September 6, 1993 THE SCIENTIST VOLUME 7, No:17 September 6, 1993 (Copyright, The Scientis

Go to Human Rights activist Keith Henson

Skeptic Tank!

September 6, 1993 THE SCIENTIST VOLUME 7, No:17 September 6, 1993 (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 *** *** SEPTEMBER 20, 1993 *** *** *** ******************************************************* 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 REALIZING ACADEMIC RESEARCH: Technology transfer between academia and industry is expanding rapidly, partly because the two sectors can help each other more now than ever before. Concerns in Congress and elsewhere that academic culture will be undermined by the increased commercial presence on campus are exaggerated, according to researchers and technology transfer officers. (First part of a two-part series) Page : 1 SCIENCE AFTER THE FLOOD: The floods that ravaged the Midwest this summer spared the major research institutions in the affected states. But for some scientists--especially environmental and agricultural researchers--whose field laboratories and areas of study were located in the path of the raging waters, the effects on work in progress were devastating Page 1 NEW SEMESTER, SAME SAD STORY: On college campuses around the United States, the school year is beginning with little relief for researchers from continued cuts in government funding, punctuated by an increasing need to comply with health-and- safety, cost-accounting, and other federal regulations that further consume time and resources. The situation has caused some scientists to leave academia altogether, but those who remain say they will muddle through Page 1 MANIFESTO FOR EQUAL RIGHTS: A coalition of women astronomers is making headway in its efforts to promote equal rights for women in astronomy and all scientific disciplines through the endorsement by scientists, scientific societies, and government agencies of a document calling for increased recognition of the contributions and needs of women astronomers and reform of the hiring and promotion practices in the institutions where they work Page 3 A CALL FOR REFORM: Penn State physicist Rustum Roy expresses his belief that news of scientific advances should reach a wide audience swiftly, that current science publishing practices retard or prevent the broad dissemination of research reports, and that a number of reforms--especially in the traditional peer- review process--are in order to correct the situation Page 11 COMMENTARY: There is no "middle ground" in the debate between scientists and animal rights defenders absent the acceptance of the necessity for the use of animals in research, say National Institute of Mental Health director Frederick K. Goodwin and University of Pennsylvania anatomy professor Adrian Morrison Page 12 GIANT DISCOVERIES: The identification of a microbe the size of a printed hyphen caused quite a sensation in the popular and even the scientific press. But its real value, according to the head of the lab in which it was identified, is in the new techniques used to pinpoint it, methods that should lead to identifying many other microbes Page 14 HOT PAPERS: A biochemist discusses his paper describing a potential inhibitor to the activity of proteins specified by HIV Page 16 MAb WORLD EXPANDING: While they have not yet turned out to be the disease-fighting "magic bullets" researchers predicted they would be, monoclonal antibodies are being used for a burgeoning number of research and diagnostic applications Page 17 A CURIOUS LOT: The winners of the prestigious MacArthur Fellowships are never told specifically why they have been chosen to receive the honor. This seems appropriate in that the personalities and accomplishments of the winners themselves often defy easy categorization and, in the case of the 13 researchers chosen this year, reflect careers that have run counter to the scientific mainstream Page 19 JAMES PANKOW, a professor of environmental chemistry at the Oregon Graduate Institute of Science and Engineering, has received the John Wesley Powell Award from the U.S. Geological Survey Page 21 NOTEBOOK Page 4 CARTOON Page 4 LETTERS Page 12 CROSSWORD Page 13 OBITUARIES Page 21 SCIENTIFIC SOFTWARE DIRECTORY Page 30 (The Scientist, Vol:7, #17, September 6, 1993) (Copyright, The Scientist, Inc.) ================================ NEXT: September 6, 1993 TI : Technology Transfer Boom Offers Scientists Rewards--And Challenges As industry-academia deals proliferate, scientists on campus must also negotiate conflicts that arise AU : FRANKLIN HOKE TY : NEWS PG : 1 *** Editor's Note: In this first part of a two-part series, academic researchers and university officials involved in technology transfer discuss its beneficial effects on academic science and society. In the second part, to appear in the Sept. 20, 1993, issue, scientists and others express concern that increasing emphasis on corporate-supported research may significantly undermine aspects of basic science on campus. *** A boom in technology transfer activity is under way on the ill- charted ground upon which academic and industry science interests overlap. Becoming dramatically visible in the 1980s--on the heels of pivotal new intellectual property law--and continuing into this decade, the increased cooperation is bringing important changes to both sectors, say researchers and technology transfer officers. This growth in the conversion of basic research findings into marketable products or services is bringing welcome new resources into academic labs and allowing researchers to see their ideas carried through to realization, observers say. And the infusion of basic research ideas into company labs is surely stimulating the development of new products. Muting, somewhat, this growing enthusiasm for academic-corporate collaborations are traditional concerns of academicians that an increased commercial presence on campus may undermine important elements in their culture--support for unfettered, curiosity- driven work, for example. More crucial to many are the questions that arise concerning conflict of interest: When a scientist's work is simultaneously supported by a university and a private corporation, where do his or her interests properly lie? And if there are choices to be made in terms of investing time and intellectual energy, which funder comes first? Faculty and administrators involved in technology transfer say they have worked to confront these difficult issues directly and that such worries are exaggerated. "An increased presence of any kind of major [social] institution on campuses carries with it advantages and risks," says David Kipnis, Distinguished University Professor of Medicine at Washington University, St. Louis. Kipnis, a diabetes researcher, also chairs the committee overseeing the joint biomedical research program between the university and the Monsanto Co., also located in St. Louis. "For example," he says, "you could just as well substitute government for industry. Too much government on campuses has created problems, where major [agencies] attempt to overdirect and micromanage research. The same thing could be true if industrial intrusion becomes excessive. Academic institutions have to always be on the lookout. We should relate with all, but make certain that our primary roles in society are not unduly influenced or subverted by these relationships." Advocates for increased corporate involvement in basic science say that funding constraints in the federal government--in particular at the National Institutes of Health--necessitate such new approaches to supporting science. And they see no threat in well-managed relationships between academic labs and companies. "As the NIH budget continues to effectively shrink, there are going to have to be alternative ways to support research, and we're going to have to find mechanisms to achieve that," says Anthony Cerami, president of the Picower Institute for Medical Research, Manhasset, N.Y. "And, in my mind, the most creative research can be done in academic institutions or research institutes, away from industry, because they don't have the quarter-to-quarter pressures that a company would have, and so they can really do things that are imaginative." Before launching the Picower in late 1991, Cerami headed a lab at Rockefeller University in New York where an antibody potentially able to block the damaging actions of a cytokine called tumor necrosis factor, or TNF, was discovered (F. Hoke, The Scientist, Feb. 22, 1993, page 1). Patents based on the findings were initially licensed to Chiron Corp., Emeryville, Calif., for development and then to the United States subsidiary of Bayer AG, Leverkusen-Bayerwerk, Germany. Cerami has collaborated with company scientists throughout the preclinical process, and a therapeutic product is now in late-stage clinical studies. "I don't really view getting support from a company any differently than getting support from [funders like] the NIH," says Cerami. "They have their objectives, and companies have theirs." Many scientists also say a prime motive for working with companies is the strong personal satisfaction they derive from seeing useful applications developed that are based on their research ideas. They recognize, too, the necessity of contributing to that process to ensure its success. "You can have a great idea, but if it doesn't end up helping people, then it's not so rewarding," says Helen M. Blau, a professor of molecular pharmacology at Stanford University's School of Medicine. "The technology transfer process helps you have that chance. For example, I'm not going to be able to, in my lab, grow cells under the quality control and in the quantities necessary for a clinical trial. So, if there weren't companies to pick up the technology and move it to the next step, it might not get there." Blau's research at Stanford found that myoblasts (muscle cells) could be useful in gene therapy to deliver recombinant proteins in the treatment of muscle disorders and other maladies like growth hormone deficiency. She is working with the biotechnology company Cell Genesys, Foster City, Calif., to develop specific applications of these findings. "It's truly exciting to be part of this process," Blau says. "And if I'm not consulted and a part of it, then it's less likely to happen." But despite increasing interactions, academic researchers are by no means unanimous in embracing industry support, which can be accompanied by over-specific direction and, often, little scientific return. "I have been reluctant over the years to take on projects that I call `hybridomas for hire,' " says Alexander Karu, a professor of biochemistry at the University of California, Berkeley. "One of my concerns has been the heavy unidirectionality of the information flow [in relationships with industry]. People who've approached me want to know a great deal about our plans and what we're doing, but we get very little feedback in terms of basic science. And my mission here is basic science." Despite these misgivings, Karu is currently developing a series of antibodies with a major chemical company, in what he characterizes as a true two-way collaboration. The company's synthetic organic chemistry expertise has complemented his own lab's capabilities very well, he says. Finding Homes For Technology University technology officers cite changes during the 1980s in the laws governing intellectual property to explain the continuing expansion of technology transfer activities. Probably the most important of these is the 1980 Bayh-Dole Act, or Public Law 96-517, which allowed universities for the first time to patent inventions based on federally funded work at their institutions. By the end of the decade, hundreds of institutions had opened patents and licensing offices to facilitate the transfer of their researchers' findings to companies where useful applications might be developed--and royalties generated. Growth in the numbers of new technology transfer offices continues to be strong. Among the institutions leading the way and providing important guidelines for others have been Stanford, the Massachusetts Institute of Technology, and Harvard University. The increased royalty income derived from licensing is an important new source of university research support, university technology officers say. But they also insist that placing research findings where they can best be developed into beneficial products is perhaps an even more important goal of the process. "This is kind of like finding homes for a lot of different technologies," says Katharine Ku, director of Stanford's Office of Technology Licensing. "The family that wants a child is the one that, at least theoretically, might be the best family. So, when we try to find a licensee, a company that's interested in devoting the resources [to development], the best licensee is the one that cares the most. Our biggest fear is that the licensee takes the license and just sits on it." Clear patent ownership by the universities has been crucial in generating company interest in investing in academic research, too, according to technology transfer officers and researchers. "Before that time, it was very difficult for a company to be assured that it could get an exclusive license to a patent that came out of research it sponsored on campus," says Duke Leahey, director of industrial contracts and licensing at Washington University. Leahey is also president of the Association of University Technology Managers. "You're not going to invest eight to 10 years and millions of dollars taking a product from its bench-type invention through definition of the product, clinical trials, and FDA [Food and Drug Administration] approval, to then hope the consumer buys it, unless you have some sort of proprietary position," says William Hoskins, director of the Office of Technology Licensing at UC- Berkeley. "The patent provides that, and an exclusive license to that patent goes even further." "Companies are really the only group with the financial and personnel resources to develop diagnostics and therapeutics," says Cerami. "And without patent protection, it makes it almost impossible for a company to be able to justify spending the very large amounts of money it takes to develop an idea into a viable product." Researchers also say that, besides managing university intellectual property, campus technology offices provide another vital service. In today's complex legal atmosphere, investigators who use a given firm's reagents, for example, may find that company later laying excessive claim to their research results. University technology offices have the expertise to help scientists steer clear of such ensnarement, while still being able to take advantage of important tools and collaborations. "We have been working in the area of recombinant antibodies," says Karu, "and we wanted to license some of the vectors from the Scripps Research Institute [in La Jolla, Calif.]