Feb. 26, 2009
The compound, a soluble epoxide hydrolase enzyme (s-EH) inhibitor, is “a first-in-class drug which may treat a suite of major cardiovascular and metabolic diseases,” said entomologist Bruce Hammock, who with UC Berkeley cell biologist Sarjeet Gill discovered the enzyme in 1969 while researching fundamental insect biology.
“This is one of the few examples of basic research in an academic laboratory moving through target validation and compound optimization all the way to the clinic,” he said.
The enzyme is involved in the metabolism of arachidonic acid, a key signaling molecule implicated in diabetes, hypertension and inflammatory disorders. “It’s an enzyme in the same arachidonic biochemical pathway where many other common pharmaceuticals such as aspirin, Advil, Aleve, Ibuprofen, Motrin and other are active,” he said.
Phase 1 evaluated the safety, safe dosage range and side effects of the drug candidate. It then entered Phase IIa.
UC Davis physicians and scientists praised the new drug as promising.
“Both diabetes and hypertension are often associated with vascular inflammation as is atherosclerosis,” Weiss said. “Last year we demonstrated that these compounds dramatically reduce atherosclerosis problem in obese mice.”
“These compounds appear useful in a variety of cardiovascular disorders,” said biochemist and food scientist Bruce German, UC Davis professor of food science and technology. “Diabetes and high blood pressure commonly occur together and a new class of drugs that addresses both is very attractive.”
Cardiologist and cell biologist Nipavan Chiamvimonvat of the UC Davis Health System and a longtime collaborator with Hammock, said many diseases tend to occur together in vascular biology. “So, a compound that addresses heart failure, as we have shown, combined with the reduction of blood pressure, inflammation and diabetes is very attractive.”
The Phase IIa clinical trial is a double-blind, placebo-controlled study. Officials will enroll a total of 150 patients with impaired glucose tolerance, mild obesity and mild to moderate hypertension.
Each patient will receive 28 days of treatment. The AR9281 enzyme inhibitor will be studied for safety, tolerability, reduction of blood pressure and various measures of glucose and lipid metabolism. Results are expected the first quarter of 2010.
The winding, twisting path that took Hammock from his lab, to collaborative research with other UC Davis scientists, to his founding of a $50 million-investment biotechnology company, to clinical trials proved as steep as the mountains he climbs.
Tracing the events that led to the discovery of the enzyme, Hammock recalled doing research at UC Berkeley four decades ago with then-colleague Sarjeet Gill. Gill discovered the enzyme in mammals. Shortly after Hammock found the novel enzyme in insects.
“Both of us have been chipping away at this problem ever since,” Hammock said. “By 1975 we were convinced that this was a therapeutic target but no one else was. When we finally found potent inhibitors for the enzyme that worked in whole animals, we had a tool to demonstrate that this was a promising therapeutic target.”
Hammock was initially interested in regulating the development of insect larvae. With the discovery of the enzyme inhibitor, however, he switched part of his research from “pest control to pain control.”
At the onset, Hammock faced two major obstacles: financing and moving the drug into clinical trials.
“Finding resources in an academic laboratory to move a first-in-class drug through clinical trials, is difficult,” Hammock said. “It costs $700 million to $1.2 billion to get a treatment to the market.”
“Publicly funded research,” the professor said, “results in many new possible pharmaceutical targets that could be exploited by either small molecule drugs or biotechnology. However, society faces a serious problem in that few of these leads are followed and there is a widely held view that universities cannot validate a target, much less optimize a pharmaceutical.”
So in 2002, Hammock founded the biotech company, Arête Therapeutics, Inc., naming the company a mountaineering term that means “sharp, steep ridge.” Specifically, the company is named for the arêtes of the Bear Creek Spire of the Sierra Nevada that he, his sons and occasionally other UC Davis faculty and students climb.
“The arêtes that climbers follow to peaks are often inspiring as well as challenging,” Hammock said.
“I founded the company because I failed to transfer technology to the public from the University of California by other means in the past,” Hammock said. “And I received nothing more than a passing interest from pharmaceutical companies at that time, but now they are very interested.”
In 2003, he and his son, also named Bruce, incorporated the company to move the materials into clinical trials.
“The collaborative and interdisciplinary environment at UC Davis permitted us, with support from the National Institute of Environmental Health Sciences, to optimize the potency and drug properties of the s-EH inhibitors to the stage where we could present a convincing picture to venture groups of compounds ready to move to the clinic.”
In 2005, the company raised more than $51 million in Series A financing led by Frazier Healthcare Ventures, Alta Partners, Three Arch Partners, Burrill & Company and Altitude Life Science Ventures.
