The sea is the universal sewer.
Jacques Cousteautestimony,
U.S. House Science and Astronautics Committee
28 January 1971
Healing Venom
Vipers, including some 200 species of serpents within the family Viperidae, are not the cuddliest of creatures. Ranging in length from the foot-long Orsini viper to the dreaded bushmaster, which can grow to more than 10 feet, all feature long, hollow fangs designed for poisoning prey. Yet, researchers suggest that the venom of these deadly reptiles may offer an array of healing agents.
At the University of Delaware in Newark, for example, Mary Ann McLane, an assistant professor in the department of medical technology, is studying the chemical structure of a viper venom protein that seems to stop the spread of tumors in laboratory mice. If her work pans out, it could lead to new antitumor drugs, according to her collaborator, Stefan Niewiarowski, a professor in the department of physiology and the Sol Sherry Thrombosis Research Center at the Temple University School of Medicine in Philadelphia, Pennsylvania.
McLane is among a growing number of academic, government, and industrial researchers who are investigating venom-based disintegrins--proteins that interact with integrins, the biochemical hooks on cell surfaces that "allow cells to talk to each other," explains Steven Houser, former president of the American Heart Association (AHA) in southeastern Pennsylvania and a professor of physiology at Temple.
Source: Senadi Vijay-Kumar
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Source:Latoxan |
Viper VIP. New research shows that venom from MacMahon's viper contains eristostatin (top left), a substance that may reduce the spread of tumors.
Why study these viper venom proteins? When a viper bites, McLane says, its venom prevents blood from clotting by blocking the sticky protein fibrinogen from binding with platelets. Indeed, Niewiarowski says, disintegrins are potent inhibitors of platelet aggregation and cell adhesion, and since the late 1980s, studies of the venom-based proteins have focused primarily on their promise as anticoagulants. Around 1986, Niewiarowski teamed up with Tur Fu Huang, chairman of the department of pharmacology at the National University of Taiwan in Taipei, to investigate the exact mechanisms by which disintegrins keep platelets from forming clusters.
Then, in 1995, a research team directed by Vincent L. Morris, an associate professor in the department of microbiology and immunology at the University of Western Ontario in London, Canada, discovered that the disintegrin eristostatin--produced by Macmahon's viper (Eristocophis macmahoni) of Afghanistan and Pakistan--dramatically reduces the spread of liver tumors in mice. When mice injected with melanoma cells were also given eristostatin, the average number of liver tumors dropped from 14.4 to 0.6 within 11 days, according to McLane, who collaborated with Morris and Niewiarowski on this work, published in the August 1995 issue of Experimental Cell Research.
Since then, McLane has been comparing the structure of eristostatin with echistatin, a disintegrin from the Middle Eastern saw-scaled viper (Echis carinatus). The goal, she says, is to learn why eristostatin is so much more effective than echistatin at blocking fibrinogen interactions and preventing the spread of melanoma cells. The two disintegrins are 68% identical, and both feature a protruding section of amino acids known as the RGD loop. Composed of arginine, glycine, and aspartic acid, the RGD loop apparently plays a major role in all interactions with integrins. When McLane altered just three of the 13 amino acids in echistatin's RGD loop, she was able to make the protein behave more like its cousin, eristostatin. Once she fully understands these structural differences, McLane says, a synthetic version of eristostatin might offer therapeutic properties.
McLane says she plans to study eristostatin's effect on metastatic melanoma cells in collaboration with Mary E. Miele, an assistant professor of medical technology at the University of Delaware. In addition, McLane has joined forces with Norma Staiano, a professor of biochemistry at the Università di Napoli Federico II in Italy, who discovered that echistatin--like eristostatin--can inhibit the spread of lung cancer cells in mice. Staiano's work was published in the October 1997 issue of the International Journal of Oncology. Of McLane's research Staiano says, "Her work has been pivotal to highlight the structural features other than the RGD locus that determine the specificity of disintegrins for integrin receptors on platelet and cell surfaces."
