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Phone :(215)243-2205 // Fax: (215)387-1266 E-mail:garfield@aurora.cis.upenn.edu ================= THE SCIENTIST VOLUME 8, No:18 SEPTEMBER 19, 1994 (Copyright, The Scientist, Inc.) =============================================================== Articles published in THE SCIENTIST reflect the views of their authors and not the official views of the publication, its editorial staff, or its ownership. =============================================================== *** THE NEXT ISSUE OF THE SCIENTIST WILL APPEAR ON *** *** OCTOBER 3, 1994 *** *** *** ******************************************************* Subscription rates for the printed edition are: In the United States: one year $58, two years $ 94 Canada : one year $82, two years $142 All other foreign : one year/air cargo $ 79 one year/ airmail $133 THE SCIENTIST (Page numbers correspond to printed edition of THE SCIENTIST) FOR SEARCHING PURPOSES: AU = author TI = title of article TY = type PG = page NXT = next article ------------------------------------------------------------ TI : CONTENTS PG : 3 NEWS TRIALS AND ERRORS: The financial pressure put on by recent high-profile clinical trial failures of several biotechnology drug candidates has created a situation in which some biotechs are cutting corners to bring their products to market--ironically, dooming them to continued rejection by the Food and Drug Administration PG : 1 HELPING HAND: Biotechnology companies increasingly are turning to independent contract research organizations to take their drug candidates through the long, exhaustive process of regulatory approval PG : 1 ODD APPLICATIONS: As the mission of the Department of Energy's national labs shifts from military and nuclear research to civilian technology, multidisciplinary collaborations with industry, academia, and other government agencies are yielding some unexpected and sometimes extraordinary projects PG : 1 LINUS PAULING REMEMBERED: Friends, colleagues, and even his sometime adversaries are recalling Linus Pauling--who died last month at age 93--as one of the most flamboyant, outspoken, and influential figures of this century, within science as well as outside it PG : 1 IS ANYBODY LISTENING? A widely distributed consensus statement advocating increased United States government funding of biomedical research has largely been ignored by science policymakers and Congress. Nonetheless, the documentUs drafters are taking heart in the diversity and prestige of its more than 200 signatories PG : 3 OPINION THE BOOK OF THE FUTURE: It is within the realm of possibility, says biochemist Elie A. Shneour, that libraries and bookshops as we know them today will fade out of widespread use in the future, as the traditional book is replaced by teleprinted volumes, ordered via computer and printed out in the reader's own living room or study PG : 12 COMMENTARY: A recent effort by French Culture Minister Jacques Toubon to require reports on scientific research funded by his nation to be published only in French was stymied, much to the relief of The Scientist's publisher, Eugene Garfield, who over the years has called for recognition of English as the "lingua franca" of science PG : 13 RESEARCH DRUGS FROM THE DEPTHS: Marine scientists and colleagues in industry, academia, and government are combing the seas in search of organisms to produce drugs to fight a variety of diseases PG : 14 HOT PAPERS: Geneticist Jean Weissenbach discusses his lab's genetic linkage map; geophysicist Steven C. Cande reports on his geomagnetic polarity time scale; molecular biologist Matti Saraste expands on the crystal structure of SH3 PG : 16 CD-ROM JOURNALS: As journal publishing enters the electronic age, scientific societies are taking the lead in preparing their publications for CD-ROM, providing easy storage and interactive capabilities PG : 17 EARLY TO PRESS: With rapid advances of research and the traditional pressure to publish or perish, some journals are responding to the demand to slash the time it takes to publish articles PG : 21 MATHEMATICIANS Jean Bourgain, Pierre-Louis Lions, Jean- Christophe Yoccoz, and Efim I. Zelmanov have won the 1994 Fields Medals PG : 22 NOTEBOOK PG : 4 CARTOON PG : 4 LEADERS OF SCIENCE PG : 10 LETTERS PG : 13 CD-ROM PUBLICATIONS DIRECTORY PG : 18 NEW PRODUCTS PG : 19 CROSSWORD PG : 22 (The Scientist, Vol:8, #18, pg.3, September 19, 1994) (Copyright, The Scientist, Inc.) ---------- WE WELCOME YOUR OPINION. IF YOU WOULD LIKE TO COMMENT ON THIS STORY, PLEASE WRITE TO US AT EITHER ONE OF THE FOLLOWING ADDRESSES: garfield@aurora.cis.upenn.edu 71764.2561@compuserve.com The Scientist, 3600 Market Street, Suite 450, Philadelphia, PA 19104 U.S.A. -------- NXT: ------------------------------------------------------------ TI : From Stud-Finding To Badger-Spying, National Labs Pursue A Host Of New And Very Different Challenges Their refdefined mission is leading researchers at DOE labs to take on unusual--sometimes bizarre--assignments AU : Karen Young Kreeger At the Oak Ridge National Laboratory in Tennessee, researchers are taking the bang out of old munitions dumps, using a special group of TNT-eating microorganisms. Meanwhile, on a weapons-test site near Lawrence Livermore National Laboratory in Livermore, Calif., a remotely operated, minature robot helps biologists study the behavior of the American badger. Scenes like this are becoming more and more common at United States Department of Energy (DOE) labs as the facilities shift from their traditional focus on weapons development and energy investigations to new applications in a wide array of disciplines. They are responding to President Bill Clinton's mandate that the labs use their capabilities for more practical, economically worthwhile purposes (B. Goodman, The Scientist, July 25, 1994, page 1). In so doing, investigators from such diverse fields as materials science, computing and information management, laser technology, and energy research are applying their expertise to solve problems in disciplines and industries as varied as biomedicine, environmental science, and the automotive industry. It is not unusual for the projects to take researchers far afield from what they've been doing in the past. Supercomputing technology, for example, which was developed at many labs to facilitate weapons research, is now being used at Sandia National Laboratories in Albuquerque, N. Mex., by computer scientists working with New York-based Citibank Corp. to reduce bank fraud. And at Brookhaven National Laboratory in New York, scientists, along with their colleagues in other DOE and university labs, are working to link the many sectors of the textile industry--the largest employer in the U.S.--via a computer network. Collaborations like these have Ropened up new vistasS for lab scientists, says Roger Lewis, director of technology utilization in the DOE Office of Technology Partnerships in Washington, D.C. In LewisUs view, these joint ventures have "exploded" since the 1989 passage of the National Competitiveness Technology Transfer Act. Other DOE officials and researchers agree, adding that although the labs' involvement in developing "offshoot" or cross-disciplinary technologies has been evolving and expanding over the last two decades, an explicit emphasis on industry collaboration is a comparatively recent development. The 1989 act established the cooperative research and development agreement, or CRADA, the purpose of which is to foster collaborative research between government labs and industry. Specifically, DOE offers private-sector partners rights to patents and other intellectual property from the joint research. DOE currently is engaged in more than 600 CRADAs with more than 500 industrial partners. The firms involved run the gamut from small, local companies to international conglomerates. For example, Oak Ridge has licensed the microbiological technology to convert TNT into a non-toxic form to nearby EODT Services, a two-year-old bioremediation company. Meanwhile, Los Alamos National Laboratory in New Mexico is pooling resources with such giants as Digital Equipment Corp., headquartered in Maynard, Mass., and Cray Research Inc. of Eagan, Minn., to work in supercomputing. Scientists at DOE labs and their industry collaborators point out that there are many more examples of such swords- to-plowshares endeavors. In fact, one lab might even branch out to collaborate with the multibillion-dollar entertainment industry. Sandia is currently considering working on projects with Walt Disney World's Epcot Center. Although officials at both Sandia and Epcot refuse to discuss details at this time, a statement from Sandia does hint at the nature of potential relationships in the future. "Walt Disney World and Sandia National Laboratories have a common interest in providing an authentic vision of the future, enabled by science and technology. . . . We are conducting continual explorations about how these common interests can be furthered through a showcase opportunity to authentically represent the future to the public," said Pace VanDevender, director of Sandia's Center for National Industrial Alliances, in the statement. Retooling Radars One defense-related radar-technology project at Lawrence Livermore Laboratory has spawned two industry partnerships so far, with about a half-dozen other applications waiting in the wings to be developed. "It's a spinoff from the Nova laser program here at Livermore,S says electrical engineer Tom McEwan of the multipurpose Rpocket radarS he developed. The cigarette-pack-sized radar sends out electrical pulses at a rate of more than 1 million per second. These bounce off an object and echo back to the detector to be interpreted on a display screen. Key advantages of the device, according to McEwan, are its low cost and high margin of safety. The hand-held radar, he claims, can be made for less than $10, and "poses no health hazard at all. The average emission level from the unit is a million times lower than a cellular phone." Zircon Inc., a Campbell, Calif.-based producer of electronic hand tools, has licensed the technology to develop a stud- finder for the do-it-yourself home-improvement market. And Amerigon Inc. in Burbank, Calif., is developing the device as a high-tech car component to warn drivers of objects or people behind them, among other automotive uses. McEwan envisions that the unit could also be used to locate earthquake survivors buried beneath fallen debris; in the sports and fitness industry; in home security; and in biomedicine. In the health-care field, he foresees, the device could be used as a high-quality stethoscope, as a non-contact patient monitor, and for three-dimensional imaging of the human body. "I showed this to a couple of M.D.'s, and they just flipped," McEwan says. Underground Activity In addition to industry-lab collaborations, many intriguing partnerships also arise from in-house research needs at the labs. Livermore laser scientist John Christensen, for example, is applying his expertise to learn more about the nonhuman creatures that inhabit the lab's land. Because of programs required by other federal agencies, such as the Fish and Wildlife Service, Livermore must monitor how certain weapons-research projects affect wildlife living on test sites. Since most of the 7,000-acre, non-nuclear-explosive test site--called Site 300--is desert, many of the areaUs animals live in burrows to escape the heat, according to recently hired wildlife biologist Jim Woollett. This habit poses a problem for monitoring such Site 300 inhabitants as the American badger and burrowing owl. Woollett went to Christensen with the dilemma. "John said, `Tell me exactly what you want.' And he went from there. It was marvelous," Woollett recalls. The result was ChristensenUs design and manufacture of a remotely operated robot that Woollett sends on spying missions down the holes of Site 300 burrowing animals. The device is called the Miniature Optical Lair Explorer, or simply MOLE. "I kind of like to describe it as an all-terrain vehicle, except that instead of having a person on top, it has a camera that rotates 360 degrees," says Woollett of the 5 x 5-inch, tethered robot, which sends images in real time to a television monitor on the surface. MOLE runs on treads taken from a toy tank; its "headlights" are red, light-emitting diodes; and its "brain" is an electronic circuit board attached to the camera. In addition to the opportunity to learn about the animals, he says, the project has given "a new awareness to a large scale of people" at the lab that life does exist below the test ground's surface. Of the MOLE project's potential for changing weapons-testing protocols, Woollett declares: "It is something that's coming. I think that it is a consideration that has just been brought to the surface, so I think that we'll see more of it in the future." Thus far, the animals don't seem to mind the intrusion. "With the red light--Lord knows why--they really don't react in an aggressive manner. At least they haven't yet," reports Woollett. Leaner, Cleaner Autos Scientists at most DOE labs are working on another sort of vehicle. "The overall goal," says Mark Smith, technical group leader for the materials processing group at Pacific Northwest Laboratory (PNL) in Richland, Wash., "is to build clean, highly efficient vehicles." Teaming up with researchers at U.S. auto manufacturing giants Ford Motor Co., Chrysler Corp., and General Motors Corp., DOE lab scientists are working on the supercar of the future. Challenged by Clinton's 1993 Partnership for a New Generation of Vehicles initiative--with a goal to produce an 80-mile-per-gallon, environmentally friendly car in the next decade--federal and industry investigators are feverishly collaborating to meet that objective. To do this, DOE labs, other federal agencies, and industry partners are developing technologies that will reduce vehicle emissions; lighten the heavier components of cars, such as the power train; and produce standard and new types of cars that will run on alternative fuels. PNL, for example, has $6 million in CRADAs with the "Big Three" automakers for fiscal year 1994. Specifically, PNL researchers are working on such items as light-weight aluminum auto parts, a hydrocarbon trap to reduce polluting emissions, and laser holographic techniques to examine fuel- combustion efficiency. Most of DOE's labs have become increasingly involved in other environmental science-related areas in the last decade, with department officials describing the labs' work in this field as a growth area. Bioremediation, alternative energy, and air and water pollution monitoring are only a few examples. In a three-year, $1.8 million CRADA, for instance, Argonne National Laboratory in Illinois is joining forces with Advanced Research Development Inc. (ARDI) of Athol, Mass., to develop a new type of solar energy material called Lumeloid. The material's inventor, Alvin M. Marks, president and chief scientist at ARDI, predicts that the material could "become a major power source for the world." Lumeloid is a stretchable, polarizing film embedded with molecular diodes--devices for conducting electricity in one direction. "When we get finished," Marks predicts, "we will have a structure which will collect light photon energy and direct that energy in one direction." Researchers on the project envision that consumers will be able to buy a roll of Lumeloid--nicknamed "solar-cell-on-a- roll"--in local hardware stores, place it in a panel and, via current-carrying wires, plug appliances directly into the sun's energy. Lumeloid's main advantages, according to Marks, are that "it's extremely clean. There's no waste generated, and it's easy to make. The [potential] decreased cost per watt is dramatic. We figure a cost of about $5 per square meter for the film and an output of 500 watts per square meter [of film] in bright sunlight." The total investment cost for the consumer, he adds, works out to be about 30 to 50 cents per peak watt, compared with $1 to $1.50 per watt for coal or oil-generated power. Marks and collaborators at Argonne also say that with its theoretical efficiency of 70 percent energy conversion, Lumeloid will need to be only about one- fifth the size of conventional solar cells to get the same amount of energy output. Material Matters DOE and the biomedical community have been involved in collaborative research in a big way for nearly a decade, with DOE's substantial support of the Human Genome Project as one prime example. There are, however, dozens of other, less publicized innovations in bioscience that have also arisen from DOE projects, agency researchers and officials note. One such effort is taking place at the Lawrence Berkeley Laboratory in Berkeley, Calif. A group of materials scientists and chemists headed by Deborah Charych has developed a biomolecular film to quickly and easily detect the flu virus. One part of the bluish-colored, double-layered film contains sialic acid sugars--a type of molecule that all known flu strains bind to--and the other part serves as the film's backbone. When an infected sample is dropped onto the film, the flu virus binds to the sialic acid sugars. This binding changes the structure of the backbone, causing the film to absorb a different wavelength of light. This changes the film's color from blue to red, indicating that the sample contains the flu virus. The film also has the potential to be used as an assay for screening new inhibitor compounds. Jon Nagy, a chemist on the team, claims that this method offers a more direct, less expensive way to detect viruses over such methods as the enzyme-linked immunosorbent assay, or ELISA. Charych says that her group is in discussions with several biomedical diagnostics companies to develop and market the film, but that as yet "no formal deals have been established." For information about interdisciplinary research at DOE contact Roger Lewis, DOE, 1000 Independence Ave., S.W., Washington, D.C. 20585; (202) 586-5388. Fax: (202) 586-8854. E-mail: roger.lewis@mailgw.er.doe.gov. (The Scientist, Vol:8, #18, pg.1, September 19, 1994) (Copyright, The Scientist, Inc.) ---------- WE WELCOME YOUR OPINION. IF YOU WOULD LIKE TO COMMENT ON THIS STORY, PLEASE WRITE TO US AT EITHER ONE OF THE FOLLOWING ADDRESSES: garfield@aurora.cis.upenn.edu 71764.2561@compuserve.com The Scientist, 3600 Market Street, Suite 450, Philadelphia, PA 19104 U.S.A. -------- NXT: ------------------------------------------------------------ TI : Clinical Trial Reversals Forcing Biotech Firms To Refine Strategy Under pressure to reap return on investment, companies are seeking ways to ensure success in designing drug tests AU : SUSAN L-J.DICKINSON TY : NEWS PG : 1 This past July, Synergen Inc. suspended clinical trials of its anti-inflammatory drug candidate, Antril--being tested to fight sepsis--for lack of efficacy. Faced with the setback to its $100 million-plus investment, the Boulder, Colo.