Arcanum is back...

The game Arcanum of Steamworks and Magick Obscura which is a classic one and was released 6 years ago is making a come back. It has sold over 5 million copies in three years time and was IGN's number one game for 2003-2004. The game is a turn-based just like the Fallout no wonder because most of the developers were from Fallout.
Check the site for more details.
http://arcanum-of-steamworks-and-magick-obscura.webs.com/index.htm

'Buckyballs' Have High Potential To Accumulate In Living Tissue

'Buckyballs' Have High Potential To Accumulate In Living Tissue

ScienceDaily (Sep. 19, 2008) — Research at Purdue University suggests synthetic carbon molecules called fullerenes, or buckyballs, have a high potential of being accumulated in animal tissue, but the molecules also appear to break down in sunlight, perhaps reducing their possible environmental dangers.


Buckyballs may see widespread use in future products and applications, from drug-delivery vehicles for cancer therapy to ultrahard coatings and military armor, chemical sensors and hydrogen-storage technologies for batteries and automotive fuel cells.

"Because of the numerous potential applications, it is important to learn how buckyballs react in the environment and what their possible environmental impacts might be," said Chad Jafvert, a professor of civil engineering at Purdue.

The researchers mixed buckyballs in a solution of water and a chemical called octanol, which has properties similar to fatty tissues in animals. Jafvert and doctoral student Pradnya Kulkarni were the first to document how readily buckyballs might be "partitioned," or distributed into water, soil and fatty tissues in wildlife such as fish.

Findings indicated buckyballs have a greater chance of partitioning into fatty tissues than the banned pesticide DDT. However, while DDT is toxic to wildlife, buckyballs currently have no documented toxic effects, Jafvert said.

"This work points out the need for a better understanding of where the materials go in the environment," he said. "Our results show they are going to be taken up by fish and other organisms, possibly to toxic levels. This, however, indicates only the potential of buckyballs to bioaccumulate. They could break down in the environment or in an organism once taken up."

Researchers do not yet know whether buckyballs will break down in the environment or will be metabolized by animals, which would reduce the risk of accumulating in fatty tissues.

"For example, we don't bioaccumulate sugars because we process sugars, but we do bioaccumulate other compounds that we don't metabolize," Jafvert said. "If we have the ability to metabolize buckyballs, we won't bioaccumulate them."

Findings were detailed in a research paper that appeared in August in the journal Environmental Science and Technology. The paper was written by Jafvert and Kulkarni.

The researchers determined the "octanol-water partition coefficient," which enables them to show how readily buckyballs would be partitioned.

"The bottom line is, if buckyballs partition favorably from water to octanol, they are also likely to partition favorably from water to fatty tissues," Jafvert said.

The researchers also are investigating whether sunlight breaks down buckyballs and other structures called carbon nanotubes, which also could have widespread industrial applications.

"We need to learn how reactive these materials are in the environment," Jafvert said. "Do they break down? What kinds of products do they form? We have learned so far that buckyballs absorb light, and they do photoreact. That's potentially a good thing because it means it won't hang around for a long period of time, reducing the exposure concentration, which would then reduce any potential toxicity that it may or may not have."

Named after architect R. Buckminster Fuller, who designed the geodesic dome, buckminsterfullerenes, or buckyballs, are soccer-ball-shaped molecules containing 60 carbon atoms. A buckyball has a width of about 1 nanometer, or one-billionth of a meter, which is roughly 10 atoms wide.

The researchers determined precisely how soluble the buckyballs are in water and confirmed that the molecules form clusters, which complicates efforts to understand how they might be dispersed by water in the environment.

"Typically, buckyballs are not found in water because their solubility is so low, but the same could be said of DDT," Jafvert said. "DDT is found in sediment, so you would assume buckyballs would also end up in sediments. That means there is also a chance that marine organisms, like worms that are eating sediment, are going to be potentially accumulating buckyballs unless they break down in the environment."

The research is affiliated with the Center for the Environment and the Birck Nanotechnology Center at Purdue's Discovery Park and is funded by the Environmental Protection Agency and the National Science Foundation through the NSF's Nanoscale Interdisciplinary Research Team, or NIRT. The work is part of a larger NIRT project at Purdue involving researchers in agronomy, civil engineering, agricultural and biological engineering, mechanical engineering, food science, and earth and atmospheric sciences.