Dozens of pharmaceutical companies are investigating disintegrins, Houser says. At Merck Research Laboratories of West Point, Pennsylvania, for instance, researchers such as Bohumil Bednar are already using synthetic versions of the RGD loop to study blood clotting events. Bednar declined to comment on the work, but his research, published in the August 1997 issue of Molecular Pharmacology, describes a technique for using RGD "mimics" as a probe for identifying key binding sites on the integrin alphaIIb beta3 in human kidney cells. Niewiarowski and many others, meanwhile, are using a similar technique to develop synthetic versions of alphaIIb beta3 antagonists, which strongly inhibit platelet aggregation.
Most disintegrin research has been funded by the AHA and the National Institutes of Health. The AHA initially supported the work because snake venoms inhibit the coagulation process, and blood clots can play a role in heart attacks, strokes, and other cardiovascular diseases, Houser says. But the research has since produced crucial fundamental insights. As researchers zero in on the specific amino acid sequences that bind with integrins, he says, they've developed a molecular probe for better understanding communication between cells. "When that information transfer becomes dysfunctional," he notes, "it can induce disease states."
Bird Flu Vaccine
In the race to develop vaccines against an ever-widening array of infectious diseases, Aviron, a biopharmaceutical research and development company located in Mountain View, California, may be leading by a nose. Working in collaboration with the National Institutes of Health and the Centers for Disease Control and Prevention, Aviron is developing a novel technology in antiviral vaccinations: the cold-adapted live influenza vaccine. A major advantage of the new technology is that the vaccine may be administered through a nasal spray, bypassing the need for injections. Currently, Aviron is using its technology to develop two candidate vaccines against the avian A/Hong Kong/97 (H5N1) influenza virus, more commonly known as the "bird flu."
The bird flu, which first appeared in humans in May 1997, is the latest in a string of what are known as "Hong Kong flu" epidemics--outbreaks that start in southeast China, where the densely packed population lives cheek to beak with large numbers of chickens, ducks, and other poultry. It is believed that the birds carry various viral strains that are then transmitted somehow--perhaps through pig intermediaries--to humans. Scientists aren't sure why or how the viruses cross over to humans, but the results in the past have been devastating, as evidenced by outbreaks such as one in 1968 that killed thousands worldwide. In December, Hong Kong officials launched what appears to have been a successful strike against the disease by slaughtering over 1 million chickens and other poultry.
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Friend or fowl? A new vaccine technology may prevent outbreaks of the avian A/Hong Kong/97 influenza virus, or "bird flu," which has recently begun to appear in humans. |
Martin Bryant, vice president of research for Aviron, says, "With the elimination of the Hong Kong poultry population, the epidemic was aborted; the virus never got up the steam to pass from one person to another. What happens is that a virus may be modified as it passes from person to person, and that did not occur." Still, says Bryant, although the bird flu didn't spread to epidemic proportions this time, it's not a matter of whether such an epidemic will come, but when--and public health officials should be prepared.
Aviron scientists are using a "reverse genetics," or recombinant, approach to introduce specific protective genes into an attenuated (weakened) master donor virus strain from which all flu vaccines are developed. The vaccine could also be used as a platform to prepare an inactivated version of the vaccine in large quantities.
Aviron's live-virus vaccines are attenuated viruses that are adapted to grow in the relatively cool nasal region as well as in the lungs. The cold-adapted flu virus triggers an immune response at the place of entry of the influenza virus, leaving the vaccine recipient free of flu but armed with immune capabilities to combat future attacks by the virus.
Exposure to the flu is believed to occur largely through inhalation of droplets containing the live virus, and some view the nasal spray as working directly at the site of infection. In a 1997 trial of 1,602 children aged six years and younger, the nasal spray vaccine showed an amazing 93% efficacy rate against culture-confirmed influenza. This efficacy rate may be due to the fact that spraying the vaccine in the nose stimulates the mucosal antibodies found in the nose, throat, and mouth, and circulating antibodies in the bloodstream. These antibodies are an added boost to the cell-mediated immune responses triggered by the traditional flu shot.
