A group led by Lawrence A. Donehower of Baylor College of Medicine, Houston, found that p53, a protein that protects against tumor formation, may also trigger early aging [Nature, 415, 45 (2002); C&EN, Jan. 7, page 23]. A commentary noted that the results raise "the shocking possibili-ty that aging may be a side effect of the natural safeguards that protect us from cancer."

David A. Cheresh of Scripps and coworkers developed anticancer polymeric nanoparticles that deliver a mutant gene sequence to endothelial cells on blood vessel surfaces [Science, 296, 2404 (2002); C&EN, July 1, page 6]. The resulting expressed protein disrupts angiogenesis, blood vessel formation needed for cancer growth. Later, a team led by Scripps's Ralph A. Reisfeld devised a new type of antiangiogenic agent: a vaccine that targets an overexpressed protein on endothelial cells [Nat. Med., 8, 1369 (2002); C&EN, Nov. 25, page 25].

Most liver cancer treatments have limited efficacy or significant toxicity. But Peter L. Pedersen and coworkers at Johns Hopkins School of Medicine showed that the alkylating agent 3-bromopyruvic acid fights liver cancer in animals with good specificity and low toxicity [Cancer Res., 62, 3909 (2002); C&EN, July 15, page 30].

	BOUND TO WORK Pavletich and coworkers elucidated the key role in breast cancer played by mutations in the protein BRCA2. They found that BRCA2 (pink ribbons) binds DNA (blue ribbons and cyan bases) and helps promote repair of double-stranded DNA breaks. Repair occurs in distinct regions (pink dots) of cell nuclei (shown in background). © 2002 SCIENCE

Mutations in the tumor suppressor protein BRCA2 were known to be related to breast and ovarian cancer, but the protein's normal role was unknown. A team led by Nikola P. Pavletich of Memorial Sloan-Kettering Cancer Center found a possible function: BRCA2 helps to repair double-stranded DNA breaks [Science, 297, 1837 (2002); C&EN, Sept. 16, page 5].

RNA interference (RNAi)--a technique in which a short double-stranded RNA that matches a specific gene sequence inhibits expression of that gene--showed growing promise this year. Phillip A. Sharp of MIT, Premlata Shankar of Harvard Medical School, and coworkers inhibited human immunodeficiency virus (HIV) replication in human cells by using short interfering RNAs (siRNAs) to silence expression of a cell-surface HIV-entry receptor or the virus's Gag protein [Nat. Med., 8, 681 (2002); C&EN, June 10, page 34]. Mario Stevenson and coworkers at the University of Massachusetts Medical School inhibited HIV replication in human cells by using siRNAs targeted to other HIV genes [Nature, 418, 435 (2002)]. And Raul Andino and coworkers at UC San Francisco used siRNAs directed at polio genes to reduce proliferation and promote clearance of polio virus in human cells [Nature, 418, 430 (2002)].

In the bacterial wars, Vincent A. Fischetti of Rockefeller University and coworkers found a viral enzyme that kills anthrax specifically and might also provide a rap-id way to detect anthrax contamination [Nature, 418, 884 (2002); C&EN, Aug. 26, page 30].

A new type of malaria vaccine--a glycosylphosphatidylinositol-protein conjugate--showed promising results in a mouse model of malaria. Peter H. Seeberger of MIT, Louis Schofield of the Walter & Eliza Hall Institute of Medical Research, Melbourne, Australia, and coworkers found that mice treated with the vaccine were "substantially protected" against malaria symptoms and death [Nature, 418, 785 (2002); C&EN, Sept. 9, page 45].

Linqi Zhang of Rockefeller University, David D. Ho of the Aaron Diamond AIDS Research Center, New York City, and coworkers isolated from immune cells a set of a-defensin proteins that may represent CD8 antiviral factor--an agent proposed to protect HIV-resistant people from developing AIDS [Science, 298, 995 (2002); C&EN, Sept. 30, page 7].