." Berkeley's technology officer, Karu says, "was very instrumental in negotiating rational arrangements by which we could use those vectors. So, [the technology office] helps in this way, when I have a question about using somebody else's reagents or materials without becoming a de facto employee or having any claim placed upon my work by the donor." "Sometimes, when companies give you reagents, they want you to sign all kinds of forms," says Stanford's Blau. "Every time I get a reagent from someone, I run the forms through the technology office here, to make sure that whatever I'm signing does not in any way interfere with my function as a professor, that I can speak and publish freely. So, the office here helps protect us." Peer-Reviewing Conflict The potential for conflicts of interest that concerns people inside and outside academia go beyond the worry that a researcher may redirect his or her research to attract more funding or to benefit a company in which the researcher may have a financial interest. They also extend to conflicts of commitment--basically, failing to reserve enough time to properly discharge university duties, such as teaching--and to exploitation of graduate students. Because the whole arena of technology transfer is complicated and relatively unexplored, say technology officers and researchers, guidelines for conduct are only just emerging on many campuses. "Universities have developed their policies in response to situations that they've been presented with," says Jim Severson, assistant director of the Office of Patents and Licensing of the University of Minnesota, Minneapolis. "Ten years ago, we couldn't have envisioned the different kinds of involvements possible." Among the most flexible and effective tools that the universities have for dealing with conflicts, they say, are disclosure and peer review. These tactics have the added advantage of tending to involve the wider community in considering these difficult issues. In most cases, researchers make disclosures to their departmental chairperson for review. On a number of campuses, faculty committees are asked to monitor individual relationships. When disputes do arise, enforcement authority often resides in a dean or other administration official. "We feel the essential first step is to have total and complete disclosure," says Stephen Sammut, managing director of the Center for Technology Transfer at the University of Pennsylvania in Philadelphia. "And then we review the cases and try to manage the conflicts of interest." The need to develop mechanisms to confront potential conflicts is seen as a high priority where technology transfer is active. "Given the complexity of commerce and academe these days," Sammut says, "if we simply put on blindfolds and made believe conflicts of interest are not going to happen, we would, number one, be fooling ourselves and, secondly, not really serving the public interest." "You shouldn't be left to your own devices when money is involved," says Washington University's Leahey. "So, you should have a conflict of interest policy and a committee that reviews things for people to remind them when they're getting a little far afield." Leahey says, too, that while the NIH and the National Science Foundation are both struggling to develop conflict of interest policies for their grantees (NIH must publish its effort by early December this year, by congressional mandate), enforcement of those policies should remain the responsibility of the individual institution. At Washington University, officials have gone further and organized an external review committee to periodically assess the university's relationship with the Monsanto Co. According to David Kipnis, all reviewers are members of the National Academy of Sciences; molecular geneticist Daniel Nathans, a 1978 Nobel Prize winner in physiology or medicine and a former Washington University graduate now at the Johns Hopkins University School of Medicine in Baltimore, is chairman of the committee. According to Kipnis, one of the most important concerns for their review committee is the potential misuse of graduate students. "[Review committee members] meet with graduate students, with post-doctoral fellows," he says, "to make sure that the arrangement has not distorted their research." Christina Jansen, a licensing officer at MIT, says students are also carefully protected at her institution. "Graduate students can end up working on projects for outside companies instead of doing their thesis research," Jansen says. "Activities detrimental to the academic teaching mission is one problem we watch out for." And at UC-Berkeley, the faculty conflict of interest committee is also sensitive to this issue. "What they're really trying to protect," says technology officer Hoskins, "is the relationship between the student and the faculty member, because the student is in a vulnerable position, working for the faculty member and also trying to pursue an advanced degree. And if the faculty member has an outside interest in a company, he could be using cheap labor for his own particular benefit." While they do take conflict-of-interest issues seriously, many researchers say that pressures to skew the aims of research or to lie about the results are not new in science nor unique to university-industry relationships. They also say that the issue of conflicts does not pose a larger threat to academic culture, as some fear. In fact, some scientists say that, rather than undermining academia, technology transfer allows basic scientists who want to see applications result from their work to see this happen while remaining focused themselves on fundamental research. "We need that kind of dialogue, that interchange, that flow of information from the basic scientists to industry to the clinic," says Stanford's Blau, "without people having to leave academia because they want to see their ideas developed and applied toward treating human disease." Blau adds that letting companies take on development tasks can free the academic researcher to return to basic investigation. "The things that I give to companies to do are things I can't or don't want to do here," she says. Some researchers also see fundamental differences in outlook between the goals of business and of academic scientists that will tend to preserve the distinctions between industry and academia. Biologist Steve Roth's experience suggests this might be the case. Roth is a former chairman of the biology department at the University of Pennsylvania, currently on leave from the university. For now, he is vice president of research and development and chief scientific officer of Neose Pharmaceuticals Inc., Horsham, Pa., a startup aimed at developing the drug therapy potential of his more than two decades of university- based research into oligosaccharides. In another year, the university has told Roth, he will have to decide whether to relinquish his university position or to leave behind Neose, a business founded on the pursuit--albeit the product-oriented pursuit--of his scientific ideas. Despite this, and the fact that the size of the project at Neose is roughly 20 times the size of his academic lab at Penn, the choice will not be easy, he says. "I'm a biologist, and that's what I've been my whole life," says Roth. "I'm mystified by how living things are organized. It's in the core of my research." And wherever you go in the university, he says, you run into people who are similarly motivated. "In the business world," he says, "you deal all day long with people who really worry only about money. And that's not in any way derogatory--these are super-intelligent, dead-honest people. But their overriding concerns are not why a maple leaf is different from an oak leaf, for example, or why a pigeon can tell the difference. For someone who's spent his entire life with the former kind of person, it's a little odd." (The Scientist, Vol:7, #17, September 6, 1993) (Copyright, The Scientist, Inc.) ================================ NEXT: September 6, 1993 TI : Academic Scientists Launch Into 1993-94 School Year With Little Hope Of Easing Serious Funding Problems While years of working under burdensome fiscal constraints have yielded strategies for coping, a gloomy mood persists AU : BARBARA SPECTOR TY : NEWS PG : 1 On campuses across the United States, academic scientists and research administrators are beginning the 1993-94 school year with no expectations of relief from the fiscal and regulatory difficulties that have marked the past several autumns. States continue to cut back on support for public and private colleges and universities; moreover, the pool of federal funding is not growing sufficiently to keep up with the increased numbers of scientists vying for grants to support their research. "There's a level of acceptance on our campuses" that the funding situation is not going to improve, says Cornelius Pings, president of the Association of American Universities (AAU). To make matters worse, research administrators say, the paperwork required to satisfy government safety, cost-accounting, and animal-care regulations is mushrooming. At the same time, stiffer indirect-costs restrictions prohibit schools from receiving government reimbursement for the hours spent on such time- consuming labor. "It's a catch between a rock and a hard place," says Earl Friese, a materials scientist who is director of sponsored research at the California Institute of Technology. "We're required to do more administration--which costs more --but the government says, `We're not going to pay for it.'<|>" The much-publicized 1991 investigation into accusations that Stanford University misused millions of dollars in federal funds has changed the way university research is regarded by Congress, says Suzanne Polmar, a biologist who is director of grant and contract administration at Yale University. "Since the Stanford mess, there's been a change in the whole culture in which universities deal with the federal government," she says. "We started as a joint, cooperative enterprise." But in recent years, she notes, universities have been viewed by the government "less and less as collaborators in the research effort. We're now viewed in the same way as defense contractors," with memories of egregious overcharging for hammers and toilets still fresh in the public consciousness. "The nature of the relationship has to be rejustified," says Milton Goldberg, executive director of the Council on Governmental Relations (COGR), a Washington, D.C.-based lobbying group representing 130 research universities. "What is the usefulness--the value to society--of fundamental research? Most of the people who understand that have passed from the scene. People are now questioning more than ever before this fundamental relationship." Exacerbating the problem for those in fields like physics, he says, is that "also passed from the scene is the Cold War and the idea that we [conduct research] in the name of defense." "There's a lot of anxiety among scientists," says Marilyn Gist Farquhar, coordinator of the division of cellular and molecular medicine at the University of California, San Diego. "There's no such thing as being relaxed about a grant [application] that's under review, no matter what you've done. The competition to obtain money and resources is so high, and it takes so much time, that it off-balances other things." Thus, she says, scientists have less time to fulfill their obligations to the scientific community, such as teaching or serving on committees. A ray of hope on the gloomy horizon, however, is that, after several years of working under budgetary and regulatory constraints, scientists and administrators say they are developing strategies to deal with them. While the mood at many universities is still dismal, prompting some researchers to leave academic science altogether, those who remain say they are creating ways to muddle through. As the era of austerity lingers on, "it gets less frustrating, [although] it doesn't get any easier," says Nina Matheny Roscher, chairwoman of the chemistry department at American University in Washington, D.C. "You get used to what the limitations are." Reviewing And Regrouping Many schools have found that the best way to cope with the crunch is to evaluate all their research programs, emphasizing the ones that are found to excel and dropping the rest. Two years ago, schools were gradually coming to the conclusion that they ought to concentrate resources on a few strong programs rather than spread them among many investigations of varying quality (R. Eisner, The Scientist, Sept. 2, 1991, page 1). Today, "almost all are doing some sort of evaluation, possibly with an eye to trimming the enterprise," says Pings of AAU's member universities. "It's an era of some restraint and adjustment," Pings says. "There's a sense that we're all in it--we all have to think out our role, decide what our niche is, and forgo some areas." Yale's Polmar speculates that eventually, schools will realize that it is no longer feasible to fund whole research programs almost exclusively through grant money. "Medical schools have been funding entire divisions on soft money," she says. "If [a program is] important to a university, then the university will have to be prepared to fund it in some way." For example, she says, "should the government be paying 90 percent of faculty salaries? That level of expenditure uses up resources, and I don't believe the supply of funding is going to grow any bigger." A positive consequence of reevaluation might be a renewed emphasis on teaching, says Robert Smith, a pharmaceutical chemist who is vice provost for research and dean of the graduate school at Washington State University in Pullman. "To keep within budget, [schools] have to consider different priorities for the faculty," Smith says. This is already happening on some campuses, including his own, he says: "I see a real shifting of emphasis in our own institution--[to a new] emphasis on teaching excellence." At Washington State, documentation of a faculty member's teaching efforts and teaching evaluations are used "as part of the portfolio [assessed in the decision-making process] for promotion and tenure." The Quest For Funds Science faculty are not the only ones whose jobs are being redefined in these cash-strapped times; academic administrators say that fund raising is becoming a bigger part of their responsibilities. American University's Roscher says she spends about 15 percent of her time in pursuit of research support from private donors and other sources: "It's spending more time than I ever thought I would spend." One way she has found to offset costs, Roscher says, is to locate government labs near her District of Columbia campus willing to share their equipment with students. "We can't possibly keep up with the latest equipment, because it's changing too fast," she says. "But the government labs are very helpful to the scientific community. If an instrument is