From Sugar To Gasoline: 'Green Gasoline' Crafted From Sugar And Carbohydrates

From Sugar To Gasoline: 'Green Gasoline' Crafted From Sugar And Carbohydrates

ScienceDaily (Sep. 19, 2008) — Following independent paths of investigation, two research teams are announcing this month that they have successfully converted sugar-potentially derived from agricultural waste and non-food plants-into gasoline, diesel, jet fuel and a range of other valuable chemicals.

Chemical engineer Randy Cortright and his colleagues at Virent Energy Systems of Madison, Wisc., a National Science Foundation (NSF) Small Business Innovation Research awardee, and researchers led by NSF-supported chemical engineer James Dumesic of the University of Wisconsin at Madison are now announcing that sugars and carbohydrates can be processed like petroleum into the full suite of products that drive the fuel, pharmaceutical and chemical industries.

"NSF and other federal funding agencies are advocating the new paradigm of next generation hydrocarbon biofuels," said John Regalbuto, director of the Catalysis and Biocatalysis Program at NSF and chair of an interagency working group on biomass conversion. "Even when solar and wind, in addition to clean coal and nuclear, become highly developed, and cars become electric or plug-in hybrid, we will still need high energy-density gasoline, diesel and jet fuel for planes, trains, trucks, and boats. The processes that these teams developed are superb examples of pathways that will enable the sustainable production of these fuels."

The process Virent discovered in early 2006, and announced at the Growing the Bioeconomy conference sponsored by Iowa State University on Sept. 9, 2008, is the subject of patent applications published last week.

That announcement was followed this month by the publication of a separate discovery of the same process in the Dumesic laboratory. Dumesic and his colleagues announce their findings in the Sept. 18, 2008 online ScienceExpress, to be followed in print in the Oct. 18, 2008, issue of Science.

The key to the breakthrough is a process developed by both Dumesic and Cortright called aqueous phase reforming. In passing a watery slurry of plant-derived sugar and carbohydrates over a series of catalysts-materials that speed up reactions without sacrificing themselves in the process-carbon-rich organic molecules split apart into component elements that recombine to form many of the chemicals that are extracted from non-renewable petroleum.

According to Dumesic, a key feature of the approach is that between the sugar or starch starter materials and the hydrocarbon end products, the chemicals go through an intermediate stage as an organic liquid composed of functional compounds.

"The intermediate compounds retain 95 percent of the energy of the biomass but only about 40 percent of the mass, and can be upgraded into different types of transportation fuels, such as gasoline, jet and diesel fuels," said Dumesic. "Importantly, the formation of this functional intermediate oil does not require the need for an external source of hydrogen," he added, since hydrogen comes from the slurry itself.

As part of a suite of second generation biofuel alternatives, green gasoline approaches like aqueous phase reforming are generating interest across the academic and industrial communities because they yield a product that is compatible with existing infrastructure, closer than many other alternatives in their net energy yield, and most importantly, can be crafted from plants grown in marginal soils, like switchgrass, or from agricultural waste.

While several years of further development will be needed to refine the process and scale it for production, the promise of gasoline and other petrochemicals from renewable plants has led to broad industrial interest.

Virent's process, called BioForming, is allowing the company to address one of the key goals of NSF's SBIR program, commercialization, and a broader NSF target, American competitiveness. A recent alliance with one of the world's largest energy companies aims to bring these alternative fuels to market, and investment from major automotive and agricultural companies from around the world are broadening the company's impact.

"The early support of NSF helped lay the groundwork for our technical, and subsequent industrial, successes," said Cortright, chief technology officer at Virent. "Our scientists now have years of expertise with our BioForming process and are rapidly moving the technology to commercial scale. We are quickly working to put our renewable, green gasoline and other hydrocarbon biofuels in fuel tanks all over the world."

Added Rose Wesson, the NSF program officer who oversaw Virent's grant, "The technology developed by Virent is extremely promising, and has been refined over the last six years. The aqueous phase reforming process used by both research is an innovative approach that may yield an important, positive impact on the energy demands of the U.S. and worldwide."