In neurochemistry research, autopsy has been the only way to diagnose Alzheimer's disease conclusively, but a team found that positron emission tomography scans of live patients injected with a labeled compound can reveal plaques and tangles characteristic of the disease [Am. J. Geriatr. Psychiatry, 10, 24 (2002); C&EN, Jan. 21, page 36].

A group led by Dennis J. Selkoe of Harvard Medical School showed that amyl-oid-b oligomers seem to be key cytotoxic agents in Alzheimer's disease [Nature, 416, 535 (2002)]. Massimo Stefani of the University of Florence, Christopher M. Dobson of the University of Cambridge, and coworkers likewise found that species that form early in protein aggregation processes are highly cytotoxic--even if the proteins are normally nondisease-associated [Nature, 416, 507 (2002); C&EN, April 8, page 7].

Bruce A. Yankner of Harvard Medical School and colleagues found that the protein a-synuclein, which accumulates in brains of Parkinson's disease patients, may inhibit a key molecular chaperone that protects neurons from cell death [Nat. Med., 8, 600 (2002); C&EN, June 10, page 34]. And Matthew J. During of the University of Auckland and colleagues used gene therapy to compensate for the loss of dopamine in rats suffering from a Parkinson's-type condition [Science, 298, 425 (2002); C&EN, Oct. 14, page 44].

The mechanism of coffee "buzz" was elucidated by Gilberto Fisone of Karolinska Institute, Stockholm; Paul Greengard of Rockefeller University; and coworkers. They found that caffeine acts as an effective stimulant by regulating a neuronal positive-feedback loop that modulates a motor-activity-related signaling pathway [Nature, 418, 774 (2002); C&EN, Aug. 19, page 35].

In the obesity field, Stephen R. Bloom of Imperial College Faculty of Medicine, London, and coworkers found that a hormone called peptide YY_3–36 reduces appetite and food intake [Nature, 418, 650 (2002); C&EN, Aug. 12, page 30]. They studied the hormone's activity and molecular targets.

In osteoporosis research, Hector F. DeLuca and coworkers at the University of Wisconsin, Madison, found that 2MD, a modified form of vitamin D₃, stimulates bone growth in rats [Proc. Natl. Acad. Sci. USA, 99, 13487 (2002); C&EN, Oct. 7, page 26]. And Stavros C. Manolagas and coworkers at the University of Arkansas for Medical Sciences, Little Rock, showed that the synthetic estrogen estren (right) reverses bone loss in mice without the adverse effects on reproductive tissues that current hormone replacement therapies sometimes have [Science, 298, 843 (2002); C&EN, Oct. 28, page 33].

The mechanism of action of nitroglycerin in angina (chest pain) relief was studied by Jonathan S. Stamler and coworkers at Duke University Medical Center [Proc. Natl. Acad. Sci. USA, 99, 8306 (2002); C&EN, June 10, page 12]. They found that nitroglycerin is converted to nitrite, and nitrite is then reduced to nitric oxide--which dilates blood vessels, relieving anginal pain.

The molecular mechanism that permits bilirubin to act as an antioxidant was found by Solomon H. Snyder of Johns Hopkins University School of Medicine and coworkers [Proc. Natl. Acad. Sci. USA, 99, 16093 (2002); C&EN, Dec. 9, page 9]. They uncovered a redox cycle involving bilirubin that consumes high concentrations of peroxyl radicals. The work could lead to therapeutic use of bilirubin.

And in three Scripps developments (C&EN, Nov. 25, page 25), Jeffery W. Kelly's group found a chaperone that aids folding of an enzyme mutated in some Gaucher's disease patients [Proc. Natl. Acad. Sci. USA, 99, 15428 (2002)]; a team led by Paul Wentworth Jr. and Kim D. Janda found protein glycoconjugate vaccines against sepsis (blood poisoning) [Angew. Chem. Int. Ed., 41, 4241 (2002)]; and Wentworth, Janda, Albert Eschenmoser, Richard A. Lerner, and coworkers found that antibodies may kill bacteria directly, a previously unknown mechanism [Science, published online Nov. 14, http://dx.doi.org/10.1126/science.1077642].

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