Today, the biotech company, based in Hayward, is dedicated to the discovery and development of novel drugs to treat type 2 diabetes, hypertension and inflammatory disorders, Hammock said. It is billed as the “world’s leading company focused on s-EH, an important enzyme for the metabolism of arachidonic acid that plays an essential role in metabolic, inflammatory and cardiovascular physiology.”
“Our main goal,” Hammock said, “was to set up a system of a science-driven company where we reduce the cost of drug registration by using very good incisive science. We also want to reward and motivate the people who do the work; provide a funding and training environment to help teach students and postgraduates to write proposals; and allow scientists to move between an academic and industrial environment in the early stage to help determine career directions.”
Another goal: a low-cost, affordable drug. “The sickest people in the world, of course, cannot pay for the drugs they need,” Hammock said. “The chemistry developed around the s-EH inhibitors allows us to make powerful but inexpensive drugs that could be produced in developing countries.”
Meanwhile, the clinical trials under way represent two firsts, said James Sabry, president and chief executive officer of Arête Therapeutics. “This is the first clinical study of a s-EH inhibitor in patients, and the first study designed to establish proof of concept that s-EH inhibition modulates glucose metabolism or blood pressure in patients with impaired glucose tolerance and hypertension."
.“AR9281 has demonstrated an excellent safety profile and activity in multiple animal models of type 2 diabetes, and has the advantage of inhibiting a novel drug target that differentiates it from currently marketed diabetes medications,” Sabry said. “With this promising drug profile, AR9281 has the potential to provide safe and effective therapy for patients with type 2 diabetes either as monotherapy or in combination with existing treatment regimens."
Said Arête’s chief medical officer Randall Whitcomb: “The Phase IIa trial will further validate the role of s-EH in the pathophysiology of disease and lay the groundwork for further exploration of s-EH inhibition in treating a broad range of serious diseases including type 2 diabetes, hypertension and inflammatory disorders.”
Hammock agrees. “The compound looks quite promising and it’s an example of how basic work in insect biology led to a $50 million company--by far the largest Series A financing of an early stage drug in many years-- and a drug in Phase II human clinical trials. This all shows the value of basic research and what we can do to help humanity.”
Hammock, who joined the UC Davis Department of Entomology faculty in 1980, holds a joint appointment in Cancer Research with the UC Davis Medical Center and directs the National Institute of Environmental Health Sciences (NIEHS) Superfund Program on the UC Davis campus, as well as the National Institutes of Health (NIH) Training Program in Biotechnology, and the NIEHS Combined Analytical Laboratory.
Elected to the prestigious National Academy of Sciences in 1999, he received the UC Davis Faculty Research Lecture Award in 2001 and the Distinguishing Teaching Award for Graduate and Professional Teaching in 2008.
--Kathy Keatley Garvey
UC Davis Department of Entomology
When a Davis resident felled a plum tree, hordes of green-eyed, apricot-colored insects tumbled from the wood.
What were they?
They buzzed like bees. They loomed larger than bumble bees. And they disliked being disturbed.
The Davis resident took them to the Bohart Museum of Entomology, University of California, Davis, for identification.
“Male carpenter bees, Xylocopa varipuncta, also known as Valley carpenter bees,” said entomologist Lynn Kimsey, director of the Bohart Museum of Entomology and professor and chair of the UC Davis Department of Entomology.
“Some of us refer to these males as ‘teddy bear' bees, because of their yellowish-brownish color and fuzzy burly bodies,” said UC Davis emeritus entomology professor Robbin Thorp, who studies pollinators. “The females are all black with violaceous (violet) reflections on their dark wings.”
All females in the plum tree holes escaped.
Carpenter bees, so named for their ability to tunnel through wood to make their nests, carve with their mandibles (jaws) but do not ingest the wood. Only the females excavate the tunnels, which average six to 10 inches in depth.
Carpenter bees, measuring about an inch long, are the largest bees in California. Their eggs are the largest of all insect eggs. The Valley carpenter bee egg can be 15mm long.
The males are territorial, Kimsey said, and can be quite aggressive. They hover and lie in wait for passing females.
“We have them around our home (in Davis) when the wisteria blooms,” she said. “Many people think they're bumble bees because of their size. They think they're fluffy yellow bumble bees.”
Thorp said he tries to convince people to learn to live with these bees as “they are important pollinators in our environment and have potential as pollinators of some crops.”
“Carpenter bees are beneficial in that they pollinate flowers in native
“These bees are not currently managed for crop pollination,” Thorp said, “but there have been some recent studies of their potential for pollination of greenhouse tomatoes. They are good at buzz pollination and can be managed by providing suitable nest materials.”
