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THE SCIENTIST VOLUME 8, No:4 FEBRUARY 21, 1994 (Copyright, The Scientist, Inc.) =============================================================== Articles published in THE SCIENTIST reflect the views of their authors and not the official views of the publication, its editorial staff, or its ownership. =============================================================== *** THE NEXT ISSUE OF THE SCIENTIST WILL APPEAR ON *** *** MARCH 7, 1994 *** *** *** ******************************************************* Subscription rates for the printed edition are: In the United States: one year $58, two years $94 Canada : one year $82, two years $142 All other foreign : one year/air cargo $79, one year/ airmail $133 THE SCIENTIST (Page numbers correspond to printed edition of THE SCIENTIST) FOR SEARCHING PURPOSES: AU = author TI = title of article TY = type PG = page NEXT = next article ------------------------------------------------------------ TI : CONTENTS PG : 3 ============================================================ NEWS OTA IN TRANSITION: With the departure of longtime director John Gibbons for the White House, and facing budgetary constraints and reorganization challenges, the Office of Technology Assessment is in a state of transition--a challenge to the skills of new director Roger Herdman, say observers PG : 1 LIBRARY SUPPORT: A committee of 130 scientists from several disciplines has united under a consultant to press for more federal funding for research libraries, which they say are unable to keep up to date with journals and books for lack of funding PG : 1 GUIDELINES ON ANIMAL USE: The National Academy of Sciences is currently revising its Guide for the Care and Use of Laboratory Animals, the influential reference used in private and public laboratories throughout the U.S. and overseas. The new guide, due out in mid-1994, is expected to accommodate changes in law since its last edition, including those in the Animal Welfare Act of 1985, and will likely take some account of animals' psychological well-being as well as their physical health PG : 1 ECOLOGICAL SCIENCE FUNDING: The National Science Foundation recently awarded in excess of $2 million in grants to more than a dozen scientists around the U.S. to support and encourage more basic and applied research into conservation biology and restoration ecology, part of a four-year program that has awarded about $10.5 million so far PG : 1 BACKING FOR BIOENGINEERING: The Whitaker Foundation has presented 14 Special Opportunity awards, in amounts ranging from $250,000 to $750,000, to establish novel training programs in the wide- ranging field of biomedical engineering PG : 3 A PUBLISHING LANDMARK: Joshua Lederberg, Nobel Prize-winning geneticist and University Professor at Rockefeller University, discusses the momentous impact that the work of researchers Oswald Avery, Colin MacLeod, and Maclyn McCarty--presented in a groundbreaking 1944 research paper--has had upon 20th-century biology PG : 11 COMMENTARY: Of his current role as publisher and editor-in-chief of The Scientist, as well as chairman emeritus of the Institute for Scientific Information, the company he launched in the 1950s, Eugene Garfield says that wearing two hats has proved to be a challenge--and an inspiration PG : 12 TEMPORARY REPRIEVE: A temporary delay in the destruction of the last remaining smallpox virus stores, housed in the U.S. and Russia, is only a small consolation to scientists whose research has centered on the mechanisms of and potential vaccines from orthopoxviruses, as the fate of the stocks is still in question PG : 16 HOT PAPERS: A computer scientist discusses his software package designed to align nucleotide or protein sequences PG : 17 VIDEO-RATE CONFOCAL IMAGING: Recent advances have made faster image acquisition possible for laser-scanning confocal microscopes. The result is video-rate "movies" of dynamic cell events, combined with the sharp resolution of confocal microscopes PG : 18 GIANT PUSH FOR SCIENCE EDUCATION: Fortune 500 chemical and health-care giant Miles Inc. is putting both a substantial monetary contribution and the time and expertise of its scientists behind a program to distribute and present special science education materials to schools near its Pittsburgh headquarters PG : 22 CATHLEEN S. MORAWETZ, a professor of mathematics at New York University's Courant Institute of Mathematical Sciences, has been elected president of the American Mathematical Society, only the second woman to hold the post PG : 23 NOTEBOOK PG : 4 CARTOON PG : 4 LETTERS PG : 12 CROSSWORD PG : 13 MICROSCOPY AND IMAGING PRODUCTS DIRECTORY PG : 20 OBITUARIES PG : 23 (The Scientist, Vol:8, #4, February 21, 1994) (Copyright, The Scientist, Inc.) ================================ NEXT: ------------------------------------------------------------ TI : Scientists Press For Boost In Federal Library Funding New committee says paper collections are threatened, but librarians say that the information glut demands new acquisitions strategies AU : FRANKLIN HOKE TY : NEWS PG : 1 A committee of more than 130 scientists from different disciplines--newly organized by a consultant with longstanding ties to several commercial academic publishers- -is calling for more federal funding for research libraries. Increasingly, they say, libraries are failing to keep collections of science books and journals up to date because they lack money for acquisitions. They warn that, in time, the declining accessibility of these materials may threaten their investigations. Librarians and scientific society officials say, however, that the problem of keeping abreast of scientific information is more complicated than the committee and its Bridgeport, Conn.-based consultant organizer, Albert Henderson, would make it appear. They say that part of the acquisitions problem is the rising cost of journals-- especially some of those produced by the commercial academic publishers. In addition, the increasing specialization of science books and journals, which results in ever-larger numbers of publications for ever-smaller readerships, is straining library budgets and facilities, they say. "Mr. Henderson's committee feels that if there were more funding of libraries, then the problem would go away," says Harry Lustig, treasurer of the American Physical Society (APS) in College Park, Md., a nonprofit publisher of scientific journals. "We are certainly in favor of more funding for libraries, more funding for research, and more funding for the dissemination of research. We applaud that, but we do not believe that the problem will go away, because there just isn't that much funding available. The amount of information scientists publish every year is still increasing by large factors--with our journals, it's something like 10 percent a year." Solutions proposed by these groups include more reliance on computer databases and document-delivery systems, more selective acquisitions that may be based partly on a title's price, and more use of interlibrary loans. While they acknowledge that more library funding would be welcome, they do not think it will prove, in the end, to be the best tactic for maintaining top-quality collections. "There's no library in the country that doesn't want more money and couldn't do great things with it," says Ann Okerson, director of the office of scientific and academic publishing for the Association of Research Libraries in Washington, D.C. "On the other hand, I think people in research libraries believe that the cost of science journals is quickly pushing all of our other acquisitions off the map." Even with more money, she says, the sheer volume of new books and journals published each year now demands that libraries develop new acquisitions strategies. "We're doomed in paper," Okerson says. "I don't think we can ever afford, anymore, to house in research libraries in a comprehensive fashion all the publications that researchers generate in paper. Our buildings will collapse." The `Virtual Library' Henderson says the problem is that library acquisitions funding has been declining as a share of university expenditures, resulting in canceled journal subscriptions and fewer book purchases. He does not accept the idea that new technologies and interlibrary loans can substitute for copies on the shelves. "I'm all for the library technologies, for the Internet and for [computer] document delivery," he says. "I love it--when it works." He says, however, that of 11 listed documents he recently ordered through an academic document delivery service, only eight were available. This is not unusual, he says. Interlibrary loans, too, are only as good as the contributing library collections, he says. "You have to have a source," Henderson says. "If you want something by interlibrary loan, that means that somebody else has to have it. There has to be a loaner as well as a borrower. As the sources dry up, you find that the failure rate increases." Taken together, he says, efforts to meet researchers' library needs without making adequate new purchases are bound to be insufficient. "This business of the virtual library is just something for nothing," Henderson says. "It's a fraud." The deficit in acquisitions funding can be traced to changes in two main government provisions, he says. One is Title II- A of the Higher Education Act of 1965, which provided federal matching grants for library acquisitions from the mid-1960s to 1980, when the Reagan administration ended this funding, according to Henderson. The other is Circular A-21, the Office of Management and Budget publication covering allowable indirect costs, a shrinking proportion of which, he says, has been used to support libraries. Henderson says the federal government should directly address the question of research library acquisitions in its science policy deliberations. Because of the large number of federally funded academic researchers and because many members of the public use the libraries, he also feels the federal government has a responsibility to provide dedicated funding in this area and not to rely on the discretion of the universities. Some of the scientists who have signed on with Henderson's committee say that they, too, are concerned that, without adequate funding, library collections may rely too heavily on high technology and be unable to properly serve researchers. "I feel threatened by the information highway undermining the accessibility of the finished document, the actual journal, per se, or the book," says committee member Jules Elias, an associate professor of histopathology at State University of New York, Stony Brook. Elias is also editor of the Journal of Histotechnology. "I love my computer, I love my Medline, I love my searches--but I want to be able to hold a journal or a book in my hand." He adds: "The book is still the book. You don't take your computer to bed with you." Research librarians insist that science collections are being well maintained, sometimes, in fact, to the detriment of other types of materials. Science journal price increases as well as the total amounts spent on those journals, they say, have outstripped those in other areas. "We've kept up with that side of the house," says Okerson, "but we've let go all kinds of other stuff--books, mostly in the humanities and social sciences, and other serials--to preserve very, very expensive science serials." She adds: "We're undergoing profound changes in the amount of information that's being published and the specialized nature of it. We now have subdisciplines with one or two hundred interested people. This is not a market." As a result, she says, research librarians are looking to technologies such as the Internet, online databases, and computer publication and distribution systems to supplement ordinary publishing. Some of these might help scientists get materials faster, Okerson says, and some might help meet the needs of more specialized researchers in a more cost- effective way than paper publishing. "Everything is changing so very quickly," Okerson says. "It's not clear to me, and it's not clear to a lot of people, that the mere act of putting more money into the system is going to be what saves the day." Who's Driving? Some committee members and others express concern that Henderson's potential consulting relationships with the for- profit journal publishers may influence the direction taken by the committee he has organized. Librarians have, at times, criticized some of these publishers' pricing structures as being excessive and as undermining their ability to maintain comprehensive journal collections. "I myself have had some problems sorting out who is driving the committee," says Palle E.T. Jorgensen, a professor of mathematics at the University of Iowa, Iowa City. Jorgensen is also editor of Proceedings of the AMS, from the American Mathematical Society. "Some of what Mr. Henderson says sounds like it's exactly what the scientists and the graduate students who use the science libraries, in fact, want and what we're concerned about. But I was a little bit worried about the committee, maybe, being influenced by some of the concerns of the commercial publishers, whereas I believe that the professional societies have a better way of getting the material to the science libraries for lower cost." Jorgensen says that Henderson included his curriculum vitae with his solicitation, so that his affiliations were clear. "He didn't put it in the headline, but he certainly didn't try to hide it," Jorgensen says. Henderson acknowledges that the purposes of the committee he has created dovetail well with his own interests and, perhaps, those of his current and potential publisher clients. "As a consultant, I need a way to market myself," Henderson says. "Espousing this cause provides me with a reason to talk to all of the major publishers that I may or may not do business with." (The Scientist, Vol:8, #4, February 21, 1994) (Copyright, The Scientist, Inc.) ================================ NEXT: ------------------------------------------------------------ TI : Internal Problems Confront OTA In Wake Of John Gibbons's Move To Key Position In White House Observers see organizational and budgetary challenges as potential impediments to office's effectiveness AU : BARTON REPPERT TY : NEWS PG : 1 A year after former director John H. Gibbons's departure to become White House science adviser, the congressional Office of Technology Assessment (OTA) is going through a difficult period of transition, reorganization, and budgetary belt- tightening. The congressional agency--which marked its 20th anniversary last year--researches and prepares evaluations and analyses that Congress relies upon heavily in making science and technology funding and policy decisions. The information in its highly regarded reports and briefing papers is also used extensively by scientists, the media, and the general public. OTA's new director, Roger C. Herdman--a physician and public health expert who for nine years headed the office's Health and Life Sciences Division--is striving to deal with budget constraints by trimming OTA's senior management, while at the same aiming to preserve its project teams of policy analysts. Herdman also has had to cope with replacing a number of senior staff members who left OTA last year either to work under Gibbons at the Office of Science and Technology Policy (OSTP) or