Stu Borman
C&EN Washington

News stories often appear quickly. Like flashes of light in the night, they disappear quickly too, sometimes never to be seen again. In the next eight pages, C&EN casts new light on some of the significant chemical research stories we covered in the year 2000.

Our selections are subjective and are not intended to be comprehensive. The stories we look back at here are not the winners of a contest; they do not represent a "best" list. In fact, looking through a year's worth of chemical research stories, one has to be impressed at the totality of research progress made over a year's time and at the tremendous number of such developments that are indeed important.

C&EN selected a necessarily small subset of these many breakthroughs to review here. We approached the principal investigators on these studies to find out what had happened to their projects since they were initially disclosed and reported on in C&EN. And we asked what other year-2000 developments those researchers would choose to highlight.

This survey of key chemical research developments of the past 12 months reveals the unremitting research efforts that provide the foundation for the advances we cover throughout the year. And it shows how research projects grow and evolve, long after the ink covering milestones in those projects has dried.

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In the area of chemical synthesis, one major story this year was the stereospecific synthesis of sucrose in 80% yield--about six times higher than that of any previous sucrose synthesis. The work was carried out by chemistry professor Stefan Oscarson and a coworker at Stockholm University, Sweden [J. Am. Chem. Soc., 122, 8869 (2000); C&EN, Sept. 25, page 52]. Discovering an efficient route to this seemingly simple and virtually ubiquitous compound--common table sugar--has been a long-sought goal of carbohydrate chemists.

"It is not possible to commercialize the synthesis of sucrose," Oscarson notes. "This must be the cheapest starting material in the world and is most efficiently made by sugarcane and beets." But he and his coworkers are currently trying to apply the new method to related bacterial and plant carbohydrate natural products that are similarly difficult to synthesize.

They have already succeeded in synthesizing a series of disaccharides containing linkages related to the one found in sucrose. These syntheses have "the same excellent stereospecificity and yields reported in the JACS paper, further demonstrating the generality of the method," Oscarson says.

Also this year, chemistry professor John F. Hartwig's group at Yale University developed a new synthetic technique that could prove important industrially.

Earlier, the researchers had discovered a catalytic photochemical method to convert the unreactive saturated hydrocarbons in petroleum and natural gas into compounds with useful functional groups on the ends [Angew. Chemie. Int. Ed.,38, 3391 (1999)]. However, its photochemical basis relegated it primarily to the laboratory-scale realm.

This year Hartwig and coworkers, in collaboration with a Shell Chemicals researcher, identified an organometallic catalyst that lets them carry out the reaction thermally instead of photochemically [Science, 287, 1995 (2000); C&EN, March 20, page 9]. Now, practical applications of industrial-scale alkane functionalization seem within view. "Heat is cheaper than light and easier to transfer to reactants," Hartwig says.

Since the report, Hartwig and coworkers have found some new catalysts for the procedure, and they are currently collaborating with the group of assistant professor Marc Hillmyer of the University of Minnesota on polymer modification by C-H bond activation.

"In the coming year," Hartwig says, "we expect to have ready for publication a new synthetic study that would be one of the first examples of preparative, selective alkane functionalization." However, he adds, "the process is still far from being feasible for commercialization."

Asked what other synthetic developments he believes were important this year, Hartwig says he has a list of several hundred he could mention, but he points out just a few--such as a study by chemistry professors Ian Manners and Mitchell A. Winnik and coworkers at the University of Toronto on the use of polyferrocenes to make iron-containing "wormlike" micelles [J. Am. Chem. Soc., 122, 11577 (2000)] and another by assistant professor Peidong Yang of the University of California, Berkeley, and coworkers on the synthesis and hierarchical assembly of inorganic nanowires for potential nanoscale electronic applications [Chem. Mater., 12, 605 (2000) and J. Am. Chem. Soc., 122, 10232 (2000)].

Other notable synthetic achievements this year, Hartwig says, include the single-step synthesis of -functionalized olefins via metathesis reactions utilizing a ruthenium alkylidene catalyst [J. Am. Chem. Soc., 122, 3783 (2000)] and the discovery of new nickel-based polymerization catalysts for the synthesis of polyethylenes and other polymers with potentially advantageous new properties [Science,287, 460 (2000); C&EN, Jan. 24, page 14]--studies carried out by chemistry professor Robert H. Grubbs and coworkers at California Institute of Technology.

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The most notable genomics event this year was the joint announcement by the international Human Genome Project and Celera Genomics, Rockville, Md., that the human genome had been substantially sequenced (C&EN, July 3, page 4). Many future scientific advances should spring from having access to what has often been called the "Book of Life."

Barbas and coworkers created this model of a designed transcription factor with six zinc finger units (green) bound to a DNA double helix (orange and red).

