upcoming Events

Atomic & Nanoscale Modification of Materials, August 16-21, Doubletree Hotel, Ventura, CA. Primarily a "top-down" approach to miniaturization, but includes some STM work. Contact the Engineering Foundation, 212-705-7835.

American Aging Association, October 20, St. Francis Hotel, San Francisco. Eric Drexler will speak on medical nanotechnology applications to aging. Contact AGE, 402-559-4416.

First General Conference on Nanotechnology: Development, Applications, and Opportunities, November 11-14, 1992, Holiday Inn Stanford/Palo Alto, Palo Alto, CA. A meeting for Foresight participants, addressing nanotechnology: the technology itself, policy issues, and business opportunities. For the interested layperson; not a research-only conference. Contact the Foresight office at 415-324-2490 or email Registration forms will be posted on our MessagePost when available, 415-948-8310 (call from the handset on your fax machine). [See above article.]

[Editor's note: Foresight's current email address is]

Table of Contents - Foresight Update 14

Recent Progress: Steps Toward Nanotechnology

by Russell Mills

I have a poor memory. That's not to say that I can't remember my friends, or anything as bad as that. It's just that my mind behaves like a sieve with regard to specifics, such as the biochemical explanation I just read yesterday, or the street I'm supposed to take to get to a friend's house. A second-rate memory did not prevent me from getting a broad education or from acquiring a good general understanding of a variety of technical areas. But it has been a major impediment to doing noteworthy scientific research.

I have recently taken actions which may change all this. The first hurdle was to convince my doctor that a problem really exists. She began to believe me only after I suggested an EEG (electro-encephalograph) test, and the test results came back showing significant abnormalities. The next step was an MRI (Magnetic Resonance Imaging) brain scan to check for large-scale problems; these images have not yet been analyzed as of this writing.

The EEG results were exactly what I wanted, but I am hoping that the MRI images show nothing awry. Why? Because EEG irregularities mean that nerve cells are misfiring in my brain--a condition for which there are drug treatments. Anything that shows up on the MRI, on the other hand, is likely to require brain surgery if it can be treated at all. I'd much rather subject my brain to a treatment based on nanometer-sized tools (i.e., drugs) than centimeter-sized tools (e.g., scalpels). True, both kinds of tools are crude and dangerous compared with their 21st Century counterparts; nevertheless, I feel that drug molecules are more advanced than knives. I look at it this way: the distinction between drug treatment and surgery may someday disappear as drug molecules of greater size and complexity are developed. Tomorrow's physicians will use medicinal nanomachines equipped with computers, sensors, and moving parts--like the ones described in Engines of Creation, and Unbounding the Future. These nanomachines are more likely to evolve from drugs than from scalpels, in my opinion. In this sense, scalpels may be an evolutionary dead end.

Medicinal nanomachines

Until recently nearly all drugs, whether synthetic or biological in origin, have been small molecules consisting of fewer than 300 atoms--too small even to span, let alone to refurbish, their biological targets. That situation is changing as proteins make their way onto the pharmaceutical stage. Nucleic acids, too, are now being readied for roles as drugs. Why proteins and DNA? Because they are polymers (molecular chains) made from readily available components; with the limitations of today's technology, polymers are much easier to assemble than molecules containing the same number of atoms connected in nonlinear patterns. The ultimate in pharmaceuticals (medicinal nanomachines) may be nonpolymeric and unavailable until nanotechnology provides assemblers to make them.

Presumably tens of thousands of useful protein and DNA drugs are waiting to be discovered. But identifying them has been a problem. Which of the 10390 different protein chains 300 amino acids long correspond to useful protein drugs? Which of the 1016 different DNA molecules 27 nucleotides long should be investigated for their ability to bind to proteins or other molecules? One approach to this problem is suggested by recent advances in the synthesis and handling of large molecular "libraries".

A research group at Gilead Sciences in California has used a DNA library to identify DNA sequences that bind and inactivate a target protein. (Nucleic acids that bind to specific molecular targets are called "aptamers".) The researchers first synthesized a pool of 1013 different DNA 96-mers (i.e., molecules 96 nucleotides long). Each molecule contained a different 60-nucleotide random subsequence and two 18-nucleotide sequences recognized by polymerase enzymes used in replicating the DNA. The pool of DNA was allowed to interact with the target protein--in this case a blood coagulator called thrombin--attached to a solid support. A small fraction of the DNA molecules stuck to the thrombin; the rest were washed away. The bound DNA was recovered, replicated many-fold, and allowed to interact again with the thrombin. Repeating this selection cycle five times led to a pool of effective aptamers in sufficient quantity for analysis. A "consensus" sequence of 12 nucleotides was found to occur with only minor variations in the 32 best aptamers. Presumably the next step will be to use the consensus sequence as an aptamer to prove that it can bind thrombin by itself. This technique seems well suited to designing DNA drugs quickly without computer simulation. [Nature 355:564-566, 6Feb92]

