- Contact: Kathy Keatley Garvey
A team of nine entomology, cancer and nutrition researchers, in work published in the June 25 edition of Proceedings of the National Academy of Sciences, found that this new class of drug molecules stabilized the natural molecules and "effectively blocked neuropathic pain" - or pain caused by nerve damage. The research, conducted on rodents, is expected to lead to an orally active drug candidate for human clinical trials.
"This discovery offers a promising new approach to controlling chronic pain in diabetics," said lead author and project scientist Bora Inceoglu of the Bruce Hammock lab based in the Department of Entomology. "We were initially looking at anti-inflammatory compounds which regulate a key branch of an inflammatory pathway. These compounds are highly selective and inhibit a key enzyme called soluble epoxide hydrolase. Inhibition of this enzyme successfully blocks pain sensations."
"Our data indicate that this drug candidate is more effective on neuropathic pain caused by diabetes than any of the prescription drugs now on the market," said Hammock, a distinguished professor of entomology who holds a joint appointment with the UC Davis Comprehensive Cancer Center.
The research is significant in that in the United States alone, diabetics total 25.8 million or 8.3 percent of the population, and millions more - estimated at 79 million - are pre-diabetic, according to the American Diabetes Association. The Centers for Disease Control and Prevention tallies the economic burden of diabetes at approximately $170 billion a year.
Professor Daniele Piomelli, director of drug discovery and development at UC Irvine and who holds the Louise Turner Arnold Chair in Neurosciences, said that the study holds promise. He was not involved with the UC Davis research.
"Current medicines do not control well chronic pain produced by damage to the nerves," said Piomelli, professor of anatomy, neurobiology, and biological chemistry. "The study by Hammock and collaborators identifies a new class of chemical compounds that could change this situation. These compounds act by boosting natural signals, produced by the body, which curb both inflammation and pain. Exploiting the body's own 'medicines' is a great approach to creating safer medicines."
Piomelli cautioned that the experiments "were conducted in animals and need therefore to be confirmed by clinical trials."
UC Davis School of Veterinary Medicine anesthesiologist and pain specialist Alonso Guedes, also not involved in the study, said that the research shows that "stabilization of a class of bioactive lipid greatly reduces pain derived from nerve lesions. This novel and emerging knowledge may help fulfill a critical medical need for millions of animals and people afflicted by such pain modalities."
For the study, the UC Davis researchers used the Type I diabetes-induced pain model.
"Although Type II diabetes, associated with obesity, hypertension and metabolic disorders, is more prevalent in humans, to study the analgesic effects we selected Type I diabetes since pain manifests in an accelerated manner," said co-researcher and pharmacology doctoral candidate Karen Wagner. "In Type II diabetes patients, the occurrence of pain is delayed by many years of pre-diabetic or diabetic state, whereas our model affords a very rapid onset of pain."
Team member Fawaz Haj of the Departments of Nutrition and Internal Medicine, a leading nutrition and diabetes expert and a collaborator with the Hammock lab on diabetes, said that, "Intriguingly, in this study, acute treatments with soluble epoxide hydrolase inhibitors did not significantly affect the diabetic status of the animals, such as blood glucose levels and responses to insulin, indicating a selective effect on pain sensation. Neuropathic pain is a major co-morbidity of diabetes and an important debilitating factor that reduces the quality of life and this study accomplished a first in showing analgesic effects of soluble epoxide hydrolase inhibitors."
The researchers worked on a physiological pathway that was largely unknown until recently. When the enzyme, soluble epoxide hydrolase, is inhibited, "what happens is that the biological effects of a group of lipid metabolites, that are degraded by this enzyme, accumulate to effective levels," Hammock said.
"It turns out that a major function of these lipid metabolites is to selectively block pain sensation while sparing other types of sensations," Hammock said.
Inceoglu described neuropathic pain as "a debilitating condition and very difficult to treat with available painkillers or analgesics. Most analgesics are ineffective while those that reduce neuropathic pain often come with a variety of side effects that negatively affect the quality of life."
Nerve damage may be the result of trauma and chemotherapy agents or even diabetes itself. In diabetes, high levels of blood glucose damage the fine endings of sensory neurons that normally transmit pain-related information, the scientists explained. The aberrant signaling from the damaged neurons is interpreted as extreme sensitivity to touch and sometimes insensitivity to heat. "Even an innocuous touch, such as buttoning a shirt or the collar rubbing against the neck, or the vibration of being in a bumpy car ride can result in extreme pain," Inceoglu said.