-based biotech was forced to lay off more than half its work force and shut down two major manufacturing facilities. Soon after, the firmUs stock price dropped almost 50 percent, and today, despite its reputation for solid research, industry analysts consider Synergen a prime takeover candidate. Synergen is not the only biotech firm that has suffered from such a debacle. In fact, since the beginning of this year, seven other such companies have been hammered by highly publicized clinical trial failures and seen dramatic drops in their stock prices as a result. With many biotechs under the gun to prove their com- mercial viability before returning to investors for another round of financing, industry participants and analysts report that some of the companies are cutting corners on the design of clinical trials--further undermining their products' chances of garnering Food and Drug Administration (FDA) approval. This Catch-22 situation underscores an urgent dilemma for the biotechnology industry, observers say. The competing forces of stockholder impatience for profitable products and the necessity of conducting exhaustively thorough testing (see accompanying story) are making their decisions about shepherding compounds to market more crucial than ever. The proper way to proceed is the subject of debate and second- guessing among corporate decision-makers and analysts. What is clear, however, is that hundreds of millions of dollars and even the future of some companies are riding on their decisions. "I find that biotech CEOs are fairly open to admitting that financial pressures are playing a role in how they run their companies," says Kenneth B. Lee, Jr., national director of New York-based accounting firm Ernst and Young's Life Sciences Practice, and coauthor of the company's prestigious annual report on the biotechnology industry. "These pressures do impact how clinical trials are approached," he adds, "and they're probably a negative factor." Analysts agree that these are tight times for biotechnology, an industry in which many companies have less than two years' cash on hand, according to Ernst and Young. The Medical Technology Stock Newsletter, published in Berkeley, Calif., recently reported that the Amex Biotech Index dropped nearly 50 percent during the first half of the year. And continuing failures in clinical trials have turned up the heat. Companies are trying a variety of strategies to face the challenge. Some are hiring contract research organizations to run clinical trials (see story on page 1); others are finding corporate partners to share the cost, risk, and potential reward of late-stage development. And some, evidently, are designing clinical trials that they hope will hasten the day that their product will be on pharmacy shelves. Nothing illegal or dishonest is occurring, experts are quick to reassure, and FDA regulations are in no way being compromised. Rather, it is in the design of the trials themselves--for example, how many extra patients to enroll to allow for natural attrition, or which indication to pursue approval for first--that some firms are trying to take shortcuts and, ironically, dooming their compounds to scientific failure. "Small, undercapitalized companies are doing this to save time and money," notes David Holveck, president and CEO of Centocor Inc., a biotech firm in Malvern, Pa. "There is no question about it." One way biotechs are trying to shave dollars and months from a project is by enrolling fewer patients in a study. Before a clinical trial begins, the company and FDA must agree on the parameters and design of the test: what clinical factors will be evaluated, and what percentage of patients showing a certain outcome will be considered statistically meaningful. But for a variety of reasons--ambiguous diagnosis, complicating symptoms, or death, for instance--some patients will always drop out of a study, so extra patients must be enrolled from the beginning. "You must empower the study with sufficient numbers if you hope to be able to answer the statistical question at the end," says Frank Martin, vice president and chief scientific officer for Liposome Technology Inc. in Menlo Park, Calif. He maintains that such a deficiency hurt Berkeley-based Xoma Corp.'s Phase III trial of the sepsis compound E5 last year. Biotechs are also trying to speed development time by enrolling patients from more sites, which would shorten the amount of time it takes to accrue a certain number of patients, and by designing hybrid Phase II/Phase III studies, rather than conducting them sequentially, according to Holveck. "Any time you compromise on numbers because of cost or time you are endangering your study," he warns. "You inject a higher degree of variable elements and heighten the risk that the trial will fail." Large drug companies will often conduct a number of Phase II studies to best determine which subpopulation of patients and what clinical endpoints to target, thus enabling them to design the full-scale Phase III trial with much less risk, Holveck says. Martin agrees, noting that a large company like Merck and Co. Inc., for instance, "would never consider skimping on the size of a trial, because [such a move] is fraught with danger. But this is where Wall Street enters into the equation. Wall Street doesn't want to wait for more people, because in this game, time is money." Clinical drug development has always been an arduous venture. Statistics from the Pharmaceutical Manufacturers Association show that it takes, on average, 12 years for a compound to move from preclinical testing through the three phases of FDA-regulated clinical trials, costing an average $359 million along the way. Moreover, the association estimates that for every 5,000 compounds originally evaluated in the laboratory, only one approved drug will result. Failure of a clinical trial can carry a big price tag. When Synergen stopped the Phase III trial of Antril, the $100 million the company had invested in the drug was exclusive of manufacturing costs, which included construction of what the firm billed at the time as "the largest pharmaceutical protein manufacturing plant in the world." The Antril failure forced Synergen to terminate 375 jobs--60 percent of its work force--and close down both its manufacturing plant and its Japan office. Synergen's stock plummeted 49 percent the day of the restructuring announcement. At the time Synergen was not criticized for the design of the Antril trialsQsufficient numbers of patients were enrolled, and the company was performing the trials in a targeted subpopulation of patients who appeared to most benefit from the drug. But some industry watchers suggest that the company should have pursued Antril's effectiveness in rheumatoid arthritis first, before tackling the complex and ill-understood syndrome of sepsis. "Companies are going after targets that are less understood in terms of basic pathophysiology, because those indications offer a higher potential payoff," observes Herbert Loveless, vice president for clinical development at Tanox Biosystems in Houston. Indeed, sepsis is responsible for an estimated 100,000 deaths in U.S. hospitals each year, and generates more than $10 billion a year in U.S. hospital bills--so it represents a lucrative target for the first company to get a therapeutic approved for use against it. "What has been missing," Loveless adds, "is a lot of the fundamental risk-assessment analysis. That is why a lot of people have lost a lot of money. If you pursue a smaller indication first, it gives you credentials--the company gains an approval, the experience of going through the approval process, and a revenue stream," notes Lee. "It's not a grand-slam home run, but it is a solid approach to building a business." Another factor exacerbating the financial losses of trial failures is that many small companies, such as Synergen, are developing expensive infrastructure--regulatory departments; clinical-trial design groups; manufacturing, marketing, and production operations--to support a single lead compound. "For Synergen it wasn't so much the failure per se," says John Groom, president and CEO of San Carlos, Calif.-based Athena Neurosciences Inc. "It was the accompanying developments built on the assumption that Antril would succeed. If they had waited to do all of the rest until after they had Phase III approval, then they would not have been burning $20 million per quarter." But developing these capabilities in sequence rather than simultaneously, according to Robert Thompson, executive vice president for research and clinical affairs at Synergen, would have added two years of development to the time between Antril's approval and when the drug reached patients. This would not only have delayed income, he points out, but also "would have been an unconscionable position for us [in treating] a life-threatening disease." Some observers maintain that negative results are inherent in the process. "It's the nature of drug development: You get bad news before good news," says James McCamant, editor of the Medical Technology Stock Newsletter. "It's just that the industry is still young. It hasn't developed a history of successes along with the failures yet, so people overreact." "Everyone knows that only one in 10 candidates make it from preclinical testing to a new drug application," acknowledges John Steuart, chief financial officer of Alafi Capital Co., an Emeryville, Calif.-based investment firm. "The problem is that naive investors are losing a lot of money because they overpaid for the stock. And many industry insiders say the concerns of anxious investors on the outside do play a role in scientific decisions, especially when the high-cost stages of advanced clinical trials are reached. "Science and business interests can be in conflict as I weigh whether to go forward with a project," Athena Neurosciences' Groom acknowledges. Clinical trial design requires a CEO to juggle several factors, including cost, potential market, and scientific potential, he says. The balance between these factors can shift in a tight economic environment. "There is no question that pressure from Wall Street enters into decisions on when to file for approval of a compound, or what calculated risks to take [in the design of a trial]," Martin points out. "I've seen it personally. In a meeting to set the time line for a trial, for example, the medical person will lay out the time frame in a best-case scenario." Companies are learning, however, that measures that offer savings may also increase the risk that a compound will not pass testing. "Rushing [clinical trials] is very shortsighted," says Larry Kurz, vice president of communications for Emeryville-based Chiron Corp. "It's almost suicidal." Susan L-J Dickinson is a freelance writer based in Philadelphia. (The Scientist, Vol:8, #18, pg.1, September 19, 1994) (Copyright, The Scientist, Inc.) ---------- WE WELCOME YOUR OPINION. IF YOU WOULD LIKE TO COMMENT ON THIS STORY, PLEASE WRITE TO US AT EITHER ONE OF THE FOLLOWING ADDRESSES: garfield@aurora.cis.upenn.edu 71764.2561@compuserve.com The Scientist, 3600 Market Street, Suite 450, Philadelphia, PA 19104 U.S.A. -------- NXT: ------------------------------------------------------------ TI : Contract Research Organizations Help Guide Compounds To Approval AU : Franklin Hoke TY : NEWS PG : 1 These days, many biotechnology and pharmaceutical firms facing the daunting road to market with a new drug are opting to get help from contract research organizations, or CROs. These service companies specialize in providing all or part of the necessary clinical trials; they also manage regulatory reviews. And their participation in the drug- development process is growing dramatically as the number of candidate compounds coming through the so-called research pipeline climbs. "Many biotech companies don't have the capabilities to do this kind of drug development," says Sara Creagh, an executive vice president with Quintiles Transnational Corp., the parent company of Quintiles Inc., a fast-growing CRO. Both are headquartered in Research Triangle Park, N.C. "Many times, even pharmaceutical companies don't have those capabilities, but little biotech companies--the new ones, the emerging ones--certainly don't." As the growing use of CROs enhances the commercial prospects for organizations, it is improving the career outlook for many individuals, as well, since--for scientists with Ph.D.'s in fields such as immunology, pharmacology, biochemistry, and physiology who also have clinical experience--the expansion of these companies represents a burgeoning area of new job opportunities. Fueling growth in the CRO sector is the enormous productivity of basic researchers at biotechnology and pharmaceutical companies, which has led to a steadily growing number of candidate drugs. It is the hoped-for result--a fully developed, profitable product--that is crucial to keeping the company afloat and its discovery- oriented scientists at their benches in the future. "That's key," says David Stump, senior director of clinical research at Genentech Inc., based in South San Francisco, Calif. "It's the business weUre in. If you're not developing drugs, all the elegant research in the world won't take you anywhere." He adds: "We're using biotechnology to produce breakthrough products. In order to clearly show that we have a breakthrough product, we have to show that it does something important in patients with disease. And the whole process has to work, from discovery to development to marketing." While recognizing the need to develop their innovative compounds in order to survive, many biotechs, especially smaller companies, may be reluctant to hire the staff necessary to plan and manage the full-scale safety and efficacy trials regulators demand. "They don't want to throw their money into building the infrastructure to develop their drugs," says CRO executive Creagh. "They want to create the drug, and then let the clinical development happen somewhere else. [CROs] let them put their resources into what they do best. A simple way to look at it is that they focus on the R in R&D, and we do the D." Among the leading CROs, in addition to Quintiles, are G.H. Besselaar Associates, Princeton, N.J.; IBAH Inc., Blue Bell, Pa.; PAREXEL International Corp., Waltham, Mass.; and Pharmaco LSR in Austin, Texas. Besselaar, the oldest and best established of the CROs, moved from small-scale consultancy status to being a full-fledged CRO in the mid- 1970s, according to CRO executives. The others grew substantially in the mid- to late 1980s and the beginning of this decade. In 1993, pharmaceutical and biotechnology firms spent about $25.6 billion on R&D, according to one industry estimate, of which approximately $17 billion went to clinical drug development. Of this amount, CROs claimed about $3.5 billion. Current annual growth rates at several leading CROs are estimated at between 20 and 30 percent by company officials. In addition to sparing the sponsoring company much of the work of drug development, CROs bring other advantages. Through specialization, they often possess clinical expertise the sponsor may not, which they are able to translate into streamlined protocol designs, efficient data collection and analysis, and complete regulatory-submissions packages, thereby shortening the overall time needed for development. With the average time needed to bring a new drug through the development process to market in the United States currently estimated at more than eight years--and with a drug's patent protection at a mere 17 years--this time saving can be critical. Moreover, industry observers point out, the pharmaceutical market today is international, requiring that sophisticated trials be designed that will be able to satisfy regulators in, say, Japan, Australia, North America, and Europe simultaneously. "There was a time five years ago when you'd do one development in Europe and you'd do one in the U.S.," notes Helen Davies, an M.D. who heads the clinical operations group at Quintiles. "Now, you do one drug development for a regulatory-submission package across the world." Providing Flexibility The larger CROs can conduct full-scale clinical trials from start to finish if asked to do so--designing the trials, recruiting investigators, managing data collection and analysis, and dealing with regulators--but this is not the only working model. The sponsoring company may want to plan and direct the entire campaign, using the CRO only for logistical support. Or the hiring company may need help with only one aspect of the process, perhaps the regulatory review phase or the more complex Phase IV trials. "The client doesn't say, `Here's a vial of white powder; call us when the drug's approved,' " says Jeffrey Lazar, an M.D. with a Ph.D. in pharmacology who is executive vice president at Pharmaco LSR. "It virtually never works like that now, although things are changing. A company may have a very rich pipeline, with more compounds than it can deal with. Its senior scientists are managing the development, but what they need are field extensions. So, they come to us for trial monitors or project managers." Genentech, for example, uses CROs in this way, seeking outside help with development while retaining ultimate control of the process. RWe use CROs for the tactical side of this much more than for the strategic side," says Genentech's Stump. "We believe strongly that our clinical scientists and our internal regulatory staff should take the lead in designing the trials, plotting out the developmental strategy for which trials will be done, when they'll be done, and where they'll be done. We'll then use a CRO as a tactical extension of us, for doing the work. "We have to have ownership of the strategy behind the process," he adds. "We've invested a lot into every product by the time it ever comes to clinical trial, so, we take a very active role." "We use [CROs] because we don't have the resources at a given moment to carry out our functions," says Richard Devlin, an immunologist and director of clinical research operations at Genetics Institute, based in Cambridge, Mass., "either because we have so many other projects--that's typically the case--or because we don't want to staff up for a project only to then have personnel on board that we might not need for some other project." Expanding Opportunities The need in the biotechnology and pharmaceutical industries for clinical researchers to design and manage trials and to shepherd regulatory submissions is expected to grow vigorously in the coming decade and beyond. At the same time, many of these companies have gone through recent cycles of downsizing, mergers, and layoffs, trimming their clinical personnel sharply in some cases. CROs are growing sharply in response to these moves, as is their own need to add new scientific and medical staff. "It's certainly a growing area," Quintiles' Davies says. "The Ph.D.'s tend to go into our medical and regulatory groups where they work on strategic-development plans and writing of final reports. And then we have a large statistical-analysis group." Biological scientists with statistical training are especially in demand at the CROs, because of these researchers' crucial role in interpreting clinical data. "Biostatisticians have a very important role in drug development, and we have a large biostatistics department," says Pharmaco LSR's Lazar. "Although all of us would like to think that a drug either works or it doesn't--it lowers blood pressure or it doesn't--life is, unfortunately, not that black-and-white." THE FDA APPROVAL PROCESS Typically, after the discovery of a new compound and preclinical laboratory and animal studies to show its safety and biological activity, a company will file what is called an investigational new drug (IND) application with the Food and Drug Administration (FDA). Unless FDA raises objections, Phase I human clinical trials can begin 30 days later. In these trials, small numbers of healthy volunteers, usually fewer than 100, help to assess basic safety and dosage levels. In Phase II trials, groups of 100 to 300 volunteers- -often with different illnesses or conditions--are given the new drug to determine target diseases and generate early data on effectiveness, safety, and dose-response curves. Phase III trials may involve thousands of volunteers, some healthy and some with the target disease or condition, in double-blind and placebo-controlled studies to establish clinical evidence of efficacy and safety. If all goes well, a new drug application (NDA) to FDA follows. Even if the drug is approved for use at this stage, Phase IV trials may yet be required to assess the drug's ongoing performance in actual patient populations. --Franklin Hoke (The Scientist, Vol:8, #18, pg.1, September 19, 1994) (Copyright, The Scientist, Inc.) ---------- WE WELCOME YOUR OPINION. IF YOU WOULD LIKE TO COMMENT ON THIS STORY, PLEASE WRITE TO US AT EITHER ONE OF THE FOLLOWING ADDRESSES: garfield@aurora.cis.upenn.edu 71764.2561@compuserve.com The Scientist, 3600 Market Street, Suite 450, Philadelphia, PA 19104 U.S.A. -------- NXT: ------------------------------------------------------------ TI : Scientists Remember The Outspoken, Linus Pauling AU : Neeraja Sankaran TY : NEWS PG : 1 Admirers and antagonists alike are remembering Linus Pauling--who died on August 19 at the age of 93--as one of the most flamboyant, outspoken, and influential figures of this century, within science as well as outside it. The two-time Nobel laureate, winner of prizes in chemistry in 1954 and peace in 1962, passed away at his home in Big Sur, Calif. He succumbed to prostate cancer, which he had been battling for about a year. "He was, in my judgment at least, the greatest and most original scientist--especially in chemistry--in the 20th century," says Norman Davidson, a professor, emeritus, of biology and chemistry at the California Institute of Technology, Pasadena, where Pauling had spent the bulk of his career from 1922 to 1963. A longtime friend and colleague of Pauling's, Davidson recalls the days when he was a junior member of Caltech's faculty and teaching assistant to Pauling for a beginner-level chemistry course. "I remember going to him before a lecture, and his announcing that he had just come up with an interpretation for the seemingly anomalous structure of hydrogen fluoride-- `sitting with my feet above my head for convenience'--and showing it to me," he remembers. According to Davidson, this sort of constant mental activity was typical of Pauling. Indeed, Pauling remained scientifically active throughout his life, treading a winding path that took him through many corridors of science from the early days of his experimental work on molecular structure of silicates and other minerals in the 1920s; through his Nobel-winning work in the early 1930s, when he applied the concepts of quantum theory and resonance to describe the nature of chemical bonds; on to the chemistry of a host of biological molecules, notably hemoglobin, antibodies, proteins, and DNA; and finally, his much-publicized and controversial interest in the beneficial effects of vitamin C. The author of many papers in these various fields, Pauling continued to publish scientific papers on his ideas until very recently. His latest publications appeared in