available at night or on weekends, they try to accommodate us." A funding challenge that has been particularly nettlesome is finding money to cover graduate student stipends. "We have increased costs for graduate student stipends because of cutbacks in state funding, at the same time as tuition is going up," says Washington State's Smith, noting that over the past three to five years tuition at his school has doubled, to $15,000. "This puts added pressure on grants," the usual source of funds for stipends, he says. "The faculty are saying, `I don't know how I can afford to have grad students.' That's another tension that's out there." Compounding the anxiety is a recent news report that the National Institutes of Health is considering limiting its training grants for grad students to 70 percent of tuition. Currently, NIH reimburses universities for anywhere from 65 percent to 95 percent of a student's tuition (Science, 261:415, 1993). Roscher says she seeks out private donors willing to support students. Other sources of help, she says, are cooperative education programs or summer internships in which students work full-time and receive a salary. "While it delays their graduation, it can provide substantial money for a short period of time," she says. Because such experiences generally offer the opportunity for students to be exposed to new equipment, she adds, they are a source of educational value as well as fiscal relief. New Avenues Of course, academic scientists bear the brunt of the burden in the quest for dollars to fund their programs, and, with federal funding sources drying up, they are increasingly turning to private foundations and to industry for support. "Investigators are becoming more active in terms of the number of proposals they submit per faculty member," says Caltech research administrator Friese. "We're seeing a higher volume of proposals going through for the same amount of dollars. People are trying harder and harder." "We have seen an increase in the number of awards--but the dollars haven't gone up," says Yale's Polmar. "Faculty need more grants to get the money necessary to do one project. That takes a lot of work on the part of a PI [principal investigator]--time that could be spent in a lab. They tend to get resentful about that." To ease the pressure on the researchers, Polmar says, the grants and contracts office at Yale--itself short-staffed, and struggling to keep up with the flow of applications--has been picking up some of the detail involved in grantsmanship. "We try to keep the stuff that [faculty] have to do for us to a minimum. We're doing more and more with less and less; we're trying to computerize as much as possible." Fred King, director of the Yerkes Regional Primate Research Center at Emory University in Atlanta, says his staff is seeking outside help in coping with the flood of paperwork required for grant applications as well as to comply with health-and-safety, animal-care, and other government regulations. "We've brought in people to design systems for processing applications and information in order to streamline the paperwork and the meetings, but make sure we still do a responsible job" of following the rules, he says. "Scientists may not be the people who are best at designing those systems, although you need to have scientists involved, of course." Forming Partnerships As it becomes more obvious that there will not be enough federal funds to go around, industry is increasingly being looked upon by university faculty and administrators as a potential sponsor of research. But recent controversy over a 10-year, $300 million deal between the Scripps Research Institute of La Jolla, Calif., and the Swiss giant Sandoz Pharmaceuticals Corp. has made many academic administrators nervous about such alliances. After Congress and NIH loudly voiced concerns over the propriety of a foreign company's taking control of research from a federally funded institution, the Scripps-Sandoz contract was renegotiated in June (C. Anderson, Science, 260:1872-3, 1993). "Universities for years have been advised to seek external funding sources, to bring in more industry dollars" to substitute for scarce federal support, says Ann Stevens, a biochemist who is associate vice president for research at Emory. "Now, we're being criticized because we might have entered into deals that were questionable. But, by and large, universities have been very careful about negotiating limited conditions for licensing technologies developed under research agreements." "We've increased the number of [corporate] contracts, as opposed to grants from NIH or the National Science Foundation, over the past three or four years greatly," says Yerkes' King. The center director says he is spending more time "generating new ideas, [determining] how we are going to work with industry." King stresses that "strategies do need to be developed" to ensure that university-industry ties produce "corporate contracts that are also good-quality science. There has to be a payoff for scientists, too. You have to be doing quality science, not just working for a company on a contract basis." If contracts aren't carefully negotiated to allow re- searchers the freedom they need, he cautions, "you can degrade your science doing something that just gets the job done for somebody." Another way for academic scientists to cope under stressed funding conditions, says UC-San Diego's Farquhar, is to collaborate with each other. NIH, for example, offers program project grants, given to a group of researchers who "pool their expertise," says Farquhar, who has received such a grant along with eight colleagues from UC-San Diego and Scripps who are teaming up to investigate the role of GTP binding proteins in membrane trafficking and cell proliferation. "I'm a great believer in collaborative research," she says. While the money crunch has made cooperative research more common than it was 10 years ago, Farquhar points out, collaboration makes sense from a scientific perspective as well as a fiscal one. "Most problems require a multidisciplinary approach, and in universities, everyone can find people with a common problem interest and complementary expertise," she says. "We can't all be right at the forefront in six or seven different approaches." Joining with others who can approach the project from varying perspectives, Farquhar says, enables a scientist to "get further faster than you can working alone." Bailing Out Yet some academic scientists are fed up with the challenge of seeking new forms of funding; many are throwing in the towel and leaving their research careers behind. "There's still a lot of pessimism around," says Farquhar. "The most pessimistic have now gone in different directions." Some biomedical scientists with M.D. degrees, she says, are opting to "get out of research and turn their attention to clinical practice because they have that option." Others are leaving academia to take jobs in industry, particularly at biotech and pharmaceutical companies. Some who wish to stay on campus might decide to abandon their research and go into administration. But seasoned observers of the quest for government funding say there is no cause for despair; scientists should just relax and be prepared to change with the times. "Folks are just going to have to do less research," says COGR's Goldberg. "It's a practical impossibility to do more work with less resources. Modern research is very capital-intensive, and it requires a good deal of investment. "But I wouldn't view that in a pessimistic way," Goldberg says. "There's a fair amount of money available to do a lot of things. Those who are competing in [the federal funding environment] are still going to be doing a lot of good work." (The Scientist, Vol:7, #17, September 6, 1993) (Copyright, The Scientist, Inc.) ================================ NEXT: September 6, 1993 TI : In Wake Of Summer's Ruinous Floods, Scientists Assess Toll On Research Institutions in the stricken states were spared, but individual researchers report significant setbacks AU : SUZANNE HAGAN TY : NEWS PG : 1 As the householders and businesspeople of the central United States try to dry out and put their lives back together following the Great Flood of 1993, an informal survey of Midwest research institutions indicates that, in general, scientists emerged relatively unscathed by the disaster. As fate--and maybe even a certain amount of intelligent advance planning--would have it, no major academic or industry science center in Minnesota, Iowa, Kansas, Missouri, or other beswamped states suffered signifi- cant damage or interruption of research activities. For the most part, their research facilities are located safely inland from the banks of the Mississippi, Missouri, Kansas, and Des Moines rivers, the waterways whose relentless midsummer overflow caused a tragic loss of human lives and property. That scientists in general escaped trauma and destruction, however, is not to say that all researchers and scientific endeavors were spared. Agricultural scientists, for example, for whom the fertile Mississippi floodplains are prime growing sites- -and, therefore, their laboratories--saw their workplaces disappear under a sea of rushing mud, as did wetlands ecologists working for government agencies such as the U.S. Fish and Wildlife Bureau. At press time, authorities were estimating that more than 1 million acres were put under water in this deluge; at least 35,000 homes were destroyed; and at least $10 billion in damage was done to property and crops. Anecdotal evidence, like that offered by Nader G. Vakili, a plant pathologist and U.S. Department of Agriculture researcher in Ames, Iowa, reveals the range of setbacks suffered by scientists in the tragic flood. Contacted by The Scientist for an interview, Vakili had just finished photographing a field where three years of his research- -half of what he'd hoped to accomplish in a five-year study of no-till farming--had been washed away by water from the Snake River. Vakili, an associate professor of plant physiology at Iowa State University, says that he plans on using the field again; but, to be on the safe side, he may add a second location next year, although this will increase his costs substantially. Farther south, along the Missouri River, soybean breeder Phil Owen, a research associate in the agronomy department of the School of Agriculture at the University of Missouri in Columbia, saw three of his planting sites along the Missouri River wiped out. He's feeling somewhat more fortunate than Vakili, however, because he has four additional sites for his studies of soybean strains under cultivation, and he can still extract meaningful data from them. Owen tests soybeans for traits such as productivity and nematode resistance. Nematode-infested sites, he points out, are especially abundant in the floodplains. He expects a busy winter in the greenhouse and anticipates expanded field testing next summer to make up for his lost work this year. He also may try to plant more sites away from the river bottoms next year, "just in case." Studying Survivors For psychologist Elizabeth Smith, an associate professor of psychiatry at Washington University in St. Louis, the flood provided solid material for the next phase of her research. As experts in the study of disaster victims, Smith and her colleague Carol North, an assistant professor of psychiatry, are currently in the process of determining which flooded areas' survivors they will survey in a study funded by the National Institute of Mental Health. This $980,000 grant, awarded in 1988, allows Smith to investigate the human aftermath of a variety of disasters, natural and otherwise. Smith assesses survivors' immediate responses, then charts the course of their recovery over time by interviewing them at one-year and three-year intervals following the event. To date, Smith has used this grant to interview survivors of a fire and three mass shootings. The initial studies examining flood survivors will be the last set of data collected under the funding provided by the grant. In addition to planning her new study, Smith has responded to the Red Cross' call for professionals to provide counseling services to flood victims. Smith expects to find most flood survivors suffering from anger, depression, and anxiety: "This flood will be much more devastating than others because many people won't be able to clean up and return; their homes have been destroyed. Many children have lost their summer vacations, their homes, and, in some cases, their schools." Among other scientists whose work was interrupted by the flooding was a group of AIDS vaccine researchers in a clinic at St. Louis University--a school, incidentally, that is far from the Mississippi River's banks. The researchers depend for their experimental vaccine studies on a regular turnout of uninfected, low-risk, heterosexual volunteers who are willing to come in for 14 or so visits over the course of a year and a half. Most volunteers, who normally arrive at the clinic at the rate of 10 to 12 a week, are women between the ages of 18 and 45. In early July, the volunteers suddenly stopped coming to the clinic. Clinic nurse coordinator Heidi Israel can't pinpoint the correlation between the flood and the loss of the volunteers. But she feels that their disappearance reflects how overwhelmed St. Louisans have come to feel: "Around Fourth of July," notes Israel, "people started sandbagging and focused on helping flood victims." They just didn't have the time or state of mind for anything but the immediate emergency. At press time, the volunteers still hadn't returned, and Israel says that she doesn't expect the situation to change for some time. Different Perspective Meanwhile, Washington University biology professor Owen J. Sexton can't get within miles of the marsh in St. Charles County, near the junction of the Missouri and Mississippi rivers, where he studies snake populations. Although he describes these snake species as well adapted to flooding, he expects that many of them will be wiped out, at least temporarily. By sheer luck, Sexton had just finished his most recent study a few weeks before the flood. Nevertheless, Sexton's view of the disaster is much the same as other scientists interviewed for this story--it was an unfortunate but useful learning experience. He regards this flood, one of four major deluges to strike the marsh within the last 40 years, as "a big opportunity to see how fast these populations bounce back after catastrophe." Sexton hopes that the Missouri Department of Conservation will allow him to continue his work at the marsh, which would be the first recovery study there, "maybe the first for a lot of places." Although most measurements of the flood's impact focus on loss, a different perspective is needed, says agricultural economist Steven J. Taff of the University of Minnesota: "The more interesting question is, what can we learn from the flood, not