to assume new positions elsewhere in the Clinton administration. Nonetheless, several OTA-watchers interviewed by The Scientist say they feel that, in view of the circumstances, the changeover from Gibbons--who in his 14-year tenure at the office is generally credited with building its prestige and influence--to Herdman has for the most part proceeded with fluency. According to Neil E. Harl, a member of OTA's Technology Assessment Advisory Council and a professor of economics at Iowa State University, Ames, "things have gone fairly smoothly. It's been a difficult time, because of budget constraints and the fact that the demands on the agency continue to be increasing .... But I think Dr. Herdman has done quite a good job of moving into Jack's [Gibbons's] position." At the same time, some observers voice concern that the ability of OTA--which was established by Congress in 1972 and began operations in 1973--to continue producing solid, carefully researched reports on a broad range of technology- related issues and policy options may be impaired by staff turnover and downsizing, the continuing budget squeeze, and other problems. Rep. George E. Brown, Jr. (D-Calif.), chairman of the House Science, Space, and Technology Committee and a member of OTA's 12-member bipartisan congressional board since establishment of the agency, indicates that he has mixed views about how well OTA has been living up to its mandate and reputation. "OTA has been really marvelously productive in looking at a wide range of subjects, and providing what I think is the best, the most objective analysis," says Brown, who is widely regarded as Congress' leading expert on science and technology issues. However, Brown adds: "I have been a little disappointed in OTA, not in the sense of the quantity or quality of its work, but [because] I have felt that it could have done--and I wanted it to do--a little larger job of making specific policy recommendations. OTA has stayed away from that pretty much. It gives choices, but it doesn't make recommendations." OTA's staff changes over the past year, Brown says, have resulted in a temporary period of "turbulence" within the agency. "The net results are going to be a short-term deterioration in both output and, possibly, quality of the product at OTA. When you lose a substantial portion of your top staff, that's what happens," he says. Brown says of OTA's overall performance: "On balance, I think it has not yet achieved the peak of its potential. It does face a problem of continually renewing itself and scrutinizing its operations to maintain the quality" of its staff and output. OTA In Transition Daryl C. Chubin, a former OTA senior associate who now heads the office of research, evaluation, and dissemination in the education directorate of the National Science Foundation, comments that "the agency is in a period of flux and reorganization, internally. It's going to get smaller, it's going to get more streamlined. Whether that means leaner and meaner remains to be seen." Shortly after Gibbons was named to the presidential science adviser post, he reportedly told a gathering of agency staff members that he had no intention of hiring away OTA managers and analysts for the White House science and technology operation. But that's not how things turned out. "Jack, in going to OSTP, hired a lot of our senior people. He staffed OSTP with OTA," Herdman observes, adding, "I think Jack told me 25 percent of his staff was from OTA." This turnover has seen the departure of two OTA assistant directors--Lionel S. Johns, who left to become OSTP associate director for technology, and John Andelin, who retired. Along with Johns, five other senior OTA staff members departed to work at OSTP. In addition, over the past year several OTA analysts have decided to leave for new jobs elsewhere in the executive branch or with other organizations around Washington. However, Herdman contends that the changes in senior staff at OTA may prove to be beneficial by allowing him to put in place a new management team and providing "considerable flexibility" to implement an ongoing reorganization effort. In an extensive interview with The Scientist (see story on page 7), Herdman explained his overall approach to revamping OTA--so that the agency can operate within a tight budget climate, but still maintain its reputation for thorough, high-quality research and policy analysis. "I don't want to whittle us down any more than I have to," he says. "The idea is to take a series of steps which allow us to generate savings, while at the same time preserving our working teams--the project director and the analysts--as much as possible, so that we can still continue to turn out the quantity and quality of reports that we traditionally have." For the 1994 fiscal year, OTA had sought a budget of $22.925 million, an increase of $1.9 million from its 1993 appropriation of $21.025 million. However, congressional appropriations committees directed that its budget be cut to $20.815 million. Over the last several years, OTA's staff has declined from a peak of 230 employees to a current level of 205. That number is to inch down further to 202 staffers in the next budget year. "If they keep cutting us, we're just going to lose productivity--we won't be able to do the same amount of work. At some point, things are going to have to give," Herdman says. In addition to its own staff, OTA makes extensive use of expert advisory panels and outside contractors to gather data and sound out the views of "stakeholders" on various sides of the issues it is dealing with. The advisory panels currently involve about 1,600 participants a year. Herdman's reorganization effort so far has included changing its structure from three divisions to two: the Industry, Commerce, and International Security Division, headed by assistant director Peter Blair; and the Health and Environmental Sciences Division, headed by assistant director Clyde Behney. Blair previously had been in charge of OTA's energy and materials program, while Behney was promoted from his former position in charge of the health program. The next step in the reorganization plan will be consolidating OTA's program structure, reducing the number of programs from the current nine probably down to six, in order to achieve further savings on management costs. According to agency officials, this move is expected to be carried out within the next couple of months. The New Director Herdman, 60, came to OTA in 1984 from Memorial Sloan- Kettering Cancer Center in New York, where he was a vice president. Previously, he had served as director of public health for the New York State Department of Health, and as a professor of pediatrics specializing in children's kidney diseases and transplantation at Albany Medical College in New York. In response to the question of whether his professional background makes it likely that OTA will devote increased attention to health-related issues, Herdman says: "I suppose it's fair to say that maybe in the minds of some it has a little greater salience--just like when Jack Gibbons was here, energy policy might have had a little greater salience because . . . he was an energy-policy guy. I am what I am. I'm a doctor, and I did health--I'm a health-policy guy. Now we have an assistant director who's an energy-policy guy, so we've sort of switched." Gibbons and Herdman also present a contrast in personal styles. According to Chubin, "Jack has wonderful interpersonal skills--his charm comes through. Rog-er is more retiring and taciturn, if you will.... But I can tell you that, one-on-one, Roger's quite effective, and even with small groups I think he's effective. If you put him in front of an audience, that's not his best setting." When Gibbons left in January 1993, Herdman became acting director of OTA. But he was not named permanent director until May, when the initial choice of a search committee under the auspices of OTA's congressional board, advanced materials expert Maxine Savitz of Morristown, N.J.-based Allied-Signal Inc., changed her mind and decided against taking the job. After Savitz's withdrawal, says Rep. Amo Houghton (R-N.Y.), a member of the congressional board, "all of a sudden we realized that we had this guy here who's darn good. We had thought it would be a fine idea to reach out and get somebody who had a little different perspective--from the outside. But Roger has done a great job here." Houghton adds that he is "not unhappy at all" with the outcome. According to Houghton, a member of the powerful House Ways and Means Committee, "They [at OTA] do an awful lot with not that much [funding]. I know what research budgets and what consulting budgets are. They get the last ounce of blood out of the stone. If the budget continues to shrink, then, obviously, they'll just have to cut back on their scope-- hopefully not on the quality." Doing A Lot With A Little In terms of staff and budget, OTA is considerably smaller than either of Congress' other main support agencies--the Congressional Research Service and the General Accounting Office. But it has become known as a highly productive operation, turning out reports that often have a wider audience among the research community, the news media, and the general public. OTA's current publications catalog lists 540 reports and briefer "background papers"--dealing with such diverse issues as Alzheimer's disease, global biotechnology research, genetic monitoring and screening, medical technology, health insurance, high-performance computing and communications, restructuring of the defense industry, disposal of chemical weapons, international technology transfer, oversight of federally funded research programs, and aviation safety. Marcel C. LaFollette, a science policy analyst at George Washington University's Center for International Science and Technology Policy, says that while OTA is primarily intended to serve the needs of Congress, its secondary function of disseminating information more widely is also important. "They are there to serve their clients [congressional committees]," LaFollette says. "But what they also do is to produce reports that are extremely valuable to educating the rest of the American public on these issues.... That's really a great deal of help if you're a legislator in South Dakota, or a citizen advocate in Montana or someplace, and you want to get up to speed in a neutral and objective way, and to see the issues laid out on both sides." OTA reports are the end product of an assessment process that can take as long as two years--including conducting background research, convening advisory panels of experts to sound out a diversity of viewpoints, using outside consultants to prepare contractor reports, writing the report by OTA staff members, then having several drafts reviewed both internally and outside the agency--before the final report is released. According to some science and policy analysts, in certain cases this drawn-out process at OTA means that the agency's reports are not timely enough, and that key decisions involved with the issue in question have already been made before an OTA study is finally issued. "Their whole process for deciding they were doing to do a report, physically doing it, and then going through an infinite number of reviews seems to get the process so protracted," says John Pike, director of the space policy project at the Federation of American Scientists in Washington, D.C. On the other hand, Pike adds, some OTA reports hit the mark in terms of both comprehensiveness and timely release. He cites a 199-page report issued last July dealing in part with the developing convergence of U.S. civilian and military weather satellite programs. The report, "The Future of Remote Sensing from Space," was prepared by an OTA team headed by project director Ray A. Williamson. Pike calls the report "really a stand-out in the sense that this is a big policy debate that is going on right now. And I think that the OTA study is really about the only piece of paper that I can point to.... It's a hot, breaking issue where they're basically the one-stop shop." Barton Reppert is a freelance science writer based in Gaithersburg, Md. (The Scientist, Vol:8, #4, February 21, 1994) (Copyright, The Scientist, Inc.) ================================ NEXT: ------------------------------------------------------------ TI : THE NEW CHIEF AT OTA TY : NEWS PG : 7 Editor's Note: Office of Technology Assessment director Roger Herdman discussed a variety of issues facing the agency during an extensive interview last month with Barton Reppert, a contributing editor of The Scientist. Following are excerpts from the interview: * On OTA's mission: "It's up to us to bring to the attention of Congress data, conclusions, and options--not recommendations, but options.... We're not a blue-sky think tank.... We need to provide practical information. And we want to be ahead. But we certainly can't afford to be looking ahead 10 or 20 years." * On OTA's priorities: "I'm keenly aware that my priorities are the priorities of my [Technology Assessment] board and the congressional committees. Although we provide some feedback, and we carry on discussions and negotiations with the committees, the fact of the matter is that what OTA works on is what the congressional committees identify as their priorities, and what our board approves." * On national information infrastructure: "We've had continuing emphasis on the national information infrastructure [the NII].... We have, right now, two major studies which look at ways in which [the NII] can help various sectors of our economy. One, we're looking at the way that the wireless technologies can be melded into the NII.... Secondly, we're looking at the ways that the NII can relate to the health sector." * On technology, health care, and computer networks: "There are a lot of pie-in-the-sky, very optimistic, not very well- defined scenarios. Let me take the health area, which I, of course, as a physician and former health person at OTA, am intimately familiar with. They talk about computerized medical records--what a wonderful thing. Well, that's 10 years away, quite frankly. Take telemedicine. I'm not so sure that the guy in Podunk needs to see on a gigabit network the actual MRI, where he could probably do just as well with somebody saying, `Look, it's normal.' ... I think it remains to be seen.... We're looking at it from the bottom up--at small projects which have been running around the country. We're actually looking at how they're financed and so on, to see what is really is working." * On computers in public education: OTA's project team has been "focusing rather narrowly on ... information technologies actually in the classroom. How do teachers use computers--they don't use them very well, and why not? How many schools have got computers, where are they, and how are they being used? How do people teach teachers--train them to get the most out of information technologies? What are information technologies really doing for kids?" * On defense industry conversion: "Defense has been a tough one for OTA recently. It's still a priority, but it's one which I think we're wrestling with. Because clearly it's a different world. What we have been focusing on . . . is the defense conversion situation--dual-use technologies, retraining, how to use the national labs for other than defense purposes, how to help industry." * On nuclear