Due to their large size, carpenter bees cannot enter tubelike blossoms such as sage, so they slit the base of corolla, a practice known as “stealing the nectar” (without pollinating the flower).
The Valley carpenter bee species is commonly found in southern California but is not all that well known in the Central Valley. “I have observed them in the field in southern California and in the Sacramento area,” Thorp said. “In the past few years, they seem to have become more common in the Davis area. I even found a dead male on my driveway (in Davis) a month or so ago.”
Carpenter bees, especially the most common species in the Central Valley, X. tabaniformis orpifex, are often mistaken for bumble bees. Like bumble bees, female carpenter bees exhibit similar size and coloration. However, a carpenter bee generally has a hairless, shiny abdomen while the bumble bee abdomen is typically covered with dense hair, and often with yellow markings.
Thorp said three species occur in California. “Of the three species, X. varipuncta (with the golden teddy bear males) and X. tabaniformis orpifex are the only two that occur in the Central Valley,” he said. “The third species, X. californica occurs primarily in the foothill areas surrounding the Central Valley.”
To build their nests, the females select telephone poles, fences, decks, railings, eaves, siding, outdoor furniture and tree trunks. They prefer bare, unpainted or weathered wood, especially redwood, cedar, cypress and pine. They generally avoid painted or pressure-treated wood.
Carpenter bees overwinter as adults in the tunnels and emerge in the spring.
Brian Turner, the Bohart Museum 's public outreach coordinator, said the sculpted holes in the chunk of plum wood that the Davis resident brought in “look professionally drilled.” The holes are elongated and intricately sculpted to contain the brood and food storage.
Turner released the male carpenter bees, but museum visitors can see the plum wood holes.
The museum, located in 1124 Academic Surge, is dedicated to teaching, research and service. It houses the seventh largest insect collection in North America. The global collection totals more than seven million specimens, and focuses on terrestrial and fresh water invertebrates.
The museum is also home of the California Insect Survey, a storehouse of the insect biodiversity of California's deserts, ountains, coast and great central valley.
Häagen-Dazs has announced that it is making a $125,000 donation to the UC Davis Department of Entomology to launch a nationwide design competition to create a one-half acre Honey Bee Haven garden at the Harry H. Laidlaw Jr. Honey Bee Research Facility at UC Davis.
From that gift, $65,000 will be used to establish the garden.
Häagen-Dazs and UC Davis will determine how the balance of the gift can best be used to benefit the health of honey bee populations.
The garden will include a seasonal variety of blooming plants that will provide a year-round food source for honey bees. It is intended to be a living laboratory supporting research into the nutritional needs and natural feeding behaviors of honey bees and other insect pollinators.
Visitors to the garden will be able to glean ideas on how to establish their own bee-friendly gardens and help to improve the nutrition of bees in their own backyards. The bee haven is expected to be the first in a series of pollinator gardens at UC Davis.
"Campus visitors will be able to see which flowers are most attractive to foraging honey bees and how to space the flowers in order to have bees flying in the most convenient areas of their gardens," he added.
Garden Design Competition
The garden design competition funded by the Häagen-Dazs brand is being coordinated by the California Center for Urban Horticulture at UC Davis. It is open to anyone who can create a proposal by using basic landscape design principles.
"This is an excellent opportunity to raise public awareness of the current plight of honey bees and to educate the public on how they can help," said Dave Fujino, director of the California Center for Urban Horticulture. "Planting a garden with honey bee friendly plants provides nutrition for the bees and has the potential to create valuable habitat corridors between agricultural sites."
Design submissions for the competition should describe a one-half-acre garden that can be installed for $65,000 or less. Submissions must include a site plan, planting plan, maintenance program and construction cost estimate.
The plans should include plant species that provide forage for honey bees, a bee-accessible water source, and environmentally friendly paths for visitors. More design specifications and lists of bee-appropriate plants can be found at the UC Davis Department of Entomology Web site.
Design plans for the Honey Bee Haven garden must be received at UC Davis by Jan. 30, 2009. Plans should be mailed to the California Center for Urban Horticulture, College of Agricultural and Environmental Sciences Dean's Office, University of California, One Shields Ave., Davis, CA 95616-8571.
The winning design, to be announced in February 2009, will be implemented, and the winning team will receive on-site recognition on the Häagen-Dazs commemorative plaque located within the garden. In addition, the winner will receive a free year's supply of Häagen-Dazs ice cream and will be included in a 2009 press announcement.
More information on the design competition can be obtained from Melissa Borel, program manager at UC Davis' California Center for Urban Horticulture, at (530) 752-6642.