Genetically Modified Crops Protect Neighbors From Pests, Study Finds

Genetically Modified Crops Protect Neighbors From Pests, Study Finds

ScienceDaily (Sep. 19, 2008) — A study in northern China indicates that genetically modified cotton, altered to express the insecticide, Bt, not only reduces pest populations among those crops, but also reduces pests among other nearby crops that have not been modified with Bt. These findings could offer promising new ideas for controlling pests and maximizing crop yields in the future.


The report will be published by the journal Science on Friday, 19 September. Science is the journal of AAAS, the nonprofit science society.

Dr. Kong-Ming Wu from the Chinese Academy of Agricultural Sciences in Beijing and colleagues analyzed data from 1997 to 2007 about the agriculture of Bt cotton in six provinces in northern China, covering 38 million hectares of farmland cultivated by 10 million resource-poor farmers. They compared that information with data on pest populations in the region, focusing on the cotton bollworm, a serious pest for Chinese farmers.

The researchers' results show that populations of the cotton bollworm were dramatically reduced with the introduction of Bt cotton, especially during the period from 2002 to 2006. They considered the contribution of temperature and rainfall along with the introduction of the genetically modified cotton, and confirmed that Bt cotton was responsible for the long-term suppression of the pests in the cotton and a host of other un-modified crops after 10 years. Dr. Wu and colleagues suggest that this may be because cotton is the main host for bollworm eggs, and reducing larval populations in the cotton consequently reduces the entire population and protects other crops.

Bt is an insecticide derived from the spores and toxic crystals of the bacteria Bacillus thuringiensis, and has been sold commercially since 1960. It is considered non-toxic to humans, animals, fish, plants, micro-organisms, and most insects. However, it is highly selective and lethal to caterpillars of moths and butterflies. Bt is currently registered and marketed for use as an insecticide in more than 50 countries worldwide. It does not contaminate groundwater because it degrades so rapidly.

The authors say that Bt technology gives China a new tool for pest control, and that all farmers in a Bt cotton-planting region will experience the benefits. "In 1992, cotton bollworms caused about a 30 percent loss in the cotton yield in northern China. Because of the high costs for pest control then, many farmers refused to plant cotton," said Dr. Wu in an email interview. "This case study of Bt cotton implies that other Bt crops, such as Bt rice, may also have great potential for agricultural practices in China. This success with Bt cotton could push forward the commercial processes of genetically modified crops in China."

Dr. Jian-Zhou Zhao, a co-author of the report, also highlights the health benefits of using Bt cotton. "Poisoning from other insecticides, and even death, was a big problem for cotton farmers in the 1990's," Zhou said. "Most farmers did not have proper protective clothes while applying insecticides with small backpack sprayers. This may be another reason that many farmers refused to plant cotton before Bt was available -- it was too dangerous and scary."

The use of Bt cotton and other genetically modified crops could provide a safer and more economical solution to pest control in many small farms around the world. Dr. Wu and the team of researchers, however, acknowledge that a major challenge to the success of Bt cotton is the potential for insects to evolve resistance to the insecticide. They insist that despite its considerable value, Bt cotton should still be considered only one component in the overall management of pests.

Authors Kong-Ming Wu, Yan-Hui Lu, Hong-Qiang Feng, and Jian-Zhou Zhao are from the State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, 100193, P. R. China.

Jian-Zhou Zhao is also affiliated with Pioneer Hi-Bred International, Inc., Johnston, IA 50131, USA. Yu-Ying Jiang is from the National Agro-Technical Extension and Service Center, Beijing, 1000026, P. R. China.

This research was supported by the Ministry of Science and Technology of China and the National Natural Science Foundation of China.

Explorers Find Hundreds Of Undescribed Corals, Other Species On Familiar Australian Reefs

Explorers Find Hundreds Of Undescribed Corals, Other Species On Familiar Australian Reefs

ScienceDaily (Sep. 19, 2008) — Hundreds of new kinds of animal species surprised international researchers systematically exploring waters off two islands on the Great Barrier Reef and a reef off northwestern Australia -- waters long familiar to divers.

The expeditions, affiliated with the global Census of Marine Life, help mark the International Year of the Reef and included the first systematic scientific inventory of spectacular soft corals, named octocorals for the eight tentacles that fringe each polyp.

The explorers have released some initial results and stunning images from their landmark four-year effort to record the diversity of life in and around Australia’s renowned reefs.