Genomics certainly contributes a lot to chemistry, but it also relies heavily on the central science. Indeed, many important developments in what has come to be called "chemical genomics" were reported in C&EN's pages this year.

One significant development in chemical genetics this year was the design of proteins that bind DNA in a highly specific manner and act like transcription factors to turn endogenous genes on and off in living cells--work carried out by molecular biology professor Carlos F. Barbas III and coworkers at Scripps Research Institute, La Jolla, Calif. [Proc. Natl. Acad. Sci. USA, 97, 1495 (2000); C&EN, Feb. 21, page 34]. These synthetic transcription factors are potentially capable of recognizing unique sites within the human genome and activating or turning off the corresponding genes--for gene therapy applications, for example.

In the transcription factors, synthetic zinc finger DNA-binding domains designed to target specific sequences are combined with effector domains that activate or repress transcription. These were the first synthetic transcription factors to achieve both inhibition and activation of endogenous genes, rather than inhibition alone.

Since that report, Barbas and coworkers have created zinc finger-based fusion proteins that add the element of ligand-dependent inducibility and allow any gene of interest to be controlled [J. Biol. Chem., 275, 32617 (2000)]. The fusion proteins are induced (activated after they reach their targets) by administering very low doses of the drugs tamoxifen or RU-486. The ligand-inducible fusion proteins are of potential use for controlled modulation of gene expression in vivo and as potential regulators of natural promoters, such as human growth hormone, erythropoietin, or vascular endothelial growth factor.

	In Ariad's RAPID technique, a therapeutic protein such as insulin (red) is linked to a protein (blue) that forms aggregates in a cell's endoplasmic reticulum. Addition of a small-molecule drug (green) breaks up the aggregates, resulting in release of the therapeutic protein.

Meanwhile, chemistry professor Peter B. Dervan and coworkers at California Institute of Technology, in collaboration with the research group of professor Mark S. Ptashne, head of the Gene Regulation Laboratory at Sloan-Kettering Institute, New York City, have created artificial transcription factors in which designed peptide activation domains are combined with DNA-binding polyamides [Proc. Natl. Acad. Sci. USA, 97, 3930 (2000)]. These synthetic transcription factors are capable of activating gene transcription in vitro, whereas previous polyamide-based transcription factors were able to repress gene expression but not activate it.

"Because synthetic polyamides can, in principle, be designed to recognize any specific sequence, these results represent a key step toward the design of small molecules that can up-regulate any specified gene," the researchers note.

In addition, staff scientist Yen Choo, professor and 1982 Chemistry Nobel Laureate Sir Aaron Klug, and coworkers at the Medical Research Council's Laboratory of Molecular Biology, in Cambridge, England, have developed a strategy for creating zinc fingers that can target more or less any 18-base-pair DNA sequence. A scientific paper on the new strategy has been submitted, and the technology is being developed commercially by Gendaq Ltd., London. "We have also devised a powerful new method of engineering ligand-inducible transcription factors, which we believe will be capable of functioning with a variety of novel chemistries," Choo says.

A group led by researchers at Ariad Pharmaceuticals, Cambridge, Mass., developed an innovative technique this year for controlling the release of insulin and other drugs inside the body. The approach--called RAPID, for regulated accumulation of protein for immediate delivery--employs engineered genes that could be introduced into people by gene therapy techniques. The work was carried out by Ariad's director of gene therapy research, Tim Clackson, and by principal scientist Victor M. Rivera and coworkers [Science, 287, 826 (2000); C&EN, Feb. 7, page 12].

In RAPID, a genetically modified gene expresses an insulin-protein conjugate (or another drug-protein conjugate). The conjugate forms aggregates inside a cell's secretion apparatus. Administering a ligand causes the aggregates to break up and the insulin (or other drug) to be secreted.

Current gene-therapy methods for regulating protein production take about a day to generate peak levels of protein. But with RAPID, ligand-induced protein secretion peaks in about two hours. In their paper, the researchers demonstrated the procedure's ability to release pulses of insulin and thus control blood glucose concentrations in mice.

Scanometric array technique (left) developed by Taton, Mirkin, and Letsinger is much more sensitive than fluorometry (right) for detecting DNA hybridization. On each of the chips, the A row represents a fully complementary interaction, whereas the G, T, and C rows represent interactions between oligonucleotides that differ by one base pair. [Courtesy of Northwestern University]

Since the report was published, they have begun to use RAPID as a general tool to dissect protein trafficking mechanisms, Clackson says. For example, he and his coworkers collaborated with a group led by James E. Rothman, head of the cellular biochemistry and biophysics program at Sloan-Kettering Institute, on use of the technique to identify a new species of "megavesicle" involved in intracellular transport [Cell, 102, 335 (2000)].