what have we lost from it." Suzanne Hagan is a St. Louis-based freelance writer specializing in science and medicine. (The Scientist, Vol:7, #17, September 6, 1993) (Copyright, The Scientist, Inc.) ================================ NEXT: September 6, 1993 TI : Women Astronomers Press Manifesto For Equal Rights AU : RON KAUFMAN TY : NEWS PG : 3 A coalition of more than 200 women astronomers appears to be making headway in an effort to promote equal rights for women not only in astronomy, but also in all scientific disciplines. This past June, the informal group issued an equal rights proclamation on behalf of their cause at a meeting of the American Astronomical Society held in Berkeley, Calif. Called the Baltimore Charter because of the site of initial discussion that created it, the document calls for a new dedication within the astronomy departments of research universities and other institutions to dismantle barriers to advancement and to change working conditions that impede the increase of women in the field (see box on page 22). Already, the charter has received the endorsement of the Association of Universities for Research in Astronomy (AURA), a consortium of 22 universities based in Washington, D.C., that operates a number of observatories in the United States, including the Kitt Peak National Observatory near Tucson, Ariz. The document's authors say that within the next year, they hope the American Astronomical Society (AAS), the National Aeronautics and Space Administration (NASA), and the National Science Foundation will also deliver endorsements for the sentiments expressed in the document. "Women should not have to be clones of male astronomers in order to participate in the mainstream of astronomical research," the charter states. "Women want and deserve the same opportunity as their male colleagues to achieve excellence in astronomy." "The advancement of women in science is an integral part of our profession," says C. Megan Urry, chief of research support at the Space Telescope Science Institute (STScI) in Baltimore and one of the authors of the charter. STScI was the location of a meeting called "Women in Astronomy" last September, during which the impetus for creating the charter began. Urry and coworkers at STScI organized the conference, which attracted more than 220 participants, who took part in a session outlining the issues, ideas, and recommendations that form the basis for the document. Urry, STScI astronomer Laura Danly, STScI associate director Ethan Schreier, and educational consultant Sheila Tobias condensed the session's discussions into the final Baltimore Charter. The two-page manifesto points to specific problems encountered by women in the field, such as "sexual stereotyping, opportunity and pay differentials, inappropriate time limits on advancement, overcritical scrutiny, and sexual harassment." It also notes, more generally, that "unequal treatment of women in the laboratory, the lecture hall, and the observatory, more subtle but at least as important as overt discrimination, creates a chilly climate which discourages and distresses women, alienates them from the field, and ultimately damages the profession." The charter recommends the implementation of or greater commitment to: * Several affirmative-action measures, including advance publication of standards for candidates in hiring, committees, and awards, and the elimination of cultural bias in such standards; more women participating in the selection process in these areas; and candidate pools that reflect the proportion of women in the field and adjust for underrepresentation of women. * Broadened criteria for hiring, assignment, promotion, and awards that recognize domestic concerns, such as child rearing, dual-career families, and reentry into the workplace. * Strong action to end sexual harassment, including substantial penalties for perpetrators, education and awareness programs, and the hiring or appointing of more women to receive complaints and participate in the review process. * Gender-neutral language and illustrations, especially in presenting astronomy to prospective students and the public. Urry says it would be irresponsible for any scientific discipline to ignore the plight of women. "Though we wrote the charter specifically for astronomy, the whole idea is very general," she explains. "We are hoping that other disciplines can take this as a starting point for their own efforts to promote women in science." She says the issues of women in professional life are much greater areas of concern in the 1990s than ever before. However, Urry says, research universities are usually very slow in changing attitudes and procedures to become more sensitive to women's issues. "What you have in many institutions is a group of intelligent, competent, talented, white men," Urry says. "A small number are quite enlightened. A small number are pretty darn prejudiced and not about to change. But the vast majority of men have the right thoughts, but really aren't motivated to change. "One of the things we have to accomplish with the charter is to persuade people that it is in their advantage, and the advantage of science, to change." The gradually decreasing number of women entering astronomy is directly related to the small number of women in tenured faculty positions, says STScI's Schreier. According to statistics he compiled, 23 percent of graduate students in astronomy are women. The number then drops to 17 percent of postdoctoral researchers. And among full professors, only 5 percent are women. Schreier's theory is that the problem of underrepresentation is a self-perpetuating one--that without tenured faculty, younger women are discouraged from trying to advance in the field. "Women are not getting enough guidance," he says. "With the number of tenured women faculty being so small, where would a grad student look for a role model?" High-energy particle physicist Vera Kistiakowsky, a professor of physics and astrophysics at the Massachusetts Institute of Technology, says that university appointments are usually made on purely subjective grounds, and therefore women are often left out. "Appointments and promotions are made on the basis of merit," says Kistiakowsky. "I've sat on enough committees to know that perception of merit is intrinsically subjective . . . and it is a male model against which all these scientists are being measured." She says the Baltimore Charter is a professional, non- radical way of saying that reservations based on an applicant's sex should be placed aside. France Cordova, chairwoman of the astronomy department at Penn State University, attended the STScI meeting last year. She says that, along with the creation of the document itself, having meetings that raise issues of sexual equality is important to finding solutions. "The problems are very big and very deep," Cordova says. "You don't just change a lot of history and behavior with a piece of paper like that. I don't think this charter is a giant leap, but it will help in moving the whole effort forward." However, Claude Canizares, the director of the Center for Space Research at MIT, who also attended the meeting, says that he hopes the Baltimore Charter will have a significant impact on the field. He says that astronomy, and many of the other physical sciences, must actively halt the exodus of women from the field. "I think this is an important milestone along the way," he says of the charter. "One of the things I realized more than ever was that the real emphasis for change has to come from the men who are already in positions of power. The fraction of tenured women faculty is still quite small. I think it's going to take a reasonable amount of activism on the part of men to help effect the necessary changes." A copy of the Baltimore Charter can be obtained from the Space Telescope Science Institute, 3700 San Martin Drive, Baltimore, Md. 21218; or call (410) 338-4707. (The Scientist, Vol:7, #17, September 6, 1993) (Copyright, The Scientist, Inc.) ================================ NEXT: September 6, 1993 THE BALTIMORE CHARTER'S PREAMBLE We hold as fundamental that: * Women and men are equally capable of doing excellent science. * Diversity contributes to excellence in science. * Current recruitment, training, evaluation, and award systems often prevent the equal participation of women. * Discriminatory mechanisms are unlikely to change by themselves. Both thought and action are necessary to ensure equal participation for all. * Increasing the number of women in astronomy will improve the professional environment, and improving the environment will increase the number of women. (The Scientist, Vol:7, #17, September 6, 1993) (Copyright, The Scientist, Inc.) ================================ NEXT: September 6, 1993 NOTEBOOK TI : An Inspiring Message TY : NEWS (NOTEBOOK) PG : 4 Faculty in Yale University's computer science department were greeted with a message from a familiar name on their E-mail early last month. Computer science professor David Gelernter, the victim of mail-bomb attack on June 24 (C. O'Kane, The Scientist, Aug. 23, 1993, page 1), was back at the keyboard. His cheery message--Gelernter jokingly referred to himself as "the department's very own official terrorist bomb victim"--was interspersed with information indicating the seriousness of the wounds he suffered. He wrote that he will need surgery to recover some degree of functionality in his right hand and hearing in his right ear. In addition he said, "I don't have much vision in my right eye at the moment, but that may improve." Nonetheless, Gelernter vowed to come back, on a limited basis, this fall. Summing up his perspective on the ordeal, Galernter wrote: "I am the luckiest man alive (emphasis on alive). Surviving the explosion was evidently a pretty neat trick on my part, and I could have been hurt much worse. Whenever I get to feeling a bit morose and missing my old right hand, I wind up thinking instead how privileged I am to be an academic in computer science; in the final analysis, one decent typing hand and an intact head is all you really need, if you wish to add the family and friends with which I am blessed." (The Scientist, Vol:7, #17, September 6, 1993) (Copyright, The Scientist, Inc.) ================================ NEXT: TI : McBrontosaurus TY : NEWS (NOTEBOOK) PG : 4 Despite the fact that the majority of dinosaurs are believed to have been herbivores, for which a Big Mac would be considerably less appetizing than a yummy stand of palm trees, Ronald McDonald Children's Charities has provided funding for what is being billed as the most ambitious excavation of dinosaur fossils ever undertaken in the Sahara Desert. The four-month expedition, begun last month, is being conducted by paleontologist Paul Sereno of the University of Chicago. The expedition is taking place in Africa, Sereno says, because it is the "least-explored continent for the story of dinosaur evolution." While Africa was drifting free of other continents 100 million years ago, dinosaurs and land plants evolved into species unique to that continent, paleontologists say. Sereno returned from a preliminary trip to the Sahara in 1990 with a six-foot-long femur bone from a brontosaurus-like dinosaur that was at least 50 feet from head to tail. A film crew and a still photographer will chronicle the expedition; the resulting documentary is scheduled to air as the season premiere of Public Broadcasting System's "New Explorers" series in the fall of 1994. (The Scientist, Vol:7, #17, September 6, 1993) (Copyright, The Scientist, Inc.) ================================ NEXT: TI : Pumping Up The Volume TY : NEWS (NOTEBOOK) PG : 4 While many participants in the animal rights debate are trying to raise the level of dialogue, at least one group's literature indicates that inflammatory rhetoric is not the exclusive domain of animal rights extremists. In announcing its "Alliance for Action" conference, to be held September 19 in Portland, Ore., the Portland-based pro-animal research group National Animal Interest Alliance (NAIA) invites potential participants to "hear the case histories from the heroes who have waged solitary battles for survival and justice against this hate movement [animal rightists]. Find out strategies that have worked to combat extremism. Come join us in support of human rights." In addition to animal researchers scheduled to speak at the conference, guest speakers include a "legislative liaison" giving "a sportsman's and trapper's perspective," an official of the Fisherman's Coalition, and a retail furrier. For information on the one-day conference, contact NAIA, P.O. Box 66579, Portland, Ore. 97290-6579; (503) 761-8962. (The Scientist, Vol:7, #17, September 6, 1993) (Copyright, The Scientist, Inc.) ================================ NEXT: TI : Interesting Alliance TY : NEWS (NOTEBOOK) PG : 4 The National Conference of Lawyers and Scientists (NCLS), an organization sponsored jointly by the American Association for the Advancement of Science (AAAS) and the American Bar Association, is calling for proposals for original papers to be presented at an invitational conference on "Legal, Ethical, and Technological Aspects of Computer and Network Uses and Abuse" to be held in mid-December 1993. Discussions will deal with such issues as access to information, privacy, security, and equity; and the role of computer users, academic institutions, industry, professional societies, government, and the law in defining and maintaining the legal and ethical standards for the use of computer networks. The deadline for submission of proposals is September 15. For information, contact Deborah Runkle, Directorate for Science and Policy Programs, AAAS, 1333 H St., N.W., Washington, D.C. 20005; (202) 326-6660. Fax: (202) 289- 4950. E-mail: values@gwuvm.gwu.edu. (The Scientist, Vol:7, #17, September 6, 1993) (Copyright, The Scientist, Inc.) ================================ NEXT: TI : On-The-Job Learning TY : NEWS (NOTEBOOK) PG : 4 The State University of New York at Stony Brook's Center for Biotechnology has established two new science student internship programs, one providing two-year research internships for undergraduates in biotechnology companies, and the other offering single-semester internships for graduate students in law offices. The undergraduate internships began this summer, with five students being placed in three Long Island, N.Y., biotechs. The law internship begins this fall, with one student each semester interning in the office of an intellectual property law firm in Garden City, N.Y. Interested companies can contact Glenn Prestwich at (516) 632-8521. (The Scientist, Vol:7, #17, September 6, 1993) (Copyright, The Scientist, Inc.) ================================ NEXT: TI : Instructive Award TY : NEWS (NOTEBOOK) PG : 4 The California Institute of Technology has established the $3,000 Richard P. Feynman Prize for Excellence in Teaching, to be awarded annually to a faculty member "who