Similar work by researchers at Massachusetts General Hospital used a DNA pool of 157-mers, containing 120-nucleotide random subsequences. Dye compounds, rather than a protein, were used as selection agents. An 18-nucleotide consensus sequence was identified after five cycles of selection. [Nature 355:850-852, 27Feb92]

An ingenious method for generating peptide libraries and screening them for binding to target molecules has been developed by investigators in Arizona. (A "peptide" is a chain of amino acids. Proteins are peptides.) Millions of resin beads were divided into 19 portions and placed into 19 reaction vessels, each containing a different amino acid. The beads' surfaces reacted with the amino acids, forming a coating one molecule deep. The beads were collected, randomized, and redistributed to the vessels, whereupon a second amino acid attached to the first. Continuing in this manner produced a collection of beads, each carrying a layer of peptides of uniform composition and length. Using a sufficient number of beads ensures that all possible peptides of the desired length are represented in the collection with high probability. The researchers in this study synthesized chains of five amino acids on their beads, then exposed the beads to a target compound to which a fluorescent dye had been chemically attached. Beads whose peptide chains had affinity for the target compound became intensely stained and could be removed with tweezers for analysis--i.e., the sequence of amino acids responsible for affinity could be determined. The amount of peptide required for analysis turned out to be only a small portion of the peptide on a single bead; therefore the beads with their attached peptide library could be used multiple times on different target compounds. [Nature 354:82-84, 7Nov91]

What may be a major breakthrough in the search for DNA drugs has been made at the Panum and the H.C. Ørsted Institutes in Copenhagen. Researchers there have developed a remarkable new form of anti-sense DNA--a DNA-like polymer that is intended to bind and inactivate segments of normal RNA or DNA. Anti-sense DNA is a hot research area and dozens of different modifications of the DNA structure have been made and tested in laboratories throughout the world. Among the properties an anti-sense drug must have are: nuclease resistance (nuclease enzymes must not degrade it before it reaches its target inside cells); sequence-specific recognition (it must inactivate only the desired nucleotide sequence in the target molecules); binding affinity (drugs targeted to RNA must remain bound until the target is degraded by nucleases in the normal course of cell maintenance; drugs targeted to DNA (i.e., to chromosomal genes), should not have to be renewed too often during therapy. The need for nuclease resistance immediately disqualifies normal DNA and RNA as potential anti-sense drugs.

The Copenhagen group used computer modeling to develop a radically different backbone for DNA, substituting a pair of amides for the normal chain of alternating phosphates and sugars that holds DNA together. The resulting PNA (polyamide nucleic acid) not only met the above criteria, its binding affinity far exceeded that of any other anti-sense compound. Unlike other anti-sense structures, which interact with double-stranded DNA by associating with the double helix, PNA pushes between the strands of the helix, displacing one strand and forming its own double helix with the other. If PNA continues to show good sequence specificity, and if it proves able to pass through membranes into the cell nucleus, then it may be the long-sought tool for turning off faulty genes and tuning up chromosomes. [Science 254:1497-1500, 6Dec91]

Dr. Vivian Cody conducts some of her drug binding studies by using virtual reality, enabling her to "virtually" reach out and feel the forces between a drug and its protein target. As she moves a small organic drug molecule near one of the protein's amino acid side chains, she can "feel" inner repulsion or attraction between the molecules. Dr. Cody, a researcher at the Medical Foundation in Buffalo, New York, works in what is called a molecular docking "virtual reality" system, located in the Department of Computer Science at the University of North Carolina in Chapel Hill. This new computer technology simulates reality as it is thought to exist at the molecular level. She manipulates graphic representations of compounds and proteins projected onto a 4x5 foot screen. As she moves the molecules the electrostatic force between them is calculated by a computer and fed into an arm. When resistance is felt in the grip it means the binding is not favorable; ease of movement means the position is promising. [Genetic Engineering News XII:8:1]