weapons dismantlement and cleanup: "We have a series of studies on cleaning up contamination from [Department of Energy] facilities, looking at dismantling nuclear weapons--the problems that we as a nation are having with where to store all this plutonium and highly enriched uranium which is left to us as a result of all these weapons.... Those environmental problems are not only problems in this country--they're problems for the countries of the former Soviet Union. And we're actually exploring some of the issues over there, in terms of helping them-- looking at the nuclear contamination and the dismantling problem." * On hiring and keeping talent at OTA: "The government doesn't compete with industry salaries for top people. That's totally out of the question. You look around OTA and, yes, there are some people with gray hair here. But our staff is basically young people.... Whatever the price we have to pay, we're going to continue to pay, so that at least we're competitive within federal service." * On maintaining OTA's assessment process: "OTA will always be accused of taking too long, and the issue has passed us by. There's nothing that I even want to do about that, to the extent that our people are going to get it right.... If it's going to be a 150-page book, it's got to be right, we can't make a mistake." (The Scientist, Vol:8, #4, February 21, 1994) (Copyright, The Scientist, Inc.) ================================ NEXT: ------------------------------------------------------------ TI : Researchers Vigilant As NAS Revises Lab Animal Guide Bench scientists, along with antivivisectionists, wonder what an updated `bible' of animal care will bring AU : FRANKLIN HOKE TY : NEWS PG : 1 Earlier this month, a National Research Council (NRC) committee held the last of three public forums to gather input for a revision of its widely influential Guide for the Care and Use of Laboratory Animals. Although publication of the new guide is not expected until next year, scientists and animal protectionists already are debating the impact of changes that might result. Among these are new guidelines addressing the psychological well- being of lab animals, specifications for animal housing, and categories of animals not previously discussed in detail. Some changes possible --new cage sizes or facility ventilation standards, for example, if these are suggested--could translate into the need for expensive lab alterations, scientists say, but others should bring a welcome harmony between the guide and new laws and regulations put into effect since the last edition, the sixth, was published in 1985. Among these are amendments to the Animal Welfare Act in 1985 and changes in Public Health Service policy that became part of the Health Research Extension Act, also in 1985. The new laws partly explain the 10-year gap between editions, says Thomas L. Wolfle, program director of the Institute of Laboratory Animal Resources (ILAR), the arm of NRC charged with overseeing the guide's revision. Previous editions of the guide have been spaced about five years apart, he says. "Those two federal laws came into being at the same time as this last edition," Wolfle says. "We wanted to wait and see what the impacts of those were, where the weaknesses in them were, and how the guide could supplement and extend them." This edition will also have a new publisher--the National Academy Press, which publishes the works of NRC and its parent organizations, the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. Previous editions were published by the Government Printing Office. The influence of the guide on research laboratories using animals is extensive. It is viewed as the standard animal-care reference for laboratories in industry, academia, and government, in the United States as well as other countries. Compliance with its dictums is required, for example, of all National Institutes of Health grantees using animals in their experiments. Another expression of the guide's influence is its use by the American Association for Accreditation of Laboratory Animal Care (AAALAC), an independent, nonprofit organization in Bethesda, Md. Many animal laboratories seek accreditation from AAALAC as proof of their adherence to laws, regulations, and current scientifically approved animal care and use procedures. Using the guide as their manual, AAALAC representatives conduct site visits and program reviews of laboratories using animals in research. "Accreditation is deemed as evidence of a high-quality operation," Wolfle says. "Most organizations, and particularly the commercial organizations, the pharmaceutical companies, want to be absolutely above reproach. They'll do whatever it takes in order to publicly demonstrate their commitment to quality animal care. And, in this country, that's how you do it." Martin Stephens, vice president for laboratory animals of the Humane Society of the United States in Washington, D.C., calls the guide the "bible" of lab animal care and use. Stephens and other animal protectionists say they have had a long wait since 1985 for another chance to contribute to the guide. "The animal research controversy and the animal rights movement really didn't come to a head until just before that time," says Stephens. "So, there wasn't much of an opportunity for that revision of the guide to be influenced by contrary views. We're hoping that this time around that will change." Performance Standards One important aspect of the guide praised by researchers and expected to survive the revision largely intact is its current emphasis on so-called performance standards. This term refers to guidelines that describe the goals for care and use while leaving the details in execution up to researchers and other on-site professionals. Engineering standards, on the other hand, define such considerations as the appropriate cage size for an animal. "Performance standards are really the only way to go," says Gale Taylor, director of laboratory animal care at the University of Illinois, Urbana-Champaign. Taylor, who testified February 2 in St. Louis before the NRC committee, is also a former chairman of AAALAC's council on accreditation and a veteran of more than 100 site visits. "If you tried to write a standard that covers the waterfront," Taylor says, "it would be extremely difficult and complex. There has to be some latitude for professional judgment." One suggestion, for example, that Taylor put before the committee concerned the recommended number of air changes in an animal care facility. "Currently, the guide says there should be 10 air changes an hour whether there's one mouse in the room or 1,000 mice in the room," Taylor says. "I'm suggesting that there may be reasons for granting exceptions to that hard standard." Another area in which Taylor is asking for professional leeway concerns animals that survive experimental surgery. Currently, an animal that survives such a procedure cannot be used in another. "There are some rare species where that becomes a real problem," Taylor says. "So, I'm asking for a provision for an informed, rational, on-site waiver of the prohibition, when based on and justified by conservation of an animal species or a particularly valuable animal model, such as some of the transgenic animals. There may only be a very few of those particular critters around." He adds: "Obviously, it can't be something horribly invasive that shouldn't be repeated. But if it is a minor surgical procedure, there should be some provision for reuse. Right now, it's a clear, distinct prohibition." Taylor also hopes for expanded advice on caring for cold-blooded vertebrates and farm animals. ILAR's Wolfle says that, generally, the performance-standards tone of the guide will be preserved. "The guide has always said that we don't know enough about all of the various species that we're dealing with," Wolfle says. "We can give guidance as to what you should achieve, but there are many ways to achieve that goal." One area in which the Humane Society's Stephens and other animal advocates hope for significant improvement is in the psychological well-being of laboratory animals, especially nonhuman primates and dogs. "The [current] guide is largely an attempt to spell out guidance on keeping animals physically healthy," Stephens says. "The environments are sterile, literally and metaphorically. It would be a sign of progress if the new edition of the guide talked about social needs and naturalistic environments and put more emphasis on psychological health and the natural behavior of animals." The area of developing, implementing, and evaluating environmental enrichment programs for nonhuman primates and canines is another in which Illinois' Taylor hopes the guide will provide guidance rather than strictures. "These are controversial issues," Taylor says. "What I'm asking for is not specific standards, but for guidelines so that the local veterinarians and animal care and use committees can develop reasonable, rational programs. How do you evaluate an environmental enrichment program for a monkey?" Stephens suggests a change in perspective might be helpful. "There's no reason why the laboratories should resemble prisons for animals," Stephens says. "They can resemble the best in a zoo environment, for example." (The Scientist, Vol:8, #4, February 21, 1994) (Copyright, The Scientist, Inc.) ================================ NEXT: ------------------------------------------------------------ TI : New Wave Of NSF Awards Underscores Agency's Commitment To Environment AU : EDWARD R. SILVERMAN TY : NEWS PG : 1 The National Science Foundation, seeking to encourage more research into conservation biology and restoration ecology, recently awarded nearly $2 million in grants to more than a dozen scientists around the United States. This marks the fourth consecutive year that NSF has committed funding to a wide variety of programs encompassing both basic and applied research that is designed to investigate threats to biological diversity. Such threats, NSF noted in announcing the latest round of grants, occurs across all geographic regions, at all levels of life, and on scales ranging from the microscopic to the oceanic. "We're gradually evolving a broader concept of ecosystems," says Joann Roskoski, acting deputy director for NSF's division of environmental biology. The division usually approves between 15 and 18 projects each year and has so far doled out about $10.5 million since the program began. "If you don't save a whole ecosystem, trying to save an individual species can be a wasted effort," Roskoski says. "You need to save the environment the species lives in. If not, what happens to the ability of that species to survive?" The goal of the grant program is to "advance knowledge of ecosystems and species under pressure," according to NSF. "When we start to take a proactive role in managing things, to conserve or restore, we have to know how to do that, and the problem is we often don't know how," Roskoski says. "If we want-ed to cure a disease in our body, we'd need to know something about our bodies. We need to think about the environment in the same way. This program helps us get fundamental information needed to design programs to manage the environment." Consequently, the research does not have to be confined to the United States, although government legislation requires that the funds be given only to domestic institutions, including museums, zoos, universities, nonprofit organizations, and research institutes. This year, the general areas of research funded by the program include assessments of the diversity contained within gene pools of different species, the fate over generations of individual gene variants within species, the effects of species diversity within ecosystems, and hormonal and behavioral factors affecting animal reproduction. Models And The Real World Among the research projects selected to receive support are a long-term study of the ecology and reproductive biology of endangered Nicaraguan cichlid fish; an investigation that, according to NSF, is the first long-term interdisciplinary field study of the reproductive biology of the cotton-top tamarin, an endangered Colombian primate; a study of the population structure of the Mexican spotted owl; an investigation of the consequences of seed dispersal by fruit-eating animals on tropical forest regeneration; and a study of the causes of extinction after rainforest fragmentation. "My research wouldn't get finished without this program," says Fred Allendorf, a professor of biology at the University of Montana, Missoula, who was awarded $250,000 to study the conservation and genetics of Pacific salmonids, a family that includes salmon and trout. "I see this [grant] program as connecting the bridge between basic and applied research," Allendorf says. "[It] divides itself between model systems and real-world problems." "I heard of the program at a meeting of the National Society of Zoologists," recalls Adrian Wenner, a professor, emeritus, of biological sciences at the University of California, Santa Barbara. "My work is just too massive an undertaking to have received funding elsewhere." Wenner's research looks at the effects that removal of honey bees from Santa Cruz Island--a largely uninhabited, 96-acre tract off the California coast--would have on native plants and their pollinators. Wenner, working in conjunction with two other scientists, received $50,000 from NSF. "We've been working for six years so far and removed 165 of 215 colonies, but we would have stopped altogether without the funding," he says. "It's a pretty big task." Those interested in applying to the program are requested to submit proposals to the Conservation and Restoration Biology Competition at the National Science Foundation, 4201 Wilson Blvd., Arlington, Va. 22230. The deadline is September 29. Edward R. Silverman is a freelance writer based in Millburn, N.J. (The Scientist, Vol:8, #4, February 21, 1994) (Copyright, The Scientist, Inc.) ================================ NEXT: ----------------------------------------------------------- TI : Whitaker Foundation Awards Aim To Inspire Innovation AU : NEERAJA SANKARAN TY : NEWS PG : 3 The Whitaker Foundation, headquartered in Washington D.C., has presented 14 Special Opportunity Awards in biomedical engineering to teams of investigators who have come up with proposals to establish novel training programs in the field. The awards range from $250,000 to $750,000. The foundation recognizes that the field of bioengineering is a meeting place for many different disciplines. Medical sciences such as physiology and pharmacology; engineering subjects like mechanical and electrical engineering and computer science; and other areas of study, such as molecular biology, materials science, and mathematics, all have a hand in shaping the field. Its influence is just as widespread, apparent in almost any facet of medicine, be it diagnosis (new imaging techniques that allow doctors to see inside the body without resorting to surgery), treatment (surgical lasers, artificial organs), or basic research (technologies like the polymerase chain reaction, or PCR; and molecular modeling of proteins). The Whitaker Foundation is one of the foremost supporters of bioengineering research in the United States, with existing grants to fund young investigators, graduate students, and institutional development (S. Veggeberg, The Scientist, March 