Discoveries at Lizard and Heron Islands (part of the Great Barrier Reef), and Ningaloo Reef in northwestern Australia, included:

* About 300 soft coral species, up to half of them thought to be new to science;
* Dozens of small crustacean species -- and potentially one or more families of species – likewise thought unknown to science;
* A rarely sampled amphipod of the family Maxillipiidae, featuring a bizarre whip-like back leg about three times the size of its body. Only a few species are recorded worldwide;
* New species of tanaid crustaceans, shrimp-like animals, some with claws longer than their bodies;
* The beautiful, rare Cassiopeia jellyfish, photographed upside down on the ocean floor, tentacles waving in the water column -- a posture that enables symbiotic algae living in its tentacles to capture sunlight for photosynthesis;
* Scores of tiny amphipod crustaceans – insects of the marine world – of which an estimated 40 to 60% will be formally described for the first time.

As well, the researchers deployed new methods designed to help standardize measurement of the health, diversity and biological makeup of coral reefs worldwide and enhance comparisons.

Preparing for future discoveries, the divers pegged several layered plastic structures – likened to empty doll houses – for marine life to colonize on the ocean floor at Lizard and Heron Islands. Creatures that move into these Autonomous Reef Monitoring Structures (ARMS), which provide shelter designed to appeal to a variety of sea life, will be collected over the next one to three years.

“Corals face threats ranging from ocean acidification, pollution, and warming to overfishing and starfish outbreaks,” says Dr. Ian Poiner, Chief Executive Officer of the Australian Institute of Marine Science (AIMS), which led the research. “Only by establishing a baseline of biodiversity and following through with later censuses can people know the impact of those threats and find clues to mitigate them.”

Dr. Poiner also chairs the Scientific Steering Committee of the CoML which, after a decade of research, will release its first global census in October 2010.

Dr Julian Caley, Principal Research Scientist at AIMS and co-leader of CoML’s CReefs project, says the three explored coral reef sites are located in two ocean basins with different levels of biodiversity.

“These site characteristics offer clues to predict patterns of biodiversity on reefs that are well known and those that aren’t.”

Previous studies have uncovered large differences in the biodiversity at the 
Great Barrier Reef's Lizard Island and, further south, Heron Island – 
30% more hard corals, 40% more fishes, for example. The cause of such 
gradients in species diversity is poorly understood, but species 
richness in the region tends to decrease with distance from the equator.

Ningaloo Reef appears to be the least biodiverse of the three sites studied, which may be related to its comparative isolation from other reef systems.

Understanding these biodiversity gradients and the influence of connectivity will help scientists predict reef biodiversity worldwide.

Expeditions to the same three sites will be repeated annually over the next three years to continue their inventory and measure impacts of climate change and other processes over time.

The number of species living on reefs is roughly in reverse proportion to body size, with microbes most numerous and larger animals such as corals and fishes smallest in number.

Says Dr. Caley: “We were all surprised and excited to find such a large variety of marine life never before described – most notably soft coral, isopods, tanaid crustaceans and worms – and in waters that divers access easily and regularly.”

“Compared to what we don’t know, our knowledge of marine life is a proverbial drop in the ocean. Inventorying the vast diversity and abundance of life across all ocean realms challenges both science and the imagination.”

First systematic inventory of soft corals on Barrier Reef

The expedition marks the first census of soft corals, named octocorals for the eight tentacles that fringe each polyp.

Researchers believe between one-third to half of the hundreds of soft corals found are species new to science.

While the colorful animals are not reef builders, they dominate some areas studied, covering up to 25 per cent of the ocean floor. They also provide important habitat for other species.

The addition of perhaps as many as 150 new species to the global inventory of soft corals is a major addition to the knowledge of this group which, despite its high distribution worldwide, remains one of the most poorly understood groups.

Despite the large number of new species already discovered, Dr. Caley believes as many new species again may be found on future expeditions. DNA barcoding will dramatically expedite the identification of these species in future, he adds.

Vultures of the sea

Researchers were intrigued as well by discoveries of various isopods, often referred to as vultures of the sea, because some feed on dead fish.

Of the many isopod species collected during the first two expeditions, approximately 100 are not yet described in the scientific literature.

Some isopods are parasitic and burrow into the flesh of live fish. Most infamous of the parasitic isopod are cymothoids – the “tongue biter” – so called because they invade a fish and eat its tongue off, essentially replacing the tongue by attaching to the host's mouth.