"Almost half of advanced diabetic patients suffer from this painful condition which worsens as diabetes progresses," Inceoglu said.
Nerve and vascular damage can lead to gangrene and amputation. In advanced stages, the nerve damage leads to life-threatening heart and kidney diseases.
Physicians face a dilemma in selecting the right painkillers for the right conditions and with the least possible side effects, the UC Davis researchers said. Over-the-counter non-steroidal anti-inflammatory drugs (NSAIDs), for example, are completely ineffective for neuropathic conditions, Hammock said. Narcotics, like opium, can be addictive; withdrawal is difficult.
"Therefore, there is a great need to discover new approaches in combating pain," Hammock said. "New medications will effectively increase the number of choices for patients and physicians in treating intractable pain. Our study shows that the novel approach is effective and may not lead to the known side effects of narcotics or anti-depressants."
"It is still too early for these new compounds to reach the stores as analgesic drugs, since FDA approval takes a decade with very thorough evaluations," Inceoglu said. "However, once the feasibility of this approach is demonstrated, hopefully a major hurdle in moving toward clinical application is overcome."
The research, funded by the National Institutes of Health, supports earlier studies at UC Davis and later at Medical College of Wisconsin that showed the natural epoxy-fatty acids are analgesic molecules.
"Although very effective in blocking pain, unlike narcotics, these molecules do not affect coordination skills of animals," Inceoglu said.
The research team included Bora Inceoglu, Karen Wagner, Jun Yang, Nils Schebb, Sung Hee Hwang and Christophe Morisseau, all of the Department of Entomology; Bruce Hammock, Department of Entomology and UC Davis Comprehensive Cancer Center; Ahmed Bettaieb of the Department of Nutrition; and Fawaz Haj of the Departments of Nutrition and Internal Medicine.
"This is an interdisciplinary effort among neurobiologists, diabetes specialists, organic chemics and analytical chemists," said Hammock. "We could not have done this without sophisticated mass spectrometry equipment."
"The emerging mass spectrometric technique allowed us to analyze the tiny amounts of natural bioactive compounds, contributing to this pain discovery," said Yang.
Hammock directs the campuswide Superfund Research Program, the National Institutes of Health Biotechnology Training Program and the NIEHS Combined Analytical Laboratory. He is a Fellow of the Entomological Society of America, a member of the prestigious National Academy of Sciences, and the recipient of the UC Davis Faculty Research Lecture Award in 2001 and the Distinguished Teaching Award for Graduate and Professional Teaching in 2008.
Hammock's initial research involved regulating the development of insect larvae.
- Contact: Mary Louise Flint
“The disease has killed thousands of black walnut trees in California’s landscape and is threatening commercial walnut trees as well,” said Mary Louise Flint, UC Cooperative Extension specialist in the Department of Entomology at UC Davis and UC Statewide IPM Program.
Thousand cankers disease has now moved into the eastern U.S., where it threatens valuable stands of black walnut timber east of the Mississippi. Once in trees, the beetle and fungus cause gradual decline and eventual death by killing the vital phloem tissue beneath the bark.
The guidelines and trapping methods were developed by a team of entomologists from UC Davis and the USDA Forest Service Pacific Southwest Research Station in Davis. In 2010 and 2011, the scientific team discovered and patented an aggregation pheromone for the beetle and conducted scientific trials in northern California.
Late in the summer of 2011, they demonstrated the efficacy of the pheromone as a flight trap bait for detecting new populations of the beetle in Tennessee, Virginia and Utah. The demonstration-research project was extended to Pennsylvania in 2012. The bait lures both male and female beetles into a small plastic funnel trap. The team worked with a commercial partner, Contech Enterprises, Inc., to develop the technology.
As the eastern black walnut resource is valued at over $500 billion, the stakes are high for containing thousand cankers disease if it is introduced into key timber-producing states like Indiana and Missouri.
The study team is also using the traps and pheromone in research in California to learn more about biology and potential management strategies for the beetle in commercial walnut orchards and wildland areas.
The trapping guidelines are presented in a full-length document with color photographs and details on identifying the beetle, a short version for use in the field, and two video clips that demonstrate how to set up and service the traps. Find them at http://www.ipm.ucdavis.edu/thousandcankers.