widely- circulated, peer-reviewed journals: Proceedings of the National Academy of Sciences (91:897-99, 1994); and Science (91:983, 1994). Inspirational Insights "He had good instincts about what was fundamentally important in biology," says Norman Horowitz, an emeritus professor of biology at Caltech. "He emphasized that the nature of the hydrogen bond made it important in biological molecules like proteins and DNA." Pauling's contributions to the flourishing field of molecular biology are acknowledged by luminaries in that field. "He brought very deep insights into explaining biological systems in chemical terms," says Francis Crick, currently a distinguished research professor at the Kieckhefer Center of Theoretical Biology at the Salk Institute of Biological Studies in La Jolla, Calif. Crick, who along with James Watson and Maurice H.F. Wilkins won the 1962 Nobel Prize in physiology or medicine for determining the "double helix" structure of DNA, says that Pauling--who also worked on the problem but provided an incorrect model-- was a very important influence. "He understood the importance of modeling based on crystallographic data--each by itself provided only half the data you wanted for a structure," says Crick. "Linus put incomplete data together to show that sometimes, but not always, you could predict the right structure. He got the a- helix and b-sheet [of proteins] right; he was wrong about g proteins and DNA." In any case, Crick adds: "He showed us how to solve the problem." Horowitz credits Pauling with being the first person to show that the gene actually controlled the structure of the protein, through his work on the chemistry of hemoglobin in sickle cell anemia patients. "Until then, we knew that the disease was inherited, and that a gene had to be present for a protein," he says. "But until Pauling showed the sickle cell hemoglobin was different from the normal, we had no idea that the gene actually controlled the structure of the protein." "Pauling may not have been the first to think about or study a problem," says John D. Roberts, a chemistry professor at Caltech, "but he brought new insights which made all the difference in arriving at the final results." Former associates at Caltech, where Pauling served as division chairman for chemistry, also remember him as a brilliant administrator. "He was important in a political way--in the sense that he was responsible in getting a lot of notable scientists to come to Caltech," Horowitz recalls. Horowitz moved to the Pasadena school from Stanford University when Pauling arranged for his supervisor, George Beadle--a 1958 Nobelist in physiology or medicine--to be appointed to the biology division in 1946. Max Delbrck, who was a winner of the Nobel Prize in physiology or medicine in 1969, also came to Caltech because of Pauling, says Horowitz. Pauling himself left Caltech in 1963, owing to tension with the school's officials regarding his enthusiastic involvement in the peace movement. He vocally promoted pacifism in the late 1940s through the 1950s. He signed many peace appeals, including the famous Mainau Declaration in 1955, which called for an end to all war and was endorsed by more than 50 Nobel laureates. Pauling campaigned against the atmospheric testing of nuclear weapons, to which end he wrote and circulated the Scientists' Bomb-Test Appeal. This document was signed by more than 12,000 scientists worldwide and personally presented by Pauling to the United Nations in 1958; for his efforts he was awarded the peace prize in 1962. However, he received very little support for his activities from Caltech, where administrators demanded that he resign his 22-year chairmanship of the chemistry division in 1958. The reason they cited was that his involvement in these activities took him from his duties in the department. "I think it was disgraceful the way Caltech treated him then," says Crick, adding that he didn't learn about the details of the resignation and Pauling's departure from the school until many years later, at one of Pauling's birthday celebrations. After leaving Caltech in 1963, Pauling spent a few years each at the Center for the Study of Democratic Institutions in Santa Barbara, Calif.; the University of California, San Diego; and Stanford University before establishing in 1973 the Linus Pauling Institute (LPI) of Science and Medicine, a publicly funded, nonprofit research organization in Palo Alto, Calif. Pauling set up the institute chiefly to further research on vitamin C, a topic that had begun to excite his interest during his tenure at Stanford. He became convinced of the beneficial effects of very high doses of this dietary supplement and, at different times in the course of the next 15 to 20 years, promoted it as a cure for colds, cancer, and heart disease. The institute, like its outspoken founder, has found itself embroiled in some controversial incidents over the years: In 1978, its cofounder and president Arthur Robinson was fired over controversies regarding data on the instituteUs anti- cancer research, which led to prolonged lawsuits until 1983. In 1993, Mathias Rath, who came to LPI as the first director of cardiovascular research in 1990, filed a lawsuit against the institute to clarify the intellectual property of his discoveries on the connections between vitamin C and heart disease. The case is still in litigation. Although Pauling continued in his conviction in the value of vitamin C, and had been taking it in large doses since the 1970s, the scientific community remains equivocal on the subject of its effectiveness, with some researchers rejecting Pauling's claims outright. "Linus deserved his Nobel Prize in chemistry, he deserved his peace prize, but was completely deluded as to the uses of vitamin C," says Victor Herbert, a professor of medicine at the Mount Sinai School of Medicine in New York City, and director of the hematology and nutrition research lab at the Bronx Veterans Affairs Medical Center. "We have shown that vitamin C supplements are lethal to people with iron overload disease, and can actually cause certain cancers," he adds. Herbert's findings are summarized in a recent editorial titled "The antioxidant supplement myth" (American Journal of Clinical Nutrition, 60:157-8, 1994). "Linus and I were actually good friends until the late 1960s," Herbert says. "We worked together during the peace movement. We got along because we were both very outspoken. But then he got delusional about vitamin C." Crick attests to Pauling's outspokenness, as well, pointing out the scientist's willingness to speculate on a myriad of different scientific problems: "Sometimes he was wrong, sometimes he was right. But he was never afraid to stick his neck out." (The Scientist, Vol:8, #18, pg.1, September 19, 1994) (Copyright, The Scientist, Inc.) ---------- WE WELCOME YOUR OPINION. IF YOU WOULD LIKE TO COMMENT ON THIS STORY, PLEASE WRITE TO US AT EITHER ONE OF THE FOLLOWING ADDRESSES: garfield@aurora.cis.upenn.edu 71764.2561@compuserve.com The Scientist, 3600 Market Street, Suite 450, Philadelphia, PA 19104 U.S.A. -------- NXT: ------------------------------------------------------------ TI : Consensus Statement' Fails To Capture Attention In Washington, D.C. AU : Barbara Spector TY : NEWS PG : 3 A "consensus statement" advocating increased United States government funding for biomedical research--endorsed by more than 230 institutions, associations, and companies and distributed widely last May--has generally been accepted in polite silence by lawmakers in Washington, D.C. The chairman of the forum at which the document was drafted says he is disappointed by the lack of attention given it by legislators and the media. At the same time, he and other framers of the statement say they are gratified that so many diverse and prestigious organizations have put their support behind the effort. "I guess I had hoped that more congressional offices and more parts of the [Clinton] administration would have taken note of the breadth of the constituents that had thought it important to prepare a statement," says Leon Rosenberg, president of the Bristol-Myers Squibb Pharmaceutical Research Institute in Princeton, N.J. Rosenberg chaired the March 9 meeting sponsored by Research!America, an Alexandria, Va.-based research-advocacy organization, at which the declaration was conceived. The document begins with the assertion that "too many Americans are suffering and dying needlessly because, as a nation, we don't invest enough in medical research." It concludes with recommendations, including calls to "incorporate the promotion of medical research as an integral element of health-care reform" and "encourage, do not obstruct, the discovery and development of innovative and effective pharmaceuticals . . . by private industry." (For the full text, see The Scientist, May 30, 1994, page 12.) Research!America president Mary Woolley estimates that the consensus statement was distributed to 2,000 individuals; it was hand-delivered to every member of Congress. The lawmakers, however, have not been quoting from the text in major speeches or using it in other publicity-generating ways. Moreover, despite the influential science and business constituencies represented among its signatories, the document has not inspired any new legislation. Dave Kohn, an aide to Rep. John Porter (R-Ill.), says that his boss is in accord with the document's tenets: "John Porter agrees with Research!America that biomedical research is an important aspect [of health care] and deserves to have very strong support." But Porter has planned no action on the statement, according to Kohn. "He received it, he generally agreed with its emphasis, but he hasn't responded in any particular way or used it in any particular way." The statement also has not made a splash in journalistic circles. While articles about it have appeared in The Scientist (B. Spector, May 30, 1994, page 1) and Wash-ington Fax--Life Science (June 13, 1994), most news organizations have ignored it. (A search of the Lexis-Nexis database for reports on the declaration turned up blank.) William T. Golden, former cochairman of the Carnegie Commission on Science, Technology, and Government who served as special consultant on scientific activities to President Harry Truman, speculates that many do not view the statement as revolutionary because it was issued by parties that stand to gain from implementation of its recommendations. "All these organizations will benefit from greater funding for scientific research. If the Association of Methodist Ministers sent such a document, they'd get attention for it," he says, citing a hypothetical, fictional nonscientific organization. "Congressmen are used to lobbyists and institutions looking for funding. It's hardly news--it's~ `dog bites man.' " Bruce L.R. Smith, a science-policy analyst at the Washington, D.C.-based Brookings Institution, says decision- makers may be ignoring the document because of deficiencies in its approach. "It doesn't deserve any attention," he says. Compared with the physical sciences, "the life sciences have been just booming in research support. [The signatories] assume they've been singled out for problems when theyUre the ones that have been spared." The authors of the text, Smith says, are "trying to make a case for continued support at a time when there's going to have to be some downsizing." But Rosenberg doubts that policymakers are disregarding the statement because they object to it. "I would find it hard to believe that anyone would take umbrage with the way the statement was framed," he maintains. "Great effort was made to be statesmanlike, to be positive, to be brief, to be constructive." Observers also speculate that the lack of response may just boil down to bad timing. "Congress is so totally enveloped with health-care reform that anything not related is pushed [down on the list of priorities]," says Susanne A. Stoiber, director of the Public Health ServiceUs Office of Health Care Reform. "Research is just not something that is at the center of attention. [Legislators] are focused on big regulatory issues [and on reform details like an] employer mandate. Research has been sort of tagging along in all this, in what I think is a fairly successful way." Wide Distribution In addition to congressional representatives, the statement was given to key figures at the National Institutes of Health, the National Science Foundation, and other agencies. Several responded with letters to Research!America president Woolley. William R. Harlan, associate director for disease prevention at NIH, wrote that the statement "is an important manifesto that responds to the changing health care scene and the challenges faced by health research." Harlan says he intends to use the statement to respond to "people [who] call me from time to time and want background information [on] who supports a particular viewpoint. I would pull it out and quote from it [but] I wouldn't send people copies; it's not my part to do that. I wouldn't be circulating it widely or saying, `This is the direction we want to go.' " Ira C. Magaziner, senior adviser for policy development to the president, in a letter to Woolley, wrote: "You expressed concern about health research under the President's health care reform proposal. This is an issue that the Administration considered carefully while formulating the President's proposal." Magaziner's letter does not refer to the document. "It was disappointing that the only response from the White House failed to even mention the statement," says Rosenberg. "As a passionate advocate of biomedical research, I wanted the president of the United States to personally notice that effort." But Woolley notes that "Science in the National Interest," a White House report on U.S. science policy issued in August (B. Reppert, The Scientist, Aug. 22, 1994, page 1), parallels key issues in the statement. Specifically, she points to the three "strategic goals" in "Science in the National Interest," which she finds reflected in the Re- search!America document: economic growth and job creation; government that is responsive to citizens' needs; and world leadership in science, math, and engineering. "The biomedical research community is tracking very closely to the administration," she says. Some of the points made in the statement are likewise reflected in the Harkin-Hatfield Fund for Medical Research amendment to the health-care reform bill (No. S2357) introduced by Sen. George Mitchell (D-Maine). The amendment, originally proposed last spring by Sens. Tom Harkin (D-Iowa) and Mark O. Hatfield (R-Ore.), would set aside 1 percent of all monthly health insurance premiums for medical research above the NIH appropriation. The statement--which "emphasizes the need to encourage investment [in biomedical research] in the public and private sector'--notes Samuel C. Silverstein, president of the Federation of American Societies for Experimental Biology and a member of the group that drafted the document, is "absolutely congruent with Harkin-Hatfield." Silverstein, John C. Dalton Professor and chairman of the department of physiology and cellular biophysics at Columbia University, acknowledges that "Harkin and Hatfield proposed that idea long before" the Research!America text was written, and had received broad support in Congress prior to distribution of the statement. Yet he believes that the consensus document nonetheless should have received more attention from legislators. "It's the broadest consensus on anything to do with biomedical research ever achieved in this country," he says. "I don't know why it didn't do better." On the other hand, Carl Feldbaum, president of the Washington, D.C.-based Biotech-nology Industry Organization (BIO), which endorsed the document, says, "I don't have regrets; I didn't anticipate that it would be widely noted much outside our community. It's a pure policy statement; I don't believe it was ever intended as a press release." Names Added A signficant cause for optimism, say framers of the statement, is the growing list of organizations that have endorsed it. Names continue to be added, even though Research!America says it has stopped soliciting sign-ons. "In some sense, that means [the statement] has taken on a life of its own: by word of mouth, hand to hand, organization to organization, institution to institution," Rosenberg says. "It's become the thing to do now for organizations--when 200-plus organizations have signed, who wants to be off the list?" Research!America has circulated to signatories and potential en-dorsers a "Consensus Statement Action Packet," including a list of "ideas on how to maximize the impact." The group suggests that associations mention it in their newsletters, write to legislators about it, and contribute op-ed pieces on the subject to local newspapers, among other activities. As a result, the statement has been publicized in several organizationsU internal publications and at conferences. "We created this statement to give our members and those who are our partners lucid, clear messages to use as they make the case for research in health-care reform," explains Woolley. "I get good feedback; people are glad it's out there." "It's got legs to it," BIO's Feldbaum says of the statement. "It's got a long half-life. We can point to it again as wide and deep support [for biomedical research] in next year's budget." He adds that he would like to see "a new consensus to implement the statement in the form of real appropriations." Research!America president Woolley says no further action is planned at the moment: "I think we have done closest to the maximum we're going to with the consensus statement." But, she adds, "We're certainly open to new ideas." For example, "as [`Science in the National Interest'] moves more to an action phase, if there's a way for the consensus statement to tie in to that process, we'll certainly do so, but these things are going to have to evolve." Rodney W. Nichols, chief executive officer of the New York Academy of Sciences and a member of the steering committee for Research!America's Fall Outreach Campaign for New York, New Jersey, and Connecticut, says the act of signing the statement in itself constitutes a role in the health-care reform process. "It doesn't matter that there aren't any pyrotechnics; those signers will be more engaged in the debate about what the country wants [and thus] confronted with all the other forces in the debate. These participants, even in the act of signing on, are involved." (The Scientist, Vol:8, #18, pg.3, September 19, 1994) (Copyright, The Scientist, Inc.) ---------- WE WELCOME YOUR OPINION. IF YOU WOULD LIKE TO COMMENT ON THIS STORY, PLEASE WRITE TO US AT EITHER ONE OF THE FOLLOWING ADDRESSES: garfield@aurora.cis.upenn.edu 71764.2561@compuserve.com The Scientist, 3600 Market Street, Suite 450, Philadelphia, PA 19104 U.S.A. -------- NXT: NOTEBOOK ------------------------------------------------------------ TI : BACK TO BASICS TY : NEWS (NOTEBOOK) PG : 4 Back To Basics In AIDS Although last month's 10th International Conference on AIDS in Yokohama, Japan, yielded little in the way of good news concerning progress to date in efforts to combat the pandemic, some researchers were able to leave the meeting with the hope that future gatherings will be less gloomy. William E. Paul, head of the National Institutes of Health's Office of AIDS Research, announced a measure to encourage innovative approaches to basic AIDS research with federal funds gained by cutting current financial support of unpromising clinical trials of AIDS-related vaccines and drugs. The move was welcomed by, among others, Bernard N. Fields, chairman of the department of microbiology and molecular genetics at Harvard Medical School in Boston, who recently called for just such a realignment of funding priorities (Nature, 369:95-6, May 12, 1994). Fields says that the research reassessment represents a realistic acknowledgment of the difficulties impeding current investigations into HIV pathology, adding that researchers should not be discouraged by their lack of progress so far. "It's really an expectations issue," he says. "If you view the problem as simple, then you're going to be disappointed when you havenUt solved it. If, on the other hand, you define it in all its glory and complexity, then you can say realistically, `Where do we need to go next on the path to solving this?' It's just that the time frame for a problem with this many unknowns was a little too optimistic." (The Scientist, Vol:8, #18, pg.4, September 19, 1994) (Copyright, The Scientist, Inc.) ---------- NXT: ------------------------------------------------------------ TI : A NEW TWIST TY : NEWS (NOTEBOOK) PG : 4 A New Twist The unusual muscle arrangement of a Papua New Guinea lizardUs tail may revolutionize robotic design, say researchers. Kevin C. Zippel, a senior biology major at Cornell University in Ithaca, N.Y., studied the biomechanics of the Solomon Islands skink's tail for his senior honors thesis in comparative anatomy. He says the way the muscles are arranged is rare in the animal world and undocumented in animal tails, describing the muscles