tion to the "careful planning and hard work" by EPA and thousands of workers in key areas such as chemicals manufacturing, hazardous materials, and wastewater treatment. EPA also credited the joint development and distribution in late 1999 of a Y2K guidance document for small and medium-sized chemical facilities by EPA, the Chemical Safety & Hazard Investigation Board, the Chemical Manufacturers Association (CMA), and specialty chemical associations for the uneventful transition to the year 2000. Synthetic Organic Chemical Manufacturers Association (SOCMA) President Edmund H. Fording Jr. acknowledges that "there was some concern" about whether small and medium-sized chemical companies were in fact prepared for Y2K. Now a few days into the new year, Fording says, "None of our members have indicated any Y2K issues so far." SOCMA cooperated with EPA in the development and distribution of the guidance document CMA President and Chief Executive Officer Frederick L. Webber says, "Y2K was just another workday in our industry." The successful transition "demonstrates once again the good that can happen when government and industry work together to solve a problem—or, as in this case, to head off a problem." Dow Chemical reported some snafus that were so minor they were anticlimactic and did little or no damage: an instrument failure on a polyethylene line in Terneuzen, the Netherlands; phone and pager problems in the Asia-Pacific region and Latin America; a power outage affecting a plant in Balaton, Hungary; and some minor computer server interruptions. Dow was not even sure these problems were Y2K related but reported them anyway in the spirit of full disclosure. The transition is "going very well, exceeding my expectations," says Doug Snoddy, global Y2K Y2K: Silent and not at all deadly program director. Dow spent about Fears that the much-vaunted Y2K com- I Bayport, Texas; Leverkusen, Germany; $84 million on Y2K-related preparations worldwide. puter bug would upset delicate chemi- and Singapore. cal reactions and processes and cause Was the Y2K bug like the Y2K moleDuPont—which figures it spent begeneral mayhem turned out to be un- cule (C&EN, Dec. 20, 1999, page 5): tween $300 million and $400 million to founded. And thus the year 2000 arrived more a theoretical aberration than a re- gird itself for Y2K—reported that "our not with a bang but with a whimper, and ality? Perhaps not. If the industry did as status is green. Everything is okay." Adds that suits the chemical industry—and thorough a job as it claims, then it got Chairman and CEO Charles (Chad) O. everyone else—just fine. the sort of result it most wanted instead Holliday Jr., "During the millennium Only the scheduledfireworksextrav- of the doomsday event some feared. change, we met the Y2K challenge and aganzas wowed the crowds in New York The chemical industry, like others, continued to serve our more than 25,000 City, Paris, London, and other world cit- spent millions of dollars updating pro- customers, joint ventures, and 80,000 ies as part of New Year's celebrations. cess equipment with date-sensitive elec- suppliers worldwide. And we did it without interruptions to our mission-critical And as planned, the new year arrived tronic chips and software. without fanfare and much more quietly The Environmental Protection Agen- or significant global systems." in chemical production centers such as I cy credited the success of the Y2K transiMarc Reisch Medical Institute investigator and laboratory chief at the New York State Department of Health in Albany. In the postgenomic era, visualizing macromolecular interactions in the cell will require an approach that goes a step beyond bioinformatics in making sense of genomic information, he says. Cryo-EM of single particles is particularly suited for this task, he suggests. The goal of Ushkaryov's research is to understand exocytosis, the process by which a cell discharges particles too large to diffuse through the cell membrane. a-Latrotoxin, which binds to nerve-cell terminals, stimulates a massive discharge of neurotransmitters into the synaptic cleft. Thus, the molecule has been used to study synaptic function, although its mode of action is complex: In addition to forming stable pores in the membrane, the toxin binds to two different receptors and may activate two different exocytosis pathways. Cryo-EM revealed that cc-latrotoxin exists as a hydrophilic dimer in the absence of divalent cations. In the presence of either Ca2+ or Mg2*, however, it forms a tetramer in which the subunits rearrange to produce a hydrophobic region that enables the toxin to "flop" onto the lipid bilayer membrane. Once it has adhered, the tetramer makes channels in the membrane so that extracellular Ca2+ can enter the cell and stimulate exocytosis, Ushkaryov explains. "But this is a very simple scenario," he says, "and I don't think people would
be so interested in the toxin if this was the only thing it could do. a-Latrotoxin also stimulates exocytosis in the absence of extracellular Ca2+, although Mg2* must be present." In fact, how Ca2+ stimulates exocytosis is an enigma that many people are trying to explain, Ushkaryov says. Although regulatory proteins that bind Ca2+ have been identified on synaptic vesicles, no one knows the mechanism by which vesicles fuse with the plasma membrane to disgorge their contents. Indeed, Ushkaryov questions whether Ca2+ influx through toxin-created membrane pores is enough to trigger the release of neurotransmitters from vesicles. He suggests that the surge might be due, in part, to neurotransmitters in the cytoplasm leaking out through the pores. In a commentary accompanying the article, electron microscopist Helen R. Saibil at Birkbeck College, London, suggests that cc-latrotoxin's efficacy derives from synergism between the different pathways. The toxin could both stimulate exocytosis and activate signal pathways releasing intracellular Ca2+, she says, setting the stage for influx of extracellular Ca2+ that would propagate the exocytosis cycle. Time will tell. "I have spent 18 years studying oc-latrotoxin and its receptors," Ushkaryov says. "Right now, we are trying to figure out how the toxin stimulates release of neurotransmitters in the absence of extracellular Ca2+." Mairin Brennan
JANUARY 10,2000 C&EN
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