Research conducted by a team of California scientists points the way to what ultimately may become a promising cancer treatment: a technique that triggers tumor regression through the injection of one of two different proteins. After injecting a single dose of either a monoclonal antibody or a synthetic protein into the vasculature surrounding tumor fragments grafted onto chick embryos, the scientists observed an astounding result: the tumors not only stopped growing, but they actually began to decrease in size.
The experiments, led by cell biologists Peter C. Brooks and David A. Cheresh at San Diego's Scripps Institute, fall into an area of cancer research called tumor angiogenesis--the process by which a tumor produces substances that support the development of new blood vessels necessary for tumor growth.
Their findings appear promising. According to the study, published in the 30 December 1994 issue of Cell, the proteins not only destroyed newly sprouting blood vessels that nourished the growing tumor but were also nontoxic to the surrounding healthy tissue. While the researchers don't claim to have found a cure for cancer, they remain hopeful that their research will have a positive impact on human cancer treatment.
Choking the flow. Blood vessels feeding human melanoma tumors (left) are disrupted by injection of cyclic RGD peptides (right).
According to Brooks, research began after his team made the initial observation that a cell surface molecule, or integrin, known as vß3, was highly expressed in the proliferating blood vessels around the tumor, but not in the tumor itself. "In order for a tumor to grow beyond one to two millimeters, they required a blood supply," Brooks explains. "Instead of targeting the therapy to the tumor, we targeted it to the vasculature around it." It's a novel approach, since the other eight compounds known to inhibit tumor angiogenesis--now in clinical trials at research institutions in the United States and Europe--are targeted to affect the tumors themselves.
In their attempts to halt tumor growth, the researchers targeted the vß3 integrin, which allows the cells lining the blood vessels to attach to and interact with the extracellular matrix. The genetically engineered monoclonal antibody developed at the Scripps Institute and a synthetic peptide developed by E. Merck of Germany both disrupt vß3 function. The monoclonal antibody is licensed to Ixsys Inc., a San Diego biotechnology company which, according to Brooks, is planning to begin clinical trials with the antibody (known as LM609) on humans in 12-18 months.
In their study, Brooks and Cheresh describe how the human body selectively allows the development and destruction of vascular cells. The vß3 integrin sends out a survival signal that normally would allow maturation into a blood vessel. "The antibody and the peptide both block the transmission of survival signals to the endothelial cells, leading to apoptosis, or programmed cell death," Brooks explains. "The tumor also dies," he adds.
To observe the impact of the proteins on tumor growth and survival, the scientists planted tumor fragments onto 10-day-old chick embryos, employing a classical model for studying angiogenesis that was pioneered by Judah Folkman, a veteran angiogenesis researcher at the Harvard Medical School. After several hours, new blood vessels had begun to form in the tumor fragments.
At the 24-hour mark, the scientists introduced either of the two proteins to some embryos, and allowed others to grow without the proteins as a control. The researchers observed a dramatically reduced number of blood vessels feeding the tumors in the embryos injected with the proteins. The tumors actually regressed and the embryos developed normally. In the control embryos, the blood vessels proliferated in their usual pattern, promoting the growth of the tumors.
"The research is very promising and has great potential," says James Pluda, an angiogenesis expert at the National Cancer Institute in Bethesda, Maryland. The experiment designed by the Scripps researchers "approaches disrupting the angiogenic pathway at a point that is different than other [studies have shown]," says Pluda.
"We're excited about having it progress," says Pluda, who oversees the development of anti-angiogenic drugs at NCI. "It's very interesting; it's also very preliminary," he cautions. The proteins could lead to unwanted side effects in other tissue, which could inhibit wound healing, for example, or possibly lead to fetal damage in pregnant women.
At this stage of research, scientists at Ixsys are completing toxicology studies to determine the extent, if any, of adverse effects of the LM609 antibody. They will also perform tests to rule out any biological properties that would discourage the use of the antibody in humans.
According to Brooks, the Scripps research team duplicated their chick-embryo test results in experiments on small sections of human skin grafted onto mice and observed a twofold reduction in tumor size. Their laboratory findings held true for a broad range of solid-tumor human cancers, including malignant melanomas and cancers of the lung, breast, pancreas, brain, and larynx.