as looking "like stacks of snow-cones." In nature, the skinkUs grasping tail winds around branches like a corkscrew, allowing one part of the tail to be rigid while other parts are flexible. It can also twist and turn in every direction. The natural design of the skink's tail could be applied to retooling robotic appendages--which are currently able to move only back and forth, up and down, and sometimes rotate--say Zippel and his adviser, John E.A. Bertram, a professor of anatomy at Cornell. (The Scientist, Vol:8, #18, pg.4, September 19, 1994) (Copyright, The Scientist, Inc.) -------- NXT: ------------------------------------------------------------ TI : ENERGETIC ACTIVITY TY : NEWS (NOTEBOOK) PG : 4 Energetic Activity Using a powerful supercomputer, two scientists are working on cracking the code of one of nature's most basic processes--photosynthesis. Chi Ho Mak, a chemist at the University of Southern California, and physicist Reinhold Egger of the University of Freiburg, Germany, used the computer to model the energy-conversion process--molecule by molecule--of bacterial chlorophyll. Their model relies on quantum mechanics to explain the flow of electrons that is responsible for converting solar energy to biochemical energy in plants and other photosynthetic organisms. Because the molecular structure of chlorophyll is so complex, applying quantum theory to explain the mechanism of photosynthesis is difficult, with calculations taking up to one month to run, say the researchers. Mak and Egger say that their work will provide insights into making solar cells with conversion efficiencies approaching that found in bacteria--almost 95 percent. (The Scientist, Vol:8, #18, pg.4, September 19, 1994) (Copyright, The Scientist, Inc.) ---------- NXT: ------------------------------------------------------------ TI : THAT'S EDUTAINMENT TY : NEWS (NOTEBOOK) PG : 4 That's Edutainment Science education and high-tech game playing merge in a new multimedia form dubbed "edutainment" by its creators. Hyper- Quest Inc. in Sarasota, Fla., will release its CD-ROM "Astronomica: The Quest for the Edge of the Universe" in October. The electronic adventure disk, targeting school- aged children, combines game features with a dramatic exploration of the universe, portrayed in full-color, three- dimensional, animated graphics. "It involves Sarah, our heroine, looking for her professor father, who has shut down the Astronomica supercomputer, which contains all the secrets of the universe," says Joanie Stewart, a Hyper-Quest spokeswoman. Indeed, the fate of the universe may depend on Sarah's finding her father--and to help her, players must solve puzzles and answer trivia questions aided by mentors like Galileo and Einstein. Music and sound effects combine with simulated holograms and other sophisticated imagery as players visit planetary surfaces and black holes. Central to the educational aspects of the CD-ROM is an up-to-date astronomy encyclopedia provided on the disk into which players can take side trips at any time for accurate information about the planets, stars, nebulae, and other intergalactic entities they may run across in the course of their adventure. For information, call Hyper-Quest at (813) 365-9800. Fax: (813) 365-8324. (The Scientist, Vol:8, #18, pg.4, September 19, 1994) (Copyright, The Scientist, Inc.) ---------- NXT: ------------------------------------------------------------ TI : FULLERENE BONANZA TY : NEWS (NOTEBOOK) PG : 4 Fullerene Bonanza Scientists at the University of California, San Diego's Scripps Institution of Oceanography have discovered the largest and most widespread collection of natural fullerenes on Earth in a massive crater in Sudbury, Ontario. The crater was formed 2 billion years ago when an asteroid slammed into Earth, which coincides with scientistsU beliefs that natural fullerenes--soccerball-shaped molecules of carbon--are created as a result of high-energy events, such as lightning strikes and in the fiery interior of stars. The Scripps researchers believe that the fullerenes were either formed from the impact of the asteroid or came from the asteroid itself, in which case their discovery would mark the first detection of fullerenes on Earth derived from an extraterrestrial form of carbon. Analysis of samples from the 37-mile-long-by-19-mile-wide crater revealed the presence of fullerenes in the range of between 1 and 10 parts per million, amounts that rival the highest production levels of man-made fullerenes, according to the scientists. The investigators speculate the reason the molecules lasted such a long time--fullerenes are known to degrade quickly at fairly low temperatures when exposed to oxygenQis that they were embedded in ore deposits at the site. (The Scientist, Vol:8, #18, pg.4, September 19, 1994) (Copyright, The Scientist, Inc.) ---------- NXT: ------------------------------------------------------------ TI : ON THE FLY TY : NEWS (NOTEBOOK) PG : 4 On The Fly Researchers at the University of Wisconsin, Madison, Medical School have found two new receptors on the fruit fly cell membrane that they say have implications for human health. The receptors are docking sites--of sorts--that growth factor proteins must enter or attach to before they can perform their cellular function. Molecular biologist F. Michael Hoffman and colleagues found that the fly receptors also attach to human growth factor proteins. The function of this group of proteins--called the transforming growth factor-b family--is essentially the same across species; they instruct undefined cells in a developing embryo to become organized. In fruit flies, the result is eyes, wings, and legs; in humans, it is bone, tissue, and organs. Applying knowledge learned from the simpler fruit fly system, Hoffman and colleagues are looking into how the proteins can stimulate bone repair of severe fractures and affect progressive tooth decay in humans. (The Scientist, Vol:8, #18, pg.4, September 19, 1994) (Copyright, The Scientist, Inc.) ---------- NXT: ------------------------------------------------------------ TI : CHILLING RESULTS TY : NEWS (NOTEBOOK) PG : 4 Chilling Results National Institute of Standards and Technology (NIST) physicists have cooled cesium atoms to the coldest temperature ever recorded for matter. Using lasers to trap the atoms in an optical lattice, scientists chilled the cesium to 700 nanokelvins, or 700 billionths of a degree above absolute zero. This temperature--zero on the Kelvin scale and -273! on the Celsius scale--is the point at which atomic thermal motion theoretically ceases. Since the 1970s, researchers have been pushing the temperature record lower and lower in an effort to improve a variety of applications, including atomic time-keeping and lithographic processes used in the semiconductor industry. NIST scientists achieved this record from a technique borrowed from colleagues at the Ecole Normale Superieure in Paris. (The Scientist, Vol:8, #18, pg.4, September 19, 1994) (Copyright, The Scientist, Inc.) ---------- WE WELCOME YOUR OPINION. IF YOU WOULD LIKE TO COMMENT ON THIS STORY, PLEASE WRITE TO US AT EITHER ONE OF THE FOLLOWING ADDRESSES: garfield@aurora.cis.upenn.edu 71764.2561@compuserve.com The Scientist, 3600 Market Street, Suite 450, Philadelphia, PA 19104 U.S.A. -------- NXT: ------------------------------------------------------------ TI : The Leaders of Science The Readers of The Scientist PG : 10 "The Scientist is a cutting-edge, thought-provoking publication. It is very important reading." - A.L. Hillman ALAN L. HILLMAN, director, Center for Health Policy at the Leonard Davis Institute of Health Economics and associate professor of medicine and health care management, School of Medicine and the Wharton School, University of Pennsylvania, Philadelphia An adviser to the White House Task Force on National Health Policy Reform, Alan Hillman started his career as a physician. He soon grew frustrated with a health care system that ignored the broader socioeconomic context of medical practice and seemed to encourage waste, such as "prescribing MRI's for headaches when no test at all would be satisfactory." This led Hillman to pursue an M.B.A. degree and closely examine the appropriate allocation of health care resources. He now forecasts key trends in health care economics as director of the University of Pennsylvania's Center for Health Care Policy, a leading academic and policy research think tank. Hillman's goal is to provide decision makers with information they can understand and apply. He believes that scientists must be able to communicate in two wolrds: that of academic scholars as well as that of policymakers, who base their decisions on succinct summaries of data. He states: "If scientists take the time to translate their research into readable and concise material, their work would be even more meaningful than it already is." For Hillman, THE SCIENTIST meets two key requirements for effective communication between scientists and policymakers- -accuracy and readability. He says: "THE SCIENTIST is a cutting-edge, thought-provoking publication. It is very important reading." (The Scientist, Vol:8, #18, pg.10, September 19, 1994) (Copyright, The Scientist, Inc.) ---------- WE WELCOME YOUR OPINION. IF YOU WOULD LIKE TO COMMENT ON THIS STORY, PLEASE WRITE TO US AT EITHER ONE OF THE FOLLOWING ADDRESSES: garfield@aurora.cis.upenn.edu 71764.2561@compuserve.com The Scientist, 3600 Market Street, Suite 450, Philadelphia, PA 19104 U.S.A. -------- NXT: OPINION ------------------------------------------------------------ TI : The Teleprinted Book Of The Future: One Researcher's Flight Of Fancy AU : Elie A. Shneour TY : OPINION PG : 12 It would appear that the book as a cultural institution is in danger of extinction. Indeed, there are those who assert that computer technology has made the library obsolete. But while important books may be read by a diminishing minority, it is a demanding and significant minority that can be disregarded only at great peril. Now, it is true that the printing, publication, and distribution of books are clearly in crisis. While more books than ever are being published, Sir Thomas Gresham's law telling us that bad money drives out the good applies with equal force to books. It is an irony that, while modern technology has created electronic typesetting and printing--which, whenever used, have dramatically reduced the cost of book production--the intensive labor, paper, distribution, and marketing expen- ses have, at the same time, risen so steeply as to jeopardize the long-term survival of the printed book as a major component of modern civilization. Today, books are published and sold in increasingly large editions to amortize their cost and generate income. This means that insignificant books endowed with great popular interest and demand can be published at a profit, while works of substance--with, as a rule, much more limited appeal--must be sold at a far higher price to survive in the marketplace. A Risky Business The inevitable consequence is that individuals and libraries are discouraged from buying them. In turn, publishers and editors--in the effort to retain their jobs in an increasingly volatile industry run mostly by bean-counters-- must think long and hard before backing a meritorious but risky manuscript for publication. The classic contemporary example that comes to my mind is the definitive biography of Harry S Truman by David McCullough, whose raw manuscript, before finally finding a publisher and eventually gaining considerable popularity, was repeatedly rejected for being too long, for being of limited interest, and for tilling already well-plowed ground. But it is not principally trade manuscripts that suffer the worst ignominies. Far more important--and their fate, therefore, far more lamentable--are works of art, history, philosophy, fiction, poetry, science, technology, and medicine, the very books that civilized society has a stake in encouraging and disseminating. In the last analysis, these are the books that encompass the record, the memory, and the substance of human civilization. Coming To The Rescue The encouraging news, however, is that the technology endangering the book as it has existed since Gutenberg is also poised to come to its rescue. The printed book has attributes of great convenience compared with every other existing form of information storage and retrieval--no matter how sophisticated--and it is unlikely to be easily superseded. It is hard to imagine taking a microfilm reader to scan in bed, reading an overhead projection on the cool edge of a running brook, or curling up with a computer display in front of a crackling wood fire. No matter what the ingenuity of man can ultimately afford, the book remains a more universally human-oriented, concentrated, and comfortable device to convey the written word than anything else thus far invented. How to retain all the ergonomic advantages of the book while doing away with its defining economic burdens is the question that my imagination addresses here. Although it is premature to outline the precise technical details that are yet to be developed, my speculative flight of technological fancy--or at least an approximation or variation of it--is within the realm of possibility for the foreseeable future. A New Kind Of Browsing Imagine, if you will, that you are at home and at loose ends. There is nothing on television or radio that appeals to you. But one of last Sunday's newspaper book reviews intrigues you. Of course, this late in the evening, libraries and most book shops are closed. If your library or shop is by any chance still open, the likelihood of finding the desired book--too new to be a best-seller--on its shelves would be very slim. And even if you were lucky enough to locate a copy, you might want to leaf through it first before borrowing or buying it. Imagine further that, in addition to television, radio, computer, and stereo, there is in your living room or study a black box--not a huge black box, but sizable enough to accommodate my fantasy. It hosts a display screen and, positioned below it, a quite capacious rectangular slot. Adjacent to the black box is a keyboard very much like the one for your computer; and on a shelf above the box is a collection of books of different sizes and colors but without titles. A visitor to your study would be surprised to see, when taking one of them off the shelf, that all its pages are blank. Indeed, these volumes contain no words--for their pages are blank visual tapes of a sort, onto which temporary typography and graphics will be imprinted and read like any ordinary book, then erased after use. The Process To imprint a blank book, you will first type a request on the black box keyboard. Your request is relayed to one of many data banks that collectively access every published book on every available subject. Sources include, for example, the Library of Congress in Washington, D.C., as well as international repositories such as the Bibliothque Nationale in Paris, which, incidentally, is today in the process of computerizing its treasures. After the request for a particular book has been entered, instructions appear on the black box screen, requiring that you specify the size of the blank volume that you wish to have printed and, if desired, the colors you wish to see used in the printing. The instructions also inform you of the price you will be charged for this service. Next, you insert the appropriate blank book into the slot in the black box, and within a minute or so the book is ejected--its formerly blank pages now in proper order and filled with text and multicolored illustrations. For economic as well as technical reasons, the book will not be a permanent addition to your library, since after a time- -perhaps a few weeks--the type will fade and eventually disappear. Of course, you can "renew" your copy by teleprinting it again if you so desire, with the cost being charged to your account. For a permanent edition, you would have to purchase the kind of costly book that is available today. A Reasonable Expectation The implications of such a scenario are staggering. Libraries as we know them might be eliminated, becoming instead repositories primarily of the most significant and enduring works, including major reference volumes. The process would eliminate the high investment costs, inconvenience, and headaches of lending libraries. It would bring to each individual potential access to the total scope of the written word on every subject and in every language. For economic reasons, popular but ephemeral books would probably exist solely in this short-lived form, stored permanently only in central data banks in digitally compressed format. The technology involved might, for example, consist of an advanced form of liquid crystal, with paper-thin, pixel-sized capacitors retaining electrical charges displaying characters for a few weeks. But, in a fantasy, the details are unimportant. My point is that it is possible to conceive of a teleprinting technology that could emulate and exceed the scope of today's Internet. Sociologist Wilbur Schramm has provided a keen insight on the subject: It took some 5 million years for mankind to advance from primitive elements of a spoken language to the written word. It took 5,000 years to move from the written word on stone tablets and parchment to movable-type printing. From Gutenberg's Bible to television, less than 500 years elapsed. Each of these major advances in information handling took, on average, one order of magnitude less time than the preceding one. If this pattern continues, it seems reasonable to expect teleprinting of books to make its appearance shortly after the beginning of the 21st century. Elie A. Shneour, a physical biochemist, is chief executive and director of research at Biosystems Research Institute, San Diego. E-mail: eshneour@ucsd.edu. (The Scientist, Vol:8, #18, pg.12, September 19, 1994) (Copyright, The Scientist, Inc.) ---------- WE WELCOME YOUR OPINION. IF YOU WOULD LIKE TO COMMENT ON THIS STORY, PLEASE WRITE TO US AT EITHER ONE OF THE FOLLOWING ADDRESSES: garfield@aurora.cis.upenn.edu 71764.2561@compuserve.com The Scientist, 3600 Market Street, Suite 450, Philadelphia, PA 19104 U.S.A. -------- NXT: COMMENTARY ------------------------------------------------------------ TI : Multilingual Capability Is Essential In The Global Science Community AU : EUGENE GARFIELD TY : OPINION (COMMENTARY) PG : 13 It was disappointing to learn that linguistic chauvinism has reared its head once again in the form of a law proposed several months ago by Jacques Toubon, France's Minister of Culture. Ostensibly, the measure promoted the purity of the French language. Among its sillier provisions, the law banned in official communications thousands of words such as "weekend" that are in common use throughout France, but are not etymologically home-grown. Not so silly in its implications is the suppressive spirit of the law, an irony in a nation so traditionally identified with democracy and the "Rights of Man." Particularly galling (no pun intended) was another of the lawUs implications, which--if the statute had remained in effect--would require all scientific papers based on publicly funded research to be published in French. Considering my past involvement with this matter, I was pleased when FranceUs Constitutional Council overturned the law (which had, in fact, been passed by the French legislature) on grounds that it would infringe on individual rights. Toubon's hobbyhorse, if set to rocking, would have been a sorry expression of nationalistic fervor likely to be (a) unenforceable, (b) an embarrassing revelation of France's inability to integrate itself maturely into today's global community, and (c) a heavy setback regarding that nation's pursuits in the international science community. Actually, my annoyance with the likes of Toubon goes back more than a quarter-century. In the 1960s, when the Institute for Scientific Information was launching the Science Citation Index and I was explaining the concept to researchers around the world, I frequently lectured in France. I couldn't help feeling uncomfortable with the frowning faces I saw when I mispronounced a word or botched an idiomatic expression. In responding to questions, I usually relied on a translation provided by an obliging French colleague, to make certain I had grasped all of the colloquial nuances. In the 1970s, I perceived a change taking place: Questions from my French audiences were increasingly asked in English, and my colleagues--still impatient with my fractured French- -suggested that I present my lectures in English. I developed my own hands-across-the-sea device, beginning lectures with brief introductions in French, then continuing in English. Not only was I understood, but also it became apparent that, in France as elsewhere, the common language of the international science community had become English, as I noted in an essay titled "The English Language: The Lingua Franca Of International Science" (The Scientist, May 15, 1989, page 12). I've addressed this subject frequently over the years, occasionally stirring up a bit