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December 10, 2001
Volume 79, Number 50
CENEAR 79 50 pp. 45-55
ISSN 0009-2347
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[Previous Story] [Next Story]CHEMISTRY HIGHLIGHTS 2001

GENOMICS AND MEDICINE. This was a landmark year for genomics: First drafts of the human genome sequence were published (C&EN, Feb. 12, page 9). Researchers from the international Human Genome Project reported on their analysis of a substantially complete version of the 2.9 billion-base-pair sequence [Nature, 409, 860 (2001)], while scientists from Celera Genomics, Rockville, Md., and 13 associated organizations published a similarly complete sequence that they obtained in a remarkably short time [Science, 291, 1304 (2001)]. The availability of the sequence data could have major implications for the development of new drugs and genetic therapies, among other uses.

PHOTO BY WALTER SMALLING
THREE BILLION LETTERS J. Craig (top right) Venter and Francis Collins were leaders of competing teams that published substantially complete sequences of the approximately 3 billion-base-pair human genome sequence this year. Sequencing instruments used in the projects--such as those shown here at Venter's company, Celera Genomics--require minimal operator intervention.
The most striking finding of both studies was that the number of human genes is surprisingly small: 30,000 to 40,000, considerably lower than the estimate of 100,000 widely cited in 1991, when the Human Genome Project began. Other animals' genomes also have been or are being sequenced, such as those of the rat and mouse.

Other important genomic and chemistry-related medical developments this year involved RNA interference (RNAi), prevention of chemotherapy-associated hair loss, a radioactive guided missile for cancer cells, obesity research, prion disease diagnostics and therapeutics, and antibacterial advances.

RNAi, a key technique for studies of gene function but formerly applicable only to lower organisms, was adapted this year for use in mammalian cells. In RNAi, a double-stranded RNA that matches a gene sequence is used to inhibit expression of that gene. Although the technique worked well in lower organisms such as worms, it shut down all protein synthesis in mammalian cells and thus couldn't be used there. However, Thomas Tuschl and coworkers at the Max Planck Institute for Biophysical Chemistry, Göttingen, Germany, found that introducing smaller double-stranded RNA fragments called short interfering RNAs (siRNAs), instead of full gene-length RNAs, eliminated the problem, permitting RNAi to be used to inhibit genes in human cells [Nature, 411, 494 (2001); C&EN, June 4, page 47].

Scientists also found this year that chemotherapy patients may be able to keep their hair. Hair follicle cells are unintentionally harmed during chemotherapy. But senior research investigator Stephen T. Davis and colleagues at then Glaxo Wellcome, Research Triangle Park, N.C., designed and synthesized compounds that render hair follicle cells less susceptible to anticancer agents [Science, 291, 134 (2001); C&EN, Jan. 8, page 25]. The compounds prevented noticeable hair loss in up to 50% of rats subjected to chemotherapy.

A technique to deliver a lethal dose of radiation to cancer cells by injecting animals with actinium-225 attached to tumor-seeking antibodies was developed by Leukemia Service Chief David A. Scheinberg and coworkers at Memorial Sloan-Kettering Cancer Center [Science, 294, 1537 (2001); C&EN, Nov. 19, page 62]. Scheinberg notes that this is the first viable technique for delivering a-particles, "the most potent cytotoxic agent available," to cancer cells. A single injection shrank tumors and extended the lives of mice with prostate cancer or lymphomas.

There has also been a "heavy" amount of interest of late in research on obesity and weight loss--such as the finding that a protein fragment allows mice to overeat and still stay thin. When Harvey F. Lodish of the Whitehead Institute, Cambridge, Mass., and colleagues there and at Genset Corp., La Jolla, Calif., injected pleasingly plump mice with a fragment of the human protein Acrp30, the mice lost weight and kept it off, even while continuing a diet high in fat and sugar [Proc. Natl. Acad. Sci. USA, 98, 2005 (2001); C&EN, Feb. 12, page 34].

7950_prion-amplification
PRION AMPLIFIERS Serono scientists (from left to right) Saborio, Soto, and Permanne developed a prion amplification technique that could aid diagnosis of mad cow disease and related conditions.
7950New_Cover
COURTESY OF BEN THROOP AND KEVIN GUCKIAN, SCRIPPS RESEARCH INSTITUTE

INVASIVE Self-assembling nanotubes containing cyclic peptides, designed by Ghadiri and coworkers, insert themselves readily into bacterial cell membranes and act as potent and selective antibiotics.