Clackson says his group has been "distributing RAPID kits . . . to the academic community to allow the potential of the system to be exploited to the fullest possible extent." And he adds that he and his coworkers have been developing RAPID-based gene transfer vectors "to move toward bona fide gene therapy applications. The proteins we are currently most interested in are parathyroid hormones to treat osteoporosis and -endorphins to treat pain. Both need to be delivered in brief pulses. We have incorporated the system into a recombinant adeno-associated virus, the vector of choice for obtaining long-term stable expression, and we are currently testing these vectors in mouse models."

	Structure obtained by Palczewski, Stenkamp, Miyano, and coworkers shows how loops at the cytoplasmic (top) and extracellular (bottom) ends connect rhodopsin's seven transmembrane -helices.

Clackson suggests that a study by cellular and molecular pharmacology associate professor Kevan M. Shokat of the University of California, San Francisco, and coworkers [Nature, 407, 395 (2000)] also belongs on any list of significant year-2000 developments in chemical genomics. In the study, Shokat and coworkers genetically engineered kinases to make them more sensitive to inhibition by small-molecule ligands and identified inhibitors for all of the sensitized kinases. Individual kinases are normally very difficult to inhibit selectively.

"This is a superb example of using innovative chemistry to solve important biological problems," Clackson says. The study "demonstrated for the first time that this approach will work and be generally useful" for identifying kinase inhibitors that can potentially be used to tease out some of the detailed interactions that occur in kinase regulatory pathways.

Also this year, T. Andrew Taton, Chad A. Mirkin, and Robert L. Letsinger of the department of chemistry at Northwestern University developed a technique for "scanometric" DNA array detection with nanoparticle probes [Science, 289, 1757 (2000); C&EN, Sept. 11, page 8]. The technique, which uses gold nanoparticles to tag bound nucleotides on DNA arrays, makes it possible to detect target DNA at a sensitivity many times greater than the fluorometric approach normally used to detect array-bound sequences.

The technique is called "scanometric" because the gold nanoparticle-tagged arrays can be "read" with conventional flatbed scanners. Using the technique, Taton, Mirkin, and Letsinger were able to detect array-bound DNA fragments at sensitivities 100 times higher than can be achieved with commercial fluorescence detectors. Potential applications include determinations of single-nucleotide polymorphisms--differences in gene sequence that serve as markers of individuality.

The technology is currently being commercialized by Nanosphere, Evanston, Ill. An assay based on the methodology "rivals PCR-based [polymerase chain reaction-based] detection systems in sensitivity," Mirkin says. "Moreover, the unique melting properties of the nanoparticle probes make the scanometric detection system four times more selective than conventional fluorophore-based assays. Nanosphere plans on developing rapid, inexpensive, PCR-less assays for both research and clinical diagnostic applications."

Meanwhile, Harvard University research fellow Gavin MacBeath and Harvard chemistry and chemical biology professor and Howard Hughes Medical Institute investigator Stuart L. Schreiber developed high-density microarrays for proteomics applications--genomewide studies of protein function [Science, 289, 1760 (2000); C&EN, Sept. 11, page 6].

The researchers attached thousands of proteins to the microarrays at a uniquely high density and in a manner that preserved their native structure and function. Fluorescence or radioactivity of labeled reagents and biomolecules that interact with proteins on the microarray surface can be used to detect catalytic processes, protein-protein interactions, and binding events.

In model of the ribosome small (30S) subunit obtained recently by Yonath and coworkers, RNA parts of the structure are white and protein portions are blue.

"We are currently pursuing a few different targeted projects aimed at identifying all the homo- and heterophilic interactions among proteins in defined families," MacBeath says. For example, his group is collaborating with that of biology professor and Howard Hughes Medical Institute investigator Peter S. Kim at the Whitehead Institute for Biomedical Research, Cambridge, Mass., to study about 200 predicted coiled coil domains in the yeast proteome [Proc. Natl. Acad. Sci. USA, 97, 12935 and 13203 (2000)]. In addition, MacBeath and coworkers have been working with a Massachusetts Institute of Technology team led by associate professor of biology Peter K. Sorger "to construct microarrays of antibodies to quantitate the relative abundance and subcellular localization of proteins in cell or tissue samples," MacBeath says.

A key future goal is the direct comparison of microarray data with proteomics results obtained using the yeast two-hybrid system--currently the primary technique for identifying protein-protein interactions in biological systems. "This should give us an idea of the relative strengths and weaknesses of the two approaches," MacBeath says.

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As the structural biology research community gears up increasingly for structural genomics--the effort to obtain the structures of whole proteomes of proteins and protein fragments en masse by automated means--some researchers continue to determine the structures of major biological proteins the old-fashioned way--that is, in a one-at-a-time manner.