demonstrates unusual ability, creativity, and innovation in teaching." The prize will be augmented by an immediate raise in the recipient's salary. Feynman, a Nobel Prize-winning physicist, taught at Caltech from 1950 until his death in 1988. (The Scientist, Vol:7, #17, September 6, 1993) (Copyright, The Scientist, Inc.) ================================ NEXT: TI : New Kids On The Block TY : NEWS (NOTEBOOK) PG : 4 Veterinary researchers at the University of Georgia have announced the birth of the first test-tube goats in the United States, twin billy goats named Willy and Nilly. The pair represent the culmination of five years of research in reproductive biotechnology at Georgia's College of Veterinary Medicine. While human in vitro fertilization has been performed for the past 15 years, producing the goats presented special challenges, says Benjamin G. Brackett, head of the department of physiology and pharmacology at the vet school: "A major obstacle was to find the conditions that will enable eggs taken from the ovary to mature appropriately prior to fertilization. In these experiments, we carried immature eggs up to the four- to eight- cell stage after in vitro fertilization." According to the researchers, the breakthrough could have major implications for goat breeding and the development of drugs that could be used on animals and humans. (The Scientist, Vol:7, #17, September 6, 1993) (Copyright, The Scientist, Inc.) ================================ NEXT: September 6, 1993 TI : CLARIFICATION TY : NEWS PG : 9 An essay titled "We'd Better Think Twice Before Eradicating All Smallpox Virus Stocks" (The Scientist, August 23, 1993, page 11) carried the byline of Lev S. Sandakhchiev, director of the Vector Laboratories of the All Union Molecular Biology Research Institute, Koltsovo, Novosibirsk, Russia. Credit was omitted for two coauthors of the essay, both of whom are also associated with the Vector Laboratories: Sergei N. Shchelkunov, head of the Laboratory of Poxviruses Molecular Biology; and Svetlana S. Marennikova, head of the orthopoxviruses collection. (The Scientist, Vol:7, #17, September 6, 1993) (Copyright, The Scientist, Inc.) ================================ NEXT: September 6, 1993 TI : Science Publishing Is Urgently In Need Of Major Reform AU : RUSTUM ROY TY : OPINION The function of science publishing today is to get information about new findings in science to at least three different communities: * Group A, the specialists working in the same field as that in which the findings were made (numbering anywhere from 10 to 1,000 scientists); * Group B, the general community of scientists and engineers who, although not in that field, are nevertheless interested in major advances in scientific areas other than their own--advances that may, indirectly or in the long term, be significant to them (probably between 1,000 and 10,000); * Group C, the general, attentive public and the policymakers who want or need to know of scientific developments that could have economic or social consequences (10,000-100,000). The classic media for science publishing--journals put out by societies and other discipline-oriented organizations--were designed only for Group A, while the media serving Group B are the short news articles in society house organs, such as Chemical Engineering News, Physics Today, and MRS Bulletin, and in such multidisciplinary publications as Science and Nature. Group C is served (very poorly, in my opinion) by the general media--including newspapers and magazines such as the New York Times, Omni, and Discover--which tend to overamplify and inappropriately dramatize the "breakthroughs" they consider newsworthy. Since maximum publicity--not accuracy--today serves both the scientist and the journalist, these and other such publications, in my opinion, tend increasingly to fall for exaggeration and hype. Meanwhile, such publications as New Scientist and The Scientist seek to bridge with both accuracy and social relevance the B and C groups. Confronted by such a menu of publishing alternatives, how does the responsible scientist announce effectively a discovery that she or he thinks would be of interest to one or all of the A, B, and C groups? The Establishment Position The route accepted by the establishment is that one should submit one's research report to a standard journal (the A group), have it go through the arcane ritual called "peer review," and--only after it has been accepted and published--send publicity releases or other notification of its findings to the wider press. The process is deficient, in my opinion, first of all because peer review--the first hurdle--is biased against innovation. In the path toward publication in the A-group journals, anything that extends beyond the current ruling paradigms of scientific thought will most likely experience inordinate delays in being considered; matters of routine science will get into print much faster. (There is an accompanying danger: that during the peer- review process, especially when an article is dealing with a dramatic discovery in a fast-breaking field and has potentially profitable application, two or three scientists--the so-called peers--and, hence, possibly their laboratories, companies, and colleagues may inappropriately be privy to advance information on a significant innovation that they can use to their own professional gain.) I strongly believe that when research results are really important, they deserve a wider academic audience than the specialized readers of the A-type journals and that, in line with this, the significant scientific innovations of today need new methods of publication. Beating The System A good example of how a creative scientist can circumvent the current publishing system in order to get his or her significant work out to the public is the case of Henry Heimlich, president of the Heimlich Institute in Cincinnati. Although Heimlich does not fit the traditional profile of the basic lab researcher working toward an esoteric advance, his approach is worthy of emulation: When he discovered his now-famous life-saving maneuver for discharging obstructive material from the windpipe, he wanted to get news of it without delay to the public who could use it. After agreeing with the editor of Emergency Medicine (a non-peer- reviewed journal) to simultaneously send out a story to the general press, he published it in the June 1974 edition of that publication (6:154-5, 1974). Newspapers all over the United States picked up and ran the news release sent to them. Although the Journal of the American Medical Association made note of Heimlich's technique in a news blurb a few months later, the technical article in JAMA did not appear until October of the following year (234:398-401, 1975). By this time, of course, the Heimlich maneuver was already saving lives all over the world. For the bench scientist, the effort to penetrate or circumvent the peer-review barrier in the way that Heimlich did can be perilous indeed to the prospect of ever seeing a research report in print. I know this from several personal, time-wasting experiences with leading science journals. For example, in October 1992, having made a scientific advance in diamond synthesis, I sent off a paper to Science, then held a press conference in Washington discussing my findings. At the press conference, I handed out copies of the paper, and I also distributed some copies by fax. After a month, Science returned the paper--unreviewed, yet rejected--on the procedural ground that preprints had been distributed, which, in Science's terms, constituted publication. An Obsolete Process For the A group, the classic model of writing a paper, submitting it to an editor, and having it go through the arcane peer-review system described above may once have been suitable for science done by an elitist minority (known to each other) with relatively high ethical standards. But the A community itself is no longer well served by this process because of several factors--and the process is clearly inadequate to address the needs of groups B and C. Among the factors are: * The volume of the current literature is so large that peers and editors have greater difficulty in determining whether work reported is really significant or has been done before. (Indeed, I believe that significant numbers of working academic scientists essentially ignore the literature as they go about their investigations.) * The peer-review process as now practiced in most journals is biased against real innovation, in part because of problems associated with selection of knowledgeable and objective reviewers. Even the key word in the term "peer review" is difficult to define: Who, for example, is a "peer" of Linus Pauling? Any assistant professor of chemistry at a university? His arch-enemies in the anti-vitamin C camp? Yet, although no clear definition of "peer" has as yet been created, the term continues to be used by the science publishing industry as its needs require. Most devotees of the process forget that the peer- review system cannot be any guarantor of correct or good science; all its practitioners really can do is check the plausibility of the case and determine whether the author got the sums right. * The current process in a peer-reviewed journal also gives an unfair advantage of from three to six months in a given field to two or three groups or individuals who are chosen to review an article. This may be no problem for pedestrian science, but it is unacceptable in many cases, especially those of interest to groups B and C. Devotees of peer review commonly assert that there are no alternatives to the system. For research proposals, however, there are dozens of alternatives in use all over the world. At the U.S. Department of Defense, for example, a knowledgeable R&D manager seeks out the very best researchers and takes the responsibility for judging the best proposals with no authority at all being given to peers. Every mid-level or higher manager in industry does the same every day with no help from peers. For publishing papers, the science community, in theory devoted to "experimentation," often appears unwilling to try new approaches for the new situations, although there have been exceptions. In 1965, I participated in the founding of the Journal of Materials Research Bulletin. This journal, which has a good impact factor in citations, runs open review either by associated editors or by anonymous reviewers. Until recently, the Proceedings of the National Academy of Sciences did not mandate peer review. Quality presumably was maintained by examining an author's previous track record. However, this is no longer true for PNAS. Recommendations I believe that new journals should be started (or new sections started in established journals) for non-reviewed papers by authors who establish their credentials by their track record. In this process, a scientist who submits a list of published works with a minimum of, say, 50 or 100 papers in the regular peer- reviewed journals could publish a paper with only a brief delay in the process for copy editing. Or any scientist with the same or an even better track record could officially communicate a colleague's paper. This scheme would achieve several goals at once. First, it would open up the system to genuinely new ideas. Second, it would speed up the process by several months. Third, it would bring some lively debate into science by having authors use the media Group B to discuss or critique the work. Fourth, it would protect the new work from some of the dangers inherent in the current system--such as the prospect of the paper's never being published. In the case of a paper reporting on what the author considers an especially impor- tant research advance that would be of interest to audiences B and C, as well as A, standard practice should entail the author's first sending the manuscript to a journal, then distributing preprints by mail and fax, or calling a press conference or doing whatever else is necessary to get the word out. Meanwhile, reporters covering such an announcement should examine carefully the claims and explicitly report the author's previous track record in the field. This is by far the best predictor of reliability. And the reporters should seek comment on the record--in radical contrast to the anonymity of peer review--from other knowledgeable colleagues on the available preprint version. The reporters should be skeptical of any claims the paper makes concerning applications of technological or economic impact, preferably ignoring them. Rustum Roy is Evan Pugh Professor of the Solid State at Pennsylvania State University's Intercollege Materials Research Laboratory in University Park. (The Scientist, Vol:7, #17, September 6, 1993) (Copyright, The Scientist, Inc.) ================================ NEXT: September 6, 1993 COMMENTARY TI : In Animal Rights Debate, The Only Valid Moderates Are Researchers AU : Frederick K. Goodwin and Adrian R. Morrison TY : OPINION (COMMENTARY) PG : 12 The article titled "In Animal Rights Debate, A `Modulating Influence' Is Misunderstood" (R. Roth, The Scientist, May 31, 1993, page 11), correctly describes the important work under way at the Johns Hopkins Center for Alternatives to Animal Testing (CAAT). Author Robert Roth rightly defends CAAT's search for in vitro and other non-whole-animal methods that can be used in developing and evaluating therapeutic products for human and animal use. Yet, in characterizing CAAT as a "modulating influence in the animal rights debate, in which extreme emotionalism and lack of rational thought are too often the major players," Roth clouds a major issue. He missteps by implying that there is a "middle ground" position, flanked on one extreme by defenders of animal research and, on the other, by animal rights advocates. No consensus can be reached between those who accept the use of animals for important human needs and those who categorically reject animal use based on a philosophy that views all forms of sentient life as morally equivalent. If the question fundamentally is whether to use animals, no middle ground exists. Use cannot be partly ethical; it is either ethical or unethical. People who genuinely want to discuss the matter with researchers must first disavow the animal rights position. To engage in middle-ground discussions with true believers in animal rights is, at best, fruitless; at worst, it provides animal rights activists with a tactic to shift the uninformed closer to the ultimate goal of total abolition of animal use. Only if one starts from the principle that the use of animals is acceptable does the issue of how animals are used address the spectrum of legitimate issues. One end of this spectrum holds that we should spare no expense to provide absolute comfort and procedural safeguards for experimental animals; a corollary of this extreme animal welfare position is that research goals have to be secondary to the absolute commitment