According to Brooks, the team collaborated with another Scripps researcher, ophthalmologist Martin Friedlander, and discovered that the protein therapy may be useful in treating several eye disorders as well, including diabetic retinopathy and macular degeneration.
Do electric and magnetic fields (EMFs) cause cancer? Researchers still don't know for sure, since the latest epidemiological look at EMF health effects contradicts some previous findings.
Power thinker. David Savitz is among those researchers moving to mechanistic studies of EMFs.
The new study, conducted by epidemiologist David A. Savitz of the University of North Carolina-Chapel Hill School of Public Health, underscores the need to identify biological mechanisms associated with EMF health effects, NIEHS officials say.
Savitz, whose work in 1988 helped spark intense public and scientific debate over the safety of EMFs, now concedes that future investigations must identify "biologically relevant exposure metrics." If properly defined, he adds, epidemiological studies may still shed light on EMF effects.
"I hate to give up on epidemiology outright, but I think that it needs to evolve," says Savitz. "We need either more innovative epidemiological studies or biological studies."
In his newly published review of 138,905 male utility workers, men exposed to high-level 60-Hertz magnetic fields were about twice as likely to develop brain cancer, although they developed only about 70% as many brain tumors as expected. Nonetheless, men subjected to extremely high-level fields experienced 2.6 times greater risk than the average American, Savitz reported with co-author Dana Loomis in the American Journal of Epidemiology (vol. 141, no. 2).
Yet, Savitz found no link between magnetic fields and leukemia, except among electricians. This finding is puzzling when compared with other recent studies.
A 1993 report by J.D. Sahl and colleagues failed to identify any statistically significant link between magnetic fields and brain cancer or leukemia among 36,000 workers at the Southern California Edison Company. Another study of 223,292 Canadian and French utility workers, published in 1994 by Gilles Theriault and associates, offered no convincing evidence of an increased brain-cancer risk among highly exposed groups. Unlike Savitz, however, Theriault reported that exposed individuals were up to three times more likely to develop certain leukemias.
Savitz was instrumental in launching numerous epidemiological studies of EMF effects. In 1988, he published a case-control study of 356 childhood cancer cases whose findings seemed to confirm a 1979 study by epidemiologist Nancy Wertheimer and physicist Ed Leeper. Among 344 Denver-area children, they reported, those dwelling within 49 to 131 feet of high-power electricity lines were two to three times more likely to die of cancers.
Despite 16 years of subsequent research, however, the debate over EMFs continues. In his latest study, Savitz carefully ruled out the effects of two other workplace carcinogens: polychlorinated biphenyls (PCBs) and solvents. But he could not account for many other variables such as cigarette smoking among test subjects or magnetic fields within homes.
Researcher Philip Cole of the University of Alabama at Birmingham questions Savitz's interpretation of the EMF data. Among 138,905 workers, brain cancer and nervous system cancers claimed the lives of 151 men: 8 fewer deaths than expected. In an unpublished evaluation of the Savitz study, Cole says this finding is in fact "negative, or at most weakly positive." But Savitz says utility workers tend to be healthier than the average American. "It's a pretty well-established phenomenon that working populations have lower mortalities from a whole range of causes," he says.
Future studies must account for more complex variables, says Wertheimer. Many researchers believe that EMFs may work cooperatively with other carcinogens to promote tumor development, she notes. Overall, the body of epidemiological research thus far suggests a relatively small increase in cancer risks (1.5 to 2.5 times greater) for those exposed to high-level magnetic fields, according to Savitz. "Savitz has done the best job possible," Wertheimer continues. "But we still don't know if [his test subjects] used electric blankets or lived in high-exposure neighborhoods. We still have a very blunt tool."
Attempts to hone that tool are being made using toxicological and basic biological studies as the focus of an EMF health effects research program directed by the NIEHS and administered by the U.S. Department of Energy.
"It didn't make sense for us to fund additional epidemiological research," says Dan VanderMeer, NIEHS director of the Office of Program Planning and Evaluation. "We decided to focus on those health conditions that have been identified in epidemiological studies."
Dubbed EMF RAPID, for Electric and Magnetic Fields Research and Public Information Dissemination, the program was authorized by Congress in October 1992. Over a five-year period, Congress authorized up to $65 million to support research and public information. The law also calls for matching private funds.