That is particularly necessary with a hard-to-crystallize transmembrane protein like rhodopsin, the light-sensitive protein in the eye. The high-resolution X-ray crystal structure of rhodopsin was obtained this year by the groups of professor of chemistry and of ophthalmology Krzysztof Palczewski and associate professor of biological structure Ronald E. Stenkamp of the University of Washington, Seattle; and Chief Scientist Masashi Miyano of the Structural Biophysics Laboratory at RIKEN Harima Institute, Hyogo, Japan [Science, 289, 739 (2000); C&EN, Aug. 7, page 11].

Rhodopsin turns light into visual signals in the retina, and scientists in the field of vision research had been looking forward to seeing its structure for many years. It is the first protein in the G-protein-coupled receptor (GPCR) class to have had its crystal structure determined.

The structure revealed some unexpected features and confirmed others that scientists had previously been able to deduce only indirectly. It is helping the vision community understand how vision works and how the protein is activated by light.

Lewis, Stermitz, and coworkers discovered that this plant natural product disables a pumping mechanism that Staph bacteria use to protect themselves from antibiotics.

"There are about 400 nonsensory GPCRs whose importance in our physiology is hard to overestimate, and they are targets for more than 60% of all drugs currently on the market or in development," Stenkamp and Palczewski note. "This is where our rhodopsin work will have the largest impact, as it will be used to model these other receptors. Our work has also shown that structural work on this class of proteins is possible." The researchers point out that as a result of the study, several companies, large and small, are now starting research programs to express, purify, and crystallize GPCRs.

Stenkamp and Palczewski look forward to the challenges posed by the structural genomics initiatives that are currently brewing, but their enthusiasm is not without skepticism. For studies of biomolecules directed at drug design, "accurate high-resolution structures are going to be needed," they note. "Whether all the results from structural genomics projects will achieve the required accuracy is not yet known."

Another major structural breakthrough this year was the determination of the atomic-resolution structures of the large (50S) and small (30S) subunits of the ribosome by three research groups, working independently. The ribosome is the RNA-translating and protein-making machinery of the cell and a major target of antibiotic drugs.

The high-resolution structure of the 50S ribosomal subunit was determined by professor and Howard Hughes Medical Institute investigator Thomas A. Steitz and professor Peter B. Moore and coworkers in the departments of chemistry, biochemistry, and molecular biophysics at Yale University [Science, 289, 905, 920, and 947 (2000); C&EN, Aug. 14, page 9]. The effort--which took five years and a total of 10 postdoc- and five technician-years to complete--increased the total RNA structural database four- or fivefold.

A month or so after that report, two other groups--that of structural biologist Ada E. Yonath of Weizmann Institute of Science, Israel, and the Max Planck Research Units for Structural Molecular Biology, Hamburg, Germany; and Venki Ramakrishnan and coworkers at the MRC Laboratory of Molecular Biology, Cambridge, England--reported independent crystal structures of the ribosome's smaller 30S subunit at or near atomic resolution [Cell, 102, 615 (2000) and Nature, 407, 327 (2000); C&EN, Sept. 25, page 39]. In addition to the structure of the small subunit itself, Ramakrishnan's group obtained structures of the subunit complexed with each of three antibiotics with antiribosomal activity.

Self-assembling actin rods (blue strands) sandwich cationic lipid bilayers (yellow) in these trilayed membranes designed by Safinya, Wong, and coworkers.

Since their report appeared, Steitz and Moore have continued working on the refinement and interpretation of the large subunit's structure. "We have also made substantial progress in determining the structures of ribosome-antibiotic complexes as well as additional substrate and product complexes," they tell C&EN. "A patent application has been filed on the use of the [ribosome large-subunit] structure for drug design, and efforts are being made to organize a company that will use the structure to develop novel antimicrobials."

Like Stenkamp and Palczewski, Steitz and Moore have some reservations about structural genomics. "It seems to us that 'low-throughput' crystallographic exploration of large biological structures will remain a crucial frontier area of research into the indefinite future, regardless of what becomes of structural biology initiatives," they note. The structures of Escherichia coli and yeast RNA polymerases as well as the ribosomal subunits "will alter the research directions of whole fields of biochemists and molecular biologists," they add. "Will the same be said about the structures of many protein fragments of unknown function" determined in structural genomics projects?

Since their paper appeared, Yonath and coworkers have completed the refinement of the structure of the functionally activated ribosome small subunit. "In parallel, our studies on complexes of this subunit with four antibiotics that bind to the small subunit allowed us not only to determine the sites of antibiotic binding but also to suggest their modes of action. These results are most exciting, since we found that each of those antibiotics developed a different [mechanistic] strategy," Yonath says.