Scientists also found that mice lacking the gene for a key enzyme stay thin despite hefty appetites. A group including assistant professor Lutfi A. Abu-Elheiga and professor Salih J. Wakil of the department of biochemistry and molecular biology at Baylor College of Medicine, Houston, found that mice genetically modified to eliminate one form of the enzyme acetyl-coenzyme A carboxylase stay thin, even when they eat 20 to 30% more food than other mice [Science,
291, 2613 (2001); C&EN, April 2, page 10]. The enzyme thus joins the growing number of possible targets for antiobesity drugs.

Researchers are trying to find better ways to diagnose mad cow disease, Creutzfeldt-Jakob disease, and related conditions. One would like to be able to diagnose these diseases in living patients, but the diseases can currently only be detected postmortem. A promising step toward a diagnostic test for live patients was the development of a simple technique for amplifying prions, the infectious form of prion protein associated with the disease. The technique--called protein-misfolding cyclic amplification--raises the level of existing prions so they can be detected more easily. It was developed by Claudio Soto, neurodegenerative diseases research head, and coworkers Gabriela P. Saborio and Bruno Permanne, of Serono Pharmaceutical Research Institute, Geneva [Nature, 411, 810 (2001); C&EN, June 18, page 9].

Graduate student Gideon M. Shaked, senior lecturer Ruth Gabizon, and coworkers in the department of neurology of Hadassah University Hospital, Jerusalem, found a form of prion in urine that can potentially indicate the presence of disease even before symptoms appear [J. Biol. Chem., 276, 31479 (2001); C&EN, July 16, page 10]. The findings suggested that a simple urine test could be developed to identify prion diseases in animals and people. Urine samples are relatively easy to obtain, whereas current tests must be carried out on brain tissue samples.

Also on the prion front (C&EN, Aug. 20, page 11), postdocs Carsten Korth and Barnaby C. H. May, professor of medicine and pharmacology Fred E. Cohen, and neurology and biochemistry professor Stanley B. Prusiner of the University of California, San Francisco, reported that two approved tricyclic drugs--the antimalarial agent quinacrine and the antipsychotic drug chlorpromazine--inhibit prion infection in cells [Proc. Natl. Acad. Sci. USA, 98, 9836 (2001)]. Human clinical trials were planned for both drugs.

Assistant professor R. Anthony Williamson and professor Dennis R. Burton of the immunology department at Scripps Research Institute, along with coworkers (including Prusiner), also identified antibody fragments that block prion formation in cells [Nature, 412, 739 (2001)]--suggesting potential therapeutic use. And prion researcher Charles Weissmann and coworkers of the Imperial College School of Medicine at St. Mary's, London, reported that an antibody prevents prions from infecting cells and cures chronically infected cells [Proc. Natl. Acad. Sci. USA, 98, 9295 (2001)], indicating that passive immunization with such antibodies might be worthwhile.

In antibacterial research, a small molecule was found capable of resensitizing vancomycin-resistant bacteria to the antibiotic [Science, 293, 1484 (2001); C&EN, Aug. 27, page 16]. Vancomycin is a drug of last resort for antibiotic-resistant infections. Gabriela Chiosis (currently assistant laboratory member and assistant attending chemist at Memorial Sloan-Kettering Cancer Center) and postdoctoral fellow Ivo G. Boneca (now at the Pasteur Institute, Paris) found synthetic compounds that cleave an antibiotic-resistant cell wall precursor. The findings suggested that such compounds might be developed for coadministration with vancomycin in humans.

Self-assembled peptide nanotubes designed by chemistry professor M. Reza Ghadiri and coworkers at Scripps Research Institute offer another promising approach to antibacterial treatment. The nanotubes are formed by self-assembled stacking of cyclic peptides having an even number of alternating D- and L-amino acids. The nanotubes insert themselves readily into bacterial cell membranes and act as potent and selective antibacterial agents, both in cell culture and in studies on mice [Nature, 412, 452 (2001); C&EN, Aug. 6, page 41].

And postdoc Joerg C. Tiller, visiting scientist Chun-Jen (Jason) Liao, and professor of chemistry and bioengineering Alexander M. Klibanov at Massachusetts Institute of Technology, along with associate professor Kim Lewis at Tufts University's Biotechnology Center, demonstrated that covalent attachment of N-alkylated poly(4-vinylpyridine) to glass surfaces makes the surfaces lethal to several types of bacteria on contact [Proc. Natl. Acad. Sci. USA, 98, 5981 (2001); C&EN, May 28, page 13]. These are the first engineered surfaces shown to kill airborne microbes in the absence of any liquid medium.


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