30, 1992, page 21). Peter G. Katona, vice president of the foundation's biomedical engineering program, says that these new special opportunity awards were created to ". . . challenge the institutions to produce innovative and effective ways of enhancing the field of biomedical engineering." Two hundred seventy preliminary applications for the award were reviewed in-house, and 125 applicants were invited to submit full proposals. The 14 final winners were selected from a total of 116 applicants by a panel of both industry and academic experts. Urban Consortium One of the larger grants ($750,000) was awarded for a proposal to establish a new Center for Biomedical Engineering in New York. This proposal is the result of a collaboration of three major institutions: City College of New York, which houses the engineering school of the City University of New York; the Hospital for Special Surgery, which is affiliated with Cornell University Medical School; and the Hospital for Joint Diseases, part of the New York University Medical School. The collaboration is the first training program of its kind in the New York metropolitan area. "One reason for establishing the center here in New York is that the city has the highest concentration of health-care delivery systems in the country, but no training program for biomedical engineers," says Sheldon Weinbaum, a professor of mechanical engineering at City Col- lege, and the principal investigator for the center. "The engineering school did not have the resources to start a large undergraduate/graduate program. With the two hospitals--the largest orthopedic facilities in the country--to provide the clinical training, it was a `perfect marriage.'" The three institutions have set up the program to incorporate an interdisciplinary curriculum with seven major themes, including the mechanics, transport, materials interaction, and imaging of cells and tissues; as well as medical instrumentation, physiology, and the socioeconomic impact of biomedical engineering. Each will have courses at both the undergraduate and graduate level. The center will be located at the school of engineering at City College, where all the courses will be taught. Students will get research and clinical experience at the two hospitals. Because of the specialization of the two hospitals in orthopedics, there will be an emphasis on training in musculoskeletal systems, says Weinbaum. "Undergraduate students will get the chance to work with physicians on both research and design proj-ects," says Peter A. Torzilli, a professor at Cornell University Medical College and the director of soft tissue research at the Hospital of Special Surgery. "This collaboration is truly unique--it's the first time public and private institutions are coming together like this." An additional thrust of this consortium will be to recruit a large number of minority students into bioengineering disciplines. "Currently, this country produces one minority graduate a year in the biomedical engineering field," says Weinbaum. "We hope to put out two or three minority graduates a year from our program alone," he says, adding that this target would be a natural outgrowth of the existing minority student body at City College. PCR On A Chip "We want to show that bioengineers can really bring something to the party," says John A. Quinn, a professor of chemical engineering at the University of Pennsylvania in Philadelphia, and the principal investigator of a proposal titled "DNA/Silicon Technology as Molecular Bioengineering." "The scientific goal of this project is to scale DNA analysis down to the nano-level, and be able to conduct procedures like PCR on a single silicon [computer] chip," says Quinn, but he says that the main purpose of the grant is to "bring about a communication between various disciplines." The program will put graduate students from engineering into medical laboratories and clinics, where they can work side by side with researchers and doctors. This close contact while working on a specific problem will give the engineers a feel for the needs of the biological scientists and demonstrate the value of engineers in a clinical setting, Quinn says. The $250,000 award will go toward supporting three full-time graduate students in bioengineering, and will provide key equipment for the project. Eyes On Neuroengineering The University of Pennsylvania is also the home for another, $500,000 special opportunity award, this one for the establishment of a new graduate program in neuroengineering. Sponsored by the department of bioengineering and the Institute of Neurological Sciences, this program will include 15 faculty members whose fields of expertise cover neurology, electrical engineering, and cognitive psychology. The effort is headed by Leif Finkel, an associate professor of bioengineering. "We have already begun to set up a central facility for neuroengineering research," says Finkel. "There will be an educational lab for graduate students with 25 new workstations, as well as rooms to conduct psychophysical and neurological examinations." The laboratory's emphasis is on vision studies. Currently, graduate students are working to simulate the processes that enable the eye to discern the shape of an object from the texture of its surface. "What distinguishes our approach is that we are looking into the biological basis for neural function and using our knowledge of animal systems to design algorithms," says Finkel. "We hope to attract students from different backgrounds," says Finkel. "A key element will be the rotation of students in different labs; for instance, a psychology major will be asked to do a rotation in an electronics lab or in computer graphics, while a computer scientist would be put into a physiology lab ." A major aim is to find clinical applications for this research, though Finkel says this should come further down along the line. "One of the good things about an award like this [the special opportunity award] is that it allows us to build the infrastructure that would eventually lead to this goal," he says. (The Scientist, Vol:8, #4, February 21, 1994) (Copyright, The Scientist, Inc.) ================================ NEXT: NOTEBOOK ------------------------------------------------------------ TI : Science-Policy Heavy Hitters Meet TY : NEWS (NOTEBOOK) PG : 4 More than 280 prominent science-policy leaders from around Washington, D.C., and across the United States turned out for a two-day "Forum on Science in the National Interest"--intended to provide input to assist the Clinton administration in shaping United States policy on basic science, mathematics, and engineering. Curiously, some of the warmest applause at the conference--held January 31 and February 1 at the National Academy of Sciences--went to speaker Sen. Barbara Mikulski (D- Md.), whose appropriations subcommittee has rattled many scientists with legislative reports stipulating that 60 percent of the National Science Foundation's budget be targeted at "strategic" research. Mikulski said her overall message was "a call to arms" for the post-Cold War era. "Now we are in a new war--the war for America's economic future.... Unless we develop a new strategy that fits the realities of the new world order, science and science funding run the risk of being left out and left behind." At the same time, Milkulski made it clear that she has no intention of scrapping all basic research--even if it doesn't qualify as "strategic": "At the heart of what we seek to do is retrieve the value of scientific activity for the post-Cold War world, without abandoning the very best of scientific inquiry or investigation. Science should continue to be the place where we test new theories, break new ground, and do that which delights scientists and mesmerizes the world--the surprise of new discoveries." (The Scientist, Vol:8, #4, February 21, 1994) (Copyright, The Scientist, Inc.) ================================ NEXT: ------------------------------------------------------------ TI : AIDS Task Force Named TY : NEWS (NOTEBOOK) PG : 4 On February 4, Secretary of Health and Human Services (HHS) Donna Shalala named 18 people to the new National Task Force on AIDS Drug Development. With representatives from industry, academia, government, and the AIDS-affected community, the task force is expected to work to remove barriers to the development of effective antivirals for AIDS (F. Hoke, The Scientist, Feb. 7, 1994, page 1). Named to the task force were: Moises Agosto, National Minority AIDS Council; Arthur Ammann, Pediatric AIDS Foundation; Stephen Carter, Bristol-Myers Squibb Co.; Ben Cheng, Project Inform; Deborah Cotton, Harvard Medical School; Mindy Fullilove, New York State Psychiatric Institute; David Ho, Aaron Diamond AIDS Research Center; Daniel Hoth, Cell Genesys Inc.; David Kessler, Food and Drug Administration; Philip Lee, HHS; Theresa McGovern, HIV Law Project; Charles Nelson, Morehouse School of Medicine; G. Kirk Raab, Genentech Inc.; Robert Schooley, University of Colorado; Edward Scolnick, Merck Research Laboratories; Peter Staley, Treatment Action Group; Harold Varmus, National Institutes of Health; and Flossie Wong-Staal, University of California, San Diego. "Drug discovery is a challenge," Wong-Staal told The Scientist, "but translating a discovery to the clinic is an even greater challenge." (The Scientist, Vol:8, #4, February 21, 1994) (Copyright, The Scientist, Inc.) ================================ NEXT: ------------------------------------------------------------ TI : High-Energy Whodunit TY : NEWS (NOTEBOOK) PG : 4 The high-energy career pressures of particle physicists have burst onto prime-time television. The Wednesday, March 2 episode of "Law & Order," NBC's critically acclaimed crime drama, features a letter-bomb murder motivated by scientific plagiarism regarding a theory of proton decay. At one point, the killer, questioned by investigators, passionately explains his view that protons may decay into positrons and neutrinos. As the investigation wraps up, the district attorney observes: "Scientists have a star system that makes Hollywood look like a socialist love-in. Only they don't keep score in money or starlets. It's reputation." Scriptwriter Ed Zuckerman was assisted in his research by Roger Cloutier, an Oak Ridge National Laboratory physicist and past president of the American Health Physics Society. Some scenes were filmed at Columbia University's Nevis Laboratory in Irvington, N.Y. (The Scientist, Vol:8, #4, February 21, 1994) (Copyright, The Scientist, Inc.) ================================ NEXT: ------------------------------------------------------------ TI : AMS Decries `Exploitive' Conditions TY : NEWS (NOTEBOOK) PG : 4 The 30,000-member American Mathematical Society passed a resolution January 11 condemning the systematic hiring of young math Ph.D.'s into part-time, poorly paid academic positions. Many institutions are under severe financial pressures, the council noted, but this should not be used as an excuse for exploitation. For several years, they said, the number of people seeking jobs in math has far exceeded the available positions, with no relief in view: "Young mathematicians in one-year terminal positions with full teaching loads must, in addition to carrying out their duties and trying to establish their own scholarly program, begin again searching for a job almost immediately after settling in--a concentration of pressures which will almost certainly have adverse effects on professional growth and morale." (The Scientist, Vol:8, #4, February 21, 1994) (Copyright, The Scientist, Inc.) ================================ NEXT: ------------------------------------------------------------ TI : Leveling Nature's Engineer TY : NEWS (NOTEBOOK) PG : 4 The South Carolina Agricultural Experiment Station of Clemson University is trying to outsmart beavers with the Clemson Beaver Pond Leveler. The Leveler masks water current flow and the sound of flowing water--the beavers' most important stimuli to construct their dams--to fool them into not damming road culverts and waterfowl impoundments. The device, designed by Gene Wood, a forest ecologist at Clemson, consists of a plastic intake pipe pierced with holes and placed inside a welded-wire cylinder, which is connected to the body of water needing protection via a carrying pipe. The holes create a waterflow too slow to be detected by beavers and the cylinder prevents beavers from testing the holes. So far, Clemson researchers say, the Leveler has been used with great success from South Carolina to Minnesota, decreasing culvert maintenance costs, allowing landowners to live peacefully with beavers, and enhancing beaver ponds for waterfowl by managing water levels. Plans are available from the Clemson Extension Service, (803) 656-3261. (The Scientist, Vol:8, #4, February 21, 1994) (Copyright, The Scientist, Inc.) ================================ NEXT: ------------------------------------------------------------ TI : COMET In The Forecast For Meteorologists TY : NEWS (NOTEBOOK) PG : 4 The University Corporation for Atmospheric Research, a nonprofit consortium that sponsors programs in atmospheric, oceanic, and related sciences, has announced its newest program. The Cooperative Program for Operational Meteorology, Education, and Training (COMET) is a series of activities developed to inform weather forecasters about the science behind their jobs and the latest in weather technology. A residence program--34 weeks of classes--will be held at COMET's headquarters in Boulder, Colo. Additionally, the Distance Learning Program expects to train 8,000 forecasters in the National Weather Service (NWS), United States Air Force, and U.S. Navy using interactive, multimedia computers. In collaboration with NWS, the Outreach Program will pump more than $400,000 into nearly 20 universities for work on understanding local weather phenomena and conduct workshops for university instructors in designing up-to-date meteorology courses. For more information, contact COMET director Timothy Spangler at (303) 497-8473. (The Scientist, Vol:8, #4, February 21, 1994) (Copyright, The Scientist, Inc.) ================================ NEXT: OPINION ------------------------------------------------------------ TI : Honoring Avery, MacLeod, And McCarty: The Team That Transformed Genetics AU : JOSHUA LEDERBERG TY : OPINION PG : 11 ***** Editor's Note: On Feb. 1, 1944, the Journal of Experimental Medicine published a scientific paper entitled "Studies on the chemical nature of the substance inducing transformation of pneumococcal types." Coauthored by Rockefeller Institute (now University) Hospital researchers Oswald Avery, Colin MacLeod, and Maclyn McCarty, the paper--preceding by a decade the Nobel Prize- winning revelations of James Watson and Francis Crick--described the discovery that genes are made of deoxyribonucleic acid, or DNA; prior to their studies, no biological assay was available to link genetic information with DNA. Immunologist and Nobelist Peter Medawar called the Avery team's isolation of genes in pure chemical form "the most interesting and portentous biological experiment of the 20th century." Another Nobelist, Joshua Lederberg--former president of Rockefeller University and now University Professor at that institution--lauds it as "the pivotal discovery of 20th-century biology." Lederberg, who received the 1958 Nobel in physiology or medicine for his