to animal comfort. The other end of the spectrum holds that humane treatment should not be a consideration if it involves any extra expense or inconvenience that animals can be treated essentially like lab equipment. Between these two extremes, the biomedical research community occupies the middle ground. We are engaged in legitimate, important debates about regulations vs. costs and about animal welfare vs. human needs, answerable only through research that encompasses the humane use of animals. Medical science has no counterpart to the statement "In no case are animal studies the foundation for progress," uttered by Neal Barnard, founder of the Physicians Committee for Responsible Medicine (AV Magazine, April 1989, page 17). Does Barnard, a physician, truly believe that vaccines, antibiotics, implantable prosthetic devices, and immunosuppressant drugs were tested willy-nilly on human patients without research and testing on animals? If he concedes that animal research played a role in early medicine, does he believe that "prevention" could eliminate genetic diseases such as cystic fibrosis, which is now closer to effective treatment because of animal research identifying the genetic anomaly? Nor can medical science rationally counter the statement of Chris DeRose, president of an organization called Last Chance for Animals, that "A life is a life. If the death of one rat cured all diseases, it wouldn't make any difference to me" (Los Angeles Times, April 12, 1989, page E12). And what should we say to the comment of Ingrid Newkirk, national director of People for the Ethical Treatment of Animals, that "Even if animal research resulted in a cure for AIDS, we'd be against it" (Vogue, September 1989, page 542)? We doubt that many scientists would knowingly stand with Newkirk and DeRose against their fellow man. The anti-intellectual, anti-scientific actions of animal rights activists have seriously harmed biomedical research and, in turn, the public. Laboratories have been destroyed; scientists vilified; their homes picketed and damaged. Research programs that promise real cures for human misery have been impeded. Animal protection "moderates" who do not condemn these activities speak volumes by their silence. There is room for emotionalism; the anger of medical scientists is both justified and healthy. Non-medical readers should investigate the situation. They'll get mad, too. Frederick K. Goodwin is director of the National Institute of Mental Health, Rockville, Md.; Adrian R. Morrison, a professor of anatomy at the University of Pennsylvania, Philadelphia, is a consultant to NIMH's Program for Animal Research Issues. (The Scientist, Vol:7, #17, September 6, 1993) (Copyright, The Scientist, Inc.) ================================ NEXT: September 6, 1993 LETTERS TI : Redundant Publication TY : OPINION (LETTERS) PG : 12 I welcomed Paul McCarthy's article "Vigilant Science Journal Editors Fight Redundancy" (The Scientist, March 8, 1993, page 1). I would like to offer the following comments in response. The first concerns the naivete of researchers who think a long bibliography is the key to recognition and promotion. Speaking as one who has served on admissions committees, academic promotion boards, editorial boards, and National Institutes of Health study sections, I can only wonder what sort of fools such aspirants take us for. In my experience, those who review candidates for admission or promotion are quite aware of what McCarthy calls redundant publication: They take it into account not only in reviewing candidates, but also in judging the quality of journals. The first thing I do when examining a bibliography is to search for meritorious contributions in well-edited journals. After these are subtracted, remaining redundancies must work to a candidate's disadvantage. I also find that most sophisticated reviewing committees are as interested in the quality of contributions as in the quantity. My second point concerns a pernicious and growing practice of journals that surely contributes to the redundancy problem. It is the trend toward listing as authors half as many names as appear in an average metro phone book. Recent issues of the New England Journal of Medicine, for example, include articles with 20 or 30 authors. Do these individuals actually believe that being one of such a crowd adds credibility or gravitas to their bibliography? The time has come for journals to devise less burdensome methods of recognizing contributors. One that comes to mind is a simple footnote that names everyone, while authorship is left to a few key individuals. Or, as sometimes happens nowadays, authorship might be attributed to a group or committee, with all names omitted. WILLIAM S. BECK Harvard Medical School Boston (The Scientist, Vol:7, #17, September 6, 1993) (Copyright, The Scientist, Inc.) ================================ NEXT: TI : Humane Society TY : OPINION (LETTERS) Patrick Cleveland accuses me of "artful use of language" (The Scientist, May 31, 1993, page 12) in my defense of the Humane Society of the United States (HSUS) against his mischaracterization of the organization (The Scientist, Feb. 22, 1993, page 10). Yet his verbal attacks border on McCarthyism, with the suppression of animal rights activism being the new goal. His main thesis is that HSUS is now a radical animal rights organization seeking to abolish all animal research and differing from other such organizations only in tactics. In Cleveland's view, HSUS's humane education efforts to nurture compassion and kindness become "attempts to redefine human moral value systems" and therefore should be examined to see if they are "brainwashing our children." The two most defining aspects of HSUS in the area of animal research are our current policy and programs. Cleveland ignores both. Instead he cites, out of context, statements and events from 1980 and 1984. His lone example of more recent vintage (1990) illustrates his confusion of the animal rights movement and the actual rights of animals. The critical question, as bioethicist Arthur Caplan has pointed out (If I Were a Rich Man, Could I Buy a Pancreas?, Bloomington, Indiana University Press, 1992), is not whether animals have rights, but how their rights are balanced against the rights of humans. At the same time, however, HSUS does not consider itself an "animal rights" organization or part of the "animal rights movement" insofar as these political labels have come to refer to organizations with abolitionist positions on using animals for research, food, and so forth. HSUS does not have such positions on these issues. Accordingly, for clarity's sake, we use the more inclusive term "animal protection" to characterize ourselves. Cleveland's ad hominem attacks divert attention from what HSUS views as the primary issue in the animal rights controversy, namely, what can and should be done to reduce the harmful use and suffering of animals in laboratories. MARTIN L. STEPHENS Humane Society of the United States Washington, D.C. (The Scientist, Vol:7, #17, September 6, 1993) (Copyright, The Scientist, Inc.) ================================ NEXT: WHERE TO WRITE: Letters to the Editor The Scientist 3501 Market Street Philadelphia, PA 19104 Fax:(215)387-7542 E-mail: Bitnet: garfield@aurora.cis.upenn.edu 71764.2561@compuserve.com ===================================== (The Scientist, Vol:7, #17, September 6, 1993) (Copyright, The Scientist, Inc.) ================================ NEXT: September 6, 1993 RESEARCH TI : Huge Microbe's Value Lies In More Than Just Sheer Size AU : MYRNA E. WATANABE TY : RESEARCH PG : 14 "Word's biggest bacterium found in a fish," declared the front- page headline in a March 1993 edition of USA Today, while the New York Times trumpeted its coverage with: "In the world of bacteria, a behemoth." Even the relatively staid science journals couldn't resist. Science announced the identification of "Monsters from the guts," and Nature's header read "Giant among the prokaryotes." The extraordinary flurry of interest--and imagery--was over an article in Nature (E.R. Angert, et al., 362:239-41, 1993) reporting the identification by microbiologist Norman R. Pace's laboratory at Indiana University in Bloomington of the largest bacterium yet known to science: Epulopiscium fisheloni. The organism, a member of the Clostridium group of anaerobes, had been, according to the report, isolated from the intestine of the brown surgeonfish, Acanthurus nigrofuscus, and it is, indeed, big--up to 600mm long by 80mm in diameter. That translates, the Times reported, to "about the size of a hyphen in a newspaper article." While grateful for the publicity that identifying the bacterium has gained for him and his colleagues, Pace believes that the media hype surrounding the organism's sheer bulk obscured the true value of his lab's achievement. In fact, Pace's interest in this specific organism is not nearly so great as is his interest in the use of techniques his laboratory staff has developed to screen microbes found in the environment. According to Pace, their work can be broadly described as "characterizing naturally occurring microbial organisms without cultivating them." Thus, the media attention given to his lab's latest find was most valuable in, if anything, drawing attention to the techniques' usefulness in opening the door to the world of as-yet-undiscovered microbes. "We know so little about the natural microbial world," says Pace. "Imagine if our entire view of biology was based on a visit to the zoo. That's exactly the situation we're in in the context of the natural microbial world." Need For Cultivation Until now, technology to study the microbial world has been limited. Under normal circumstances, an individual bacterium will not yield any information about itself by being taken from its natural environment, stained, and viewed under a microscope. Since it can be effectively studied only in numbers, it must be grown in media to produce colonies. Carl Woese, a professor of microbiology at the University of Illinois, Urbana-Champaign, and coauthor of several papers with Pace, explains that the problem with understanding the microbial environment is that until now, available methods limited researchers' ability to find, let alone identify, microorganisms. Newer biochemical techniques, such as using probes with known complementary DNA or RNA codes from identified organisms, along with DNA sequencing, could revolutionize microbiology, many researchers agree. "A large fraction of the bacteria [have] been studied by enrichment culturing," Woese points out. "We artificially enrich and then select those [bacteria] which grow best on the media of our design"--that is, bacteria grown on artificial nutrient media such as agar enriched with amino acids, salts, and other molecules. The media becomes the bacteria's environment, and those bacterial strains that grow best into colonies on the media are the ones with which scientists currently are best acquainted. However, enrichment culture, although the basis of much of our knowledge of bacteriology and microbial pathology, is of very limited use in exploring the entirety of the world of living microbes. Enrichment culturing is highly selective; according to Pace, only between 1 in 1,000 and 1 in 100,000 of bacteria present in a given environment will grow on enriched culture media. Thus, while a single bacterium in a particular soil sample may be identified through enrichment culturing, the sample may well contain tens of thousands of other organisms that can't be grown in the available media and will thus remain unknown. It follows, Woese points out, that "the natural distribution of microorganisms tends to be very different from the collection we have in the laboratory." Innovative Approach Pace's technique, however, can be used on organisms that, as yet, have not been amenable to enrichment culturing: It involves the amplification of DNA that has been extracted from a bacterial cell. The resulting clones are then sequenced and compared with known sequences for ribosomal RNA (rRNA). This allows determination of what is called a "phylotype," or the position where this organism fits in the known bacterial phylogeny. Additionally, hybridization probes complementary to specific regions of the rRNA are synthesized and used both to confirm that the DNA in question came from the specific organisms being studied and to aid in screening other organisms. In the research on Epulopiscium, DNA amplification was done in Pace's lab via polymerase chain reaction (PCR), reproducing ribosomal DNA (rDNA) that codes for small subunit rRNA. In this case, the fact that Epulopiscium hybridized with a bacteria- specific hybridization probe and not one for eukaryotes established that Epulopiscium is a bacterium. The organism tentatively had been identified as a protozoan in earlier work (L. Fishelson, et al., Science, 229:49-51, 1985). W. Linn Montgomery, an ichthyologist at Northern Arizona University in Flagstaff, was one of the original discoverers of the organism, and his doubts that it was a protozoan led him to persuade Pace to examine it. Pace, viewing this as a good opportunity to establish the usefulness of his technique, showed the microbe to graduate student Esther R. Angert, who was just beginning her studies with Pace at Indiana. Pace asked her: "Look here, do you want to study this?" Samples of preserved surgeonfish gut contents were supplied to the laboratory by Kendall D. Clements of James Cook University, Townsville, Queensland, Australia. The organisms are so big that Angert was able to pick them out of the intestinal samples under a microscope, impossible to do with smaller bacteria. Microbiologists, including Pace, willingly acknowledge the tech- nique's limitations. For example, Bruce Hanna, an associate professor of clinical pathology at the New York University School of Medicine, who is using probes to identify the bacillus that causes tuberculosis, says, "It's not going to replace everything. First of all, it's very laborious and very expensive." Angert's research illustrates the complexities. She began work in 1990 and finally came up with "the right ribosomal RNA" in the fall of 1991. She then had difficulties, she says, "getting a clean enough Taq polymerase." Fortunately, a colleague was able to isolate and sufficiently purify the enzyme. Pace explains that even though the work is expensive, research money is available for studying high-temperature organisms, as they are thought to hold the greatest commercial opportunities as sources of thermostable enzymes. Whither Epulopiscium? Now that the Epulopiscium study is completed, Pace's group is concentrating on microorganisms from high-temperature environments at Yellowstone National Park. They already have identified organisms that, Pace says, "are more different from known organisms than known organisms are from one another." And what will become of the giant symbiotic Epulopiscium? Angert believes that