Honey Bee Disappearance
Honey bees, which pollinate more than 100 different U.S. agricultural crops, valued at $15 billion, are dying from an unexplained phenomenon known as colony collapse disorder. First identified three years ago, the disorder is characterized by hive abandonment. The bees disappear, often leaving behind the honey and the immature bees, which die if not fed by the worker bees. In recent years, the nation's beekeepers have reported losing from one-third to all of their bees.
Bee experts suspect that a multitude of causes, including pesticides, diseases, parasites, stress, climate change and malnutrition, are contributing to the dramatic decline in honey bee populations.
Seasonal food shortages lead to malnutrition in the bees, making them more susceptible to diseases.
The Häagen-Dazs brand in February of this year launched the "Häagen-Dazs Loves Honey Bees" campaign. The company committed a combined $250,000 donation for bee research to UC Davis and Pennsylvania State University. It also formed a seven-member scientific advisory board, created an educational Web site and introduced the new Vanilla Honey Bee ice cream flavor.
During the last several months, the public has generously responded to the Häagen-Dazs brand's call to action by donating more than $30,000 to support honey bee research at UC Davis. In addition, numerous companies have launched programs that are donating a percentage of their sales to support UC Davis honey bee research. For example, Whole Foods Markets generated more than $10,600 in direct and matching gifts through its in-store promotions.
Anyone interested in donating to UC Davis honey bee research may obtain information at this UC Davis site.
About UC Davis
For 100 years, UC Davis has engaged in teaching, research and public service that matter to California and transform the world. Located close to the state capital, UC Davis has 31,000 students, an annual research budget that exceeds $500 million, a comprehensive health system and 13 specialized research centers. The university offers interdisciplinary graduate study and more than 100 undergraduate majors in four colleges — Agricultural and Environmental Sciences, Biological Sciences, Engineering, and Letters and Science — and advanced degrees from five professional schools: Education, Law, Management, Medicine, and Veterinary Medicine. The UC Davis School of Medicine and UC Davis Medical Center are located on the Sacramento campus near downtown.—Pat Bailey and Kathy Keatley Garvey
* Lynn Kimsey, chair, UC Davis Department of Entomology, (530) 752-5373, email@example.com
* Eric Mussen, apiculturist, Harry H. Laidlaw Jr. Honey Bee Research Facility, (530) 752-0472, firstname.lastname@example.org
* Dave Fujino, director, California Center for Urban Horticulture, (530) 754-7739, email@example.com
* Pat Bailey, UC Davis News Service staff, (530) 752-9843, firstname.lastname@example.org
* Kathy Keatley Garvey, communications specialist, UC Davis Department of Entomology, (530) 754-6894, email@example.com
Nov. 24, 2008
Michael Branstetter, a doctoral candidate in entomology at the University of California, Davis, won a coveted President’s Prize for his oral presentation on ants at the 56th annual Entomological Society of America (ESA) meeting, held Nov. 16-19 in Reno.
Branstetter delivered an illustrated presentation on “Phylogeny and Biography of the Ant Genus Stenamma: Uncovering the Evolutionary Origins of Mesoamerican Taxa.” Stenamma is a little studied genus of leaf litter ants.
He competed in the Revisions and Evolution Section, moderated by scientists from Laurentian University, Ontario, Canada, and the Smithsonian Institution, National Museum of Natural History, Washington, D.C. Following his presentation, judges and spectators asked questions, an integral part of the competition.
Fourteen graduate students from throughout the United States participated in the Revisions and Evolutions Section.
Branstetter, a native of Toledo, Ohio, received his bachelor of science degree from Evergreen State College, Olympia, Wash., where he studied entomology, evolution and ecology.
The recipient of several grants, Branstetter has collected ants in Costa Rica, Guatemala, Honduras, and in Chiapas, Mexico. His collecting trips are funded by the National Science Foundation’s Biodiversity Surveys and Inventories program as well as National Geographic. Principal investigator of the grant is John Longino of the Evergreen State College.
Branstetter’s next collecting trip will be a two-month excursion in Guatemala next May and June. He will be in charge of an international group of students who will be collecting leaf litter throughout the country.
This is the second consecutive year that a UC Davis graduate student in systematics has won the President’s Prize at the ESA meeting, said Lynn Kimsey, chair of the Department of Entomology and director of the Bohart Museum of Entomology. Last year Nate Hardy, student of professors Penny Gullan and Peter Cranston, won the prize for his “A New Mealybug Subfamily Classification Based on Integrated Morphological and DNA Sequence Data.”