Using animal models, EMF RAPID grant recipients are testing epidemiological findings related to leukemia, breast cancer, brain tumors, and other diseases, VanderMeer reports. In addition, molecular and cellular studies are addressing possible biological mechanisms, including immune-system suppression, direct or indirect DNA changes, disruption of cellular communications, and impacts on melatonin, a hormone that blocks tumor formation in vitro.
EMF RAPID funds were also used to expand an existing NIEHS animal study conducted as part of the National Toxicology Program. At the IIT Research Institute (IITRI), a 21,000-square-foot laboratory makes it possible to expose 2,400 animals to magnetic fields under highly controlled conditions, says Gary Boorman, chief of the Pathology Branch in the NIEHS Environmental Toxicology Program. Principal investigator David L. McCormick of IITRI exposes rats and mice to magnetic fields to assess reproductive, immunological, and carcinogenic effects, as well as melatonin levels.
In all studies, researchers are trying to replicate robust effects, says Michael Galvin, a general physiologist at NIEHS. "An effect that appears only once and is not robust enough to be replicated consistently or demonstrates a so-called Cheshire cat effect would be difficult to assess," Galvin notes.
Wertheimer worries that NIEHS researchers may fail to identify a health hazard because they are focusing on whether EMFs initiate tumors. In fact, she says, EMFs may promote cancer development only when tumors are initiated by some other agent. "The idea of direct DNA damage is still foremost in their minds," Wertheimer says of NIEHS officials. "I don't think that's what we're dealing with here." However, according to VanderMeer, NIEHS is also supporting mechanistic studies of possible EMF effects on cell signaling, cell membrane function, tissue and organ systems, and free radicals. "These mechanisms," says VanderMeer, "are important irrespective of whether EMFs may act as direct or indirect carcinogens."
The NIEHS decided to emphasize tumor initiation because research groups in Canada, Sweden, and Germany were already investigating co-promotion effects, Boorman says. But, he adds, EMF RAPID funds will support two co-promotion studies at IITRI. Using genetically engineered rodents with a known cancer susceptibility, McCormick's team will assess whether EMFs speed tumor development among animals exposed to carcinogens such as diethylnitrosamine. Plans for additional promotion studies using a rat breast cancer model are also being developed at NIEHS.
In a December 1994 report, the General Accounting Office questioned an Army assessment that the U.S. chemical weapons stockpile can be safely stored until 2004. This is Congress's latest deadline for the Department of Defense to destroy stockpiled unitary chemical weapons--those that contain a single lethal agent.
Of concern are 478,000 M55 rockets stored at sites in five states and on Johnston Atoll in the Pacific Ocean. According to GAO and technical consultant Sandia National Laboratories in Albuquerque, New Mexico, these stockpiled M55 rockets are unstable as stored and inadequately monitored by the Army, the Department of Defense's lead service in chemical matters. Deadly Sarin
Initially, Congress directed the Department of Defense to destroy M55s and the rest of the stockpile by 30 September 1994. When the Army fell behind in implementing its $8.5 billion on-site incineration program, Congress extended the deadline to 2004 and asked the Army to evaluate the stockpile's physical and chemical integrity. The Army's July 1993 report--based on inspection and laboratory data and old stockpile assessment reports--said the stockpile was safe for now but uncertain beyond 2004. Congress asked GAO to review the Army's estimate and contingency plans if something goes wrong.
Responding to the GAO report and recommendations made in 1994 by the National Research Council, the Army Chemical Demilitarization and Remediation Activity, based at Aberdeen Proving Ground, Maryland, released a statement February 16 that said work would begin in fiscal year 1995 to determine the storage life of leaking and nonleaking M55 rockets.
Each M55 rocket consists of a warhead that carries 10 pounds of nerve agent (GB) and an explosive charge, and a solid-rocket motor with a nitroglycerin-based propellant and a stabilizer that keeps heat from building up as the propellant decomposes. If the decomposing propellant gets too hot or acidic, the M55 could autoignite.
All stockpiled weapons contain a mustard/blister agent (H) or one of two nerve agents (VX or GB). M55s carry GB, and, the Army report adds, nerve agents, especially GB, become acidic over time and can corrode metal warheads of rockets, mortars, and projectiles.