of controversy. Seventeen years ago, in a two-part Current Contents essay ("Le Nouveau Defi Americain," Essays of an Information Scientist, Philadelphia, ISI Press, Vol. 3, pages 88-102, 1977-78), I reported on the reaction of Michel Debre, former Prime Minister of France, to an article I had published the year before in the French journal La Recherche. In the article, I had suggested that French science--in part owing to linguistic nationalism--was too provincial and that its researchers should publish in English. Debre claimed that my suggestion posed a threat to French tradition "from which people could not recover" and warned that "a nationalist revolt" might ensue "if we follow Garfield" (La Recherche, 7:956, 1976). Well, the passage of time has proved Debre wrong. I took great pleasure in the French Academy of Sciences' decision to publish not only an English contents page, but also extended resumes in its Comptes Rendus; likewise my reaction to the routine inclusion of English texts in the journals of the Institut Pasteur. The academy, the institute, and French publishers such as Gauthier-Villars realize that survival in the international science arena is directly linked to their publishing in English. (One might only speculate on the outcome of the Montaigner-Gallo dispute had Montaigner and his colleagues published their important studies in French- language journals exclusively.) For Jacques Toubon and other Francophiles who still cling to their misguided linguistic dreams, I must repeat a challenge I made almost 20 years ago: The French language will not decline because French scientists publish in English--as long as French mothers and fathers continue to speak French to their children (even if they grow up to become scientists). But in order to become significant players in the international science arena, French scientists cannot refuse to learn English. Neither France nor the French language will ever suffer for having encouraged the development of a strong cadre of internationally recognized multilingual scientists. Moreover, the need for multilingual capability is not limited to the French. The pursuit of familiarity with, if not fluency in, languages other than one's own should be fundamental in the education of anyone hoping to participate effectively in the modern research world. For reasons that the French should understand very well, I urge American parents to introduce children to other languages as part of the cultural development they will need in order to succeed and fully enjoy careers in the global economy. (The Scientist, Vol:8, #18, pg.13, September 19, 1994) (Copyright, The Scientist, Inc.) ---------- WE WELCOME YOUR OPINION. IF YOU WOULD LIKE TO COMMENT ON THIS STORY, PLEASE WRITE TO US AT EITHER ONE OF THE FOLLOWING ADDRESSES: garfield@aurora.cis.upenn.edu 71764.2561@compuserve.com The Scientist, 3600 Market Street, Suite 450, Philadelphia, PA 19104 U.S.A. -------- NXT: LETTERS ------------------------------------------------------------ TI : NO COMMON GROUND AU : FREDERICK SPERLING TY : OPINION (LETTERS) PG : 13 No Common Ground Regarding the news article in the May 30, 1994, issue of The Scientist reporting on the perennial animal research debate [N. Sankaran, page 3]: Any new panel, at any level, official or nonofficial, is doomed to failure, since no common ground exists for discussion between researchers and animal rights activists. The quote by John McArdle, scientific adviser to the Jenkintown, Pa.-based American Anti-Vivisection Society- -"The ultimate goal is to replace animals with other methods, since we believe it is immoral and unethical to use animals"--plainly indicates that a rational discussion is impossible and agreement with the activists is wishful thinking. I pointed this out at a National Institutes of Health conference a few years ago. It is just as true now as it was then. That conference degenerated into name-calling and personal attacks by the animal rights participants. No agreement of any kind was reached. I personally resent being characterized as immoral and unethical by McArdle and his ilk. It might be interesting to investigate the sympathies and ties of these moral and ethical animal rights advocates with those who perpetrated terrorist acts against laboratories. It has been shown time and time again that appeasement is ineffective, as any act of appeasement with animal rights activists will be. Frederick Sperling Professor Emeritus, Pharmacology and Toxicology Howard University College of Medicine 5902 Mount Eagle Dr., #407 Alexandria, Va. 22303 (The Scientist, Vol:8, #18, pg.13, September 19, 1994) (Copyright, The Scientist, Inc.) ---------- NXT: ------------------------------------------------------------ TI : RADIOIMMUNOASSAY AU : FREDERICK C. GREENWOOD TY : OPINION (LETTERS) PG : 13 Radioimmunoassay With reference to the article by Rebecca Krumm in the May 16, 1994, issue of The Scientist on radioimmunoassays [page 17]: A possible quantitative measure of the current use of radioimmunoassay (RIA) might be the data prepared by the Institute for Scientific Information on the number of references, over the years, to "preparation of iodine-131- labeled human growth hormone of high specific activity." This was a preliminary report of the method published by W.M. Hunter and F.C. Greenwood in Nature, 914:495-6, 1962. This report and the full report, published by F.C. Greenwood, Hunter, and S. Glover, Biochemical Journal, 89:114-23, 1963, were both named Citation Classics. In Current Contents No. 26, June 26, 1989, page 16, I tried to explain the apparent paradox in an article entitled "Longevity of immunochemical methods that work." I spent much of my scientific life in England looking at hormone levels, first in urine and then in blood, and the labeling technique developed by Hunter and myself allowed us to develop the first growth hormone RIA. But it also allowed the beautiful technique of S.A. Berson and R. Yalow [Journal of Clinical Investigation, 38:1996, 1959] to come out of the closet of the very highly skilled research lab into more mundane practice. I have long since recognized that measuring systemic hormones in plasma is but one minor aspect of the endocrine system, and my research here in Hawaii, with my wife, Gillian D. Bryant-Greenwood, has focused on the even more challenging problems of examining autocrine/paracrine aspects of endocrinology using a human model system--the human fetal membranes. Nevertheless, I enjoyed very much your article. It has been fun to see a Cadillac method metamorphose into a Volkswagen Beetle! Frederick C. Greenwood Professor of Biochemistry Director, Pacific Biomedical Research Center University of Hawaii at Manoa 1993 East-West Rd. Honolulu, Hawaii 96822 (The Scientist, Vol:8, #18, pg.1, September 19, 1994) (Copyright, The Scientist, Inc.) ---------- NXT: RESEARCH ------------------------------------------------------------ TI : Researchers Plumb Depths To Fight A Wide Array Of Human Diseases AU : Karen Young Kreeger TY : RESEARCH PG : 14 As his boat rocks gently on the Caribbean Sea a few miles off the coast of Jamaica, William Fenical dons his scuba gear, slips overboard, and disappears into the warm waters. Although deep-sea diving is a pleasure for Fenical, taking the plunge, in this case, is by no means a recreational pursuit. Fenical is a marine chemist at the Scripps Institution of Oceanography in San Diego, and the object of this dive is to gather samples from the feathery seaplume, a type of coral. Back in his lab at Scripps, Fenical and colleagues will extract a substance called pseudopterosin from the soft- bodied creature. Working with clinicians, physicians, and other biomedical researchers, Fenical's industry collaborators will soon be conducting clinical trials using the compound to find new and better ways to combat inflammatory diseases. Throughout the world, marine scientists and their partners in industry, academia, and government are now searching for more effective drugs to treat a variety of diseases, including AIDS, cancer, and asthma. These international research collaborations draw on expertise from numerous disciplines: Ecologists, biochemists, oncologists, cell biologists, microbiologists, molecular biologists, pharmacologists, and clinicians are just some of the researchers involved in these efforts. "Our program represents marine science--the discovery side," says Fenical of his part in a multidisciplinary research team at Scripps, which is run by the University of California, San Diego. "We're the ones that get into the water and get the materials and have a big freezer back at the lab to store the stuff. We extract, isolate, and identify the material. And once we do that, we collaborate." Compounds have been extracted from marine plants and animals for centuries--Pliny the Elder described the toxic properties of sea hares in the genus Dolabella more than 2,000 years ago. Modern interest in drugs from the sea resurfaced about four decades ago. But the current wave of activity has welled up in the last five to 10 years, researchers agree. "The majority of drugs are discovered in nature, certainly historically. Drugs from natural sources have been the foundation of the treatment of human disease," says Fenical. But "why do we need to discover new drugs from the sea?" he asks. Because, say Fenical and others, some organisms that cause disease have evolved resistance to currently used drugs, and medical science has conquered only a small portion of human disorders. So what does the sea have to offer biomedicine that researchers can't get on the land or in a test tube? Fenical explains: "Marine animals have evolved two basic mechanisms to survive: physical defenses, such as spines and shells; and chemical defenses, which you find in soft-bodied animals that swim around in the ocean and are completely left alone." "These animals are noxious as hell. So we go to these highly chemically defended invertebrates, and for one reason--we know they're rich in unusual organic compounds." Fenical notes, however, that when his group began its investigations they foresaw no direct connection between defense and anti- disease activity. That they have found this relationship in some sea creatures was "just serendipity," adds Fenical. According to David Newman, a chemist at the Natural Products Branch of the Division of Cancer Treatment at the National Cancer Institute (NCI), such connections are just what NCI scientists are counting on to find treatments for several types of cancer as well as AIDS. One of NCI's first contracts associated with marine organisms was initiated in 1985 with the Australian Institute of Marine Sciences to collect plants and animals on the Great Barrier Reef. Two compounds derived from marine animals are currently in Phase I and II trials as anti-tumor agents, and others are "in the pipeline," says Newman. A Hot Field The potential for finding new, efficacious drugs from the sea is only one part of the overall surge in the larger field of marine biotechnology in the last decade. According to Oskar Zaborsky, president of the Institute for BioEnviron- mental Information and Studies (IBIS), a nonprofit organization located in McLean, Va., there are three very active areas in this growing discipline (see story on page 15). "One is the drug area--that sort of can't be denied--the second is specialty enzymes from marine microbes [M.E. Watanabe, The Scientist, May 30, 1994, page 14]. And the third one is aquaculture." Interest in marine biotech is "exploding,' says Rita Colwell, a marine microbiologist and president of the Baltimore-based University of Maryland Biotechnology Institute. "I wrote an article published in Science in 1983 [R.R. Colwell, "Biotechnology in the marine sciences," 222:19-24], and since then more than 1,000 papers have been published on marine natural products and various aspects of marine biotechnology. Also since then, funding in the United States has grown to about $80 million, if you take into account both federal and private industry." Total federal funding for marine biotechnology for fiscal year 1993 was nearly $50 million. The Marine Biotechnology Investment Act, which was passed in the House of Representatives, is also expected to pass the Senate at the close of the current session, according to David Attaway, director of the marine biotechnology program for the National Sea Grant College Program in the National Oceanographic and Atmospheric Administration. The act authorizes $20 million for each of its first two fiscal years and $25 million for each of two subsequent fiscal years to fund research in marine biotechnology. "Of course," says Attaway, "it's not often that authorized amounts reach appropriated amounts. This authorization sets the limit; the appropriation sets the amount." Congress has already increased the budget for the Sea Grant Program for fiscal year 1994 by $3.2 million, according to Attaway. This amount was earmarked for marine biotechnology research. NOAAUs Sea Grant conducted a special call for proposals to utilize these funds, receiving 256 grant applications requesting a total of $25 million for the first year of research. Attaway says that although the proposals were top-notch, Sea Grant could fund only 20 of them. A Broad Approach One way to find new drugs from any natural source is to gather samples and test them broadly on cultures of cells. Investigators from all over the world collect samples from marine systems--as well as rainforests, deserts, and just about every other ecosystem on Earth--and send them to NCI's Natural Products Repository in Frederick, Md., which houses more than 500,000 samples of plants, marine life, and microorganisms. Here they are stored, extracted, and screened for activity against a variety of tumor-forming cancers--such as breast, colon, and prostate cancer--for which there are no effective drugs. Preliminary testing against HIV using extracts from seaweeds is also under way. Kenneth Rinehart, a chemist at the University of Illinois in Urbana, is working with NCI on two compounds that may prove useful for a number of cancers. Didemnin B, a substance extracted from a marine animal called a tunicate and found in the western Caribbean Sea, is currently in Phase II clinical trials for non-Hodgkin's lymphoma and a type of central nervous system tumor. However, this extract--which is the marine compound at the most advanced stage of development for use as an anti-cancer agent--has remained in Phase II for five years because of debilitating side effects. "I'm on the edge," says Rinehart about the results so far in the didemnin B trials, "because patients' responses to it varied from complete to partial, with only about 20 percent of them showing this response. But people at the NCI were very pleased with that. "But, I'm not convinced that didemnin B is the best didemnin to be using. There is a new one called dehydro-didemnin with six times the potency as didemnin B," he says. This new tunicate compound is owned by a Spanish pharmaceutical company called Pharmarmor. ET 743--another compound derived from Caribbean tunicates-- is currently in preclinical trials and is "scheduled for Phase I trials after the first of the year," says Rinehart. Thus far, ET 743 has not "encountered any serious toxicology problems and its activity in vivo looks very good against leukemia, melanoma, ovarian sarcoma, and breast and lung cancers." Given these and other drugs that are in various stages of testing, Rinehart says he "is very hopeful" that several new compounds will be on the market in the coming years. Also taking a "shotgun approach" to testing marine compounds for new drugs is David Manyak, president and chief executive officer of Oceanix Biosciences Corp. in Hanover, Md., a biotechnology firm with about 30 employees. Manyak says his company obtained Novascreen--a receptor- binding assay--from Baltimore-based Nova Pharmaceutical Corp. more than a year ago to simultaneously screen dozens of substances derived from marine organisms. "We're most interested in screening for compounds to treat central nervous system disorders such as epilepsy, Parkinson's disease, and Huntington's disease," says Manyak. He says Oceanix is also interested in screening for anti- infective agents. To do this, the company has a research agreement with the University of Maryland Center of Marine Biotechnology (COMB). "We have an exclusive license to screen a collection of marine microbes from COMB. So we are building up copies of those microbes internally and that library numbers 5,000," says Manyak. "We are screening 40 to 60 receptors at once, so we think we'll have a very high probability of finding new drugs in a number of categories just because of the breadth of our library of microbes and screening activities." A Narrow Approach Rather than screen several types of marine organisms for potential antidisease activity, Fenical is concentrating his efforts on one type of organism, which he hopes can be used for a variety of applications. His group's main interest is identifying anti-inflammatory agents to treat such diseases as arthritis, asthma, and psoriasis. "When we became committed to investigating inflammatory diseases, we realized that we had focused our efforts very narrowly," Fenical says. "But that turned out to be a wise decision because we were able to bring together sufficient expertise to construct a well-informed research program. "Our goal is to create new drugs which are far superior than existing drugs. We obviously don't wish to reinvent the wheel." The substance at the most advanced stage of development in the labs of Fenical and colleagues is pseudopterosin, a chemical extracted from the seaplume, which he calls a "very potent anti-inflammatory." Pseudopterosin "will be in clinical trials within the next few months," he says. Fenical and his academic colleagues are working with Thomas Sharp, executive vice president and director of research and development at OsteoArthritis Sciences Inc., a two-year-old biotechnology firm with about 35 employees located in Cambridge, Mass. Sharp reports that pseudopterosin will soon be tested as a topical anti-inflammatory for dermatitis. "We expect to submit an investigational new drug application [to the Food and Drug Administration] at year end," he says. "The exciting thing about this project is that this drug has a novel structure and is unrelated to currently available drugs to treat dermatitis," Sharp says. "We believe it will have fewer side effects than currently available drugs." Environmental Connections The collaboration between biomedicine and marine sciences does not end at the lab or hospital doorstep. IBIS's Zaborsky says that scientists searching for new remedies to fight human disease are taking a growing interest in the burgeoning field of marine biodiversity and its preservation. The reason for this meeting of seemingly divergent disciplines, he says, is "partly the need for new drugs and, for myself and others, the shared conviction that there is a logical connection between biodiversity and biotechnology, which can be positively reinforced. "If people have drug-development programs, they can couple these with biodiversity programs, so what is found in nature can be preserved. What we [IBIS] try to do is look at that in combination with the National Cancer Institute and the National Institute of Allergy and Infectious Diseases." For example, Zaborsky recently submitted a proposal--with NCI--entitled RInternational Cooperation in Marine Biotechnology for Pharmaceutical Development and Preservation of Marine Biodiversity" to the State Department. The proposal requests funds to set up an international framework to link academic, industry, and government research in these areas. (The Scientist, Vol:8, #18, pg.14, September 19, 1994) (Copyright, The Scientist, Inc.) ---------- WE WELCOME YOUR OPINION. IF YOU WOULD LIKE TO COMMENT ON THIS STORY, PLEASE WRITE TO US AT EITHER ONE OF THE FOLLOWING ADDRESSES: garfield@aurora.cis.upenn.edu 71764.2561@compuserve.com The Scientist, 3600 Market Street, Suite 450, Philadelphia, PA 19104 U.S.A. -------- NXT: ------------------------------------------------------------ TI : MEETING GROUNDS FOR MARINE BIOTECHNOLOGISTS TY : RESEARCH PG : 14 For more information on marine natural products and pharmaceuticals, contact: American Society for Microbiology 1325 Massachusetts Ave., N.W. Washington, D.C. 20005-4171 Phone: (202) 737-3600 Fax: (202) 942-9340 (For the appropriate E-mail address, call the above number.) Michael Goldberg, Executive Director David Schlessinger, president American Society for Molecular Marine Biology and Biotechnology P.O. Box 51456 Pacific Grove, Calif. 