Still more discoveries

Other major finds included many potentially new polychaetes, a class of marine animals known as “bristle worms,” a relative of leeches and earth worms. Up to two-thirds of species found at Lizard Island alone are thought to be undescribed.

The scientists' studies also included seaweeds, urchins, and lace corals. More formally known as Bryozoans, lace coral colonies consist of asexually budded (and therefore genetically identical) individuals. Colonies form large intricate structures which bear no resemblance to the structure of the individual.

“Amazingly colorful corals and fishes on reefs have long dazzled divers, but our eyes are just opening to the astonishing richness of other life forms in these habitats,” says CoML Chief Scientist Ron O’Dor. “Hundreds of thousands of forms of life remain to be discovered. Knowledge of this ocean diversity matters on many levels, including possibly human health – one of these creatures may have properties of enormous value to humanity.”

Says Dr. Nancy Knowlton of the Smithsonian Institution, Washington, another principal investigator with CReefs: “The new Australian expeditions reveal how far we are from knowing how many species live in coral reefs around the globe. Estimates span the huge range from1 to 9 million.”

CReefs has embarked on a mission to create a more precise estimate of reef species by the time of the first CoML synthesis report in 2010.

Adds Dr. O’Dor: “Even at the low end of this range, we must wonder why nature has evolved such prolific diversity on coral reefs. While they are icons of diversity, the processes that have generated and maintained coral reef biodiversity are still unknown.

Expeditions

Each of the three expeditions (Lizard Island, April 2 - 22, Ningaloo June 5 - 25 and Heron, Aug 25 - Sept 14) was three weeks in duration and included about 25 members.

Researchers adapted sampling methods and applied these in a wide range of habitats, including sampling diversity in dead coral heads -- the skeleton of a coral emptied of the fleshy animal that once lived inside. Samples were obtained by enveloping small dead coral heads in a bag and carefully chiseling off the base to capture all of the animals inside. A single dead coral head can yield more than 150 individual crustaceans, molluscs, and echinoderms. Worldwide, these dead coral heads host many thousands of species and their use is emerging as an important tool for assessing coral reef biodiversity.

As with the ARMS devices, the collection and analysis of biodiversity in dead coral heads is being standardized to promote the comparability of research worldwide.

Funding for the work was provided from several sources: BHP Billiton (the giant multinational resources company), the Great Barrier Reef Foundation, the Census of Marine Life, and AIMS, which leads the Australian node of the international CReefs project. As well, the Australian Biological Resources Study is funding follow-up taxonomic work, including DNA barcoding of organisms in support of the Barcode of Life initiative.

Generous support has also been provided by the many consortium partners.

Led by AIMS, the distinguished group of institutions in the consortium includes the Australian Museum, the Museum and Art Gallery of the Northern Territory, Museum Victoria, the Queensland Museum, the South Australian Museum, the Western Australian Museum, the University of Adelaide, Murdoch University, the South Australian Herbarium, and the Smithsonian Institution.

CoML Census of Coral Reef Ecosystems (http://www.creefs.org)

The Australian expedition is part of an unprecedented global census of coral reefs, CReefs, one of 17 Census of Marine Life projects.

Coral reefs are highly threatened repositories of extraordinary biodiversity and therefore have been called “the rainforests of the sea,” but little is known about the ocean’s diversity as compared to its terrestrial counterpart.

Important issues being addressed by CReefs Australia include:

* How many species live on coral reefs?
* How many of these are unique to coral reefs? and
* How does this diversity respond to human disturbance?

CReefs, led by scientists at AIMS, the Smithsonian Institution, and the Pacific Islands Fisheries Science Center of the National Oceanic and Atmospheric Administration (NOAA), aims to census life in coral reef ecosystems, to consolidate and improve access to coral reef ecosystem information scattered throughout the world, and to strengthen tropical taxonomic expertise.

The biodiversity data generated will be made publicly available through the Ocean Biogeographic Information System (OBIS) (http://www.iobis.org), an initiative of the Census of Marine Life.

A three-week CReefs expedition to Hawaii’s French Frigate Shoals in 2006 discovered more than 100 potential new species and/or location records and advanced understanding of marine biodiversity in the Hawaiian Archipelago.