microbiologists will be able to use this bacterium, which is large enough to allow insertion of microprobes, to directly study bacterial physiology, a process that cannot be carried out with most known bacterial species. The organism itself leaves many scientific questions unanswered. First of all, large bacteria similar to Epulopiscium have been found within intestinal tracts of herbivorous animals. For example, Angert explains, "there are similar organisms in guinea pigs. How did they get there?" Angert's study also found similar bacteria in the intestine of Naso tuberosus, the humpnose unicornfish, another herbivorous surgeonfish relative. These symbionts clearly established themselves within the animals' digestive tracts many generations ago. Researchers wonder: What is their precise physiological function in the gut--and why did they grow so large? Montgomery believes that the bacteria "may enhance lipolytic activity in the main intestine. We know they greatly suppress pH locally in the mid-intestine." This, however, is only a part of a long-term coevolu-tionary relationship. Gareth Nelson, curator of ichthyology at the American Museum of Natural History in New York, describes Acanthurus nigrofuscus, the big microbe's surgeonfish host, as an Indo-Pacific cosmopolitan fish species living throughout the Pacific and Indian Oceans. Both he and Montgomery note that the true taxonomic status of the species is unknown and it, because of its broad distribution, is unlikely to be one valid species and is more likely to be at least several separate species. Montgomery, who has been studying the surgeonfish for many years, says that Epulopiscium or similar microbes have been found in the intestinal tracts of this fish from many parts of its range-- South Africa, Hawaii, Tahiti, Australia, and the Red Sea. Angert's research showed that different types of the microorganism inhabit the intestines of Australian fish and the same purported species of fish found in the Red Sea. Questions that arise include: Did the bacteria evolve along with the fish, and can you study the phylogeny of the fish by studying the molecular evolution of the bacteria? "I think, in terms of coevolutionary stories, this has some great potential," Montgomery says. And the bacterium itself, according to microbiologist James Staley of the University of Washington in Seattle, leads to some interesting speculation: "What is the upper size limit for bacteria? Is there some sort of reason why the cell can't get any larger than this? " Some advocates of Pace's approach suspect that it will be criticized by the plate-and-cultivate researchers, who are used to working with organisms they can colonize in culture, rather than with one or two organisms, as Pace is doing. But NYU's Hanna, who runs the clinical microbiology laboratory at New York's Bellevue Hospital Center, is clearly impressed. "I think what they have done is very unique and interesting," he says. "They don't know what they're looking for .... Sometimes, it's the only thing you can do." Myrna E. Watanabe is a biotechnology consultant based in Yonkers, N.Y. (The Scientist, Vol:7, #17, September 6, 1993) (Copyright, The Scientist, Inc.) ================================ NEXT: September 6, 1993 TI : PAYING PROPER ATTENTION TO THE MICROBIAL WORLD AU : MYRNA E. WATANABE TY : RESEARCH PG : 14 Indiana University microbiologist Norman Pace has been profoundly interested in RNA since his work as a graduate student in the laboratory of Sol Spiegelman at the University of Illinois. Indeed, all of his 140 scientific publications deal, in some manner, with RNA. As time and technology have progressed, Pace has concentrated more and more on RNA as a key to molecular evolution. His laboratory currently has two foci: studying RNase P, an enzyme that, in part, is composed of a catalytic RNA; and developing methods for screening and analyzing environmental microbes. It is this latter focus that leads Pace to be a vocal advocate for the study of microbial biodiversity. "The microbial world established the biosphere; the microbial world still supports the biosphere," he says. Researchers need "to find out what's out there and what are they really doing," he says. He and University of Illinois microbiologist Carl Woese-- considered by Pace to be the father of rRNA phylogeny (L. Holland, The Scientist, May 14, 1990, page 22)--point out that people making a big ruckus today about the need for preserving biodiversity are speaking about only a very few species of plants and vertebrate animals, largely ignoring the microbial world, which is much more vast and is necessary for all life. For example, without microorganisms there would not be degradation of organic matter--no biological recycling. They further point out that nowhere on the surface of the Earth is microbe-free, including the oceans and even within rocks. "They grow throughout the first few miles of the surface of the planet," says Woese. Woese adds that by studying the origins of microbes, microbiologists also are studying human origins. "The eukaryotic cell that became a plant cell did not invent photosynthesis," says Woese. He explains that the origins of both chloroplasts and mitochondria will be found in organisms similar to the microbes that were captured by the earliest cells. For their sheer longevity, microorganisms as a group deserve more scientific attention. "How old are microorganisms?" asks Woese rhetorically. "Three point five billion [years] is a conservative estimate," he answers, with 3.8 billion years as a more realistic estimate. Scientists cannot search back farther than that because that is the age of the earliest rocks. The Earth is 4.5 billion years old. --M.E.W. (The Scientist, Vol:7, #17, September 6, 1993) (Copyright, The Scientist, Inc.) ================================ NEXT: September 6, 1993 TI : SUGGESTED READING TY : RESEARCH PG : 15 * H.W. Jannasch, et al., Nature, 342:834-6, 1989. * W.L. Montgomery, P.E. Pollak, Journal of Protozoology, 35:565-9, 1988. * G.J. Olson, C. Woese, FASEB Journal, 7:113, 1992. * D.M. Ward, et al., Advances in Microbial Ecology, Vol. 12:219- 286 (ed. K. C. Marshall, New York, Plenum, 1992). * C. Woese, Microbiological Reviews, 51:221, 1987. (The Scientist, Vol:7, #17, September 6, 1993) (Copyright, The Scientist, Inc.) ================================ NEXT: September 6, 1993 HOT PAPERS TI : CELL BIOLOGY TY : RESEARCH (HOT PAPERS) PG : 16 S. Dalton, R. Treisman, "Characterization of SAP-1, a protein recruited by serum response factor to the c-fos serum response element," Cell, 68:597-612, 1992. Stephen Dalton (Roche Institute of Molecular Biology, Nutley, N.J.): "Transcription factors often have separable DNA binding and activation domains, indicating that they are functionally modular. This is well illustrated by experiments showing that GAL80 repressor protein can be made into an activator by fusing it to a heterologous transcription activation domain (J. Ma, M. Ptashne, Cell, 55:443-6, 1988). With this property of transcription factors, an assay has been developed using yeast that enables protein-protein interactions to be detected in vivo (S. Fields, O.K. Song, Nature, 340:245-6, 1989). "Our work is an early example of how this type of approach can be successfully applied to screen for novel interacting proteins in vivo. Our goal was to identify and characterize cDNA clones encoding proteins that form part of a growth factor-regulated transcription complex with the human c-fos serum response element (and the already cloned serum response factor). With an activation domain-tagged cDNA expression library, cDNAs were isolated encoding proteins that complexed with a serum response element in yeast. Our efforts identified a group of factors with similar structure (SAP-1, elk-1), which interact with the c-fos serum response element/SRF complex. Further work has established that the elk-1 protein is a target for a mitogen-activated protein (MAP) kinase (R. Marais, et al., Cell, 73:381-94, 1993; C. Hill, et al., Cell, 73:395-406, 1993). This recent work has accelerated progress in efforts to understand how signals generated by growth factors at the cell surface modulate patterns of gene expression. "The approach of using activation domain-tagged cDNA libraries to screen for proteins that interact with already characterized proteins is now being used with considerable success in many labs. One can imagine limitless situations in which this type of assay could be used by investigators to identify new interacting components in their systems. Substrates for kinases, ligands for receptors, components of signaling pathways, transcription factor complexes, and so forth are all obvious situations in which this approach has potential applications. Furthermore, tagging proteins with activation and DNA-binding domains is proving to be a popular approach for investigating in vivo interactions between already characterized multiprotein complexes. It will be interesting to see if activator-tagged library interaction screens of the type discussed here will be generally successful for proteins besides transcription/replication factors, especially those involving factors not normally localized to the nucleus." (The Scientist, Vol:7, #17, September 6, 1993) (Copyright, The Scientist, Inc.) ================================ NEXT: September 6, 1993 TI : BIOCHEMISTRY TY : RESEARCH (HOT PAPERS) PG : 16 L.A. Kohlstaedt, J. Wang, J.M. Friedman, et al., "Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor," Science, 256:1783-90, 1992. Thomas A. Steitz (Howard Hughes Medical Institute, Department of Molecular Biophysics and Biochemistry, Yale University): "Interfering with the activity of proteins specified by the human immunodeficiency virus (HIV) is one strategy for treating AIDS. The currently approved anti-AIDS drugs (AZT, ddI, and ddC) act through HIV reverse transcriptase, which incorporates them into the DNA viral copy being synthesized, resulting in DNA chain termination. An emerging approach to designing new pharmaceuticals is to use the three-dimensional structure of the target protein to craft small molecule inhibitors that fit the protein surface snugly and thus bind tightly. To engage in this protein structure-based rational drug design requires knowledge of the complete three-dimensional structure of the protein that is the target. The first HIV protein whose structure has been determined is the protease, which is now the target of extensive rational drug design efforts. "In our 1992 Science article we describe the first crystal structure of HIV-1 reverse transcriptase (RT) at a resolution sufficient to trace the course of the polypeptide backbone and gain new insights into its mechanism. The structure, even at this initial phase, will be of use for making and solving additional crystal forms of the enzyme, designing strategies to inhibit the enzyme, understanding the structural bases of mutations that render it insensitive to drugs, and developing new inhibitors. RT was co-crystallized with a noncompetitive inhibitor, Nevira-pine, a potential anti-AIDS drug that facilitated obtaining crystals of RT that diffract to at least 2.8 resolution. This crystallization strategy is now being followed by other laboratories to obtain improved crystals of this enzyme. Perhaps the most surprising and striking aspect of the structure of the heterodimer is the observation that the polymerase domains in the p66 and the p51 subunits have very different structures although they have the same amino acid sequence. We hypothesized that this asymmetric structure allows formation of the large binding site for tRNA that is the replication primer and the viral genome template. Use of the same polypeptide for more than one function allows viruses to increase the information capacity of their small genomes. "This structure determination of RT and the future structural work that it facilitates will be important in the rational design of new inhibitors of HIV RT and the modification and improvement of existing inhibitors. Chemists at Boehringer Ingelheim Corp. of Danbury, Conn., under the direction of Julian Adams, have made a modification to Nevirapine, guided by the structure, that now more effectively inhibits all of the RT mutant enzymes that are resistant to the unmodified Nevirapine. At best, the structure can only suggest ideas for new--and modifications of known-- inhibitors as well as eliminating many unfruitful directions of inhibitor design. However, the protein structure may serve to bias the random walk toward the synthesis of new pharmaceuticals and thereby increase the pace of their development." (The Scientist, Vol:7, #17, September 6, 1993) (Copyright, The Scientist, Inc.) ================================ NEXT: September 6, 1993 TOOLS & TECHNOLOGY TI : Antibody Suppliers Offer An Array Of Inventive Lab Tools AU : RICKI LEWIS TY : TOOLS & TECHNOLOGY PG : 17 Monoclonal antibodies (MAbs) haven't quite lived up to researchers' early expectations that they would be "magic bullets" in the clinic, zeroing in on abnormal cells and sparing the healthy ones. Nonetheless, in the laboratory, the number of applications of these preparations of pure, single-type antibodies are soaring. "From a research standpoint, MAbs will provide tremendous tools in identifying protein markers and changes in gene expression. >From a diagnostic standpoint, MAbs will be the best tools out there," says Claire Thuning-Roberson, director of the Goodwin Institute for Cancer Research Inc. and president and chief executive officer of its recently formed for-profit subsidiary Goodwin Biotechnology Inc., both in Plantation, Fla. And that's why antibody suppliers are very busy. "Time is valuable and critical to researchers. They often prefer an antibody that they can just grab off the shelf, rather than going through the labor and development time" needed to derive their own antibodies, says Douglas McAllister, president of ViroStat Inc., a Portland, Maine-based antibody supplier. Today, the diverse uses of MAbs include detecting respiratory viruses, pregnancy, drugs of abuse, and turf grass disease. MAbs are a continuing and growing presence in the basic life sciences and in biotechnology, their uses paralleling research trends. Why Antibodies? An antibody is a protein manufactured by an animal's immune system's B cells in response to a foreign molecule, or antigen. In vivo, the antibody response is polyclonal--different B cells zero in on different parts, or epitopes, of the target. The polyclonal antibody response sends several different types of antibodies into the blood serum. Polyclonal antibodies are valuable as tools to detect more than one antigen, such as the different proteins in the tangles of an Alzheimer's disease sufferer's brain, or mirror-image forms of an enzyme. MAbs have long been a favorite tool of biologists because of their great specificity. In 1975, Georges Kohler and Cesar Milstein at the Medical Research Council