93950 Phone: (408) 655-6214 Fax: (408) 373-1254 E-mail: fh.dap@forsythe.stanford.edu Dennis A. Powers, president A three-year-old journal, Molecular Marine Biology and Biotechnology (Blackwell Scientific Publications Inc., Boston), associated with ASMMBB, is the only United States journal that covers basic and applied marine biotech. Contact Powers for more information on the journal. American Society of Pharmacognosy Department of Pharmacognosy School of Pharmacy University of Mississippi University, Miss. 38677 Phone and fax: (601) 232-7026 E-mail: pgclark@vm.cc.olemiss.edu Alice Clark, president (The Scientist, Vol:8, #18, pg.14, September 19, 1994) (Copyright, The Scientist, Inc.) ---------- WE WELCOME YOUR OPINION. IF YOU WOULD LIKE TO COMMENT ON THIS STORY, PLEASE WRITE TO US AT EITHER ONE OF THE FOLLOWING ADDRESSES: garfield@aurora.cis.upenn.edu 71764.2561@compuserve.com The Scientist, 3600 Market Street, Suite 450, Philadelphia, PA 19104 U.S.A. -------- NXT: ------------------------------------------------------------ TI : THE MANY FACES OF MARINE BIOTECH AU : KAREN YOUNG KREEGER TY : RESEARCH PG : 15 Marine biotechnology covers a broad range of topics. According to a new book on the subject, entitled Marine Biotechnology, Volume I: Pharmaceutical and Bioactive Natural Products (D.H. Attaway, O.R. Zaborsky, eds., New York, Plenum Press, 1993), the discipline is defined simply as "the use of marine organisms or their constituents for useful purposes in a controlled fashion." Don Renn, director of exploratory technology at FMC Corp. in Rockland, Maine--a company that has been producing products from seaweeds for the biomedical research and development market for almost three decades--makes two main distinctions beyond the book's definition. He explains that marine biotech can mean either manipulating plants and animals genetically to obtain useful products from them such as in some aquaculture ventures; or using products derived from marine organisms for high-tech purposes such as gels for molecular biological techniques or in pharmaceuticals. Some institutions even divide their departments along the disciplines that encompass marine biotech. According to Madilyn Fletcher, director of the Center of Marine Biotechnology at the University of Maryland Biotechnology Institute in Baltimore, three areas of research cover the center's activities: aquaculture and fisheries molecular biology and biotechnology; natural products and processes; and marine pollution and bioremediation. The natural products component includes marine pharmaceuticals, she says. --K.Y.K. (The Scientist, Vol:8, #18, pg.15, September 19, 1994) (Copyright, The Scientist, Inc.) ---------- WE WELCOME YOUR OPINION. IF YOU WOULD LIKE TO COMMENT ON THIS STORY, PLEASE WRITE TO US AT EITHER ONE OF THE FOLLOWING ADDRESSES: garfield@aurora.cis.upenn.edu 71764.2561@compuserve.com The Scientist, 3600 Market Street, Suite 450, Philadelphia, PA 19104 U.S.A. -------- NXT: HOT PAPERS ------------------------------------------------------------ TI : GENETICS TY : RESEARCH (HOT PAPERS) PG : 16 J. Weissenbach, G. Gyapay, C. Dib, A. Vignal, J. Morissette, P. Millasseau, G. Vaysseix, M. Lathrop, "A second-generation linkage map of the human genome," Nature, 359:794-801, 1992. Jean Weissenbach (Genethon, Evry, France): "In 1991, the French Muscular Dystrophy Association and the Center for the Study of Human Polymorphisms (CEPH) created Genethon, a laboratory whose goal was to provide the scientific community with human genome maps that would hasten the localization and identification of human disease genes. "The first version of the Genethon genetic linkage map was published in October 1992. Its advantage lies in the fact that it is composed of 813 simple tandem repeats (microsatellites), notably (CA)n motifs, which are widely distributed throughout the human genome. As first shown by J.L. Weber and P.E. May (American Journal of Human Genetics, 44:388-96, 1989), these markers are highly informative in that they are highly polymorphic, which means that an individual is likely to possess two different alleles for a microsatellite at a given locus. Genetic mapping was previously based on other kinds of markers, such as restriction fragment-length polymorphisms, which are frequently biallelic and have limited usefulness in tracing inheritance patterns. This map has already been used for localization of genes for at least 15 genetic disorders that are caused by single-gene defects, such as colorectal cancer, glaucoma, and one form of dwarfism. "We recently published a second version of this map consisting of 2,066 markers (G. Gyapay et al., Nature Genetics, 7:246-339, 1994) and are working on a third and final version, which will contain about 5,000 microsatellites. Using these maps as tools, the scientific community should now be able to rapidly localize any disease due to a single defective gene and begin to study disorders that result from defects in more than one gene. Markers from this linkage map have already been integrated into CEPH/Genethon's physical map, which consists of overlapping YAC (yeast artificial chromosome) clones that span about 90 percent of the human genome (D. Cohen, I. Chumakov, J. Weissenbach, Nature, 366:698-701, 1993). These maps can now be used as starting points for positional cloning strategies, which will lead to precise identification of guilty genes and, subsequently, to an understanding of their function." (The Scientist, Vol:8, #18, pg.16, September 19, 1994) (Copyright, The Scientist, Inc.) ---------- WE WELCOME YOUR OPINION. IF YOU WOULD LIKE TO COMMENT ON THIS STORY, PLEASE WRITE TO US AT EITHER ONE OF THE FOLLOWING ADDRESSES: garfield@aurora.cis.upenn.edu 71764.2561@compuserve.com The Scientist, 3600 Market Street, Suite 450, Philadelphia, PA 19104 U.S.A. -------- NXT: ------------------------------------------------------------ TI : MOLECULAR BIOLOGY TY : RESEARCH (HOT PAPERS) PG : 16 A. Musacchio, M. Noble, R. Pauptit, R. Wierenga, M. Saraste, "Crystal structure of a Src-homology 3 (SH3) domain," Nature, 359:851-5, 1992. Matti Saraste (European Molecular Biology Laboratory, Heidelberg, Germany): "Many proteins that function in the signaling pathways of animal cells or yeast are made up of distinct domains. These are common to a number of proteins and have structural or functional independence. The SH3 domain is one such mobile protein module. "SH3 was discovered by comparing amino acid sequences among several different signaling and cytoskeletal proteins. It was called `Src-homology 3,' after Src, the prototype protein tyrosine kinase. The SH3 domain is often accompanied by the SH2 domain, which is made up of about 100 amino acids and recognizes a peptide containing a phosphorylated tyrosine in a specific sequence environment. SH2 is a module that is used for specific interactions between phosphorylated receptors and their downstream partners in signal transduction. SH3 seems to be involved in protein- protein interactions that are intrinsic to the activating and inactivating processes of signal transduction and cytoskeletal dynamics. However, its specific function is not as well characterized as that of SH2. "These common protein domains often have a small size, which--together with their biological importance and ability to be expressed in bacteria--has encouraged their study among structural biologists. We determined the first SH3 structure using X-ray crystallography. The work was mostly done by two Ph.D. studentsQAndrea Musacchio, in our group, and Martin Noble, working with Dr. Rik Wierenga. This report was followed by a cascade of homologous structures obtained by both X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy. All SH3 domains have the same basic core, made up of two orthogonal b-sheets. They vary in their surface loops, which have different sizes and conformations. "In our paper we commented on how the amino acids that are evolutionarily conserved within this family come together in space to form a smooth platform at one end of the molecule. This surface path is particularly rich in aromatic amino acids. We postulated that this surface is involved in binding another protein, forming the basis for defined interactions between some of the signaling molecules. The li-gand that binds to the aromatic surface appears to be a proline-rich peptide. Multiple adjacent proteins form a rigid peptide that places the flanked or terminal amino acids in fixed positions in space. These nonproline residues may give the specificity to the SH3-binding motifs. "The molecular details of the SH3-mediated interactions are not yet known. But the structural information helps in the design of accurate biochemical experiments that can test current models and hypotheses." (The Scientist, Vol:8, #18, pg.16, September 19, 1994) (Copyright, The Scientist, Inc.) ---------- WE WELCOME YOUR OPINION. IF YOU WOULD LIKE TO COMMENT ON THIS STORY, PLEASE WRITE TO US AT EITHER ONE OF THE FOLLOWING ADDRESSES: garfield@aurora.cis.upenn.edu 71764.2561@compuserve.com The Scientist, 3600 Market Street, Suite 450, Philadelphia, PA 19104 U.S.A. -------- NXT: ------------------------------------------------------------ TI : GEOPHYSICS TY : RESEARCH (HOT PAPERS) PG : 16 S.C. Cande, D.V. Kent, "A new geomagnetic polarity time scale for the late Cretaceous and Cenozoic," Journal of Geophysical Research, 97:3917-51,1992. Steven C. Cande (Scripps Institution of Oceanography, University of California, San Diego): RThe geomagnetic polarity time scale is a cornerstone of the geosciences, providing the means for precise global correlation and the chronological framework for all modern time scales. The first geomagnetic polarity time scale that covered the entire Cenozoic era was constructed in the early days of the plate tectonic revolution in the late 1960s from a few carefully selected marine magnetic profiles (J. Heirtzler et al., J. Geophys. Res., 73:2119-36, 1968). This time scale not only was extremely valuable but also proved to be very durable. Although there have been many revisions to the time scale since 1968, they involved--for the most part--applying new calibration points to the magnetic anomaly spacings determined in the original time scale. "Over the years it became apparent that the original anomaly spacings that formed the core of the Cenozoic time scale needed to be revised. For example, global studies of seafloor spreading rates were finding synchronous spreading rate changes in all the oceans. Although such a phenomenon might be real, we speculated that it could also reflect errors in the time scale. Consequently, we systematically reanalyzed marine magnetic profiles from several different oceans, and attempted to derive a more accurate set of magnetic anomaly spacings--the basic starting point for calculating a new time scale. Our analysis included looking for evidence of very short polarity reversals, which show up as `tiny wiggles' in the magnetic anomaly record. We then came up with a carefully selected set of calibration points and derived a revised time scale. "We noted in our paper that with our revised time scale many of the previous indications of synchronous spreading rate changes have been eliminated. Other geoscientists who use our new time scale have since found that it gives more reasonable sedimentation rates. Because of this apparent improvement in accuracy, the time scale has been widely used. "Recently other researchers have independently derived a magnetic polarity time scale for the late Cenozoic from the study of high-resolution climate records, assuming that their variability is forced by the well-known variations in the Earth's orbital parameters. One direction of our future research involves reconciling and merging the results of the `astronomical' time scale (which is based on high-resolution climate records) with our time scale, which is based on marine magnetic anomalies." (The Scientist, Vol:8, #18, pg.16, September 19, 1994) (Copyright, The Scientist, Inc.) ---------- WE WELCOME YOUR OPINION. IF YOU WOULD LIKE TO COMMENT ON THIS STORY, PLEASE WRITE TO US AT EITHER ONE OF THE FOLLOWING ADDRESSES: garfield@aurora.cis.upenn.edu 71764.2561@compuserve.com The Scientist, 3600 Market Street, Suite 450, Philadelphia, PA 19104 U.S.A. -------- NXT: TOOLS & TECHNOLOGY ------------------------------------------------------------ TI : New Journals On CD-ROM Help Scientists To Build Personal Libraries AU : Franklin Hoke TY : TOOLS & TECHNOLOGY PG : 17 Sitting at her computer, a biochemist studies an on-screen page from the journal Protein Science, published on CD-ROM by the Protein Society of Bethesda, Md. Embedded in the article text is a reference to a figure, with a special icon in the margin at that point. With a double-click of the computer mouse on the icon, a full-color image of a protein structure appears. A few additional commands allow the molecule to be rotated in space, tumbled in any direction, for a different view. Elements of the molecule can be selectively highlighted and intramolecular distances measured. The animated, interactive protein image is called a kinemage and is an eye-catching example of the new capabilities that digital publishing--especially of scientific journals on CD- ROM--now offers biological researchers. The added features extend the existing advantages of CD-ROMs, such as the fact that scientists can quickly search their electronic journal holdings by title, author, or keywords, which they cannot do directly with their print copies. Also, because of the large storage capacity of CD-ROMs--about 650 megabytes-- researchers building a personal library of journals on disk can save valuable space in their offices or labs. And CD- ROMs on the shelf rather than in the university library are accessible and complete--issues are never missing. In just the past few years, the number of scientific societies publishing journals in electronic form has jumped (see accompanying list). In addition, the sophistication of such publications has improved greatly over earlier efforts, many of which were little more than basic American Standard Code for Information Interchange (ASCII) files, simple computer text packages unable to handle equations and scientific symbols. Several societies have CD-ROM journal projects in development, scheduled to reach members soon. Although commercial publishers are interested in facilitating electronic publishing, in many cases it is scientists and their professional societies who are tkaing the lead in developing innovations digital journals. "I'm a working scientist," says Stephen H. White, a professor of physiology and biophysics at the University of California, Irvine. White also expends a considerable amount of his energies as the electronic publishing coordinator for Protein Science. "The only reason I do this is that I'm absolutely convinced that, at this early stage [of electronic publishing], working scientists have to be involved to create products that will really serve us well. This electronic medium has to be mroe useful and more convenient thatn the print medium. If we make it that way, then it will thrive. And if we don't make it that way, it will die." For the most part, the journals are being designed--and priced--with the individual bench scientist in mind as the user, rather than, say, academic libraries. Most disks, usually containing one year's journal issues, are less tan $100 for society members. Librarians, in fact, are somewhat skeptical of the CD-ROM's staying power as an electronic medium, anticipating and preferring journals to be published over the linked computer systems of the worldwide Internet, according to scientists and society officials. "Our concern was that this be a useful product to the researcher at the bench," says Walter Peter, deputy executive director of the American Society for Microbiologoy (ASM), Washington, D.C., which provides all 11 of its journals on CD-ROM. "We're a membership organization with about 40,000 members, and we designed these products for them. Not all libraries are entralled with the notion of getting subscriptions on CD-ROM. Most of them would prefer to have direct line or to continue with print." In time, scientific journal publishing is expected to graduate to the Internet. However, the virtues of journals on CD-ROM for individual scientists are likely to sustain the disks' viability for some time, according to scientific publishers. "People are talking about CD-ROM as an interim product on the way to an Internet interface," observes Charles Muller, publishing projects manager, in Woodbury, N.Y., for the American Physical Society (APS), which is headquartered in College Park, Md. "But CD-ROM is still a very practical way for individual subscribers to build a personal library, to be able to have many issues of a journal on one disk that just sits very neatly on your shelf." Muller notes that APS is working to develop CD-ROM versions of two of its journals--Reviews of Modern Physics and Physical Review Letters. Searching For Standards One difficulty for the scientific user is that standards have not been established for the software programs used to search and display the information in electronic journals, as well as for the supporting file formats--although a few combinations of programs and file formats are beginning to emerge as dominant. "One of the biggest problems we face is that organizations that are involved in producing CD-ROMs all seem to want to have their own viewer interface," White points out. "You don't want to install a different search engine on your hard drive for each journal that you get on CD-ROM," says Victor Bloomfield, a professor of biochemistry at the University of Minnesota, St. Paul, and editor of Biophysical Journal, published by the Biophysical Society, Bethesda, Md. "One wishes that there were some standards." Bloomfield says that the society is currently participating in an experimental CD-ROM publishing project with the journal's printing company to assess which combination of search and display software will best serve the readers. A trial disk containing three months of the journal was sent in April to a group of subscribers. According to Carol Gross, a research scientist in the biochemistry department at Minnesota who has been tallying responses to the disk, users want a more attractive and more capable product than they received, and the society is now considering alternatives. One combination they are studying would use a search engine called WordKeeper, from William Byrd Press, Richmond, Va. WordKeeper is based on a product called CD-Answer from Dataware Technologies Inc., Cambridge, Mass., and a display program entitled Acrobat from Adobe Systems, Mountain View, Calif. Acrobat creates its full-color page display from the PostScript files used by many desktop publishing systems and by many printers to typeset pages. This is the same combination that ASM will be using for its 11 journals beginning in January 1995. ASM has provided its journals on CD-ROM since January 1993, but using scanned, or bit-mapped, images of the printed page for display, which contain less information than do the Acrobat files. "We're going to use Adobe Acrobat files instead of bit- mapped pages, so that we will have page images on the screen with high-resolution graphics in place,S says Peter. "You won't have to link to a graphics file when you have a page image up. [Acrobat] takes the PostScript files that we use now for setting journal pages and emulates pages on the screen, which is a great advantage, because it's an all- electronic pathway for both the printed page and the CD- ROM." The American Institute of Physics (AIP), headquartered in College Park, Md., also uses Adobe Acrobat for its CD-ROM version of the Journal of Vacuum Science and Technology. A different approach is used to produce Protein Science, with its kinemages. The underlying file is created using Standard Generalized Markup Language, or SGML. Some scientists and librarians involved in electronic publishing predict that SGML is likely to develop as the standard file format used by journals published over the Internet. Thus, they note, the choice of SGML to produce the CD-ROM may be a wise step if online publishing is the goal. A browser called DynaText, from Electronic Book Technologies Inc. of Providence, R.I., is then used to display and navigate the journal. Lightbinders Inc., based in San Francisco, produces the Protein Science disks. The same combination is used by the American Society for Biochemistry and Molecular Biology (ASBMB), Bethesda, Md., to produce its CD-ROM version of the Journal of Biological Chemistry. According to Charles C. Hancock, executive officer of ASBMB, the result is an inviting display of the journal with helpful links between the text and additional information or graphics. "When you look at it on the screen, it looks like something that's nicely printed," Hancock says. "It does not look like a word processor has been at it. It also has hypertext links, so that if you want to see a footnote, thereUs a special icon for footnotes--you just double-click on that [with the computer mouse] and the footnote comes up. If, in the text, you come to a reference--reference 24, for instance--it's in a different color than the normal text. You double-click on that and it goes immediately to reference 24." APS's Muller notes that the print version of Physical Review Letters is already being produced using SGML, so that the society will have the option of choosing DynaText as the browser for the CD-ROM version, although other choices are still possible. Muller says that additional factors might support