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Apromising development in AIDS drug research this year was the discovery by Merck scientists of the first family of compounds capable of inhibiting human immunodeficiency virus (HIV) integrase. Integrase is essential to the virus' ability to infect host cells, but researchers had previously been unsuccessful at inhibiting it and thus blocking HIV's ability to incorporate its genetic material into immune system host cells. By screening chemical libraries of more than a quarter of a million compounds for inhibition using a preassembled recombinant integration complex, Daria J. Hazuda, Michael D. Miller, and coworkers in Merck's antiviral research department found compounds in the diketo acids family that shut down the integration process and stop HIV from replicating in cells [Science, 287, 646 (2000); C&EN, Jan. 31, page 24].

The principal AIDS drugs in current use target the HIV enzymes reverse transcriptase and protease. HIV integrase-targeted drugs therefore represent a potentially new class of anti-HIV agents, and the diketo acid inhibitors discovered at Merck are lead compounds for the discovery of such agents.

In follow-up work since their original report, the Merck researchers have made significant progress in understanding the detailed mechanism of action by which the diketo acids inhibit integrase [Proc. Natl. Acad. Sci. USA, 97, 11244 (2000)]. And they've identified a series of diketo acid derivatives that inhibit HIV replication at potencies up to 100-fold higher than those of the parent compounds [J. Med. Chem., published Nov. 28 ASAP,]. In fact, one of these derivatives is only twofold less potent than the commercial protease inhibitor indinavir, and it exhibits no cytotoxicity in cell culture at concentrations up to 50 micromolar.

Melt-processible PTFE, developed by Tervoort, Smith, and coworkers, can be shaped by a standard extruder.
Oxygen molecules (green) adsorbed on carbon nanotubes cause changes in electronic properties, Zetti and coworkers have found. ©1999 Keith Bradley

In the antibiotic arena, two groups developed agents this year that kill bacteria by first disabling their defense mechanisms. Associate professor Kim Lewis of the department of chemical and biological engineering at Tufts University, Medford, Mass.; chemistry professor Frank R. Stermitz of Colorado State University, Fort Collins; and coworkers discovered that the plant natural product 5'-methoxyhydnocarpin-D (5'-MHC-D) disables a pumping mechanism that Staphylococcus aureus bacteria use to protect themselves from antibiotics [Proc. Natl. Acad. Sci. USA, 97, 1433 (2000); C&EN, Feb. 21, page 6].

The agent disables the resistance-conferring pump, permitting antibiotics to accumulate in the bacteria and kill them--"the first case of synergy between plant antimicrobials documented at the molecular level," according to Stermitz. The discovery could lead to the development of drugs to treat antibiotic-resistant bacteria--including "superbugs" resistant to multiple antibiotics.

For example, the researchers obtained a bactericidal effect by using 5'-MHC-D in conjunction with the wide-spectrum antibiotic ciprofloxacin. And since the initial report, the Colorado State University group has synthesized 5'-MHC-D derivatives that are as much as 20 times more active than the parent compound against the Staphylococcus aureus resistance pump [J. Nat. Prod., 63, 1140 (2000) and J. Med. Chem., in press].

"Why are the myriad of antimicrobials produced by plants fairly ineffective or narrow-spectrum, as compared to antibiotics like streptomycin or penicillin that are produced by microorganisms and fungi?" Lewis asks rhetorically. "We propose that many if not all plant antimicrobials are extruded by multi-drug-resistance pumps of microbial pathogens."

For example, rhein, the main antimicrobial agent of rhubarb, has no effect against E. coli at concentrations of over 500 g per mL, at its limit of solubility. But growth of a mutant E. coli lacking the bacterium's major multi-drug-resistance pump was completely inhibited by rhein at 8 g per mL.

"A combination of rhein with multidrug-resistance pump inhibitors might turn it into a new effective systemic antimicrobial," Lewis says. "Tufts and Colorado State have applied for a patent on combination medicinal or antiseptic use of several antibiotics with multi-drug-resistance pump inhibitors."

A related strategy reported this year was the development of bifunctional aminoglycoside agents that kill bacteria by targeting a specific RNA sequence essential for bacterial protein synthesis and also targeting enzymes bacteria use to modify and disable antibiotic drugs. The work was carried out by chemistry professor Chi-Huey Wong and coworkers at Scripps Research Institute and associate professor of biochemistry Gerard D. Wright and coworkers at McMaster University, Hamilton, Ontario [J. Am. Chem. Soc., 122, 5230 (2000); C&EN, May 29, page 12].

Since the work was reported, Wong says, "we have prepared a number of derivatives around the lead and developed new combinatorial syntheses of dimeric aminoglycosides to improve the binding affinity to bacterial RNA and the inhibitory activity against resistance-causing enzymes. New derivatives with a better activity profile have been discovered, and the technology has been licensed by Optimer Pharmaceuticals, San Diego, Calif., for development of new-generation antibiotics to combat the problem of drug resistance."