In addition to Flint, members of the UC Davis and USDA scientific team and authors of guidelines are Steven J. Seybold, insect chemical ecologist, USDA Forest Service, based at Pacific Southwest Research Station in Davis; Paul L. Dallara, postdoctoral research scientist in the Department of Entomology at UC Davis; and Stacy M. Hishinuma, graduate student, Department of Entomology at UC Davis.
- Author: Jeannette E. Warnert
“I started and just kept going,” said Charlie Summers, a research entomologist who was first affiliated with UC Berkeley and later affiliated with UC Davis. Summers ends a 42-year stretch at Kearney when he retires June 30.
Summers grew up on a family farm in Utah and always knew he wanted a career in agriculture. He said he decided at age 12 to go to college, “when I was at the wrong end of a short-handled hoe.”
Summers earned bachelor’s and master’s degrees in zoology and entomology respectively at Utah State University in Logan, Utah, and a doctorate degree in entomology at Cornell in 1970, the same year he started at Kearney.
“The job at Kearney was an absolutely perfect fit for me,” Summers said. “It was a dream job. I look forward to coming to work every morning and would sometimes shake my fist at the sun going down at night. I’ve loved every minute I’ve been here.”
Summers studied a wide range of pest problems in field and vegetable crops. He developed economic thresholds for more than a dozen pests and management strategies for equally as many crops. Among the most challenging pests was the alfalfa weevil, he said. It has been particularly unresponsive to biological control and host plant resistance.
“It is one of the insects that has defied everything we’ve thrown at it except pesticides,” Summers said.
Silverleaf whitefly also posed a tremendous challenge during his career. Silverleaf whitefly was first found in the United States in Florida poinsettia crops during the mid-1980s. Eventually it made its way to a wide range of crops in California, resulting in severe economic losses to growers. Heavy applications of traditional chemicals needed to control the pest caused growers’ costs to increase. The production of some crops ceased altogether because of the extent of silverleaf whitefly damage.
In time, Summers and his colleagues developed a protocol for monitoring and managing the silverleaf whitefly. Light populations are controlled by native and introduced parasites and predators. More severe infestations must still be treated with pesticides.
Another major challenge was the corn leafhopper. The pest first made its way to California in the early 1940s, but didn’t become a serious problem until the end of the 1990s, when it was found to transmit corn stunt disease.
“Corn stunt disease caused plants to form few or no ears of corn. Some farmers’ yields were cut in half,” Summers said. “We worked out a strategy for scheduling planting to avoid the most serious damage. That’s worked out well for growers.”
Crops grown on silver mulch produced significantly higher yields of marketable fruit than did those grown on bare soil, the researchers concluded. Reflective mulch has been used by organic and conventional farmers up and down the valley and in Southern California to grow vegetables. Home gardeners have also applied these research results to garden beds by using aluminum foil as mulch.
Although Summers did not technically have a Cooperative Extension component to his position – he was among the last scientists hired to devote 100 percent of their time to research – Summers made it a point to work closely with farm advisors and specialists to convey research results to farmers.
“Extension work has been one of the most enjoyable things I’ve done,” he said. “I’ve worked with farm advisors on research projects, farm calls and given hundreds and hundreds of extension talks at their grower meetings.”
Summers has also authored more than 200 articles, book chapters and research papers, most of them peer reviewed.
Over the years, Summers said, the objective of his job – to help farmers develop successful pest management strategies – stayed the same, but technological advances dramatically changed the way he did his work.
“We’ve had the advent of computer technology, the use of mathematical models, work that can now be done at the DNA level. It’s put a whole new face on our ability to do research,” he said.
Nevertheless, he said, nothing can replace what he considers the essence of the Agricultural Experiment Station model: to personally assist growers.
“To me that’s the most important job we performed,” Summers said. “I hope this work continues.”
In retirement, Summers plans to move back to Utah to live near his sister and nephews and spend time pursuing his favorite pastime, fly fishing.
“I’ll be living 15 minutes from the Wasatch Mountains,” Summers said. “There’s a lot of good fishing there.”