the selection of DynaText. "[Publishers] can compose the master file for the CD-ROM with DynaText software on personal computer workstations," he says, "and then just send that master file to a CD [production] house. It's touted to be a very good in-house system of CD-ROM composition." The American Chemical Society (ACS) in Washington, D.C., uses a proprietary software package called OPTI-WARE, licensed from Online Computer Systems in Germantown, Md., for the CD-ROM versions of Biochemistry and the Journal of the American Chemical Society. This system presents scanned images of journal pages, but also provides hypertext links to higher-resolution graphics, as well as tables and other elements, according to Susan Barclay, assistant editor of directories and databases at ACS. Despite the capabilities of each system used to produce scientific journals on CD-ROM, the variance in technology is a limiting factor for the field of electronic publishing overall, scientists say. When journal publishing moves to the Internet, as it is expected to do at some point, the issue of setting standards will become even more important. "If everybody adopted the same standards, we would be able to read everybody's journals online," says White. "And that's what the electronic library is going to be about. Once all journals adopt the same technology, then the true electronic library will be a possibility." Risky Business One reason CD-ROMs may be a more durable medium than some expect is that they are physical objects that can be bought, sold, and used in a familiar way. For publishers, important questions concerning control over their products must be answered before widespread publication via the Internet will become possible. "The problems of going online--they just haven't solved them yet," says Peter. "There's an ease of use [with CD-ROM]. You just pop it in like you would a floppy and run it, whenever you feel like it, for as long as you like, and you pay for it once. I'm not sure what the economic models are going to be for journals online." "This is a frightful concern for publishers," adds Muller. "And, as far as I know, nobody has a handle on it. Nobody knows how these issues are going to be resolved. When I go to conferences now on online publishing, many publishers are just shaking in their boots during the whole conference. They don't know what technology they should spend their money on. And whatever they spend their money on, they're going to spend a lot of money very quickly." "There are many, many questions about electronic publishing," agrees White. "Certainly, how to make it cost- effective for publishers is at the top of the list. The problem is that nobody has any experience, because it hasn't happened before." "Most of us feel that a few years from now we will be [publishing online]," says Bloomfield. "But I don't think we feel a great need to rush into it. "There's a lot of concern about how you get paid for the product. We don't expect to make a profit from the product, but we do need to earn enough to finance the editorial office, peer reviewing, and distribution aspects of it, so that we can't just give it away. The CD-ROM is great in terms of publishers being able to keep ahold of their product." Still, Bloomfield contends, Internet publishing promises such pronounced advantages over CD-ROMs that the questions demand answers. "Science is an interconnected web of communication," he says. "And it doesn't do to just search one year of one journal [on CD-ROM]. What you really want to be able to do is a much broader, interconnected search. That's why the Internet seems, in the long run, much more plausible." "In this world that we're in, the CD-ROM is a transient affair," says White. "The Internet is the future. Delivering the data directly is the future." (The Scientist, Vol:8, #18, pg.17, September 19, 1994) (Copyright, The Scientist, Inc.) ---------- WE WELCOME YOUR OPINION. IF YOU WOULD LIKE TO COMMENT ON THIS STORY, PLEASE WRITE TO US AT EITHER ONE OF THE FOLLOWING ADDRESSES: garfield@aurora.cis.upenn.edu 71764.2561@compuserve.com The Scientist, 3600 Market Street, Suite 450, Philadelphia, PA 19104 U.S.A. -------- NXT: ------------------------------------------------------------ TI : SCIENTIFIC JOURNALS ON CD-ROM PROLIFERATE TY : TOOLS & TECHNOLOGY PG : 17 The following scientific societies produce journals on CD- ROM or have active development projects in the works. For more information on society memberships or journal subscriptions, contact the societies directly at the telephone numbers given. * American Chemical Society (ACS), Washington, D.C., (202) 872-4600 (Biochemistry, Journal of the American Chemical Society) * American Institute of Physics (AIP), College Park, Md., (301) 209-3100 (Journal of Vacuum Science and Technology) * American Physical Society (APS), College Park, Md., (301) 209-3200 (Reviews of Modern Physics, in development; Physical Review Letters, in development) * American Society for Biochemistry and Molecular Biology (ASBMB), Bethesda, Md., (301) 530-7145 (Journal of Biological Chemistry) * American Society for Microbiology (ASM), Washington, D.C., (202) 737-3600 (Clinical and Diagnostic Laboratory Immunology, Journal of Bacteriology, Journal of Virology, Molecular and Cellular Biology, Applied and Environmental Microbiology, Journal of Clinical Microbiology, Antimicrobial Agents and Chemotherapy, Infection and Immunity, Microbiological Reviews, Clinical Microbiology Reviews, International Journal of Systematic Bacteriology) * Biophysical Society, Bethesda, Md., (301) 530-7114 (Biophysical Journal, experimental project in progress) * Protein Society, Bethesda, Md., (800) 99-AMINO (Protein Science) (The Scientist, Vol:8, #18, pg.17, September 19, 1994) (Copyright, The Scientist, Inc.) ---------- WE WELCOME YOUR OPINION. IF YOU WOULD LIKE TO COMMENT ON THIS STORY, PLEASE WRITE TO US AT EITHER ONE OF THE FOLLOWING ADDRESSES: garfield@aurora.cis.upenn.edu 71764.2561@compuserve.com The Scientist, 3600 Market Street, Suite 450, Philadelphia, PA 19104 U.S.A. -------- NXT: ------------------------------------------------------------ TI : SUPPLIERS OF SCIENTIFIC PUBLICATIONS ON CD-ROM TY : TOOLS & TECHNOLOGY PG : 18 The following publishers provide a variety of publications on CD-ROM. For more information, please use the Reader Service Card inserted in this issue. Annual Reviews Palo Alto, CA Circle No. 137 on Reader Service Card Butterworth-Heinemann Stoneham, MA Circle No. 138 on Reader Service Card Chapman & Hall New York, NY Circle No. 139 on Reader Service Card CRC Press Boca Raton, FL Circle No. 140 on Reader Service Card Elsevier Science Publishing New York, NY Circle No. 141 on Reader Service Card Institute for Scientific Information Philadelphia, PA Circle No. 142 on Reader Service Card The Johns Hopkins University PRess Baltimore, MD Circle No. 143 on Reader Service Card Kluwer Academic Publishers Norwell, MA Circle No. 144 on Reader Service Card Lightbinders Inc. San Francisco, CA Circle No. 145 on Reader Service Card J.B. Lippincott Hagerstown, MD Circle No. 146 on Reader Service Card The MIT Press Cambridge, MA Circle No. 147 on Reader Service Card Oxford University Press Cary, NC Circle No. 148 on Reader Service Card Random House New York, NY Circle No. 149 on Reader Service Card Scientific American Medicine New York, NY Circle No. 150 on Reader Service Card VCH Publishers New York, NY Circle No. 151 on Reader Service Card (The Scientist, Vol:8, #18, pg.18, September 19, 1994) (Copyright, The Scientist, Inc.) ---------- WE WELCOME YOUR OPINION. IF YOU WOULD LIKE TO COMMENT ON THIS STORY, PLEASE WRITE TO US AT EITHER ONE OF THE FOLLOWING ADDRESSES: garfield@aurora.cis.upenn.edu 71764.2561@compuserve.com The Scientist, 3600 Market Street, Suite 450, Philadelphia, PA 19104 U.S.A. -------- NXT: ------------------------------------------------------------ TI : NEW PRODUCTS TY : TOOLS & TECHNOLOGY PG : 19 Millipore Announces Immobilon Sequencing Membranes Two new Immobilon membranes, both constructed of a polyvinylidene fluoride (PVDF) base, have been developed for specific western blotting and sequencing applications. The Immobilon-PSQ membrane reportedly has higher binding capacity than does standard PVDF, which ensures sample retention after microtransfer and subsequent processing. The membrane can be used for blotting and direct sequencing of small and rare proteins with automated sequencers. The Immobilon-CD membrane facilitates sequencing of N-terminally blocked proteins blotted to its surface. Its cationically derivatized matrix permits reversible immobilization of the sample so that blocked protein bands can be digested and eluted off the membrane surface for peptide mapping. Millipore Corp., Bedford, MA Circle No. 152 on Reader Service Card Labconco Introduces WaterPro HPLC/UF Hybrid Polishing Station The WaterPro PS polishing station is designed for diverse applications requiring both high-performance liquid chromatography-grade and pyrogen-free ultrafiltered water. Type I water is dispensed from a cabinet-mounted valve, and pyrogen-free water is delivered through a gun mounted on the dispensing station. The system uses carbon filtration, deionization, organic adsorption, and ultrafiltration water- purification technologies. The ultrafilter periodically flushes itself to maintain total organic carbon values of less than 10 parts per billion, and an ultraviolet reactor eliminates trace bacteria. Water is produced on demand; therefore, no storage tank is used. Labconco Corp., Kansas City, MO Circle No. 153 on Reader Service Card Multi-Channel Syringe Pipettes From Hamilton These four- and six-channel syringe pipettes are designed to transfer DNA samples by microplate row or column to sequencing gels, nylon membranes, or another microwell plate. These are offered in addition to the company's eight- and 12-channel syringe pipettes, so users may now transfer samples from 0.2 ul to 10 ul. Needle diameters are available for sample loading between 0.2 mm or thicker polyacrylamide gel casting plates, and for sample loading between 0.4 mm or thicker plates. Hamilton Co., Reno, NV Circle No. 154 on Reader Service Card Jandel Releases Version 1.2 Of SigmaScan/Image Software Version 1.2 of SigmaScan/Image for Windows measurement software includes more than a dozen new features for automating measurements from digitized photographs, charts, maps, blueprints, electrophoresis gels, microscope specimens, and other scientific and technical images. Among the new features available on the software upgrade are gray- level-based floodfill measurements, multiple-image splicing, image-annotation enhancements, and the Jandel Application Manager. In addition, the package enables users to save color and gray-level data for each pixel to and from the data worksheet. Jandel Scientific Software, San Rafael, CA Circle No. 155 on Reader Service Card Corning Costar Corp. Unveils New Series Of Microcentrifuges Researchers can choose from among three Costar 5Centrifuges: a fixed speed and two variable-speed models, with or without solenoid locking covers. The maximum speed of 10,000 rpm (5,600 x g) is suitable for separating DNA from agarose or acrylamide gels. Two rotors are supplied: a six-place for 1.5 and 2.2 ml tubes, and a 12-place for 0.6 ml tubes. Corning Costar Corp., Cambridge, MA Circle No. 156 on Reader Service Card Molecular Probes' New Gram Stain Kit Molecular Probes' LIVE BacLight Gram Stain Kit, a fluorescence-based assay, consists of two stains that, when applied to living bacterial cells, allow viable organisms to be analyzed quickly, without the need for fixing or washing cells. When stained with the two fluorescent dyes in this kit, gram-positive cells appear orange-red while gram- negative cells appear bright yellow-green. The LIVE BacLight Gram Stain is sensitive enough to analyze low numbers of bacteria in the presence of background material. The reagents can also be adapted for use with a fluorometer or a fluorescence microplate reader to quantitiate the relative proportion of gram-positive and gram-negative bacteria in a sample. Molecular Probes Inc., Eugene, OR Circle No. 182 on Reader Service Card Spyglass Slicer For Volumetric Visualization Spyglass Slicer, a volumetric data-analysis tool for Windows/Windows NT, reads a variety of data and image formats, including HDF (float and byte), netCDF, and binary and ASCII matrices. It also can convert stacks of 2D, HDF, binary, and ASCII data files as well as read HDF, Windows Bitmap, Targa, and TIFF image files. After the data are imported, the software uses ray tracing to render data as volumes, slices, or isosurfaces. Full control of alpha values makes it possible to make any object or data value transparent, translucent, or opaque for advanced volumetric rendering. Spyglass Inc., Savoy, IL Circle No. 157 on Reader Service Card National Biosciences Upgrades OLIGO Primer Analysis Software Version 5.0 of OLIGO Primer Analysis Software for Windows assists scientists in selecting the optimal oligonucleotides for the polymerase chain reaction (PCR), sequencing, hybridizations, and other applications. The new features include an oligonucleotide database for importing and exporting oligonucleotide sequences and data; a PCR primer search function to locate all cross-compatible primers; automatic degenerate primer selection from an amino acid sequence; hybridization time calculations; automatic searching for ligase chain reaction primers; batch searching for unique oligos in multiple files; and restriction enzyme searches. National Biosciences Inc., Plymouth, MN Circle No. 158 on Reader Service Card Waters Unveils HPLC System This high-performance liquid chromatography (HPLC) system with mass spectral compound detection capabilities contains a mass spectrometry detector in a user-oriented format that is designed to be simpler, more compact, and more economical than any mass spectrometers adapted for HPLC work. An interactive diskette is available that contains information on the following: * system description; * mass spectrometry; * photodiode array detection; * Millennium technology; and * validation requirements. Waters, Milford, MA Circle No. 183 on Reader Service Card Perkin-Elmer Offers New Buffers For Capillary Electrophoresis Perkin-Elmer has introduced a selection of pre-made buffer solutions for capillary electrophoresis (CE) that are of high purity and meet stringent quality specifications. The selection of buffer solutions includes sodium phosphate at pH 2.5, sodium acetate at pH 4.0, sodium phosphate at pH 7.0, sodium borate/phosphate at pH 8.0, and sodium tetraborate at pH 9.0. The solutions come in 40-millimole concentrations, providing dilution flexibility for simplified methods development. Also available is a 200- millimole sodium dodecyl sulfate (SDS) solution for micellar electrokinetic capillary chromatography, for analysis of small, neutral compounds. Perkin-Elmer, Norwalk, CT Circle No. 184 on Reader Service Card Novocastra Offers p53 Antibodies Five clones of anti-human p53 antibody in unconjugated, biotinylated, and fluorescein-labeled form are available for use in immunohistochemistry, flow cytometry, and western blots. Also available are monoclonal and polyclonal antibodies to the MDM2 protein, reportedly the latest p53 binding protein to be discovered. Four anti-p53 clones are mouse monoclonals, and one is a rabbit polyclonal. Vector Laboratories is the exclusive United States distributor for Novocastra Laboratories. Vector Laboratories Inc., Burlingame, CA Circle No. 159 on Reader Service Card DAKO Introduces New Conjugated Antibodies The RPE-Cy5 fluorochrome-conjugated antibodies have been specifically optimized for flow cytometric applications, producing a sharp peak with an emission wavelength around 680 nm. The high fluorescence intensity of RPE-Cy5 conjugated antibodies is said to make them well suited for analyzing cell populations with low antigen expression. The company also offers CD3, CD4, CD8, CD13, and CD19 conjugated with this fluorochrome. DAKO Corp., Carpinteria, CA Circle No. 161 on Reader Service Card Nikon's Water-Immersion Microscope Objective Debuts The 60x water-immersion microscope objective is designed to resolve detail in living specimens at or close to the theoretical limit for optical performance at depths as great as 200 microns below the cover glass. The highly corrected 60x CFN Plan Achromat objective has a 1.2 numerical aperture and a 220-micron working distance. It has high transmission and chromatic correction for wavelengths in the near ultraviolet through the red spectrum, useful for confocal, fluorescence, and DIC microscopy. The lensU cover glass correction collar allows 0.15mm to 0.18 mm thick cover glasses to be used with critical correction. Nikon Inc., Instrument Group, Melville, NY Circle No. 162 on Reader Service Card CAChe Scientific Releases New Line Of Chemistry Software The company's new WorkSystem computer-aided chemistry software has been designed for the Apple Macintosh PowerPC desktop computer. The software features a stereoscopic three-dimensional graphics display and an intuitive user interface. It has a variety of applications for molecular modeling; prediction of chemical properties, structure, and reactivity; and experiment setup and documentation. CAChe Scientific Inc., Beaverton, OR Circle No. 163 on Reader Service Card Spire's MacSpec Software For Mass Spectral Analysis The software package enables users to extract and analyze information from gas chromatography mass spectrometry (GC- MS) data. With simple drawing tools, users can enter structures of up to 64 atoms or groups containing any element in the periodic table. Once entered, portions of the molecule may be "lassoed" to obtain formula and mass, at high or low resolution. Users may then build lists of formulas, calculate expected isotope patterns for each, and produce a simulated spectrum. Complex patterns with overlapping peaks may also be simplified. Spire Software, Maplewood, NJ Circle No. 160 on Reader Service Card PerSeptive Offers Interferon Enzyme Immunoassay Kits The new TiterZyme human interferon-g (IFN-g) and mouse IFN-g sandwich immunoassay kits are available for quantitative determination of human and mouse levels in serum or cell- culture supernatant. The kits feature detachable well strips, coated with the specific IFN-g antibody, for flexibility and consistency in simultaneous runs. These assays have sensitivities of less than 1 pg/ml in buffer and serum diluent. Each kit contains stable reagents for 96 tests, including a procedure with standard curves. PerSeptive Diagnostics Inc., Cambridge, MA Circle No. 164 on Reader Service Card Interleukin ELISA Kit From Genzyme The Predicta IL-1b ELISA kit facilitates rapid, sensitive, and specific measurement of IL-1b in human serum, plasma, and tissue-culture fluid specimens. The assay can measure IL-1b in a range from 3 to 256 pg/ml, and no measurable interference or cross-reactivity to IL-1 receptor antagonist is detected, according to the company. Each kit contains 96 precoated breakaway wells on a microtiter plate and the reagents needed to perform multiple runs. Genzyme Corp., Cambridge, MA Circle No. 165 on Reader Service Card (The Scientist, Vol:8, #18, pg.19, September 19, 1994) (Copyright, The Scientist, Inc.) ---------- WE WELCOME YOUR OPINION. IF YOU WOULD LIKE TO COMMENT ON THIS STORY, PLEASE WRITE TO US AT EITHER ONE OF THE FOLLOWING ADDRESSES: garfield@aurora.cis.upenn.edu 71764.2561@compuserve.com The Scientist, 3600 Market Street, Suite 450, Philadelphia, PA 19104 U.S.A. -------- NXT: PROFESSION ------------------------------------------------------------ TI : Journals Feel Pressure To Speed The Publishing Process AU : Ricki Lewis TY : PROFESSION PG : 21 With the electronic age having arrived, new technology shortening the production phase of publishing, and the pace of research rapidly accelerating, science journals are being pressed to slash the time from receipt of article manuscripts to publication. Correspondingly, it seems that researchers are becoming less willing to wait several months or longer for their papers to get into print. "Usually it takes about a year from the time you submit a paper until it actually comes out, especially if reviewers think something is wrong and the paper is bounced around," says Charles E. Lessman, a professor of biology at the University of Memphis. "It might take a year and a half to be published. It is frustrating. Journals should be able to do better." The Race Is On Despite the prestige of publishing in large-circulation, multidisciplinary journals, researchers are responding quite enthusiastically to new ventures promising faster publication, say editors. "A journal that can print an article in one month gives a way to attract top papers, particularly in a competitive field. So it is to a journal's advantage to be fast," says Monica Bradford, managing editor of Science. Bradford reports that at her journal the time between submission and publication averages 20 weeks. However, she adds, the process may be speeded up for articles with public-health implications, those in very competitive areas, or those containing "ground-breaking information." The reasons for the quickening pace of publication are both old and new. A huge effort such as a genome project, for example, can lead to a torrent of papers from a variety of research groups. In such "hot" areas, a delay of a few months as a manuscript goes back and forth between author and editor could mean the difference between being credited for discovering a gene or just confirming a competing group's discovery of it. Traditional pressures--which are mounting these days because of heightened competition for scarce jobs--contribute to scientists' desire to see their work in print as soon as possible. Indeed, this is leading to a backlog of unpublished manuscripts in journal offices. "The publish-or-perish phenomenon is still on," says Martha Davis, an assistant professor in the department of agronomy at the University of Arkansas in Fayetteville. "Especially in academia, there is no promotion or tenure if a researcher hasn't published so many articles, and that's true in some industries, too. Because of this, some scientists report partial experiments, so they can publish two articles instead of one. That adds a lot of volume," says Davis, who is the author of Scientific Papers and Presen-tations: A Graduate Student Handbook, scheduled for publication next year by San Diego-based Academic Press. The Route To Rapid Publication Journal editors are responding to the demand for faster publishing in some innovative ways, merging the speed of new communications technology with the ability to keep the human parts of the process on track. "People want to publish quickly--and that's what a good editor is all about, making quick work of the review process and mediating between reviewers and authors," says Harvey Bialy, a molecular biologist who is research editor at Bio/Technology, published by Nature Publishing Co. in New York. Bialy says that by sending manuscripts out for review within two days of receipt, getting comments back within two weeks (including verification of practical procedures described in papers), and then overseeing revisions, he gets most papers published within two to four months of acceptance. But some journals can beat even Bio/Technology's fast timetable. Advances in Scientific Research (ASR), which debuted in April, promises publication within one month of receipt. "The idea of a rapid-publication journal was the result of discussions with many of my colleagues throughout the years," says David Philips, who is the cofounder, along with physicist David Newman, of the La Jolla, Calif.