contributions in genetics, was a young researcher at nearby Columbia University in New York during the period of momentous achievement at Avery's Rockefeller lab. In the following essay, Lederberg describes that achievement, recounts the controversy it spawned, and assesses its impact on subsequent investigations. A version of this essay appeared in a recent issue of the journal Genetics (136[2]:423-26, 1994) and is used here with permission. ***** The publication 50 years ago this month in the Journal of Experimental Medicine of a research report by three Rockefeller University Hospital investigators--Oswald Avery, Colin MacLeod, and Maclyn Mc-Carty--marked the opening of the contemporary era of genetics, its molecular phase. The reverberations continue, now dominating large sectors of biomedical science and biotechnology, and have established the centrality of genetics in biological thought. The trio's findings can be dissected into the following observations, claims, and tacit extrapolations, which may be paraphrased as: * Certain bacteria (pneumococci) have clonally inherited attributes, notably serospe-cific polysaccharide capsules. These are associated with virulence and can be selected for accordingly, by inoculation into mice or by serological reagents. * The genetic anlage, or determinants, of these attributes can be transferred from clone to clone by cell-free extracts: the phenomenon of transformation. The transformed cells faithfully transmit their new phenotype to succeeding clonal generations. * The chemical structure of that transforming principle is DNA, to the exclusion of protein or other macromolecules. Founded on these claims, the radical ideas emerged that: * Bacteria have discrete, autonomous genes analogous to those of higher life forms--namely, Drosophila. * The gene is DNA; and the transformation phenomenon affords the first bioassay for genes extractable in vitro. * Accordingly, bacteria might be favored subjects for genetic investigation and, eventually, for technological application of molecular genetic science. First Reactions I recite these principles with some nostalgia: They are precisely how they came across to me as an undergraduate already working on neurospora at the Columbia University zoology department in New York City. Elsewhere, I have noted how these principles vectored my own career aspirations into the pioneering of bacterial genetics (J. Lederberg, "Genetic recombination in bacteria: A discovery account," Annual Review of Genetics, 21:23-46, 1987). Studying in the academic archipelago called New York, I was uniquely well situated to observe and sometimes participate in the debate, since Rockefeller was just across town. Alfred Mirsky, a senior biochemist at Rockefeller, was a frequent visitor to my department at Columbia, where he was collaborating with Arthur Pollister. From 1942 on, I heard a good deal about the progress in Avery's laboratory, and reprints of the "Avery et al." article were circulated in the department. I borrowed one from Harriett Taylor (later Ephrussi-Taylor), a graduate student working on yeast budding kinetics, who would shortly join Avery's laboratory for her postdoctoral research. My personal exclamatory notes were "... unlimited in its implications...Direct demonstration of the multiplication of transforming factor...Viruses are gene-type compounds..." While Mirsky was the principal herald, he also was a dogged critic of the claim that DNA, alone, had proved to be the exclusive chemical substance of transforming activity (A.E. Mirsky, A.W. Pollister, "Chromosin, a desoxyribose nucleoprotein complex of the cell nucleus," Journal of General Physiology, 30:117-48, 1946). That was indeed a difficult proposition: Avogadro's number is a formidable protagonist in that contest. It meant that one microgram of a biopolymer might still have more than 10 trillion molecules. Even if 99.99 percent pure, that still allows for the possibility of a million contaminating molecules of other kinds. My stance was sympathetic to Mirsky's: I felt that so crucial a claim should not be impulsively engrafted into the corpus of science. More important than doctrinal conversion was that the issue was squarely on the table and could be settled--one way or another--by overwhelming experimental analysis. History Of Controversy Previous fiascoes had darkened the history of biopolymers: for example, Wendell Stanley's initial assertion in 1935 that crystallized Tobacco Mosaic Virus is a pure protein. Avery himself was an epitome of caution, having had to weather similar skepticism that pneumococcal polysaccharide, devoid of protein, was a type-specific antigen. The main fruit of the debate was to stimulate a range of further inquiries: Erwin Chargaff on the base composition of DNA, for example, and my own on other modes of gene recombination in E. coli. Maclyn McCarty, later joined by Rollin Hotchkiss, added much to the repertoire of enzymatic and analytical refinements for the exclusion of protein from the DNA preparations. Conceptually, DNA in the 1940s was an unlikely candidate for biological specificity. The root problem was the unavailability of any homogeneous sample of DNA appropriate for detailed chemical analysis. This would have to await studies with tiny DNA viruses, and much help from precisely targeting restriction enzymes. DNA was then believed to be a monotonous structure, perhaps even merely a tetranucleotide. The protein enthusiasm evoked by the successful crystallization of enzymes in the 1930s then dominated most biochemists' attention. Antecedents In fact, the idea of DNA's bearing biological specificity was more popular at the beginning of the 20th century: "A tempting hypothesis...is that nuclein, or one of its constituent molecular groups, may in a chemical sense be regarded as the formative centre of the cell which is directly involved in the process by which food-matters are built up into the cell-substance," wrote E.B. Wilson (The Cell in Development and Inheritance, 2d ed., New York, Macmillan Publishing Co., 1906, page 340). By 1925, Wilson was discouraged and misled by the apparent loss of chromatin (basophilia) in the nucleus of the growing oocyte: "These facts afford conclusive proof that the individuality and genetic continuity of chromosomes does not depend upon a persistence of `chromatin' in the older sense (i.e., basichromatin). It is the expression of a morphological organization that is not destroyed by those chemical and physical transformations that lead to a netlike structure and a change from the basophilic to the oxyphilic condition" (E.B. Wilson, The Cell in Development and Heredity, 3d ed., New York, Macmillan Publishing Co., 1925, page 351). Just as these words were being written, Robert Feulgen developed the fuchsin-bisulfite cytochemical reaction that offered the first authentic cytochemical indicator for DNA, and restored confidence in the continuity of the DNA content of the chromosome (G. Clark, F.H. Kasten, History of Staining, Baltimore, Williams & Wilkins, 1983). The biological interpretation of the pneumococcus transformation was also fraught with uncertainty. Theodosius Dobzhansky and, later, Andre Boivin persisted in describing the phenomenon as a "directed mutation," and it was given overtones of "cytoplasmic inheritance" by Tracy Sonneborn; these were all rhetorical devices intended to seal off a vaguely understood phenomenon from the sureties of chromosomal inheritance. Nothing was known of chromosomes or genes in bacteria at that time: A certain leap of faith was required to relate the transformation--and therefore, in turn, DNA--to mendelizing genes, like those of fruitflies and garden peas. For many years, the only marker studied had been the capsular polysaccharide. In that setting, even Harriett Ephrussi- Taylor in 1951, reporting from the Rockefeller Institute, remarked, "... no bridge can be seen leading over into classical genetics" and, in private correspondence, criticized my own efforts to do precisely that. Among early comments from geneticists, that of Hermann Muller's, in 1947, was closest to the mark: "[The] pneumococcus results then becomes that of [a] type of crossing over, though on a more minute scale....[involving] viable bacterial `chromosomes' or parts of chromosomes [penetrating] the capsuleless bacteria and in part at least taken root there....However, unlike what has so far been possible in higher organisms, viable chromosome threads could also be obtained from these lower forms for in vitro observation, chemical analysis, and determination of the genetic effects of treatment" (H.J. Muller, "The gene," Proceedings of the Royal Society of London, B134:1-37). Confirmation In a retrospection over prior hypothetical interpretations of the Avery team's transforming principle, seven alternatives to it could be listed (J. Lederberg, "Genetic transduction," American Scientist, 44:264-80, 1956). * It was a specific mutagen with a special ability to direct a particular gene to mutate in a definite direction. * It was a polysaccharide autocatalyst (perhaps as a complex with DNA) that primed an enzymatic reaction for polysaccharide synthesis. * It was a bacterial virus, which on infecting the bacteria provoked capsular synthesis as a host reaction. * It was an autonomous cytoplasmic gene or a morphogenetic inducer. * It might be acting at a distance without penetrating the bacterium. * It was a fragment of the genetic make-up of the bacterium, the only one to have been tested to that time. * It was a sui generis element for which no general conception should be adduced. Some of these were not logically distinguishable, but were no less strongly held semantic strongholds. The notion that the transformation was indeed a gene transfer by DNA was eventually solidified by new work using markers other than the capsule, and especially by the linkage of mannitol fermentation and streptomycin resistance. The notion also was bolstered by other phenomena of gene transfer, such as conjugal exchange in E. coli and virus-mediated transduction in Salmonella. Finally, the monopoly of the pneumococcus on transformation--and this was a notoriously difficult experimental system--was broken by Hattie Alexander and Grace Leidy's 1951 report on Hemophilus (H.E. Alexander, G. Leidy, "Determination of inherited traits of H. influenza by desoxyribonucleic acid fractions isolated from type-specific cells," Journal of Experimental Medicine, 93:345-59), so that a stream of other workers could provide mutual confirmation and reinforcement about the biological interpretations. Eventually, the debate about DNA chemistry petered out by sheer exhaustion of the critics and the conceptual plausibility of DNA as gene introduced in 1953 by James Watson and Frances Crick's double helix model. Alfred Hershey and Martha Chase's 1952 study of the injection of phage DNA into E. coli lent further support to the "DNA only" view; however this was quantitatively less rigorous than McCarty and Hotchkiss's prior work on the pneumococcus. Even after 1953, Hershey himself was still referring to something more than DNA as a possibility. It might be said that rigorous proof was concluded--by Arthur Kornberg and Har Gobind Khorana--in the 1960s only with the in vitro synthesis of biologically active DNA. Recognition The 1944 Avery paper originally was published in a medical journal of the Rockefeller Institute that was not habitually read by geneticists of that time. This has led some commentators to compare the launching and reception of the research team's claims to the so-called prematurity of Mendel's ideas in the last third of the 19th century. Mendel was little known--and for the most part ignored--by his contemporaries. But I would argue that the critical reception initially given to the Avery et al. paper exemplifies the critical scientific meth-od at its most functional. Far from being ignored, the paper enjoyed almost 300 citations between 1945 and 1954, according to data from the Institute for Scientific Information. Indeed, it became so well known during that decade that it was often cited by indirection--that is, without specific reference. As for charges that the Avery team's findings were "premature," this might mean--as it does in any case in which "prematurity" is attributed--that (a) data did not exist at the time to explain all of the paradoxes and challenges of the new discovery; or that (b) the audience of the time was incapable of understanding the challenge implicitly presented. The touchstone is plainly in the operational reaction. For the Avery team--as it has been for others, such as Barbara McClintock--the operational reaction comprised open controversy and active inquiry. For Mendel, it meant oblivion, and a long delay before rediscovery. Fortunately, such examples are few and far between. In the long run of scientific advance, for a work to be ignored is perhaps only slightly worse than to be swallowed whole. A lot of revisions loom ahead even for our well-established dogmas. Importance Acknowledged That Avery, MacLeod, and Mc-Carty failed to win the Nobel Prize has repeatedly been a subject of critical remark. In 1970, Wendell Stanley openly apologized for not having been more attentive to that lack of recognition, after he had won his own prize in 1946. In 1958, it fell to me to plan my own Nobel lecture, the first in the field of genetics since Muller in 1946. Rather than recite my own work on bacterial recombination, I thought it more important to acknowledge how genetics had been totally transformed by the Avery team's discoveries, and this acknowledgment was indeed embodied in my lecture (J. Lederberg, "A view of genetics," Les Prix Nobel en 1958, Stockholm, Imprimerie Royale P.A. Norstedt & Soner, 1959). Avery had consummated this research at the very end of his career, and died in 1955 before a full round of recognition could be fulfilled. The survivor of that team, Maclyn Mc-Carty, has written a vibrant memoir that is a model for expert and methodical tackling of very difficult technical problems (The Transforming Principle, New York, W.W. Norton & Co. Inc., 1985). It displays the highest ideals of the scientific personality, and leaves no doubt of the importance of his role, together with that of his colleagues, in the pivotal discovery of 20th-century biology. Spanning more than a decade of often-frustrating effort, that discovery is an outstanding example of the feedback of clinically motivated inquiry to the most basic issues of fundamental biomedical science. Genetics, especially as we explore the human genome, will be fraught with many more like opportunities and-- precisely because of their pervasive applications--with commensurate dilemmas. Many institutional arrangements today nurture such transdisciplinary and vertically integrated research, which is often the arena of the most revolutionary advances. In 1944, the Rockefeller Institute was perhaps the only site in the United States where that could have been possible. Joshua Lederberg is University Professor at Rockefeller University, New York. (The Scientist, Vol:8, #4, February 21, 1994) (Copyright, The Scientist, Inc.) ================================ NEXT: COMMENTARY ------------------------------------------------------------ TI : Wearing Two Hats: A Challenge And An Inspiration AU : EUGENE GARFIELD TY : OPINION (COMMENTARY) PG : 12 When The Scientist first appeared in late 1986, it did so