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In the area of materials chemistry, researchers discovered this year that a protein-lipid complex with a novel structure forms spontaneously when the structural protein actin is mixed with a cationic membrane material. The complex adopts a remarkable tubular-capsule shape resembling the structure of bacterial cell walls. The research was carried out by Cyrus R. Safinya and Gerard C. L. Wong of the materials, physics, and biochemistry and molecular biology departments at the University of California, Santa Barbara, and coworkers [Science, 288, 2035 (2000); C&EN, June 19, page 11]. (Wong is now an assistant professor of materials science and engineering at the University of Illinois, Urbana-Champaign.)

The capsules are stacks of trilayered membranes in which each cationic lipid bilayer is sandwiched between two actin layers. Gaps between the membrane layers can hold molecules of various types. Potential applications of the dramatic new material include controlled delivery of drugs and chemicals. "In addition to being useful in the biotech industry, it may also be possible to exploit these systems as nanoscopic 'molds' for the templated synthesis of nanostructured semiconductors and catalytic materials," Wong says.

At about the same time, researchers at the Swiss Federal Institute of Technology (ETH), Zurich, Switzerland, were working on a solution to a long-standing problem in fluoropolymer processing. Senior research fellow Theo Tervoort, polymer technology professor Paul Smith, and coworkers identified a set of parameters that permit the fabrication of a wide range of new poly(tetrafluoroethylene) (PTFE) products using conventional melt-processing methods [Macromolecules, 33, 6460 (2000); C&EN, Sept. 4, page 11].

The global annual market for PTFE is in the $2 billion range, according to Smith, but until now the polymer could not be melt-processed because of the extremely high viscosity of its molten state. Therefore, only simple products could be made from PTFE, using costly and inefficient production methods such as powder compaction and subsequent machining. A way around the problem was to introduce comonomers into the PTFE chain, but they can degrade some of PTFE's key thermal and chemical properties. Also, copolymerization is expensive.

Tervoort, Smith, and coworkers instead found a narrow set of material characteristics that permit melt-processing of PTFE in standard extruders. They envision applications such as blow-molded containers, films, fibers, bags, complex parts that cannot be machined, polymer granules, polymer blends, and novel adhesives and hot melts.

"We have continued to make advances in the area," Smith and Tervoort tell C&EN. "We have expanded the range of viscosities and molecular weight ranges of PTFE that can be processed from the melt. Most notably, we have made considerable progress in melt-spinning of PTFE fibers at commercially interesting rates--hundreds of meters per minute--and produced filaments with mechanical properties that rival those of the much more expensive and less stable FEP [fluorinated ethylene-propylene] and PFA [perfluoroalkoxy] copolymers."

The researchers have started a company called Omlidon Technologies LLC, in Wilmington, Del., that owns the new PTFE technology, will further develop it, and will license it to others. "We are negotiating with three companies to produce the new raw materials and expect to sign one or more agreements within the next month," say Smith and Tervoort.

 "Much of the chemical industry feels that it got burned by early investments in advanced materials, and therefore many have elected not to pursue research on novel materials," they continue. "As a result, the gap between pioneering academic research and industrial activities continues to grow rapidly. Our work on PTFE--in which we resolved a 60-year-old problem by applying simple physical chemistry--demonstrates that there still are numerous problems with [industrial] materials that are worth solving, both from an intellectual and technology point of view."

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Fullerene and nanotube research has been especially hot this year, with significant breakthroughs following closely upon each other.

For example, a collaborative group created a long-sought structure--the bowl-shaped C₂₀, the smallest fullerene ever obtained and the smallest possible species that can be considered a fullerene. The compound was produced by emeritus professor of chemistry Horst Prinzbach and assistant professor of physics Bernd von Issendorff at Albert Ludwigs University, Freiburg, Germany; chemistry professor Lawrence T. Scott of Boston College; and coworkers [Nature, 407, 60 (2000); C&EN, Sept. 11, page 5]. The structure could help scientists attain a better understanding of how fullerenes form.

And last month, a Japanese and a Chinese group, working independently, reported syntheses of the smallest possible carbon nanotubes--graphite cylinders with a diameter of only 4 . The smallest nanotubes discovered previously were 5 to 7 in diameter. The work was carried out by Lu-Chang Qin and Sumio Iijima of NEC Corp., Tsukuba, Japan, and coworkers, and independently by Ning Wang, Zi-Kang Tang, and coworkers in the physics department at Hong Kong University of Science & Technology [Nature, 408, 50 (2000); C&EN, Nov. 6, page 9].

The Japanese group formed their tiny nanotubes inside larger nanotubes, whereas the Chinese team prepared their 4--diameter nanotubes as single-walled nanotubes (SWNTs) in the pores of a zeolite material. The Chinese nanotubes were determined to be metallic in nature, suggesting their potential use as wires for molecular electronics devices.