- Author: Sarah Yang | Media Relations scyang@berkeley.edu, (510) 643-7741
By the end of the century, almost all of North America and most of Europe is projected to see a jump in the frequency of wildfires, primarily because of increasing temperature trends. At the same time, fire activity could actually decrease around equatorial regions, particularly among the tropical rainforests, because of increased rainfall.
The study, to be published Tuesday, June 12, in Ecosphere, an open-access, peer-reviewed journal of the Ecological Society of America, used 16 different climate change models to generate what the researchers said is one of the most comprehensive projections to date of how climate change might affect global fire patterns.
"In the long run, we found what most fear — increasing fire activity across large parts of the planet," said study lead author Max Moritz, fire specialist in UC Cooperative Extension. "But the speed and extent to which some of these changes may happen is surprising."
"These abrupt changes in fire patterns not only affect people's livelihoods," Moritz added, "but they add stress to native plants and animals that are already struggling to adapt to habitat loss."
The projections emphasize how important it is for experts in conservation and urban development to include fire in long-term planning and risk analysis, added Moritz, who is based at UC Berkeley’s College of Natural Resources.
UC Berkeley researchers worked with an atmospheric scientist from Texas Tech University to combine over a decade of satellite-based fire records with historical climate observations and model simulations of future change. The authors documented gradients between fire-prone and fire-free areas of Earth, and quantified the environmental factors responsible for these patterns. They then used these relationships to simulate how future climate change would drive future fire activity through the coming century as projected by a range of global climate models.
"Most of the previous wildfire projection studies focused on specific regions of the world, or relied upon only a handful of climate models," said study co-author Katharine Hayhoe, associate professor and director of the Climate Science Center at Texas Tech University. "Our study is unique in that we build a forecast for fire based upon consistent projections across 16 different climate models combined with satellite data, which gives a global perspective on recent fire patterns and their relationship to climate."
The fire models in this study are based on climate averages that include mean annual precipitation and mean temperature of the warmest month. These variables tend to control long-term biomass productivity and how flammable that fuel can get during the fire season, the researchers said.
Variables that reflect more ephemeral fluctuations in climate, such as annual rainfall shifts due to El Niño cycles, were not included because they vary over shorter periods of time, and future climate projections are only considered representative for averages over time periods of 20-30 years or longer, the authors said.
The study found that the greatest disagreements among models occur for the next few decades, with uncertainty across more than half the planet about whether fire activity will increase or decrease. However, some areas of the world, such as the western United States, show a high level of agreement in climate models both near-term and long-term, resulting in a stronger conclusion that those regions should brace themselves for more fire.
"When many different models paint the same picture, that gives us confidence that the results of our study reflect a robust fire frequency projection for that region," said Hayhoe. "What is clear is that the choices we are making as a society right now and in the next few decades will determine what Earth’s climate will look like over this century and beyond."
Study co-author David Ganz, who was director of forest carbon science at The Nature Conservancy at the time of the study, noted the significance of the findings for populations that rely upon fire-sensitive ecosystems.
"In Southeast Asia alone, there are millions of people that depend on forested ecosystems for their livelihoods," he said. "Knowing how climate and fire interact are important factors that one needs to consider when managing landscapes to maintain these ecosystem goods and services."
The researchers noted that the models they developed focused on fire frequencies, and that linking these to other models of fire intensity and vegetation change are important next steps.
"Our ability to model fire activity is improving," said Moritz, "but a more basic challenge is learning to coexist with fire itself."
The Natural Sciences and Engineering Research Council of Canada, the U.S. Forest Service, the National Science Foundation and The Nature Conservancy helped support this study.
RELATED INFORMATION
- Climate change to spur rapid shifts in fire hotspots, projects new analysis (2009 UC Berkeley press release)
- Author: Sarah Yang | Media Relations scyang@berkeley.edu, (510) 643-7741
The paper, published in the June issue of the peer-reviewed journal BioScience, and led by researchers at the University of California, Berkeley, synthesizes 20 years of research throughout the country on the ecological impact of reducing forest wildfire risk through controlled burns and tree thinning. It comes as California braces for a potentially bad fire season, particularly in the southern Sierra where precipitation was half its normal level.
"We need to act, because climate change is making fire season longer, temperatures are going up, and that means more fire in many regions, particularly ones with a Mediterranean environment," said study lead author Scott Stephens, UC Berkeley associate professor of fire science.