Protein machines

Thomas D. Pollard, in a report on the Proteins as Machines symposium at Indiana University last October, defines protein machines as "the driving units that produce macromolecular movement in living organisms". These include the rotary motors of bacterial flagella, the linear motors responsible for muscle contraction and for transportation of materials within cells, the polymerases that copy DNA and RNA, and the pore structures that selectively move molecules through membranes. Pollard says that in every case we lack sufficient information to explain the mechanisms operating at the molecular level. A central question is exactly how energy is used by the motors. In one hypothesis, the motors randomly attach and detach to a substrate (or "track"); during attachment they undergo an energy-consuming change of shape that moves their center of mass along the track. Another suggestion is that the energy biases the affinity of the motor for its substrate, causing the motor to attach preferentially when random thermal vibration puts it in an extended position. [Nature 355:17-18, 2Jan92]

Protein design

A group at UC Berkeley has developed a general method for incorporating "unnatural" amino acids into proteins, using components of the protein synthetic apparatus taken from bacteria and yeast, and a gene taken from a virus. In a preliminary application of their technique they made several versions of the much-studied enzyme T4 lysozyme. In each version an unusual amino acid was substituted for the amino acid alanine at position 82 along the protein chain--a position at which two helical segments of the molecule are joined together. A comparison of the thermal stabilities of the resulting proteins gave insight into the effect of structural details upon the behavior of a protein. Information gained through this technique will be of use in designing proteins out of normal amino acids; it is not a practical method for manufacturing modified proteins. [Science 255: 197-200, 10Jan92]

Nanosensing and manipulation

A new breed of scanning tunneling microscope (STM) has been developed at Sandia National Laboratories in New Mexico. Called the interfacial-force microscope (IFM), it overcomes the STM's tendency to become unstable when scanning at certain distances from a sample. The IFM owes its stability to a capacitor and force-feedback electronics which replace the mechanical cantilever that hold the probe tip in STMs. This arrangement permits the measurement of forces between probe and sample over the entire range of separations, including contact. Unfortunately an inverse relation exists between tip radius and sensitivity; this translates into a trade-off between resolution along the z-axis (perpendicular to the sample) and that along x and y. Thus, the tips presently being used are about 500 nm in radius; they can sense surface irregularities along the z-axis of about 0.2 nanometers (about the size of an atom), and are expected to improve soon by a factor of 100, but their x-y resolution is limited to several tens of nanometers. [Nature 356:266-267, 19Mar92]

John A. Sidles at the University of Washington, Seattle, has designed a microscope based on nuclear magnetic resonance (NMR), the phenomenon on which medical magnetic resonance imaging is based. It is hoped that such a device, when built, would enable mapping of individual hydrogen nuclei in a surface, providing enough information to determine the three-dimensional structure of proteins and other complicated molecules. [Science News 141:150, 7Mar92]

Carbon structures

The use of carbon as a structural material for nanotechnology was originally proposed by Eric Drexler based on what was then known about diamond. As luck would have it, the past few years have seen a surge of research interest in the chemistry of pure carbon. One goal of this research has been to find easier ways to make diamond, since diamond is of increasing industrial importance. More recently, attention has focused on fullerenes, highly stable chemical structures related to graphite. Whereas graphite consists of carbon atoms bonded in a hexagonal lattice (like chickenwire) to form flat sheets, fullerenes are closed cage-like molecules in which the lattice is curved and contains pentagons as well as hexagons. Carbon's versatility is proving to exceed all expectations, adding weight to the argument for a carbon-based nanotechnology.

From the NEC Corporation in Tsukuba, Japan, comes a report of graphitic microtubules collected from the negative end of a carbon electrode used for making fullerenes. Upon examination with a transmission electron microscope the tubules proved to consist of a series of two to fifty coaxial cylindrical layers. Individual layers were hexagonal lattices of carbon atoms separated by 0.34 nanometers. The smallest cylinders were 2.2 nm in diameter, which would make them roughly 50 to 60 carbon atoms in circumference. (It would be interesting if someone could now measure the strengths of the microtubules and the friction generated by differential rotation between the layers.) [Nature 354:56-57, 7Nov91].

Making diamonds out of graphite requires pressures of 30-50 GPa (gigapascals) or heating to 1200 K in the presence of a catalyst. Researchers at CNRS in Grenoble, however, recently discovered that diamonds can be made more easily by compressing the fullerene C60 to a pressure of 20 GPa at room temperature. C60 is a closed "cage" of 60 carbon atoms; it has a spherical shape. [Nature 355:237-239, 16Jan92]

Table of Contents - Foresight Update 14

Foresight thanks Dave Kilbridge for converting Update 14 to html for this web page.

From Foresight Update 14, originally published 15 July 1992.
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