An international team of taxonomists and crew collected and photographed several potentially new species of crabs, corals, sea cucumbers, sea quirts, worms, sea stars, snails, and clams. Many other species familiar in other ocean areas had never been recorded around Hawaii.

Among other global activities, CReef associates in India this year convened to review the success of a series of 17 recommendations made to government in 1998, ranging from the establishment of marine protected areas and related legislation to the creation of a National Coral Reef Research Center.

Meanwhile, US and Mexican researchers have chronicled a century of research on 46 named coral reefs of the southern Gulf of Mexico. The chronicle links to GulfBase (http://www.gulfbase.org), a database listing species inhabiting southern Gulf reefs (2057 species) and islands (298 species), reflecting greater-than-expected biodiversity there.

The chronicle (http://www.tamu.edu/upress/BOOKS/2007/tunnell.htm) reveals that reef condition is better further offshore, away from population centers, and in areas of low rainfall and runoff, according to lead editor Wes Tunnell, Vice Chair of the US National Committee for the Census of Marine Life.

The Census of Marine Life (http://www.coml.org) is a global network of researchers in more than 80 nations engaged in a 10-year initiative to assess and explain the diversity, distribution, and abundance of marine life in the oceans – past, present, and future. The network will release the first Census of Marine Life in 2010.

Early Parenting Plays Key Role In Infants' Physiological Response To Stress

Early Parenting Plays Key Role In Infants' Physiological Response To Stress

ScienceDaily (Sep. 19, 2008) — In infancy, genes are the key influence on a child's ability to deal with stress. But as early as 6 months of age, parenting plays an important role in changing the impact of genes that may put infants at risk for responding poorly to stress.

That's the message from a new study by researchers at the University of North Carolina-Chapel Hill, Pennsylvania State University, the University of North Carolina-Greensboro, and North Carolina State University. It appears in the September/October 2008 issue of the journal Child Development.

The researchers looked at 142 infants who had been placed in a stressful situation—being separated from their mothers—when they were 3, 6, and 12 months old. They measured infants' heart rates while they were exposed to the stressor, isolating a cardiac response called vagal tone. Vagal tone acts like a brake on the heart when the body is in a calm state, but during a challenging situation, this brake is withdrawn, allowing heart rate to increase so the body can actively deal with the challenge.

They also collected DNA to determine which form of a dopamine receptor gene the infants carried; specific forms of this gene are related to problems in adolescence and adulthood including aggression, substance abuse, and other risky behaviors. To assess the mothers' behavior as high or low in sensitivity, they also videotaped the mothers and their infants playing together for 10 minutes when the babies were 6 months old.

Both genes and parenting were found to be important to the infants' development of the way in which the brain helps regulate cardiac responses to stress. At 3 and 6 months old, those infants with the form of the dopamine gene associated with later risky behaviors did not display an effective cardiac response to the stressor (a decrease in vagal tone which takes the brake off the heart so it can respond appropriately), while those infants with the non-risk version of the gene did. At these early ages, the researchers found, it didn't appear to matter whether mothers were sensitive or not.

However, by the time the infants were 12 months old, the pattern changed. Infants with the risk form of the gene who also had mothers who were highly sensitive now showed the expected cardiac response while they were exposed to the stressful situation. Those infants with the risk form of the gene who had insensitive mothers continued to show the ineffective cardiac response to the stressor. These findings suggest that although genes play a role in the development of physiological responses to stress, environmental experience (such as mothers' sensitive care-giving behavior) can have a strong influence, enough to change the effect that genes have on physiology very early in life. The researchers suggest this may be because of the cumulative effect on infants of exposure to their mothers' behavior.

"Our findings provide further support for the notion that the development of complex behavioral and physiological responses is not the result of nature or nurture, but rather a combination of the two," says Cathi Propper, research scientist at the University of North Carolina-Chapel Hill and the study's lead author. "They also illustrate the importance of parenting not just for the development of children's behavior, but for the underlying physiological mechanisms that support this behavior.

"Lastly, infancy is an important time for developing behavioral and biological processes. Although these processes will continue to change over time, parenting can have important positive effects even when children have inherited a genetic vulnerability to problematic behaviors."

The study was funded by the National Science Foundation.