The absence of needles is seen as an advantage in getting the vaccine to people who are afraid of shots, particularly children, who are one of the primary vectors of influenza. Says Bryant, "The first wave of any epidemic in a community usually starts with kids." Plus, because it's a simple nose-spray, the vaccine wouldn't need to be administered by a health-care professional. Eventually, the vaccine may even be available over the counter.
The Aviron live-virus vaccine is currently undergoing late Phase III trials. The company hopes to present its product for license review by the Food and Drug Administration by mid-1998. Although a bird flu epidemic appears to have been temporarily staved off, Bryant says, "We may not use it this time, but there will be a time when we will. We are working hard to be ready before it comes."
The State of the Science on Endocrine Disruptors
As research on endocrine-disrupting chemicals flourishes worldwide, international groups are working to coordinate research activities being conducted by organizations around the globe. The International Programme on Chemical Safety (IPCS), a collaborative program of the World Health Organization (WHO), the International Labour Organization, and the United Nations Environment Programme, is leading an effort to conduct a global inventory of ongoing research activities related to the health and ecological effects of endocrine-disrupting chemicals, and is working to develop an international assessment of the state of the science on endocrine disruptors. The Organisation for Economic Co-operation and Development (OECD) is leading international efforts on delineating testing methods for endocrine disruptors.
On 16-18 March 1998, the IPCS, in coordination with the OECD, convened a joint meeting in Washington, DC, with a steering committee of scientific experts to provide guidance for these projects. The steering group was made up of representatives from Canada, Finland, Germany, Italy, Sweden, the Netherlands, Mexico, Japan, the United Kingdom, and the United States. The objectives of the meeting were to discuss the structure and content of the global inventory and to define the objectives and scope of the international state of the science assessment document, as well as develop an outline and guidelines for development of the document.
Participants were asked to discuss a working definition for endocrine-disrupting chemicals, and it was agreed to define an endocrine disruptor as an exogenous substance or mixture that alters the function of the endocrine system and consequently causes adverse health effects in an intact organism or its progeny or subpopulations. A potential endocrine disruptor is defined as an exogenous substance or mixture that possesses properties that might be expected to lead to endocrine disruption in an intact organism or its progeny or subpopulations.
The global inventory of research on endocrine disruptors is intended to serve as a communications tool, providing information exchange among scientists worldwide. This will allow for the examination of current research efforts, and aid in identifying research gaps and developing strategies to address such gaps. The steering committee was asked to address four main issues concerning the inventory--structure and content of the inventory, criteria for inclusion of research projects, a communications strategy, and a timetable and oversight for the inventory.
The global inventory will be built on ongoing inventory efforts in the United States, Canada, and the European Union. The steering committee determined that the top priority in developing the inventory should be to integrate existing databases from these three sources into a single on-line database, which will be available to researchers worldwide as well as to the general public. The integration of the database is being coordinated by the U.S. EPA. Robert Kavlock, director of the reproductive toxicology division of the EPA, says he and others are now in "data collection mode" and are working to update and combine databases from both government and nongovernmental organizations. Kavlock says the database will be useful for funding organizations to ensure that research they support is complementary to other research efforts, and to individual investigators in identifying others around the world with common research interests. Kavlock says he is optimistic that the database will be completed by the end of this year. The current U.S. database is available on line at http://www.epa.gov/endocrine.
The IPCS is simultaneously working to develop a state of the science assessment report. The steering committee members discussed the objectives of the report, and determined that the document is intended to build on existing assessment documents--including what is known about the health and ecological effects of endocrine disruptors--and identify what uncertainties remain. The document is intended to help direct future research on endocrine disruptors. The committee members stressed that the document will focus on science and not on risk assessment. They also noted that the document will emphasize global issues, such as transboundary migration of environmental contaminants.