Also this year, assistant professor of chemistry Hongjie Dai and coworkers at Stanford University reported a way to use nanotubes as chemical sensors. They found that the conductance of semiconducting SWNTs changes rapidly in the presence of compounds like nitrogen dioxide and ammonia, making it possible for the nanotubes to essentially detect these gases [Science, 287, 622 (2000); C&EN, Jan. 31, page 7].

Whitesides and coworkers found a way to get tiny circuit components such as copper dots, wires, and LEDs to self-assemble into microcircuits, one of which is shown sitting on a penny. [David Gracias/Harvard University]

Since the study was published, Dai and coworkers found that when a nanotube is coated with a submonolayer of palladium metal, the nanotube's conductance becomes sensitive to molecular hydrogen. The researchers are currently trying to modify nanotube sidewalls to facilitate protein immobilization, with an eye toward the potential development of sensitive and reversible nanotube biosensors.

A related development was the discovery by physics professor Alex Zettl of the University of California, Berkeley, and Lawrence Berkeley National Laboratory and coworkers that the electronic properties of nanotubes are also sensitive to atmospheric oxygen [Science, 287, 1801 (2000); C&EN, March 13, page 8]. The group found that the electronic characteristics of nanotubes could be "tuned" reversibly by small amounts of adsorbed gases. Once again, sensor applications are possible.

A step toward practical applications of nanotubes was the discovery of a way to produce SWNTs as long ribbons and fibers--a form that was previously inaccessible. Materials scientist Philippe Poulin of the Paul Pascal Research Center at the University of Bordeaux I, Pessac, France, and coworkers were responsible for the findings [Science, 290, 1331 (2000); C&EN, Nov. 20, page 9].

In the nanotube-spinning process they developed, a dispersion of SWNTs in solution is injected from a capillary tube into a more viscous solution flowing in the same direction. Fluid forces cause nanotubes emerging from the capillaries to align and stick together. The resulting fibers are strong and stable enough to be tied into tight knots without breaking, whereas conventional carbon fibers are fairly brittle. Potential applications include advanced materials, electrical cables, and artificial muscles. Poulin and coworkers are working with a start-up company called Nanoledge, in Montpellier, France, and with Honeywell to develop the technology.

Meanwhile, staff scientist Gregory P. Lopinski and principal research officers Danial D. M. Wayner and Robert A. Wolkow at the Canadian National Research Council's Steacie Institute for Molecular Sciences, Ottawa, have devised a method for fabricating other types of nanostructures. The researchers reported a self-assembly procedure in which organic molecules attach covalently to a silicon surface in neat rows with controllable nanometer-scale dimensions [Nature, 406, 48 (2000); C&EN, July 10, page 10]. The arrangement of atoms on the solid's surface directs incoming organic molecules into the row formations.

"We have tackled the big barrier facing all scanned-probe-based strategies for making little things--that is, the need until now to make things slowly and serially," Wolkow tells C&EN. "Our approach allows an unlimited array of initiation points to be defined, and then the simultaneous and rapid growth of many identical nanostructures." The work has potential applicability to the development of nanoscale electronic components and tiny devices that interact with biological systems.

"It is an exciting time," Wolkow says. "Just a few years ago we had virtually no detailed understanding of the inorganic-organic interface. Today we can give an atom-by-atom accounting of a significant variety of organic molecule-silicon interactions. As a result, molecular device concepts that were imagined but out of reach 20 years ago are now tantalizingly close to being realized."

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Ateam led by chemistry professor George M. Whitesides of Harvard University made a conceptual breakthrough in molecular electronics this year when the researchers demonstrated the ability of small modular electronic components to self-assemble spontaneously into working three-dimensional electronic microcircuits [Science, 289, 1170 (2000); C&EN, Aug. 21, page 7]. The technology could lead to new types of electronic components and networks. They were able to demonstrate both serial and parallel circuit devices.

The self-assembling microelectronic systems have attracted "astonishingly wide interest," Whitesides tells C&EN. "We are going forward with more sophisticated systems, but it's too early for [commercialization]. That's maybe three to five years away."

Whitesides suggests that another significant molecular electronics development this year was the creation of an ordered colloidal iron-platinum material by staff member Shouheng Sun and coworkers at IBM's Thomas J. Watson Research Center, Yorktown Heights, N.Y. [Science, 287, 1989 (2000); C&EN, June 12, page 37]. The substance is "a plausible technological candidate for a rational nanomaterial," Whitesides says.

Previous attempts to prepare such iron-platinum materials yielded disordered products with a broad distribution of particle sizes--problematical characteristics for use in magnetic devices. But the IBM material has a relatively uniform and controllable particle size, suggesting magnetic recording uses.