"The propellant is unstable and so is the chemical agent," says Donna Heivilin, GAO's director of Defense Management and NASA section and author of the 1994 report to Congress, "and the M55 design makes it hard to physically separate the propellant from the GB. If the propellant blows up, the chemical agent would disperse. This is what makes the M55 more dangerous [than other stockpile weapons]."
Threats to stockpile storage include earthquakes, plane crashes, tornadoes, accidents during handling and maintenance, autoignition of the propellant, and chemical leaks from the warhead. And the potential danger to human life is immense, even if one rocket ignited, because, according to the Army's 1994 report, M55 Rocket Storage Life Evaluation, "the resulting explosion and fire in a storage igloo could involve many of the 4,000 rockets that typically are stored together."
"The congressional mandate is that the Army dispose of these [unitary chemical weapons] in the safest, most environmentally sound fashion," says Craig Williams, national spokesperson for the Chemical Weapons Working Group, an international coalition of environmental and ecological groups. "But the Army's focus is on the comparative risk of continued storage versus incineration. We've been trying for years to broaden the scope of that analysis to include comparisons among continued storage, reconfiguration, reconfiguration with partial neutralization, and incineration."
Reconfiguration, Williams says, "involves moving the M55s to a munitions detonation-containment building, using robots to disassemble the munitions, separating chemical agents from other components, and partially neutralizing the by-products. Then we'd have hazardous waste, which isn't great. But what we have now are rockets and mortars ready to launch and send nerve agents randomly into communities. We'd have reduced the risk of exposing chemical warfare agents to facility workers and the community to zero."
At the Army Chemical Demilitarization and Remediation Activity at Aberdeen Proving Ground, Mark Evans, special assistant to the program manager, says this is easier than it sounds. To neutralize the M55s, he says, "we'd have to build 90 percent of the demilitarization [high temperature incinerator] facility we plan to build anyway. We are updating cost estimates for rocket separation, but there are no good neutralization techniques for VX and GB, and we'd produce a lot of waste. The Army believes that if the risk assessments show the rockets can be stored through 2013, our incineration program is the safest method."
The neutralization proposal seems to indicate that construction of the demilitarization facilities could be sped up, but that's not true, according to Evans. A facility at Tooele Army Depot in Utah is built and is in testing, Johnston Atoll's facility is operational, and there are contracts to build and operate facilities at Anniston Army Depot in Alabama (to be completed in 1999), Umatilla Depot Activity in Oregon, and Pine Bluff Arsenal in Arizona (both to be completed in 2000). The Blue Grass Army Depot facility in Kentucky would be operational by 2002.
Over the next year, the Army will examine two approaches for determining the storage life of nonleaking M55s. The Army's approach combines relatively new data on propellant chemistry with a probabilistic method for evaluating storage life. According to this method, the chances of autoignition are less than one in a million before 2013. A second method derived by Hercules Corporation, the propellant manufacturer, estimates the chances of auto-ignition are less than one in a million before 2043.
There are no estimates on autoignition for leaking M55s, which have been found at all six munitions storage sites. Such leaks, caused by corrosion that eats small holes in the metal warheads, let chemicals or vapors escape inside or outside the weapon. External leaks can be quickly detected by monitoring. Internal leaks can't be detected without disassembling the weapon, and a 1985 Army assessment of M55 rockets estimated that 1-3% had internal leaks.
But no one knows the extent of the hazard these leaks pose; the GAO report says the Army has never sampled the leaking munitions because it considers them too dangerous. The Army says there is insufficient evidence to determine, as the GAO report concluded, that leaking rockets have a shorter storage life than nonleaking rockets.
"It is not known if leaking M55 rockets could autoignite during handling if agent were to come in contact with energetic material found in the burster and fuse," the Army statement says. "Previous assessments of the stockpile stability have raised the possibility, but there is insufficient data to reach a conclusive determination. The Army will determine what effects, if any, the agent has on energetic material."
Responding to GAO's call for a contingency plan for emergency disposal of the M55, the Army says it will develop a plan that outlines the steps it will take if the rockets' deterioration accelerates.