under the aegis of the Philadelphia-based Institute for Scientific Information. I founded ISI in 1954, and over the years it has become known and respected as the publisher of Current Contents and the supplier of other products, such as the Science Citation Index. These services provide researchers with timely, comprehensive data on the publishing achievements of their peers and of research institutions worldwide. Meanwhile, The Scientist--in its comparatively brief existence as the science community's only newspaper--also has grown dramatically. As its publisher and editor-in-chief, I have overseen its development to the point at which, in 1994, it is delivering news and career guidance to well over 50,000 readers biweekly. I'm told that, although The Scientist became an independent publication more than five years ago--with no direct business or financial ties to ISI--many in the science community still find it difficult to disassociate the two institutions. This is not surprising, since I continue to wear two hats--as ISI founder and The Scientist's publisher. Let's clarify the matter: In my current role as ISI's chairman emeritus, I consult on the company's activities and represent it at meetings in the United States and abroad. I also will be contributing a new monthly column in Current Contents called "Citation Comments." As for The Scientist, I will continue to direct my energies toward the ongoing development of a publication seeking to address the urgent informational, intellectual, and professional needs of its readership. This past December, the individuality of the two organizations was made clear indeed when The Scientist moved its headquarters from the ISI building--which it had occupied for more than seven years--to a brand-new suite of offices just a block away, in the University City Science Center. For those unaware of the move, The Scientist's new address is 3600 Market St., Suite 450, Philadelphia, Pa. 19104. Our new phone number is (215) 386-9601. While The Scientist and ISI are distinctly separate entities, my predilection toward citation-based analyses of the scientific literature--the heart of ISI's efforts and a significant factor in The Scientist's coverage--will no doubt be evident in the future editorial components of both enterprises. For example, the "Citation Classics" feature in ISI's Current Contents has presented, over the past 15 years, more than 5,000 commentaries by authors of significant research publications. While this feature no longer will be included in Current Contents, we plan shortly to introduce it in The Scientist, augmenting the commentaries already appearing in our popular "Hot Papers" section. In The Scientist, the focus of these entries will be on landmark papers and books published during the past few decades; they will treat particularly those research reports concerning discoveries--such as the polymerase chain reaction-- that have had extraordinary impact on the way modern science is done. We will be adding additional elements to The Scientist's editorial mix this year; I'm sure our readers will be pleased to hear, for instance, that we're planning the resumption of book reviewing on a regular basis. And we already have made significant moves toward making our publication much more available and usable electronically. In a Commentary last year ("Electronic Publishing Extends Reach Of Scientists--And Of The Scientist," The Scientist, Feb. 8, 1993, page 12), I announced the implementation of The Scientist, free of charge, on NSFnet and the Internet. (Instructions for electronic access appear on page 3 of each issue.) Over the past year, tapping into The Scientist electronically has evidently become very popular. The number of accesses is increasing dramatically. (It is impossible, of course, to measure the full extent of this acceptance, since each file transfer protocol executed by a single user makes the information available to an unlimited number of other researchers.) Now, we are expanding access through the Electronic Newsstand, a new commercial service on the Internet, through which individual articles published in The Scientist can be conveniently ordered at a nominal fee. Clearly, The Scientist is making its mark--in both its print and electronic versions. And, clearly, ISI continues to play a major role in shaping the behavior of the research community. Wearing two hats is not always easy. But, for me, the satisfactions are well worth the effort and investment. (The Scientist, Vol:8, #4, February 21, 1994) (Copyright, The Scientist, Inc.) ================================ NEXT: LETTERS ------------------------------------------------------------ TI : Animal Models AU : GABOR KALEY TY : OPINION (LETTERS) PG : 12 In response to a commentary by Frederick K. Goodwin and Adrian R. Morrison ("In Animal Rights Debate, The Only Valid Moderates Are Researchers," The Scientist, Sept. 6, 1993, page 12), Neal D. Barnard states that he has been misinterpreted in regard to his statements about animal experimentation (Letters, The Scientist, Nov. 15, 1993, page 12). No one has been misinterpreting Barnard's stand on animal experimentation, as his position is and has been crystal clear. As president of the egregiously misnamed Physicians Committee for Responsible Medicine, he wants to stop all use of animals in research and education. He does not consider that research performed on animals is useful in promoting human and animal health and mistakenly calls for replacing all animal models with nonanimal models in testing and experimentation. When thalidomide was approved in Europe for human use without extensive testing in animals, the tragic effects of the drug on fetal development became apparent only in human babies. Had the Food and Drug Administration not insisted on stringent and extensive animal testing, the thalidomide tragedy might have reached the same enormous proportions here in the United States as it did in Europe. If Barnard's efforts were to be successful, then testing of all new drugs, novel modalities of treatment, and surgical procedures would have to be performed on human subjects. If he and his supporters persist in their views, then the only moral stand they can choose is to renounce, in a medical emergency, the right to all treatments that are based on testing or research using animals. This, of course, they are not ready or willing to do. Barnard says that "it is time to stop ... this expensive and gruesome activity" of animal experimentation. These are the views of an irresponsible extremist whose inhumane activities must be forcefully denounced at every turn by allwho are dedicated to conquering disease, and human and animal suffering. GABOR KALEY Department of Physiology New York Medical College Basic Sciences Building Valhalla, N.Y. 10595 (The Scientist, Vol:8, #4, February 21, 1994) (Copyright, The Scientist, Inc.) ================================ NEXT: ------------------------------------------------------------ TI : Animal Models AU : BALDUR RAGNARSSON TY : OPINION (LETTERS) PG : 12 On the subject of animal experimentation (D. Hubel, "Animal Rights Movement Threatens Progress Of U.S. Medical Research," The Scientist, Nov. 15, 1993, page 11), it is worth mentioning that researchers at the Keio University of Tokyo have recently developed a silicon model of a rat, designed to save lives of research animals. This model has both artificial intestines and blood vessels and is well suited for use in student laboratory exercises. Although this novel invention cannot replace all laboratory animals, it certainly is an affirmative step in decreasing their number. In my teaching I have found that despite the animal rights propaganda aimed at teachers and their students, most students come to their own conclusions on this subject. It is certainly the feeling of most of my students that animal experiments are justifiable when the object of the research is to save human lives. I have found, however, that most of my students resent animal experiments as practiced by the cosmetics industry. BALDUR RAGNARSSON Sandgerdi School Sandgerdi, Iceland E-mail: baldurr@ismennt.is History Of Science (The Scientist, Vol:8, #4, February 21, 1994) (Copyright, The Scientist, Inc.) ================================ NEXT: ------------------------------------------------------------ TI : History of Science AU : THOMAS H. JUKES TY : OPINION (LETTERS) PG : 12 Franklin Hoke ("History of Science Societies Sprout Up Nationwide, With More Researchers Studying Lessons Of The Past," The Scientist, Nov. 15, 1993, page 1) has a very interesting article on the proliferation of history of science societies. Perhaps it should be added that the American Institute of Nutrition (AIN), alone among societies that are members of the Federation of American Societies for Experimental Biology (FASEB), has a Committee on the History of Nutrition, and also has published a two-volume, 1,162-page compilation of the biographies of 128 Founders of Nutrition Science, retrieved from their publication in the Journal of Nutrition over the past 62 years. The archivist of AIN is William J. Darby, who maintains the large collection of nutritional memorabilia at Vanderbilt University. THOMAS H. JUKES Department of Integrative Biology University of California, Berkeley 6701 San Pablo Ave. Oakland, Calif. 94608 (The Scientist, Vol:8, #4, February 21, 1994) (Copyright, The Scientist, Inc.) ================================ NEXT: ------------------------------------------------------------ TI : (The Scientist, Vol:8, #4, February 21, 1994) (Copyright, The Scientist, Inc.) ================================ NEXT: RESEARCH ------------------------------------------------------------ TI : Poxvirus Research Advances May Stay Stock Destruction AU : MYRNA E. WATANABE TY : RESEARCH PG : 16 On Dec. 31, 1993, the last stores of the smallpox (variola) virus were to be destroyed simultaneously in Russia and the United States, according to an agreement arranged through the World Health Organization (WHO). If the agreement had been effected, it would have been the first intentional destruction of a human disease and its causative organism. The date has passed, however, and the stores remain intact. But researchers throughout the world who have been studying the orthopoxviruses--the array of poxviruses endemic to many animal species--and who have been clamoring for a five- to 10-year reprieve for variola for potential further study do not consider this a complete victory, since the fate of the virus is yet to be finally decided. WHO's Committee on Orthopoxvirus Infections, which originally recommended the destruction of the smallpox virus, now is awaiting the completion of sequencing of the viral genome, being done at the Centers for Disease Control and Prevention (CDC) in Atlanta and NPO "Vector," a company related to the Institute of Molecular Biology in Koltsovo, Novosibirsk, Russia. Once this is completed to the committee's satisfaction, which had not yet occurred at press time, the fate of the virus may--or may not--be sealed. Arguments abound as to whether the virus, a scourge of mankind for centuries, should be destroyed (L.S. Sandakhchiev, The Scientist, Aug. 23, 1993, page 11; Nature, 366:711, 1993 [an editorial]; B.W. Mahy, et al., Science, 262:1223-4, 1993; and W.K. Joklik, et al., Science, 262:1225-6, 1993). Even luminaries such as Nobel laureate David Baltimore (Science, 263:13, 1994), who favors destroying the stores, have added their opinions to the fray--both pro-destruction and anti-destruction. Those supporting destruction say that once sequencing is complete, the virus itself is no longer necessary. They also say that, once destroyed, smallpox ceases to be a potential threat to public health, be it from accidents, military use, or terrorism. On the other side of the question, many researchers on poxviruses say they are not impressed with those arguments and believe that having the virus in its functional form offers much more information for science than the mere record of its genetic code can possibly impart. They further stress that the smallpox virus has evolved along with its host, humans, and its strategies to evade the human immune system are very specific, but are only beginning to become known. "Only a fraction of the mechanisms employed by the poxviruses to counter host defenses have been identified," explains David Pickup of Duke University in Durham, N.C. Research Tightly Controlled Research with the smallpox virus is tightly controlled by WHO and is confined to centers with P4 containment facilities, the highest-security containment for diseases--although some scientists say that work on individual genes of smallpox is not particularly dangerous and could be carried out in less secure facilities. At present, the smallpox virus is used only in sequencing research. But work on other poxviruses runs the gamut from basic research on enzyme and genetic systems (because they are similar to those in animal and plant cells) to studies of pathogen-host interactions to use as vectors for vaccines against diseases unrelated to poxviruses. Persuasive arguments against destroying the virus at this time result from research findings of a number of leading investigators in molecular virology. These scientists consider each poxvirus as a veritable pharmacopoeia of compounds that suppress the immune response. Virologist Chris Upton, an assistant professor in the department of biochemistry and microbiology at the University of Victoria in British Columbia, Canada, has been studying the myxoma virus, a virulent poxvirus endemic to European rabbits. Working with molecular virologist Grant McFadden and others while at the University of Alberta, Edmonton, in Canada, Upton found that this virus has receptors for gamma interferon (IFN-g), one of the molecules that directs the host's immune cells to respond to an invading virus. Upton, McFadden, and colleagues also have been studying protein receptors for tissue necrosis factor (TNF), present in the rabbitpox virus. TNF, like IFN-g, is acytokine. McFadden explains that in the host, cytokines bind to cytokine receptors, resulting in an immune response. The "fake" receptors, produced by the poxvirus, bind the cytokines, preventing the host's immune response from occurring. Pickup, an assistant professor of microbiology, and colleagues at Duke University and at Immunex Corp. in Seattle have been studying some cytokine inhibitor proteins in the cowpox virus-- serine protease inhibitors (serpins). One of these proteins inhibits the enzymatic conversion of interleukin-1b to an active form. In a normal host response to virus, interleukin-1b should result in an inflammatory response with increased numbers of inflammatory cells and increased chemotactic factors that stimulate migration of inflammatory cells to the area. Other serine proteinase inhibitors have been found in poxviruses. McFadden points out that "we don't know which serine proteinase the virus is attacking ... all we know is the virus uses it to inhibit inflammation." McFadden and others envision such proteins as becoming useful pharmaceuticals to modulate immune responses. An `Accessible System' Researchers also are studying poxvirus gene expression. Among these are Bernard Moss of the Laboratory of Viral Diseases at the National Institute of Allergy and Infectious Diseases (NIAID) and his former postdoctoral student, Cynthia Wright of the Armed Forces Institute