Study Helps Stop Drugs Slipping Through Safety Net

Study Helps Stop Drugs Slipping Through Safety Net

ScienceDaily (Sep. 19, 2008) — Recent advances in genetic screening will lead to safer pharmaceutical drugs, with reduced adverse side effects, if the methods are incorporated in clinical development. A rallying call to bring key scientists into this growing field of pharmacogenics, the application of genetics to drug development and safety, was made recently at a major conference organized by the European Science Foundation (ESF) in collaboration with the University of Barcelona.

Growing use of pharamacogenetics will not just reduce side effects, but also speed up the process of drug development by helping eliminate unsuitable candidates at an earlier stage and enable researchers to concentrate on the most promising compounds. The potential benefits are therefore enormous, with pharmacogenetics playing a major role in the emerging era of personalized medicine where drugs and treatments are increasingly tailored to the circumstances and genetic makeup of individuals and sub-groups within populations. It will complement existing methods, in particular animal testing, which although valuable sometimes fails to identify critical side effects that may be caused by individual genetic traits, or combinations of genes specific to the human species as a whole.

"It was confirmed by the conference that we need to ensure we have the appropriate study designs including randomised controlled trials to unravel the complexity of variable drug responses, and we need to embrace the new technologies such as whole genome scans to identify novel and known genetic predisposing factors," said the conference chair Munir Pirmohamed from the University of Liverpool in the UK.

Side effects can be caused by many factors relating to drug transport, immune response, and sometimes unexpected metabolic pathways, but as Pirmohamed noted, they fall into two main categories, type A and type B. "The majority (80-90%) of adverse drug reactions are type A – they are predictable from the known pharmacology of the drug, are dose-dependent, and can be alleviated by reducing or identifying the correct dose for the patient," said Pirmohamed, who gave the example of the anti-coagulant warfarin, widely used to prevent thrombosis in susceptible patients by inhibiting blood clotting. But without any blood clotting, patients would sooner or later bleed to death, so clearly warfarin must be given in the correct dose, finding the tight window between dangerous clotting and unstoppable bleeding. The point is that the correct dose varies between individuals, and this is where pharamacogenetics comes in. "Genetic factors can be important here," said Pirmohamed. While Type A reactions can often be picked up in animal testing or from general clinical analysis before human trials begin, pharmacogenetics has an important future role to play in establishing the correct dose for individuals.

Type B accounts for most the remaining 10%-20% of adverse drug reactions, including a variety of bizarre or unexpected responses that may be genetically dependent or alternatively shared by all people who take the drug.

Animal testing and other existing methods are much less successful at identifying Type B reactions however, which are more likely to go undetected until human trials begin. Indeed pharmacogenetics will also play an important role in uncovering these potentially lethal Type B reactions, including those involving the immune system's memory cells.

"The immune system is important in adverse reactions, and this conference did focus on certain aspects of predisposition to immune mediated reactions," said Pirmohamed. There was particular interest in the role of the HLA (Human Leukocyte Antigen) system, which directs the production and operation of immunity proteins, and is the source of the individual variation in immune response that leads both to population-wide protection against disease, and rejection of incompatible blood, tissue, or donated organs. This variation in HLA genes can also cause adverse reactions to certain drugs in some individuals but not others, leading in some cases to liver damage for example. "It is clear from the conference, and from the findings over the last few years, that the HLA system plays a major role in predisposing to certain immune mediated adverse reactions," said Pirmohamed.

Some drugs cause adverse reactions much more commonly among particular ethnic groups, resulting from particular alleles of HLA genes whose selection has been favoured by conditions in a given part of the world. One example is the anticonvulsant drug carbamazepine used to treat epilepsy, which can cause Stevens-Johnson syndrome. This is a severe allergic reaction causing skin rashes and lesions.

The ESF conference set the stage for developing methods of identifying such adverse reactions in advance by seeking associations between genes that may indicate where unexpected problems or severe reactions may occur. In particular it helped identify future targets and research objectives, said Pirmohamed.

"As with any other conference, the aim is for world class scientists to present their latest work, and for the audience to then consider whether it would be appropriate to incorporate particular techniques or methodologies into their work, and to individually decide how to do it. I know for many attendees, this did happen. It certainly did for me!"

The ESF/University of Barcelona conference, Pharmacogenetics and Pharmacogenomics: Adverse Drug Reactions, was held in the Costa Brava, Spain, in July 2008.