Sandia further recommended that the Army immediately expand its stockpile monitoring to include propellant samples from nonleaking and leaking munitions at each storage location. But the Army, whose safe-storage-life projections of nonleaking M55s are based on measuring master samples of rocket propellant stored at Picatinny Arsenal in New Jersey, says it will continue using master samples for periodic assessments after it verifies the master samples still represent propellant stored in the field.
Master samples are used, Evans says, because "we have to think about putting workers at risk who extract propellant sample from fully loaded chemical munitions. We use machines to cut the rounds apart in a room with 28-inch-thick walls because of the potential for problems."
The Army tests will include taking field samples from Tooele, where some rockets were partially dissassembled years ago, and from Johnston Atoll, where some of the rockets have leaked.
"If we do all those tests," says Evans, "and the propellant is different from the master samples, we'll need to initiate a much more extensive field-sampling program, and that will cost a lot of money. If we believe it's different and worse, you may see us try to expedite activities at rocket sites." GAO agrees samples should be taken from all sites, but says expanded monitoring won't answer all questions about stockpile stability.
"We have reason to believe that propellant and agent affect each other, but we don't know if it changes anything," Evans adds. "Only one data point indicates that it may. We need to move from 'it may' to 'it does' or 'it doesn't.'"
Deadly Sarin
The death of 10 people and the injury of 5,000 more in the terrorist attack on the Tokyo subway system March 19 serves as a tragic reminder of the lethal potential of nerve agents.
The organophosphate sarin (isopropyl methyl phosphonofluoridate), also known as GB, has been identified as a component of the gas used in the attack. Sarin was first developed in Nazi Germany. At lethal doses, it can cause death within seconds when inhaled. At more moderate doses, it can cause nausea, diarrhea, and interfere with mental ability.
Sarin primarily affects the respiratory and nervous systems (see Munro et al., EHP 102:18-38). Subtle changes in EEG patterns and increases in rapid eye movement during sleep were observed in a group of workers one to six years after accidental exposure. Brain damage has resulted at concentrations of sarin high enough to induce convulsions. Respiratory effects include bronchoconstriction, wheezing, and increased airway secretions.
Like other organophosphorus compounds, sarin works by inhibiting acetylcholinesterase, an enzyme that breaks down the neurotransmitter acetylcholine, thus overstimulating the nervous system. Once sarin enters the blood, it can penetrate the blood-brain barrier. In the case of sarin, death is caused by depression of the brain's respiratory center.
Pupil constriction, or miosis, has been observed up to 60 days after exposure to sarin. Eye pain and dim vision may also occur. Transient, prolonged changes in psychological function, manifested as depression, nightmares, confusion, and deficits in motor skills and intellectual ability have been observed in individuals exposed to organophosphate insecticides, which are similar in structure to sarin.
However, unlike some organophosphate insecticides, long-term effects have not been documented for sarin. "Sarin itself should not cause any long-term health effects," said Nancy Munro of the Oak Ridge National Laboratory in Oak Ridge, Tennessee. "[It is] highly unlikely to cause carcinogenicity."
Indeed, studies have shown that sarin is neither carcinogenic, genotoxic, or teratogenic. Delayed effects such as organophosphorus-induced delayed neuropathy (OPIDN) may be more of a concern. Although OPIDN has not been associated with sarin exposure, it has been documented in people exposed to organophosphate insecticides. OPIDN usually occurs within 5-30 days of exposure, beginning with weakness, tingling, and muscle twitching, and progressing to paralysis of the toes, hands, and thighs. Recovery is slow and incomplete. The problem, according to Michael Ellis of the University of Texas Medical Branch Poison Center in Galveston, is that organophosphorus compounds accumulate in lipid tissues such as fat and nerves.
But, like Munro, Ellis emphasizes that long-term effects are not the concern with sarin: "This stuff was made to kill people," he says. The ease of concocting deadly agents such as sarin has stimulated questions about public safety worldwide. |
Since the end of the Cold War, the CIA, which is facing budget cuts, has been searching for new ways to use its spying equipment, which is no longer being used to its full capacity. In October 1992, the CIA selected a team of 70 civilian environmental scientists to work with officials to examine whether the CIA's spy equipment could be used to provide information on the environment. The idea was presented by Vice President Al Gore, who had long believed that the CIA's records contained valuable information on climate, land use, oceans, and atmospheric conditions.