of Pathology in Washington, D.C. Moss explains that, unlike other DNA viruses that replicate within the nucleus of the host cell and utilize the host's proteins during replication, poxviruses replicate within the cytoplasm, and generate their own proteins for replication in a sort of self- contained system. "They have genes for most of the proteins involved in gene expression," says Moss. Biochemical research on the lowly vaccinia virus, a poxvirus of unknown origin that is so similar to smallpox that it is used as the source of smallpox vaccine, may elucidate methods of gene expression in higher organisms. Wright, who is working with the vaccinia virus, is studying genes for transcription factors. One of these factors is RNA polymerase. Wright points out that her work is not done specifically to study the poxviruses, but rather because the enzyme is similar to the RNA polymerase II found in eukaryotic cells and this is an "accessible system." Because of the similarities between poxvirus gene products and those of cells of higher organisms, molecular virologists are studying many aspects of these viruses. For example, studies such as those conducted by NIAID's Moss and colleagues target poxvirus RNA. Vaccinia has been used as a smallpox vaccine since the time of Edward Jenner, who discovered vaccination, nearly 200 years ago. Unbeknownst to Jenner, the vaccine worked because of genetic similarities between vaccinia and the smallpox virus. Enzo Paoletti, research director of Virogenetics Corp. in Troy, N.Y.; Moss; and others have discovered that genes from other cells can be inserted into vaccinia, which is now a laboratory virus, not endemic to any animal species, resulting in a recombinant vaccinia virus expression vector. The recombinant vaccinia may be used as a live-virus vaccine. Moss's lab at NIAID is not the only one working worked on such vaccines. Recombinant poxvirus vaccines are being developed at CDC, Wistar Institute in Philadelphia, the University of Alabama at Birmingham, Virogenetics, and several research laboratories in China. Joseph Esposito, chief of CDC's poxvirus section and director of CDC's WHO Collaborating Center for Smallpox and Other Poxviruses, says CDC researchers are actively pursuing recombinant vaccines using poxviruses. They currently are working, among other projects, on an oral rabies vaccine for raccoons based on the raccoonpox virus. By inserting the gene for rabies glycoprotein into raccoonpox, they have produced a "quite successful" vaccine, says Esposito. The oral rabies vaccine, currently in trials, that has recently received much publicity was developed by Wistar Institute in conjunction with Transgene SA, a French biotechnology company, and is based on the vaccinia virus. Esposito says the U.S. Department of Agriculture has some reservations about releasing a vaccinia recombinant into the environment. Raccoonpox, on the other hand, according to Esposito, is indigenous in and innocuous to raccoons, and thus poses no safety hazards. Virogenetics is taking a slightly different approach to recombinant poxvirus-based vaccines. Paoletti explains that the company is using two basic vectors: NYBAC, a highly attenuated vaccinia virus derivative, and ALVAC, a canarypox virus. NYBAC20is a vaccinia with a deletion of 18 reading frames, eliminating its virulence. According to Paoletti, this renders the vaccines much safer than those using standard vaccinia virus. Virogenetics is using NYBAC in a rabies vaccine, as a candidate vaccine for HIV, and will be using it in a malaria vaccine. The canarypox virus on which ALVAC is based cannot replicate outside of birds, says Paoletti, making it safe for use in humans and for veterinary use outside of birds. A vaccine based on ALVAC for HIV-AIDS is in human clinical trials and a human rabies vaccine is being developed by Virogenetics. Andrew Ball, a molecular virologist at the University of Alabama, is attempting to make a highly attenuated vaccinia recombinant using an RNA-dependent RNA replication system. Ball points out that part of the reasoning for destroying smallpox is to eliminate vaccination with the vaccinia-based virus. "At the end of [the] vaccination campaign," Ball says, "vaccination was as severe a threat as smallpox." Ball reasons that a safer vaccinia would be one that is highly attenuated but would produce massive amounts of protein. The problem with this, he says, is that, usually, attenuated strains of virus do not replicate as well as unattenuated strains, produce a lower immunogenic stimulus, and offer protection from disease that is "less solid." Ball hopes to be able to make a construct in which the vaccinia is so attenuated that it does not replicate any of its DNA, but only RNA. Although it is unlikely that the smallpox virus will ever be used to produce a vaccine, researchers expect that the virus will yield numerous specific compounds and mechanisms specifically evolved to evade the human immune response. "These viruses are a factory of anti-immune molecules," McFadden says. Because scientists do not yet know what these anti-immune molecules are and how they work and, according to researchers, the genome alone does reveal how the virus functions and reacts within the environment, they feel the smallpox virus stores should be kept around--at least for a few years. Meanwhile, until WHO makes a decision, the debate as to whether to destroy the virus will continue and, as Moss points out, "It may turn out that we leave the virus in the freezer for five more years and no one will want to do more experiments." Ball, who believes that sequencing the virus was a mistake because it makes the DNA code available for possibly nefarious purposes, nonetheless considers this debate a minor blip in scientific history. "Now [that] it's been sequenced, I don't think it matters whether it's been destroyed or not," he says. "The present debate over whether it's being destroyed, over 10 years' time, I think, will look foolish." Myrna E. Watanabe is a biotechnology consultant based in Yonkers, N.Y. (The Scientist, Vol:8, #4, February 21, 1994) (Copyright, The Scientist, Inc.) ================================ NEXT: ------------------------------------------------------------ TI : POXVIRUS MEETING IN APRIL TY : RESEARCH While the debate on destruction of the smallpox virus persists, poxvirus researchers are busily preparing abstracts of their work for the 10th International Poxvirus Meeting, to be held in Banff, Alberta, Canada,. April 30 to May 5 this year. Grant McFadden a molecular virologist at the University of Alberta in Edmonton, is one of the meeting's organizers. "Advances on the interaction between poxviruses and the immune system promise to be very exciting," McFadden says. He says that abstracts are pouring into his office. The topics to be discussed include virus gene expression, viral pathogenesis, recombinant vectors, poxvirus based vaccines, and novel strategies for virus virulence. The meeting is being co-organized by Rico Wittek of University of Lausanne, Switzerland. For information about the meeting, contact McFadden via fax: (403) 492-9556. --M.E.W. SUGGESTED READING: A. Ball, Journal of Virology, 66:2335-45, 1992. M. Barinaga, Science, 258:1730-31, 1992. J.J. Esposito, et al., Vaccines 92: Modern Approaches to New Vaccines Including Prevention of AIDS, eds. F. Brown, et al., Cold Spring Harbor, N.Y., Cold Spring Harbor Laboratory Press, 1992, pages 321-329. F. Fenner, et al., Smallpox and Its Eradication, Geneva, World Health Organization, 1988. L. R. Gooding, Cell, 71:5-7, 1992. R. F. Massung, et al., Nature, 366:748-751, 1993. B. Moss, Science, 252:1662-1667, 1991. B. Moss, et al., Journal of Biological Chemistry, 266:1355-8, 1991. C. A. Ray, et al., Cell, 69:597-604, 1992. C. Upton, et al., Science, 258:1369, 1992. C. F. Wright, A. M. Coroneos, Journal of Virology, 67:7264-70, 1993. (The Scientist, Vol:8, #4, February 21, 1994) (Copyright, The Scientist, Inc.) ================================ NEXT: HOT PAPERS ------------------------------------------------------------ TI : MOLECULAR BIOLOGY TY : RESEARCH (HOT PAPERS) PG : 17 M. Pagano, G. Draetta, P. Jansen-Durr, "Association of cdk2 kinase with the transcription factor E2F during S phase," Science, 255:1144-7, 1992. M. Pagano, R. Pepperkok, F. Verde, W. Ansorge, G. Draetta, "Cyclin A is required at two points in the human cell cycle," EMBO Journal, 11:961-71, 1992. Giulio F. Draetta (Mitotix Inc., Cambridge, Mass.): "The ordered progression of a eukaryotic cell through the cell cycle is absolutely required for maintaining the cellular homeostasis. Cells need to monitor events such as DNA replication, nuclear division, and cytokinesis, and let them occur only after any prior step has been completed. The interaction between individual cells and their surrounding environment also determines whether a cell should continue to divide or differentiate. Critical regulators of cell cycle progression were originally identified in yeast and, afterward, in higher eukaryotes. After the discovery of the human cdc2/cyclin B protein kinase complex and of its activation prior to mitosis, an apparent discrepancy arose in the field, since it was found that while in yeast cdc2 is required for both S phase and mitosis, in mammalian cells cdc2 is activated only prior to mitosis. Studies led by Ed Harlow's laboratory (Massachusetts General Hospital, Charlestown) had identified several cDNAs encoding cdc2-like proteins that were named cdk kinases (cyclin-dependent kinases). "We demonstrated that a kinase complex distinct from cdc2/cyclin B, the cyclin A kinase, is active during a broad cell cycle period, in S phase through its association with cdk2 and in G2 through its association with cdc2. Microinjection of cyclin A antibodies into G1 cells prevented entry into S phase, while injections in G2 prevented entry into mitosis. We proposed, therefore, that the cdc2/cyclin A complex is required for the G2/M transition and the cdk2/cyclin A complex is required for S phase. We indeed demonstrated that cdk2/cyclin A forms an active kinase complex in S phase with the transcription factor E2F, and given that E2F activation is critical for the transcription of S phase-specific genes, this interaction must play a critical role for cell cycle progression. "A more recent work (M. Pagano, et al., Journal of Cell Biology, 121:101-11, 1993) has shown that microinjection of antibodies to cdk2 into G1 cells prevents entry into S phase as well, demonstrating that in mammalian cells, cdk2 kinase complexes--it is now known that cdk2 associates with both cyclin A and cyclin E--are critical regulators of early cell cycle events." (The Scientist, Vol:8, #4, February 21, 1994) (Copyright, The Scientist, Inc.) ================================ NEXT: ------------------------------------------------------------ TI : MOLECULAR BIOLOGY TY : RESEARCH (HOT PAPERS) PG : 17 S. Matsuda, H. Kosako, K. Takenaka, K. Moriyama, H. Sakai, T. Akiyama, Y. Gotoh, E. Nishida, "Xenopus MAP kinase activator: identification and function as a key intermediate in the phosphorylation cascade," The EMBO Journal, 11:973-82, 1992. Eisuke Nishida (Department of Genetics and Molecular Biology, Institute for Virus Research, Kyoto University, Japan): "MAP kinases have been described as serine/threonine kinases that are activated commonly by various growth factors and tumor promoters in mammalian cultured cells. They are now thought to function as key molecules in a variety of signal transduction processes. As MAP kinases are unique in requiring both tyrosine and threonine phosphorylation to become active, it was hypothesized that two kinds of protein kinases, a serine/threonine kinase and a tyrosine kinase, might function as direct upstream activators for MAP kinases. In this paper, however, we revealed that a single 45-kilodalton protein factor from Xenopus-mature oocytes is sufficient for activation of Xenopus MAP kinase in vitro, and that microinjection of this purified 45-kilodalton protein factor (MAP kinase activator) into immature oocytes results in rapid activation of MAP kinase. "Furthermore, this MAP kinase activator was shown to be inactivated by protein phosphatase 2A treatment in vitro. Since then, studies from a number of groups, including ours, have shown that MAP kinase activator is a dual-specificity kinase that catalyzes phosphorylation of both tyrosine and threonine residues of MAP kinase; thus, the activator has been named MAP kinase kinase (MAPKK). Taken together, these findings revealed the existence of a kinase cascade system consisting of MAPKK kinase, MAPKK, and MAP kinase in cells. "Subsequent protein microse-quencing and cDNA cloning studies based on purification of MAPKK suggested that the MAP kinase cascade mentioned previously may be conserved in a variety of signal transduction pathways from yeasts to vertebrates, and genetic and biochemical work on Drosophila and yeasts supported this suggestion. Furthermore, a recent important finding that protooncogene products, Ras and Raf-1, lie upstream of the MAPKK/MAP kinase cascade evoked a large number of studies clarifying one major intracellular signaling pathway. "Major questions that remain are: What are the roles of the MAPKK/MAP kinase cascade in various signal transmission pathways? What are targets of MAP kinases? How is the MAP kinase cascade regulated?" (The Scientist, Vol:8, #4, February 21, 1994) (Copyright, The Scientist, Inc.) ================================ NEXT: ------------------------------------------------------------ TI : COMPUTER SCIENCE/LIFE SCIENCES TY : RESEARCH (HOT PAPERS) PG : 17 D.G. Higgins, A.J. Bleasby, R. Fuchs, "CLUSTAL V: improved software for multiple sequence alignment," Computer Applications in the Biosciences, 8:189-191, 1992. Des Higgins (European Molecular Biology Laboratory, Heidelberg, Germany): "CLUSTAL V is derived from an earlier set of programs (Clustal 1,2,3, and 4) that I wrote in Paul Sharp's laboratory in Dublin. This package was designed to allow molecular biologists to take a set of unaligned, homologous nucleotide or protein sequences and produce an accurate multiple alignment, automatically and quickly. When one considers that this is such a common, time-consuming task, there were surprisingly few practical methods for doing this until the late 1980s. A simple extension of the usual `dynamic programming' methods, widely used for two-sequence alignment, quickly becomes uncomputable for even a small number of sequences. "The breakthrough came from using the fact that homologous sequences are related to each other phylogenetically; one can use the underlying treelike relationship between the sequences to align the sequences progressively (D.