The committee members also discussed the development process of the document. The process will provide opportunities for multisectorial input, and will also include rigorous international peer review. The document will require the participation of approximately 25 authors, according to Terri Damstra, team leader of the WHO/IPCS Interregional Research Unit, who is the responsible IPCS officer overseeing the project. Damstra says the steering committee is now working to select potential authors, who will be chosen on the basis of scientific expertise. The committee has developed a preliminary outline, which will be expanded upon by prospective authors in the next few months.
The steering committee noted that, although the first meeting was limited to scientific experts, the future process will be open to the public and include input from multiple interests. The final document will be published as a WHO document that organizers hope will be available in the spring of 2000.
Landfills: Is Wetter Better?
Over the past 30 years, garbage landfill designers have gone to great lengths to halt groundwater pollution. In a well-designed modern landfill, caps keep water out, liners and liquid removal systems control any water that does enter, and groundwater pollution is not a significant problem. But new landfills are so dry that garbage can take many decades to decompose. That may be too long, according to Robert Ham, professor emeritus of civil and environmental engineering at the University of Wisconsin at Madison, and author of a new study on landfill decomposition that has been accepted for publication in the Journal of Environmental Engineering.
At intervals of one, two, and six years after placing bags of waste in landfills in Florida, Pennsylvania, and Wisconsin, Ham and his colleagues exhumed the bags and weighed the garbage that remained. They found that most food items had degraded significantly, with faster decay occurring in moister conditions. Newspaper, however, was the most decay-resistant of all the materials tested--even more so than disposable diapers. In a dry, well-capped Wisconsin landfill, newspaper lost only 5.6% of its dry weight in six years. But in a Florida landfill that lacked the clay cap that is required on new landfills, newspaper lost 7.4% of its weight in the first year, and 17% by the second year (the six-year samples could not be located in Florida). Ham says the study shows that garbage does degrade in a dry, modern landfill, but that it degrades much faster when moisture is present. Thus, Ham calls moisture the "master variable" in the decomposition rate.
The rate of decomposition has been largely ignored in the quest for safer landfills. But Ham says faster decomposition is better, because landfills produce the highest concentrations of various substances in toxic leachate (water that contains dissolved chemicals from the garbage) and the greenhouse gas methane while the garbage is actively decomposing. When anaerobic bacteria devour garbage, they produce methane, which is often recovered from landfills and burned to generate electricity. Ham says rapid decomposition would raise the rate of methane generation, improving the economics for recovery and, thus, reducing emissions to the atmosphere.
The present policy of dry landfills may be good for groundwater, Ham says, but it is "causing problems over the long haul by postponing decomposition until years after the waste is emplaced." He expects that decay could take as long as 50 years in modern landfills.
Instead of the "dry tomb" approach described above, Ham advocates building "bioreactors" where decomposition would be accelerated. The idea interests some landfill operators. "It's very important for financial reasons," says Martin Felker, manager of landfill engineering at Waste Management, a garbage hauling corporation based in Oakbrook, Illinois. The faster the waste degrades, Felker notes, the more waste will fit in a particular site. Furthermore, rapid degradation could also reduce the duration of monitoring groundwater and methane around landfills. Monitoring and recovering contaminated leachate at closed landfills costs Waste Management hundreds of millions of dollars every year, Felker adds. The EPA requires monitoring for 30 years after a landfill is closed; if decay were more rapid, the hazard would abate faster, he points out. Rapid decomposition could also benefit neighbors of landfills. Presently, Ham says, the parties responsible for a landfill may be out of business before leakages of leachate or methane occur, preventing the recovery of damages.
But will bioreactors be safe? Ham thinks they can be. For one thing, they would retain the key features of modern landfills, including the methane recovery equipment and the clay and plastic bottom liners that prevent leachate from escaping. The major alteration would be to modify the cap that now prevents rainwater from entering, and to recirculate leachate or even add water to keep the garbage wet enough to decay.