The task force was given access to the satellite system run by the National Reconnaissance Office (NRO), whose name was classified until last year, to determine if the equipment could be applied to environmental science. The CIA conducted a series of 13 experiments to determine whether the systems could be used to measure environmental changes such as greenhouse gases, ocean temperatures, polar ice thickness, and forest and desert boundaries.
The satellites contain devices that are able to take very detailed photographs at close range through telescopes in all types of weather and light conditions. An example of how this equipment could be used for environmental purposes lies in the former Soviet Union. Dozens of launch clusters and about 1600 missile silos are located along a trans-Siberian railway. The CIA satellites have been photographing this area daily for decades. As a result, the CIA has years of data on the snow melt in that area, which is an indicator of climate change.
The CIA also has years of ocean data as a result of submarines in the Arctic collecting sea ice measurements daily for decades. Sea ice is also an important factor in climate change measurements.
The task force completed its initial report last December, and it was circulated throughout the intelligence community on a classified basis. The scientists found that, indeed, the CIA's archives and collection devices could provide invaluable information on climate change. The report is not a policy document; it merely discusses the possibilities.
Among the possibilities that the task force discussed is the satellite tracking of changes in vegetative and desert boundaries, which may indicate global climate change. Also, the report says that underwater listening systems could monitor fluctuations in ocean temperature by measuring changes in ocean sound speed over long distances.
The report also addressed forests and biodiversity. Currently, scientists have access to civilian satellite photographs of the world's forests taken by LANDSAT, which produces infrared color images of land areas and oceans. But the LANDSAT photos are not nearly as precise as the CIA's satellite photographs. LANDSAT can only achieve resolution of 10 meters, while the NRO can reach up to 10 inches. While LANDSAT can only take broad pictures of forests, the NRO satellites can zoom in to count the number of trees in an area and determine what species they are. The task force report says that scientists could combine LANDSAT data with NRO data to obtain detailed information on forests.
The report also discusses the use of a spy device that uses infrared technology to analyze the chemical composition of plumes of missiles as they streak across the sky and other heat patterns, such as factory emissions. The device could be used to analyze the reflection of sunlight off a forest canopy to determine the chemical composition of forests. This would provide information on whether forests contain certain chemicals that are necessary for healthy vegetation.
The report says that the CIA also has the ability to scan for forest fires. The Defense Support Program early-warning satellites, which are designed to detect missiles emerging from silos, could be used to detect forest fires.
The CIA could also use its Global Positioning System to track ice floes and ocean buoys to provide further information about ocean temperature, salinity, and current. U.S. Navy undersea listening devices that monitor the ocean for submarines could be used to track whale migration and listen for storms, undersea volcanoes, and earthquakes.
Although the possibilities sound promising, the plan may not materialize due to several problems. For example, the CIA could decide that the risks of revealing too much about the intelligence structure outweigh the potential benefits to environmental scientists. Even if the CIA produces environmental data, the agency plans to disguise the origin of the data so that scientists may not be able to determine where the information comes from. Some scientists are bothered by the idea of secrecy surrounding the CIA information.
"The cultural antagonism here is that the fundamental tenet in science is that you tell everyone everything, and the fundamental tenet in intelligence is that you don't tell anyone anything," John Pike of the Federation of American Scientists told E Magazine.
Scientists also worry that some of the results the CIA presents will not be reproducible because civilian scientists do not have access to the same type of equipment that the CIA does. Another problem scientists foresee is that the process of gathering environmental information may be too expensive, especially in a time of massive federal budget cuts.
Finally, the new Republican-dominated Congress, which is largely against increased spending for the environment and for increased defense spending, may believe that the proper role of the CIA does not include collecting scientific data or any data other than that of national security.
The mighty mosquito. A combination of factors, including climate change, could increase the epidemic potential of malaria-carrying mosquitoes.
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Hoping to provide a tool that could aid scientists and world health authorities in stemming the spread of malaria throughout the world, a team of four scientists from The Netherlands has created a mathematical model that could predict the impact of global climate changes on malaria risk worldwide. Findings from their recent research published this month in EHP (pp. 458-464) suggest a widespread increase in risk due to the geographical expansion of areas suitable for malaria transmission.