-based, for-profit Institute for Advances in Scientific Research, which publishes ASR. Philips is a physicist and chemist now interested in environmental sciences who has held research positions at Stanford University and the University of California, San Diego. Newman held a position at the University of Michigan. Philips and Newman say they keep their promise by tapping into a network of expert reviewers who work fast, and by asking authors to help. "When we receive a manuscript, we do a quick internal review, then send it to a number of peer reviewers," Philips says. "We ask reviewers if they can read and return the paper in 72 hours. If they can't, we thank them and find other reviewers. Then we send the comments to the author, and there's some back-and-forth a few times. Of course, the speed of the whole process also depends upon the author." Lessman, who coauthored a paper with his graduate student that was recently published in ASR, confirms that the journal works quickly: "They indeed did it in a week. We faxed it [the manuscript] in, we had comments back a week later, we made changes and resubmitted it. That's the way things should be." Gary Evans, a professor of chemistry at Bemidji State University in Minnesota, had a similar experience. "It was less than 40 days from submission until I was looking at reprints," he says. "Usually, you don't even hear from the journal editor in 40 days." As if the challenge of publishing quickly weren't enough, the new journal also has a very wide focus, accepting papers in physics, chemistry, biology, environmental sciences, and interdisciplinary studies. "To accommodate such a broad range of disciplines, we interact with a network of scientists who provide editorial and technical support," Philips says. The journal's willingness to accept innovative research articles is what attracted Lessman in the first place. His coauthor, Angela Ventura, had written up part of her master's thesis as a paper. Lessman suggested to Ventura that she submit the article to ASR. "This particular work was quite different, unusual," he says. "We centrifuged Rana pipiens [leopard frog] cells and tried to look at how different factors control movement of the nucleus." Because this is the type of descriptive science typical of work early in the century, Lessman felt it might be too unconventional to be accepted by a more established journal. Publisher Philips reports that he is very pleased with the response to two ads and a postcard campaign inviting submissions. Exact circulation figures are not yet available, he says; the third issue is scheduled for publication this month. Several hundred copies are being printed, according to Philips; they are being sent to libraries and individuals who responded to the ads. Another fairly new venture is Rapid Communications of Oxford, England, a subsidiary of the International Thomson Organization. Rapid Communications was founded in 1990 by Ivan Klimes, formerly an editor at Elmsford, N.Y.-based Pergamon Press. After extensive market research identified neuroscience as a field ripe for rapid publication, the founder distributed a leaflet in June 1990 announcing the creation of NeuroReport, guaranteeing publication of papers 12 weeks after submission or sooner. Within days of the announcement, papers began arriving by fax, and the pace of submission has increased ever since. "NeuroReport is a testimony to the fact that a rapidly published journal can be successful," says Kate McKay, who until recently was vice president of Rapid Communications of America. The company closed its New York office earlier this month because it found that it could accomplish its work via fax and electronic mail from its office in England. "We have a high rejection rate because the number of submissions is incredible," McKay says. The journal receives, on average, five submissions every day. McKay credits "word of mouth in the neuroscience community" with the high submission rate. "Researchers say, `If you've got something hot and want it out quickly, go here,' " she explains. Rapid Communications currently publishes 24 journals in addition to NeuroReport. As is also true of ASR, the key to Rapid Communications' ability to work swiftly is the fax machine. A paper is faxed to the relevant journal, where an editor faxes it to appropriate reviewers. A reviewer has five days to fax the paper back to the journal, which then faxes it to the author, who also has five days to respond to the review. Authors help by limiting page length, preparing art, and not seeing proofs, which stimulates them to submit higher quality papers, the editors says. NeuroReport now publishes within nine weeks of submission. So far, finding reviewers who are both expert enough and have the time to perform a rapid review has not been a problem, say Philips and McKay. "You simply get on the phone or the computer and network," Philips explains, "It often happens by word of mouth--someone knows someone who knows someone who knows someone, and ultimately ou reach someone who has both quality and time." Maintaining Quality Several editors of mainstream serials interviewed for this article do not doubt that it is possible to regularly publish an issue's worth of peer-reviewed papers prepared within a month of submission. "It probably is feasible, if they liberally use fax and E-mail," suggests Charles Bertsch, head of the journals department at the American Chemical Society (ACS) in Washington, D.C. "It all goes very quickly if done right." But such a peedy process may result in a sacrifice of quality, cautions Kevin Davies, editor of Nature Genetics. "When a journal guarantees that any paper will be published in a certian amount of time from submission, that's prejuding the review process," he says. "A journal should focus on promising quick processing once a paper is accepted." Fast-tracking is possible at any journal if an editor suspects that a paper will sail through the review process, as recently happened at Nature Genetics with a paper describing the gene that cuases Crouzon syndrome, a defect of the face and head bones. The papers received on August 10 and was published in the September 1 issue. "It was reviewed and accepted in five days, revised in five days," Davies reports. "We worked overtime, and faxed figures and E-mailed like crazy. Another shortcut was that we set the text [in type] before the final decision was made, assuming it would be accepted." But Davies stresses that this wasn an unusual case: "We can make such preparations for exceptional papers," Other shortcuts include permitting only vital changes in proofs and "sacrificing niceties," such as consistency in reference terminology. "Every journal starting up these days promises more rapid publication," says Davies. "For example, Human Molecular Genetics, our competitor, began in April 1992, about when Nature Genetics did. They made a similar promise of a certain number of weeks from submission to publication. They have kept to it and are doing well." Ads for this Oxford University Press journal claim: "In 1993, Human Molecular Genetics had the fastest average receipt to publication time of any genetics journal." Paul Ginsparg, a physicist at Los Alamos National Laboratory in New Mexico, provides a service that combines rapid access to recent research with interactive capabilities: E-Print Archives, which supplies current and archival preprints online to 20,000 physicists worldwide. "One of the primarily useful things about E-Print Archives is not the rapidity of communication, but access to the older papers," he says. "People find it much easier to click a button on a screen than to go across the street to the library, look through journals, and maybe find that the one they want is off to the bindery." A complete online journal, the Online Journal of Current Clinical Trials, was started by the American Association for the Advancement of Science (AAAS) in collaboration with a computer library service in July 1992. However, few subscribers signed up for the journal. Rather than undertake a huge marketing campaign itself, AAAS recently sold the venture to London-based Chapman & Hall, a subsidiary of Thomson (J. Kaiser, Science, 265:867, 1994). Will electronic publishing become too fast for peer review? So far, those interviewed for this article seem to think that peer review can indeed keep pace. "Electronic publishing should have nothing to do with peer review," says Bialy. "When everyone is wired in correctly, it will accelerate peer review by saving mailing." Ginsparg thinks that the question is moot because peer review, at least in fields like his own, in which the readers are experts, isn't even necessary. "I'd rather have 30 percent more papers to read in one to two weeks of their submission than see them six to nine months after submission with some small amount of filtering provided by peer review," he says. Although they take longer to be disseminated than online services, print science journals are unlikely to be put out of business soon, their editors say. They note that there's still something to be said for reading a paper journal on the train or out by the pool. "In terms of archival and reference aspects, people want to have papers in a journal that libraries have, and are not out in the electronic ether," says Bio/Technology's Bialy. Ginsparg says there's room in the scientific community for both print and online publication: "It's like asking if you can make the transition from radio to television; suddenly you have an extraordinary new set of possibilities." But like radio--which is still alive and well despite television and VCRs--print journals, at least for the near future, will continue as a primary outlet for the dissemination of scientific information. Ricki Lewis is a freelance science writer based in Scotia, N.Y. (The Scientist, Vol:8, #18, pg.21, September 19, 1994) (Copyright, The Scientist, Inc.) ---------- WE WELCOME YOUR OPINION. IF YOU WOULD LIKE TO COMMENT ON THIS STORY, PLEASE WRITE TO US AT EITHER ONE OF THE FOLLOWING ADDRESSES: garfield@aurora.cis.upenn.edu 71764.2561@compuserve.com The Scientist, 3600 Market Street, Suite 450, Philadelphia, PA 19104 U.S.A. -------- NXT: ------------------------------------------------------------ TI : FOR MORE INFORMATION TY : PROFESSION PG : 21 Advances in Scientific Research 4275 Executive Square, Suite 800 La Jolla, Calif. 92037 Phone: (619) 546-2979 Fax: (619) 453-4932 E-mail: ascires@cerf.net E-Print Archives (Paul Ginsparg) Los Alamos National Laboratory MSB285 Los Alamos, N.Mex. 87545 Phone: (505) 667-7353 Fax: (505) 667-5585 E-mail: hep-th@xxx.lanl.gov (Use the word "help" in "subject" line.) Rapid Communications of Oxford The Old Malthouse Paradise Street Oxford OX1 1LO U.K. Phone: 44 865 790 447 Fax: 44 865 244 012 or 44 865 793 533 E-mail: rapidcom@vax.oxford.ac.uk Publishers of 25 journals: Anti-Cancer Drugs Behavioural Neurology Behavioural Pharmacology BioMetals Blood Coagulation and Fibrinolysis Cancer Causes and Control Chromosome Research Clinical Autonomic Research Clinical and Experimental Metastasis European Journal of Cancer Prevention European Journal of Neurology Glycosylation and Disease Imaging Immunology and Infectious Diseases International Clinical Psychopharmacology Journal of Orthopaedic Rheumatology Mediators of Inflammation Melanoma Research NeuroReport Obesity Surgery Pharmaceutical Science Communications Primary Care Psychiatry Psychiatric Genetics Quality of Life Research World Journal of Microbiology and Biotechnology (The Scientist, Vol:8, #18, pg.21, September 19, 1994) (Copyright, The Scientist, Inc.) ---------- WE WELCOME YOUR OPINION. IF YOU WOULD LIKE TO COMMENT ON THIS STORY, PLEASE WRITE TO US AT EITHER ONE OF THE FOLLOWING ADDRESSES: garfield@aurora.cis.upenn.edu 71764.2561@compuserve.com The Scientist, 3600 Market Street, Suite 450, Philadelphia, PA 19104 U.S.A. -------- NXT: ------------------------------------------------------------ TI : Russian, Belgian, And Two Frenchmen Rake In Honors As 1994 Fields Medalists AU : NEERAJA SANKARAN TY : PROFESSION (PEOPLE) PG : 22 Four mathematicians--Jean Bourgain, a professor at the Institute for Advanced Study, Princeton, N.J.; Pierre-Louis Lions of the University of Paris-Dauphine in France; Jean- Christophe Yoccoz, University of Paris-Sud, Orsay, France; and Efim I. Zelmanov, a professor at the University of Chicago currently on leave from the University of Wisconsin, Madison--have been awarded the 1994 Fields Medals. The medals were presented during the International Congress of Mathematicians, held August 3 through 11 in Zurich, Switzerland. The Fields Medals--officially known as the International Medals for Outstanding Discoveries in Mathematics--are presented every four years to two to four individuals under the age of 40 in recognition of both their existing work and the promise of future achievements. Unlike the Nobel and other big prizes, however, the Fields Medals carry no monetary award. Winners are decided upon by a committee within the International Mathematical Union--a professional mathematical society of worldwide membership, headquartered this year in Rio de Janiero, Brazil--which arranges the International Congress. Thirty-four individuals have been honored since 1936. `Triumphant' Work Zelmanov, 38, was recognized for his work in the area of abstract algebra and group theory, specifically for his proof of a mathematical conjecture called the restricted Burnside problem, named for British mathematician William Burnside. "In 1902, Burnside formulated a conjecture on what makes a group finite," explains Zelmanov. "He said that if imposed, two restrictions--a [fixed] number of generators and periodicity--are enough to make a group finite." Though this conjecture--known as the Burnside Problem--was shown to be false in 1968, Zelmanov states that in a few important cases it still holds true. He furnished proofs for these special cases, called the restricted Burnside problem (E.I. Zelmanov, "A solution of the restricted Burnside problem in 2-groups," Mathematics of the USSR-Sbornik, 72:543-565, 1992). Zelmanov, who moved to the United States in 1990, did most of his work on the problem while a professor at the Academy of Sciences of the USSR in Novosibirsk, Siberia, where he completed his doctorate in 1980. Zelmanov's colleague Jonathan Alperin at the University of Chicago refers to the Russian mathematician's achievements as "a real triumph." Versatility According to Princeton UniversityUs Charles Feffer-man, himself a 1978 Fields medalist, Bourgain, 40, has made "very deep contributions" to several areas of mathematics. Bourgain's particular areas of expertise in mathematics are: the geometry of infinite dimensional spaces; harmonic analysis, which is the study of complicated vibrations; and non-linear wave equations. Educated in his native Belgium (Ph.D. from the Free University of Brussels, 1977), Bourgain came to the Institute for Advanced Study earlier this year. Previously, he held a professorship at the Institut des Hautes Etudes Scientifiques in Paris. According to the Science Citation Index of the Institute for Scientific Information, Philadelphia, Lions, 38, has published more than 30 original mathematical papers in the past four years alone. His versatility is exemplified in the wide variety of mathematical topics his papers cover, including partial differential equations, numerical analysis, and calculations for such scientific methods as image processing, fluid mechanics, and the viscosity of solutions. Yoccoz, 37, is the youngest of the medalists this year, and like Lions hails from France. His most recent publication, a seminal paper on hyperbolic sets entitled "Homoclinic tangencies for hyperbolic sets of large Hausdorff dimensions," appears in Acta Mathematica (172:91- 136, 1994). --Neeraja Sankaran (The Scientist, Vol:8, #18, pg.22, September 19, 1994) (Copyright, The Scientist, Inc.) ---------- WE WELCOME YOUR OPINION. IF YOU WOULD LIKE TO COMMENT ON THIS STORY, PLEASE WRITE TO US AT EITHER ONE OF THE FOLLOWING ADDRESSES: garfield@aurora.cis.upenn.edu 71764.2561@compuserve.com The Scientist, 3600 Market Street, Suite 450, Philadelphia, PA 19104 U.S.A. -------- NXT: ------------------------------------------------------------ TI : UC-San Francisco Physiologist Assumes Directorship Of NIH Neurological Institute AU : NEERAJA SANKARAN TY : PROFESSION (PEOPLE) PG : 22 Zach W. Hall, formerly a professor of physiology at the University of California, San Francisco, has assumed the directorship of the National Institute of Neurological Disorders and Stroke (NINDS), in Bethesda, Md. He began in his new job September 1. NINDS is the agency within the National Institutes of Health (NIH) for research on brain and nervous-system disorders. As director, Hall will be in charge of an annual budget of more than $630 million, which goes toward maintaining a staff of about 700 scientists and administrators, as well as supporting research at various institutions across the United States. Coming into the position, he says, he has "no set agenda." "This is a tremendously exciting period for the neurosciences," Hall says. "I hope to be able to work cooperatively with the other [NIH] agencies to promote both extramural and intramural research programs." A particular challenge for the institute, he says, will be in the clinical applications of fundamental neuroscience research. "Neurologists have always had elegant ways of diagnosing various disorders," he says, adding that treatments have not emerged at the same pace. "In the coming decade we should be able to apply our findings from basic research more effectively toward treating neurologic diseases." Other areas of neurology that Hall sees as making great progress are developmental neurobiology and central nervous system physiology. A native of Atlanta, Hall, 56, studied English (B.A. 1958) at Yale University, New Haven, Conn., and received a Ph.D. in biochemistry from Harvard University, Cambridge, Mass., in 1966. He came to UC-San Francisco's department of physiology in 1976, and headed the biomedical sciences graduate program there from 1992 until his appointment at NINDS. --Neeraja Sankaran (The Scientist, Vol:8, #18, pg.22, September 19, 1994) (Copyright, The Scientist, Inc.) ---------- WE WELCOME YOUR OPINION. IF YOU WOULD LIKE TO COMMENT ON THIS STORY, PLEASE WRITE TO US AT EITHER ONE OF THE FOLLOWING ADDRESSES: garfield@aurora.cis.upenn.edu 71764.2561@compuserve.com The Scientist, 3600 Market Street, Suite 450, Philadelphia, PA 19104 U.S.A. --------

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