Also this year, professor of chemistry Larry R. Dalton at the University of Southern California (USC) and the University of Washington, Seattle, and coworkers used a new type of conjugated organic molecule to create an electro-optic device with dramatically improved performance, compared with current technology [Science, 288, 119 (2000); C&EN, April 10, page 12].

The device operates on less than 1 V and transduces electrical data into optical information at a rate of more than 110 gigahertz. An electro-optic device that could operate at such a high speed on less than 1 V had long been sought for its potential ability to improve the efficiency of fiber-optic and satellite communication systems. A potential application of the new technology is the reduction of lengthy Internet download times resulting from delays that occur when digital data are transferred to fiber-optic cables.

"A number of prototype devices have been demonstrated, and the performance is pretty clearly superior to alternative technologies," Dalton says. A company called Lumera, Bothel, Wash., "has been formed to produce polymeric electro-optic materials-based devices and to market them starting in 2001."

Moreover, several major corporations are evaluating the technology. "It is likely that partnerships will be formed and that R&D and commercialization efforts will be launched by a number of companies," Dalton says.

Since the group's Science paper was published this spring, they've improved the electro-optic activity of their polymeric materials by a factor of two, reduced the materials' optical transmission losses dramatically, and enhanced the materials' thermal and photochemical stability. In their latest research efforts, electro-optic chromophore compounds have been incorporated into dendrimers, which inhibit some unfavorable interactions that tend to impede performance.

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In work this year at the interface between chemistry and physics, a research group led by chemist James K. Gimzewski and physicist Christoph Gerber at IBM Research, Zurich, reported a novel molecular recognition technique based on detection of tiny mechanical forces induced by binding of complementary DNA strands [Science, 288, 316 (2000); C&EN, April 17, page 8].

The researchers attached oligonucleotide monolayers on silicon cantilever arrays and then put the arrays in solutions containing complementary oligonucleotides. Hybridization of the DNA fragments caused the cantilevers to bend, and the researchers monitored these motions with laser beams. The system was sensitive enough to detect single base pair differences in interacting oligonucleotides, and it was also capable of recognizing specific protein-protein binding interactions.

The technique could be used to develop new types of biomolecular detection systems and devices in which the power--literally--of molecular recognition could be used to drive nanomachines. Other potential application areas include gas sensing, medicine, fragrance design, and even astrobiology, according to Gerber. "There is great interest in commercialization," he says. "Two companies are collaborating with us in this direction."

At the same time, laser physicist Robert W. Schoenlein and colleagues at Lawrence Berkeley National Laboratory discovered a technique for producing unusually fast and bright X rays--subpicosecond pulses of synchrotron radiation that combine atomic-scale space resolution with ultrafast time resolution [Science, 287, 2237 (2000); C&EN, March 27, page 7].

In the technique, high-energy electrons are struck with femtosecond laser pulses and then bent by a magnet, generating X rays. The duration of the resulting X-ray pulses is equivalent to that of the laser pulses--in the range of hundreds of femtoseconds. Synchrotrons can normally produce soft X-ray pulses of only about 30-picoseconds duration--too slow to resolve atomic vibrations.

The fast, bright X rays will potentially be used to probe ultrafast phase transitions and chemical reactions. Schoenlein notes that a dedicated X-ray beamline based on the technique is just being completed and that it will provide time resolutions in the 100-femtosecond range.

Finally, in the energy arena, one key development this year was a demonstration that hydrocarbons like butane and diesel fuel could be used to produce electricity in a new type of fuel cell without first being converted to hydrogen, as had previously been necessary.

In fuel cells, electric power is produced by electrochemical reactions. Substances like methane and methanol had been investigated in the past as potential fuels for fuel cells, with limited success. But chemical engineering professors Raymond J. Gorte and John M. Vohs and a coworker at the University of Pennsylvania developed electrode materials that make it possible for hydrocarbons like butane to be used in fuel cells [Nature, 404, 265 (2000); C&EN, March 20, page 11]. They successfully demonstrated the technology using a variety of hydrocarbons, including alkanes, alkenes, and aromatics.

There has been "considerable industrial interest in the work," Gorte says, "and we are hopeful that the concepts we developed will be commercialized." He notes that he and his coworkers "have made several very interesting discoveries since theNature paper appeared"--such as a way to make the new fuel cells more efficient. In addition, the researchers have extended the work to "the direct oxidation of liquid fuels, without reforming," Gorte says. "To my knowledge, this is the first time anyone has even tried to do something like this, let alone demonstrated success."

News of chemical research developments tends to whiz by us and is sometimes forgotten as weeks and months go by. Individually, many of these stories might seem to report progress that is tentative and limited. But as we look back on the chemical research enterprise as a whole over a period of a year, we see a level of achievement that offers great promise for the future.

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