-F. Feng, R.F. Doolittle, Journal of Molecular Evolution, 25:351-60, 1987). This was not an entirely new idea, but Feng and Doolittle showed how to do it quickly and accurately. What I tried to do with the original Clustal programs was to take the progressive alignment strategy and make it efficient enough to work quickly, even for large datasets, on small computers (at that time, 8086-based, IBM- compatible microcomputers). Having developed the package on microcomputers, it was then a trivial step to move it to larger machines, such as workstations and mainframes. "More recently, with my colleagues Rainer Fuchs (Heidelberg) and Alan Bleasby (Daresbury Laboratory, Warrington, England), I completely rewrote the package in C and added in a number of new features. I converted the old package into a single, menu-driven program called CLUSTAL V (V for 5; the old programs were numbered 1 to 4), which is largely self-explanatory. The main new features include the ability to calculate phylogenetic trees after alignment (with a bootstrap option) and a facility for aligning old alignments with each other. With this program, it is possible, in simple cases, to completely automate the generation of phylogenetic trees from unaligned sequences." (The Scientist, Vol:8, #4, February 21, 1994) (Copyright, The Scientist, Inc.) ================================ NEXT: TOOLS & TECHNOLOGY ------------------------------------------------------------ TI : New Confocal Systems Allow Real-Time Views Of Cells AU : FRANKLIN HOKE TY : TOOLS & TECHNOLOGY PG : 18 In just the past few years, technical advances have made possible laser-scanning confocal microscopes able to produce kinetic images of living cells. Depending on the system, neuroscientists and other researchers now can capture images at up to video rates--30 frames per second--or, sometimes, faster. Additionally, they can record those images digitally, or with a video recorder, or with a 35 mm camera. They can view cell events on a monitor or directly through the oculars of the microscope. When laser-scanning confocal microscopes first began appearing in laboratories in the mid-1980s, many cell biologists found themselves somewhat teased by the powers of the instruments. Capable of extraordinarily sharp images of living cells and their internal structures, these instruments were also too slow in building a digital image, at one or two images per second, to show many dynamic events--potentially, the very reason for looking at living cells. Now, with the faster systems, new kinds of whole-cell investigations have become possible, including, for example, detailed studies of the roles played by calcium and other ions in cell signaling. Calcium-release waves of extremely short duration passing across a cell can now be tracked with these confocal instruments. "We get patterns of calcium liberation which change rapidly, on a time scale of a few tens of milliseconds," says Ian Parker, a professor of psychobiology at the University of California, Irvine. Parker's laboratory is working with oocytes, or immature egg cells, of an African toad, studying second-messenger pathways with a personal computer-controlled system called ODYSSEY from Noran Instruments Inc. of Middleton, Wis. A workstation-based version of the system, called ODYSSEY INTERVISION, is also available. "One of the things we discovered is a phenomenon we've called calcium puffs, which are just brief flashes of calcium, little spots of calcium that suddenly pop up," Parker says. "They last 100 milliseconds or so. With a regular confocal microscope, it would be a matter of chance if you ever saw one of these things at all. And you certainly couldn't follow its course in the way that we can." A Growing Family Besides Parker's Noran system and its more powerful relative, other laser-based confocal instrument systems capable of fast image acquisitions are the ViewScan DVC-250 from Bio-Rad Laboratories of Hercules, Calif.; the INSIGHT PLUS from Meridian Instruments Inc. of Okemos, Mich.; and the RCM 8000 from Nikon Corp. of Melville, N.Y. They range in price from just under $100,000 to more than $200,000, depending on system and accessory choices. The strength of an ordinary confocal microscope, retained by the new, faster systems, is its ability to reject out-of-focus light, or flare, from areas within a cell that are outside the plane of focus. To do this, a point of laser light under computer control is scanned across a specimen, usually fluorescently labeled, at a set depth. The entire plane of focus is illuminated by this beam, but sequentially--point by point--rather than simultaneously, as would be the case with a traditional light microscope. Light returning from the specimen then passes through a pinhole aperture called a spatial filter. It is the spatial filter that defines the confocal microscope; the filter has the effect of screening out light from all but the focal point. The remaining sharply focused light strikes a photomultiplier tube, and, with computer assistance, is used to construct an image, called an optical slice. A large amount of the illuminating light is lost at the pinhole aperture in the confocal process, which is one reason laser light sources have proved so important. Because of the initial intensity of lasers, the in-focus light reaching the photomultiplier tube retains enough brightness to create full images. The confocal microscope can create these images even when the specimen is relatively thick or translucent, and optical slices from different depths can be used to build striking three- dimensional images of a cell. Coupled with the faster image- capture rates now possible, confocal images are opening up many new lines of cell dynamics investigations. "There's a whole world of physiology applications, where people are interested in knowing, `What does this ion do in a living system?'" says Shannon Hall, a Bio-Rad technical specialist. "That ion is most commonly something like calcium or hydrogen. We've known for some time that these types of ions are mediators in physiological interactions, but we really didn't know what was happening. If we can trace them very exactly, then we can have a very good idea what's going on. And that's where confocal comes in." Tactics And Tradeoffs Whether capable of "real-time," video-rate, or even faster imaging, laser-scanning confocal microscopes in this group fall into two categories: point scanners and slit scanners. Each of the two approaches to creating kinetic images has its strengths and weaknesses. For the most part, tradeoffs between resolution and speed are necessary, and the individual researcher's needs will dictate which system is appropriate. The point scanners are, in essence, traditional laser-scanning confocal microscopes with features that allow faster imaging than was previously possible. These include technological improvements in the scanning process as well as computer hardware and software advances in instrument control and data handling. The Nikon and Noran instruments fall into this category. The slit scanners do not use a point of light to scan the specimen, but instead scan with a thin line of light and use a narrow slit opening for detection. This tactic allows the entire field of view to be scanned in a single pass, with correspondingly faster image acquisitions. Additionally, the slit scanners offer the ability to directly view confocal images of the specimen through the eyepiece of the microscope, without the need to display the images on a monitor. The Bio-Rad and Meridian instruments are included in this group. Some loss in image quality does result from using the slit opening as opposed to the pinhole aperture. The Z-axis resolution--the focal depth--is somewhat diminished along the length of the slit. The advantages of slit scanning systems, however, are considerable. The direct-viewing capability makes them easier to use than other confocal systems, more like a familiar light microscope, and the images are in true color--even if that color is fluorescent red and green. Because of their speed, they are often used to quickly screen specimens in large numbers, sometimes for later, more detailed work on a traditional confocal microscope. "It doesn't sound very sexy to say we're looking at more slides than we did with the point scanner," says Brian Matsumoto, director of the integrated microscopy facility of the Neuroscience Research Institute at the University of California, Santa Barbara. "But in terms of experimental analysis, being able to look at a larger sample size may be more critical than the higher resolution," he says. "It may be more significant, because now you can start doing statistical analyses of the cells." Using the Meridian INSIGHT PLUS, institute researchers are performing an array of histopathology studies of cell response to drugs and physical trauma. They sometimes then move to a standard Bio-Rad confocal microscope for follow-up studies, according to Matsumoto. Point scanners, while generally capable of better resolution than slit scanners, must also take the time to make multiple passes across a specimen in order to create an image. To create separate images at video rate--30 frames per second--requires impressive speed, precision, and data handling. Noran's ODYSSEY INTERVISION system and Nikon's RCM 8000 system are both capable of these rates. The Noran system allows the researcher to control the tradeoffs between several critical factors. For example, the image resolution in pixels can be altered against time, so that, at the lowest resolution, 240 images per second are achievable. The Nikon system, developed by Roger Tsien, a professor of pharmacology and chem- istry at the University of California, San Diego, features software designed to counter a type of distortion to which point scanners are subject. "Most systems sweep one way [across a specimen] and then come back to the beginning, or they sweep side to side," explains Ilene Semiatin, a Nikon spokeswoman. "As they go from one side to the other, the mechanics of it are such that the system slows as it gets to the end of a sweep, speeds up in the middle, and then slows again as it gets to the end. Since the images are being created digitally, the fact that there is not a steady speed creates minor distortions." Over the course of the many passes that go into a point-scanned confocal image, the cumulative distortion can be substantial, Semiatin says, and Tsien's software controls the instrument hardware so as to compensate for this effect. Some of these new, faster confocal systems--those with powerful workstations controlling the instruments--are capable of capturing, manipulating, displaying, and storing separate images at video rates. Other systems used professional-quality video systems to capture analog versions of the kinetic cell images. Either way, the separate images are then available for later image analysis. The systems able to capture digital data directly from the microscope retain the most information for later analysis. Video recorder-based systems suffer some information loss, because they must go from a digital source to an analog record and then back again, although researchers say the degradation is not significant for many experimental purposes. (The Scientist, Vol:8, #4, February 21, 1994) (Copyright, The Scientist, Inc.) ================================ NEXT: ------------------------------------------------------------ TI : SUPPLIERS OF MICROSCOPY AND IMAGING PRODUCTS TY : TOOLS & TECHNOLOGY PG : 20 The following vendors offer instruments and/or accessories for use in research microscopy and imaging applications. Please call the companies directly for more information concerning their products. Advanced Imaging Concepts Inc. 301 N. Harrison St. Princeton, N.J. 08540 (609) 921-3629 Fax: (908) 274-1974 Alpha Innotech Corp. 14743 Cataline St. San Leandro, Calif. 94577 (800) 795-5556 Fax: (510) 483-3227 Amarel Precision Instruments 78 Schuyler Baldwin Dr. Fairport, N.Y. 14450-9196 (716) 223-2372 Fax: (716) 223-3413 Amray Inc. 160 Middlesex Turnpike Bedford, Mass. 01730 (617) 275-1400 Fax: (617) 275-0740 Biological Detection Systems Inc. 15200 Omega Dr. Suite 105 Rockville, Md. 20850 (301) 990-0100 Fax: (301) 990-8391 Bio-Rad Laboratories Life Science Group 2000 Alfred Nobel Dr. Hercules, Calif. 94547 (510) 741-1000 Fax: (510) 741-1055 Boeckeler Instruments Inc. 3280 E. Hemisphere Loop Building #114 Tucson, Ariz. 85706-5024 (800) 552-2262 Fax: (602) 573-7100 Cell Robotics Inc. 2715 Broadbent Pkwy., N.E. Albuquerque, N.Mex. 87107 (505) 848-0590 Fax: (505) 344-8112 Chui Technical Corp. 252 Indian Head Rd. Kings Park, N.Y. 11754 (516) 544-0606 Fax: (516) 544-0809 Compix 230 Executive Dr. Mars, Pa. 16046 (412) 772-5277 Fax: (412) 772-5278 Coreco Inc. 6969 Trans-Canada Highway Suite 113 St. Laurent, Quebec H4T 1V8 Canada (514) 333-1301 Fax: (514) 333-1388 Dage-MTI Inc. 701 N. Roeske Ave. Michigan City, Ind. 46360 (219) 872-5514 Fax: (219) 872-5559 Dalsa, Inc. 605 McMurray Road Waterloo, ON, Canada N2V 2E9 (519) 886-6000 Fax: (519) 886-8023 Data Translation Inc. 100 Locke Dr. Marlboro, Mass. 01752-1192 (508) 481-3700 Fax: (508) 481-8620 Digital InstrumentsInc. 520 E. Montecito St. Santa Barbara, Calif. 93103 (805) 899-3380 Fax: (805) 899-3392 Ektron Applied Imaging 23 Crosby Dr. Bedford, Mass. 01730 (617) 275-0475 Fax: (617) 271-1977 Fine Science Tools Inc. 373 G Vintage Park Dr. Foster City, Calif. 94404 (800) 521-2109 Fax: (415) 349-3729 Focus Graphics Inc. 1163 Triton Dr. Foster City, Calif. 94404 (800) 288-6226 Fax: (415) 377-0598 Hamamatsu Photonic Systems Div. of Hamamatsu Corp. 360 Foothill Rd. P.O. Box 6910 Bridgewater, N.J. 08807 (908) 231-1116 Fax: (908) 231-0852 Imaging Technology Inc. 55 Middlesex Turnpike Bedford, Mass. 01730-1421 (617) 275-2700 Fax: (617) 275-9590 Infinity Photo-Optical Co. 706 Mohawk Dr. Suite 15 Boulder, Colo. 80303 (303) 499-6282 Fax: (303) 499-2454 Inovision Corp. 2810 Meridian Pkwy. Suite 148 Durham, N.C. 27713 (919) 361-4609 Fax: (919) 361-5876 Leco 3000 Lakeview Ave. St. Joseph, Mich. 49085 (616) 983-5531 Fax: (616) 983-3850 Leica Inc. 111 Deerlake Rd. Deerfield, Ill. 60015 (708) 405-0123 Fax: (708) 405-0147 Meridian Instruments Inc. 2310 Science Pkwy. Okemos, Mich. 48864 (517) 349-7200 Fax: (517) 349-5967 Nikon Inc. 1300 Walt Whitman Rd. Melville, N.Y. 11747-3064 (516) 547-8568 Fax: (516) 547-0306 Noran Instruments Inc. 2551 W. Beltline Highway Middleton, Wis. 53562 (608) 831-6511 Fax: (608) 836-7224 Olympus Corp. 4 Nevada Dr. Lake Success, N.Y. 11042-1179 (516) 488-3880 Fax: (516) 328-9503 Optronics Engineering 175 Cremona Dr. Goleta, Calif. 93117 (805) 968-3568 Fax: (805) 968-2046 Perceptics Corp. 725 Pellissippi Parkway Knoxville, Tenn. 37932-3350 (615) 966-9200 Photometrics 3440 E. Britannia Dr., #100 Tucson, Ariz. 85706-5006 (602) 889-9933 Fax: (602) 573-1944 Polaroid Corp. Scientific Market 575 Technology Square, 2M Cambridge, Mass. 02139 (617) 577-3619 Fax: (617) 577-2410 RML Associates Inc. 8751 E. Hampden Suite BIO Denver, Colo. 80231 (303) 751-0700 Fax: (303) 755-2735 Scanalytics/CSPI 40 Linnell Circle Billerica, Mass. 01821 (508) 663-7598 Fax: (508) 663-0150 Spectra-Tech Inc. 652 Glenbrook Rd. Stamford, Conn. 06906 (800) 243-9186 Fax: (203) 357-0609 Storage Concepts Inc. 2652 McGaw Ave. Irvine, Calif. 92714 (714) 852-8511 Tardis Systems Inc. 901 18th Street Suite 301 Los Alamos, N. Mex. 87544 (505) 662-9401 Fax: (505) 662-6780 TopoMetrix 5403 Betsy Ross Dr. Santa Clara, Calif. 95054 (408) 982-9700 Fax: (408) 982-9751 Upstate Technical Equipment Co. Inc. P.O. Box 14450 Fairport, N.Y. 14450 (716) 377-6455 Fax: (716) 377-6455 WYKO Corp. 2650 E. Elvira Rd. Tucson, Ariz. 85706 (602) 741-1044 Fax: (602) 294-1799 Xillix Technologies Corp. 2339 Columbia St. #200 Vancouver, BC, Canada V5Y 3Y3 (315) 652-1385 Xibion Electronic Systems 8380 Miralani Dr. San Diego, Calif. 92126 (619) 566-7850 Fax: (619) 566-2032 Carl Zeiss Inc. One Zeiss Dr. Thornwood, N.Y. 10594 (914) 681-7645 Fax: (914) 681-7445 (The Scientist, Vol:8, #4, February 21, 1994) (Copyright, The Scientist, Inc.) ================================

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