Laboratories, Cambridge, England, developed a way to obtain such antibodies by fusing a mouse's B cell, which supplies the single antibody type, to a mouse's cancer cell, which immortalizes the cell line (G. Kohler and C. Milstein, Nature, 256:495-7, 1975). A dramatic example of the specificity of a MAb was the so-called poppy seed defense. To investigate several questionable cases of military personnel whose urine tested positive for opioids, five soldiers at the Forensic Toxicology Drug Testing Laboratory at Tripler Army Medical Center in Honolulu gorged on breads and pastries whose generous garnishes of poppy seeds were carefully quantitated. Four of the five volunteers tested positive for opioids on standard tests. A MAb, however, helped exonerate them by differentiating more specifically among the chemical presences detected--it homed in on 6-monoace-tyl morphine, a metabolite found in the sweets but not in opioid drugs. But making a hybridoma cell that produces precisely the antibody type needed for a particular experiment is labor-intensive and time-consuming. And that's where companies come in--supplying antibodies (monoclonal and polyclonal) and providing contract services to nurture and select hybridomas, then scaling up secreted MAb products. According to Bret Wien, president of Research Diagnostics Inc., Flanders, N.J., a researcher's investment in developing a hybridoma may be worthwhile if the work requires large quantities of the antibodies, but the results may be unpredictable. "A lot of research centers make their own [antibodies]--but sometimes they find that the antibody doesn't do what they want it to do," he says. Another plus to purchasing antibodies--either standard or custom- produced--is that they can be labeled to a user's specifications. Commonly used conjugates in medical imaging applications include radiolabels such as indium-11, iodine-131, and technetium-99m. Goldmark Biologicals, Phillipsburg, N.J., provides a range of services for its colloidal gold conjugates, including supplying pre-gold-labeled antibodies or kits for researchers to do their own labeling, as well as offering custom-gold-labeling of antibodies. Gold labeling coats a suspension of fine gold particles with antibodies, making them visible in the light or electron microscope (W. Faulk and G. Taylor, Immunochemistry, 8:1081-3, 1971). The technique is sometimes combined with a silver enhancement step. Other common labels for antibodies include algal pigments called phycoerythrins and the standard compounds fluorescein and biotin. The great diversity of antibody companies covers almost any research need. Some suppliers' catalogs list hundreds of products, representing a veritable zoo. Organon Teknika Corp., Durham, N.C., for example, sells antibodies from guinea pigs, cats, rabbits, dogs, goats, swine, sheep, chickens, cows, horses, monkeys, and other animals. Accurate Chemical and Scientific Corp., Westbury, N.Y., offers an equally extensive catalog. Some companies focus their product line. "ViroStat specializes in infectious-disease antibodies. Our respiratory products are always in demand, such as respiratory syncytial virus, adenovirus, and influenza virus," says McAllister. MAbs from Repligen Corp., Cambridge, Mass., and Viral Testing Systems, Houston, bind to key HIV glycoproteins. And Stress Gen Biotechnologies Corp. in Victoria, British Columbia, Canada, specializes in stress-related proteins. Sufficient MAbs for 100 to 200 determinations typically cost a few hundred dollars. Custom MAb services run higher--but for good reason, as a look at services provided by the Berkeley Antibody Co. (BAbCO) of Richmond, Calif., illustrates. Birth Of A MAb In developing a MAb, researchers first immunize and test mice for an antibody response. Next, they isolate B cells from the animals' spleens and fuse them by exposure to polyethylene glycol with mouse myeloma cells. The resulting hybridomas can then be cultured in 96-well plates, and those secreting antibodies identified. After three weeks of growth, the researchers test supernatants from secreting hybridomas against various antigens to determine their specificities. The hybridoma selected is then expanded and cryopreserved. The total price tag for development and support of a hybridoma ranges from $7,000 to $14,000, and the process takes four to six months. Most projects require two spleens, each yielding about 100 million B cells. One in a million B cells successfully fuses with a cancer cell to form a hybridoma. BAbCO's clients are predominantly academic, says Tracy Clark, innovative products manager, although several biotech companies and larger pharmaceutical firms are included in the group. Clark heads a company effort to develop novel MAbs that will eventually be commercially available. "For example, we have generated antibodies against estrogen and progestin receptors, cyclic AMP, growth hormone, and prolactin," she says. For academic researchers with limited budgets, a popular option is the National Cell Culture Center in Minneapolis, a National Institutes of Health research facility located on the premises of Cellex Biosciences Inc. (Cellex staff received a five-year grant from NIH to establish and run the center.) "We are charged with doing large-scale cell culture for university researchers doing basic research. They send in a cell line, and we play with the media, use bioreactors, produce one gram or as much as 30 to 40 grams," of the MAb, says Mark Hirschel, director. "NIH picks up laboratory expenses, overhead, providing equipment. All the clients have to come up with are consumables, such as media and serum," he adds. Holding an NIH grant is not a prerequisite for using the center, but doing basic research is, "as long as ultimately the results of the research will be available in the public domain," he says. Humanization Some firms work to make animal MAbs more like human MAbs. "MAbs were going to be the magic bullet in the 1970s--but there were problems. You couldn't inject mouse antibodies into humans, because the body would generate antibodies to the antibodies. So now there are efforts to humanize MAbs, cutting up the antibody so it is still active, but the immune system isn't activated," says Wien. Researchers take many clever routes to humanizing MAbs, including creating mouse/human hybrid hybridomas, cloning human antibody genes in bacteria, or taking a murine antibody apart, amino acid by amino acid, and building a human version. Viral Testing Systems, for example, produces all-human MAbs against parts of HIV. The company's scientists take an antibody-producing B cell from an HIV-positive individual and fuse it with a cell from lymphoid tumor cell line. They then culture cells that produce antibodies while monitoring for the virus. The client gets HIV antibodies from a human hybridoma system, with no risk of viral contamination. The attraction of monoclonal antibodies is that their specificity can be applied to nearly any research situation to dissect the molecular underpinnings of biological phenomena. MAbs have become crucial tools in studying cytokine interactions, signal transduction, stress response, and carcinogenesis. One area currently of great interest is cell adhesion, which is mediated by cell adhesion molecules, or CAMs. These proteins and glycoproteins protrude from cells, orchestrating their interactions in a wide variety of processes, including cellular differentiation in the embryo, cancer biology, wound healing, inflammation, and blood clotting. For example, analysis of CAM activity reveals that the slow movement of white blood cells through capillary walls to the site of an injury is actually a complex, coordinated sequence of molecular attractions and attachments. The white blood cell is initially slowed by CAMs called selectins, which coat the cell, halting its turbulent circulatory rush by binding carbohydrates on the endothelial cells that form the tile-like wall of the capillary. Then, chemo-attractants secreted by the damaged tissue orient the white blood cell by activating other CAMs on it called integrins. Finally, integrins bind adhesion receptor proteins extending from the capillary wall at the site of the injury. This pulls the white blood cell between the endothelial cells, clearing a path to the injury site. MAbs can help researchers dissect this leukocyte trafficking and other cellular adhesion processes by isolating individual steps. And antibody firms are capable of supplying the MAb tools that can make this happen. Becton Dickinson Advanced Cellular Biology, San Jose, Calif., for example, offers several selectins, integrins, and other CAMs in its CAMFolio Monoclonal line of products. Another CAM supplier is Endogen Inc., Boston, which has an agreement with the Houston-based M.D. Anderson Cancer Center to commercialize adhesion MAbs. Selectins and integrins have been the objects of intense research interest for a few years. Newer are the cadherins, CAMs that control cell sorting during development. "Cadherins are a major player in morphogenesis, but the most exciting aspect is that down regulation of cadherins is associated with the invasiveness of tumors," says John Bliss, director of marketing at Zymed Laboratories Inc., South San Francisco, Calif., the U.S. distributor of anti-cadherin MAbs for TaKaRa Biomedicals Ltd. of Shiga, Japan. "You can use MAbs to cadherins to study the cause and effect of metastasis," he says. "It looks like metastasis is related to cadherin binding, but no one knows how yet." The MAbs became available in June. Ricki Lewis is a freelance science writer based in Scotia, N.Y. Her human genetics book will be published this fall. (The Scientist, Vol:7, #17, September 6, 1993) (Copyright, The Scientist, Inc.) ================================ NEXT: September 6, 1993 TI : ANTIBODY SUPPLIERS TY : TOOLS & TECHNOLOGY PG : 18 The following companies are among those supplying antibodies to research laboratories. Berkeley Antibody Co. (BAbCO) 4131 Lakeside Dr., Suite B Richmond, Calif. 94806 (510) 222-4940 Fax: (510) 222-1867 Products: custom-developed MAbs, $7,000-$14,000 Research Diagnostics Inc. Pleasant Hill Rd. Flanders, N.J. 07836 (201) 584-7093 Fax: (201) 584-0210 Products: various MAbs against immune system cells, $325-$400 for 200 determinations (purified) or 100 determinations (conjugated) Viral Testing Systems Corp. 600 Travis St. Houston, Texas 77002 (800) 323-2437 Products: 100 mg human anti-HIV MAbs, $375-$490 ViroStat Inc. P.O. Box 8522 Portland, Maine 04104 (207) 883-1491 Fax: (207) 883-1482 Products: MAbs to respiratory viruses, 100 mg $115-$140 Zymed Laboratories Inc. 458 Carlton Court South San Francisco, Calif. 94080 (800) 874-4494 Fax: (415) 871-4499 Products: anti-cadherin MAbs, 100 mg for $295 (The Scientist, Vol:7, #17, September 6, 1993) (Copyright, The Scientist, Inc.) ================================ NEXT: September 6, 1993 TI : MacArthur Fellows Swim Against Scientific Mainstream AU : LEE KATTERMAN TY : RESEARCH PG : 19 Over the last 13 years, the Chicago-based John D. and Catherine T. MacArthur Foundation has surprised and pleased 414 scientists, artists, writers, and social activists by providing them with a prestigious five-year, unrestricted MacArthur Fellowship. The program's goal is to honor individuals whose accomplishments and creativity indicate that this award is likely to spur them to still greater heights. "This is perfect," is how Margie Profet, one of this year's winners, puts it. Profet, 34, a research associate at the University of California, Berkeley, says her MacArthur Fellowship will give her the means to concentrate on finding evolutionary explanations of human physiological traits, such as menstruation, instead of having to support herself by working for other scientists and doing her own work on the side. A MacArthur Fellowship is also special because the processes of nominating and selecting awardees are completely confidential. Fellowship winners are given little insight into why they have been chosen, nor do they receive instructions for how to spend their grants, which range from $160,000 to $375,000, varying with the recipient's age. This year, 13 of the 31 new MacArthur fellows are scientists. What kind of researcher attracts the admiration of the foundation's secret selectors? Since the anonymous committee members cannot be interviewed, The Scientist asked the awardees themselves to speculate on what may have led to their selection. Doing Their Own Thing Several scientists speak of their willingness to swim against the mainstream. Take energy efficiency expert Amory Lovins, 45, director of research and cofounder of the Rocky Mountain Institute in Snowmass, Colo. Lovins and his colleagues at the institute examine problems related to energy, water, agriculture, transportation, security, and the links among them. He says that ideas bucking the conventional wisdom are an "overly abundant resource at the institute. We try to think of ways to solve one problem without making a lot of new ones. "Most of us here describe our hierarchy of needs as: save the world, have fun, and make money, in that order." Being selected is a validation of some "unusual" career choices for Ellen Silbergeld, 47, chief toxics scientist with the Environmental Defense Fund in Washington, D.C., and a professor of epidemiology and toxicology at the University of Maryland Medical School. Silbergeld studied history as an undergraduate, later taking up environmental medicine and neuroscience. Her position at the Environmental Defense Fund meant leaving the National Institutes of Health, where she had been a research scientist in neuroscience and reproductive toxicology for nine years. Silbergeld now uses real-world problems--for example, investigations of why lead causes brain damage--to guide her basic research in neuroscience. Social Consciousness Public policy concerns have been prominent in the scientific careers of several other 1993 MacArthur fellows, as well. Jane Lubchenco, a marine biologist at Oregon State University, says that, compared to 10 years ago, when she focused on teaching and basic research, she now spends much more time on applied problems at the "interface of basic research and human activity." Lubchenco, 45, recently headed the Sustainable Biosphere Initiative for the Ecological Society of America, a committee that set priorities for future ecology research according to the needs of pressing environmental problems. "We need to make some pretty drastic changes [in our approach to the environment] if we hope to achieve sustainability," she says. Frank von Hippel, 55, a physicist and a professor of public and international affairs at Princeton University, speculates that his work in developing a technical underpinning to nuclear disarmament probably played a big part in being selected for a MacArthur Fellowship. Another Princeton physicist who received a MacArthur Fellowship this year is 53-year-old Robert Williams of the university's Center for Energy and Environm