The idea of bioreactors is catching on fast. Debra Reinhart, associate dean of the school of engineering at the University of Central Florida in Orlando, who has consulted on the issue for the EPA, says about 100 landfills nationwide are using some form of accelerated decomposition with no reports of leakage. While short-term concerns such as possible clogging of recirculation systems remain to be investigated, she says, "[In the long term] this is certainly protective of groundwater, because you are treating the source of the contamination over a shorter period. When the barriers fail, the leachate will be less toxic. . . . This will become the state of the art in the near future."
The landfill industry is intrigued by the idea of shifting to bioreactors. "There's no reason it should not be done, or can't be done," says Ed Repa, director of environmental programs at the Environmental Industries Association. Another industry group, the Solid Waste Association of North America, expects to publish a white paper on bioreactors in June.
To help determine safety and optimize the technology, Ham is now consulting with a major waste hauler about building a state-of-the-art landfill to test a variety of advanced decomposition techniques. If the landfill fails, he says, liners and a leachate collection system would already be in place to prevent groundwater contamination. And if it works, it could save future generations the expense of monitoring thousands of landfills for at least 30 years after closure.
In 1966, Congress signed the National Sea Grant College and Program Act, which authorized "the establishment and operation of sea grant colleges and programs by initiating and supporting programs of education and research in the various fields relating to the development of marine resources." Today's National Sea Grant College Program, a consortium of 29 U.S. universities in partnership with the National Oceanic and Atmospheric Administration (NOAA), addresses such issues as aquatic resource management, environmental quality, and economic competitiveness. NOAA adminstrator James Baker calls it "one of the best examples in the country of a successful partnership between the federal government and the nation's best universities." The program's Web site, located at http://www.mdsg.umd.edu/ NSGO/index.html, is not only a treasure trove of data from the past three decades' work but also a springboard for the work that still needs to be done.
The What Is Sea Grant? link describes the goals and mission of the National Sea Grant Program and the means, such as science education and technology transfer, by which the program meets those goals and achieves that mission. From this page, users may browse the Sea Grant's 1995-2005 Network Plan, which outlines how the program plans to address the issues of economic leadership, coastal ecosystem health and public safety, and education and human resources over the next few years. The Sea Grant Results--Making A Difference link leads to a newsy e-zine that describes ongoing research by various Sea Grant branches.
The 29 Sea Grant Colleges link enables users to access the Web sites of each of the member programs. This page also contains links to related projects and programs within the National Sea Grant Program. For instance, the Louisiana Sea Grant Legal Program, located at the Louisiana State University Law Center in Baton Rouge, maintains a page of resources for those interested in the judicial aspects of protecting U.S. waters.
The National Sea Grant Depository link leads to an archive, located at the University of Rhode Island in Narrangansett, of all the documents generated by Sea Grant-funded projects. By following the National Sea Grant Depository link, users may search a database of depository holdings, browse recent additions to the collection, submit a request to borrow archive materials, or order a subscription to the quarterly Sea Grant Abstracts, which summarizes most of the literature received by the National Sea Grant Depository.
The Sea Grant Sponsored Research link lists current research and outreach projects, such as the Oyster Disease Research Program and the Nonindigenous Species Research and Outreach Program. This link also includes searchable bibliographies of literature generated by Sea Grant-sponsored research projects.
The News link takes users to the Sea Grant Media Center, which is packed with National Sea Grant news releases, tip sheets, and radio interview transcripts, as well as links to online publications and related Web sites, and a calendar of marine science-related events. This link also lets users order Sea Grant Program publications and subscribe to the Sea Grant News e-mail news service. The What Is New? link on the home page allows readers to browse the most recent news releases.
The Funding & Fellowships link lists open requests for proposals, as well as employment vacancies within the National Sea Grant Program and overviews of the National Sea Grant Federal Fellows and Industrial Fellows programs. The Directories link offers searchable databases of program staff across the nation, and the Selected Publications link allows quick, direct access to the most commonly requested publications.
Last Update: June 18, 1998