The study authors, which included scientists from the U.S. Forest Service and six research universities in the United States and Australia, relied upon data from the U.S. Fire and Fire Surrogates Study, in addition to a wide range of other studies. Together, the studies represented a broad spectrum of ecological markers, detailing the effects of fuel-reduction treatments on wildlife, vegetation, bark beetles, soil properties and carbon sequestration.
"Some question if these fuel-reduction treatments are causing substantial harm, and this paper says no," said Stephens. "The few effects we did see were usually transient. Based upon what we've found, forest managers can increase the scale and pace of necessary fuels treatments without worrying about unintended ecological consequences."
A few of the researchers’ specific ecological findings include:
- For the first five years after treatment, some birds and small mammals that prefer shady, dense habitat moved out of treated areas, while others that prefer more open environments thrived. The study authors said these changes were minor and acceptable.
- When mechanical tree thinning was followed by prescribed fire, there was an increase in the overall diversity of vegetation. However, this also included non-native plant species. The researchers recommend continued monitoring of this effect.
- Only 2 percent or less of the forest floor saw an increase in mineral soil exposure, which could lead to small-scale erosion. Other soil variables, such as the level of compaction, soil nitrogen and pH levels, were temporary, returning to pre-treatment levels after a year or two.
- Increases in bark beetles, a pest that preys on fire-damaged trees, was short-lived and concentrated in the smaller diameter trees. Researchers noted that thinning out a too-dense forest stand improves tree vigor and ultimately increases its resilience to pests, in addition to fire.
The results of this paper may help inform an analysis of one of the larger prescribed fires in the history of the U.S. Forest Service. Called the Boulder Burn, the proposed treatment covers 6,000-9,000 acres in the Southern Sierra Nevada's Sequoia National Forest and is tentatively set to begin by late fall.
"This paper is more comprehensive and definitive than any other article I've seen," said Malcolm North, research scientist with the U.S. Forest Service and an associate professor in forest ecology at UC Davis. "In one place, it summarizes the state of the science in fuel-reduction treatments, and to my mind, it shuts the door on those who say that any type of fuels treatment is detrimental to the forest. If done properly where surface fuels are reduced, treatments work. It's time to get on with it."
Nearly a century of fire suppression and the preferential logging of large-diameter trees, which are better able to withstand forest fires, have left forests vulnerable to more destructive, albeit less frequent, wildfires, the researchers said. In addition, the lack of fire has hindered nutrient cycling in forests and the proliferation of certain plant species, such as the sequoia, that rely upon fire to promote seed dispersal.
This realization led to the gradual re-emergence during the past 20 years of fuel-reduction as a forest management tool. The goal is simple: Thin or remove overly dense stands of trees, ground vegetation and downed woody debris in a carefully controlled way before they become fuel for a raging wildfire. When low- or moderate-intensity controlled burns are not an option, fire-prone trees are mechanically removed or shredded on site.
Such techniques are an attempt to emulate the frequent fires common in California for thousands of years. Before 1800, Stephens said, an estimated 1.1 million acres of forest burned annually in California, including wildfires ignited by lightning and other natural sources, and blazes set intentionally by Native Americans as a way to manage or alter landscapes. Most were blazes of low-to-moderate intensity that more than 80 percent of the trees could survive, unlike the catastrophic wildfires of modern times.
"Today, the combination of wildfires and fuel-reducing treatments only touch 6-8 percent of the land that used to burn annually before 1800, and fuel-reducing treatments alone only affect 1 percent," said Stephens. "That's a pittance. At that level, treatments are just triage rather than fire prevention."
To approach levels that have a chance of reducing wildfire risk in the long term, he said, the amount of land to be treated in a year would need to increase to 2-4 percent — still low compared to historical levels.
Stephens noted that two-thirds of the fuel-reduction treatments in the western United States rely upon mechanical thinning, which would be much more costly than prescribed burns to scale up. In the southeast region, the use of prescribed fire dominates.
In the West, particularly in California, the biggest challenge to expanding controlled burns is the potential reduction in air quality during treatment, said Stephens.
"We have a choice," he said, "of dealing with lower levels of smoke from prescribed fires that may only be needed every 15 years or so, and which can be timed for optimum wind conditions, or acute levels of smoke from catastrophic fires that can last for months when they hit."
The U.S. Department of Agriculture-U.S. Department of the Interior Joint Fire Science Program helped support this research.