According to the study by Willem J.M. Martens and colleagues, climate changes expected during the next century could potentially alter both the distribution and incidence of malaria--a disease believed to afflict more than 300 million people and kill more than 1.5 million each year. Malaria parasites, plasmodium, develop inside mosquitoes and enter the human bloodstream through mosquito bites. The parasites develop through many growth stages and ultimately cause host red blood cells to erupt, resulting in flulike symptoms. The parasite's life cycle depends on transmission between mosquito and humans. Malaria incidence depends on several factors--the abundance of the anopheline mosquito species, human behavior, and the presence of malaria parasites. Anthropogenic climate change may impact the incidence of the disease as well, by affecting the behavior and geographic distribution of the mosquitoes, as well as the life cycle of the parasite. Climate change could also influence factors such as vegetation and the availability of breeding sites.
To predict and assess such changes, the scientists employed an integrated mathematical model to estimate the possible spatial shift in areas prone to malaria transmission, considering possible changes in the worldwide burden of malaria due to changes in climate. The model incorporates three interrelated modules, or systems: the climate system, the malaria system, and the impact system. These systems are linked together in a straightforward manner, with output from one system serving as input for the next.
To generate climate scenarios, the research team used a climate assessment model known as IMAGE (Integrated Model to Assess the Greenhouse Effect) to simulate greenhouse gas emissions and their effect on global mean temperature. The simulated global mean temperature changes are then converted into regional seasonal temperature and precipitation changes by standardizing the output of a General Circulation Model (GCM).
The mathematical model also incorporates the basic reproduction rate of plasmodium, which researchers defined as the average number of secondary infections produced when one infected individual enters a host population where everyone is susceptible. The basic reproduction rate is used to calculate the critical density threshold necessary to maintain parasite transmission. Researchers also defined the epidemic potential of malaria as the reciprocal of the vector population's critical density and used this as a comparative index for estimating how changes in temperature and precipitation patterns may affect malaria risk. Scientists worked other submodels into their research as well, including a standard population model and an epidemiological model for infectious diseases.
According to Martens, this study, part of an ongoing project begun in 1992 at the Dutch National Institute of Public Health and Environmental Protection, goes a step beyond previous research in this area: "Most other studies focused only on climate change effects on mosquito populations. We modeled the climate system, mosquito system, and human system in order to arrive at [a] better understanding of the complex interactions between [them]," Martens said.
Martens said he and his colleagues pursued this project because little attention had been given in the past to assessing possible adverse health effects of global environmental disturbances through environmental modeling systems. "Most of the studies focus on just one aspect and do not pay attention to the possible synergistic health effects," he explains. "We try to fill this gap in scientific research."
This model shows further promise because it attempts to identify regions and populations vulnerable to the disease. In their study, Martens and his colleagues show that climate changes will expand the boundaries of geographic regions susceptible to malaria transmission, and thus bring about a widespread increase in potential malaria risk. According to the study, a global mean temperature increase of several degrees in the year 2100 increases the epidemic potential of the mosquito population in tropical regions twofold, and more than 100-fold in temperate climates. And, the study concludes, there is a risk of reintroducing malaria into nonmalarial areas.
"It is an excellent study," said Robert Mendelsohn, an economist and professor of forest policy at the Yale School of Forestry and Environmental Studies, who studies the economic impact of climate change in the United States. "It is exactly the kind of thing that needs to be done." Mendelsohn said the study is valid in that it considers not only ecological factors, but predicts where malaria could and should appear, and how climate could affect these areas. However, Mendelsohn says, the study fails to adequately address artificial intervention by humans and how that might affect malaria risk due to climate changes. "I was hoping they would address what could happen if man were involved," he says. While the model promises to serve as a useful tool for scientists and public health policy-makers, the research team cautions that any increase in malaria risk must be interpreted along with "the change in malaria transmission associated with the socioeconomic development, population growth, and the effectiveness of control measures."
Climatologist Laurence Kalkstein of the University of Delaware's Center for Climatic Research, who worked on a model to assess the spread of dengue, another tropical disease spread by the mosquito, praised the Martens study. "I believe it's a good attempt to bring together factors to slow the spread and emergence of malaria," he said. "We're working with [the researchers] to provide a more sophisticated climatological component for the model."
While preventive and protective measures including vector control are available to individuals, families, and communities at risk for contracting malaria, scientists and health officials worldwide continue in their search for a viable malaria vaccine. At this point, the greatest hope appears to rest with a vaccine known as SPf66, formulated by Colombian physician and chemist Manuel Elkin Patarroyo. The first malaria vaccine, SPf66 targets the later, more complex blood stages of the malaria parasite and functions to prevent disease rather than to prevent infection.
"The Patarroyo vaccine is a major breakthrough in the scientific efforts to elicit protective immunity in humans by artificial immunization," says Renato Gusmao, director of the Pan American Health Organization's division of communicable diseases and prevention control in Washington, DC. One advantage of SPf66, according to Gusmao, is that it is a synthetic peptide free of biological impurities. Clinical trials have shown it to be nonimmunogenic, safe for human use, and partially effective (31-67%) in reducing symptoms of malaria disease caused by the P. falciparum mosquito.
While recent clinical trials have shown promise, some within the international scientific community evince skepticism toward SPf66 as an effective antidote in widespread use. Gusmao says that one problem lies in production methods. Because the vaccine has been produced by an experimental laboratory, potential production volume is limited and lot-by-lot production is subject to variations, according to Gusmao.
"The next step is the construction of a GMP [Good Manufacturing Practices]-level production plant," Gusmao says. Standard, high-volume production will allow increased coverage for the massive clinical trials needed to overcome the statistical weakness of the trials published to date. Such a facility would also give scientists a chance to tinker with the vaccine's formulation--improving the standard peptide by remodeling it, improving or changing the vaccine's adjuvant, and altering the drug's dosage or route of administration.
According to Gusmao, a GMP plant is expected to begin production in 1997. "Hopefully, the continuous efforts of Dr. Patarroyo's group to improve the basic SPf66 will [make it] available for GMP production at that time," he says.
Meanwhile, research efforts are underway to develop two different vaccines: one to block transmission and one to block infection. However, Gusmao says, "both developments have failed to show significant levels of protective immunity thus far."
While the quest for a useful, widely available vaccine continues, government and public health officials around the world will continue their struggle to counteract the devastating effects of the disease on the populations most at risk. Early diagnosis and immediate and adequate treatment, along with established preventive and protective measures, remain the chief weapons in the battle against malaria. Tools such as the Martens model for predicting the incidence of malaria may yield valuable information on the subtle interplay between environmental, biological, and climatological factors and malaria risk.
In the aftermath of tax season, some people may be looking for examples of federal money being put to good use. One such example can be found on the Internet. The federal government has an extensive World Wide Web (WWW) server that is a tremendous information resource and is available free of charge to anyone who can log on. Within this single Web server, located at the URL http://www.fie.com/www/us_gov.htm, is a wealth of information on all branches of the federal government: executive, legislative, and judicial.
Sites under the executive branch include information on all of the cabinet level agencies under the control and direction of the president and the departments within this branch including, for example, Defense, Education, Energy, and Health and Human Services. Each department listing has subheadings (hyperlinks) that may be located by clicking on them. In addition, access to the White House Server allows users to tour the White House, become acquainted with the presidential family (Socks included), and keep up to date on the president's latest statements. Users may also read a copy of the vice president's National Performance Review.
Under the legislative branch of the Web server, users can access the House of Representatives home page and obtain information on legislative schedules, membership of House committees, and how to contact their representative. As of March, the only information located under the hyperlink to the Senate is provided by Senator Edward Kennedy (D-Massachusetts). As of yet there are no hyperlinks set up under the judicial branch site. These areas may be under construction, as they are listed in the federal budget for 1995.
By far the bulk of information on the federal government Internet site is located in the executive branch department hyperlinks. These resources allow researchers to obtain information about possible research opportunities and find information on grants and contracts from a particular federally funded institute: at some sites, grant applications may be obtained simply by downloading them. Examples of some of the hyperlinks available include the Army's Environmental Technology Office, the National Marine Fisheries Service, the Department of Energy's Office of Environment, Safety and Health, the National Institutes of Health, Lawrence Livermore National Laboratory's Biology and Biotechnology Research Program, the National Biological Survey, the National Academy of Sciences, and the National Science Foundation.
Last Update: July 29, 1997