--Kathy Keatley Garvey
UC Davis Department of Entomology
See published paper in PNAS (Embargoed lifted at 2 p.m. Pacific Standard Time, Aug. 18, 2008)
Link to video from Walter Leal lab
Listen to BBC interview of Walter Leal from Web site or link directly to: MP3 or WAV.
“We found that mosquitoes can smell DEET and they stay away from it,” said noted chemical ecologist Walter Leal, professor of entomology at UC Davis. “DEET doesn't mask the smell of the host or jam the insect's senses. Mosquitoes don't like it because it smells bad to them.”
DEET's mode of action or how it works has puzzled scientists for more than 50 years. The chemical insect repellent, developed by scientists at the U.S. Department of Agriculture and patented by the U.S. Army in 1946, is considered the “gold standard” of insect repellants worldwide. Worldwide, more than 200 million use DEET to ward off vectorborne diseases.
Scientists long surmised that DEET masks the smell of the host, or jams or corrupts the insect's senses, interfering with its ability to locate a host. Mosquitoes and other blood-feeding insects find their hosts by body heat, skin odors, carbon dioxide (breath), or visual stimuli. Females need a blood meal to develop their eggs.
Said Miller: "For decades we were told that DEET warded off mosquito bites because it blocked insect response to lactic acid from the host -- the key stimulus for blood-feeding. Dr. Leal and co-workers escaped the key stimulus over-simplification to show that mosquito responses -- like our own -- result from a balancing of various positive and negative factors, all impinging on a tiny brain more capable than most people think of sophisticated decision-making.”
“This new work corrects long-standing erroneous dogma, and shows that recent work on DEET mode-of-action published in the flagship journal, Science, apparently was flat-out wrong,” Miller said. “One of the great attributes of science is that, over time, it is self-correcting."
Leal said previous findings of other scientists showed a “false positive” resulting from the experimental design.
The UC Davis work, “Mosquitoes Smell and Avoid the Insect Repellent DEET,” is published in the Aug. 18 edition of the Proceedings of the National Academy of Sciences (PNAS).
Mosquitoes detect DEET and other smells with their antennae. Leal and researcher Zain Syed discovered the exact neurons on the antennae that detect DEET (N,N-diethyl-3-methylbenzamide). These neurons are located beside other neurons that sense a chemical, 1-octen-3-ol, known to attract mosquitoes.
The UC Davis investigators set up odorless sugar-feeding stations, some containing DEET, and found that DEET actively repelled them. The mosquitoes they used were Culex quinquefasciatus, also known as the Southern house mosquito. The mosquito transmits West Nile virus, St. Louis encephalitis, and lymphatic filariasis, a disease caused by threadlike parasitic worms.
“Despite the fact DEET is the industry standard mosquito repellent, relatively little is known about how it actually works,” said UC Davis research entomologist William Reisen. “Previous studies have suggested a 'masking' or 'binding' with host emanations. Understanding the mode of action is especially important because DEET is used as the standard against which all other tentative replacement repellents are compared.
Reisen said that Leal and Syed “have performed an exhausting series of sophisticated, directed, yet straight-forward experiments to determine that the mode of action of DEET is mostly due to the response of a specific sensilla to DEET. Although there may be some host odor 'binding,' the critical finding that DEET inhibited sugar feeding clearly showed that mosquitoes of both sexes detected DEET and were repelled, even without a host being present.”
Said Major Dhillon, president of the American Mosquito Control Association and district manager of the Northwest Mosquito and Vector Control District, Riverside: “It certainly is a breakthrough. In the future, this new knowledge can be incorporated into developing new repellents and may be in control strategies for Culex quinquefasciatus and other mosquitoes.”
Research chemist Uli Bernier of the Mosquito and Fly Research Unit, USDA Agricultural Research Service, described the UC Davis study as “an excellent explanation.” Bernier, who studies how repellents impact mosquitoes' feeding behavior, said the Leal-Syed work “presents as a very logical basis to help us understand how DEET is perceived by the mosquitoes, and this work provides an excellent explanation to link physiological processing within the mosquito to the (macroscopic) behavioral response that we observe in laboratory bioassays with this repellent."
Leal, a past president of the International Society of Chemical Ecology, received the 2007 Silverstein-Simeone Lecture Award for his innovative research on how insects detect smells and communicate within their species. He is a former chair of the UC Davis Department of Entomology.
Download high-resolution photo, Culex quinquefasciatus (Kathy Keatley Garvey, UC Davis Department of Entomology)
Download high-resolution photo of Culex quinquefasciatus on arm (Kathy Keatley Garvey, UC Davis Department of Entomology)
Download high-resolution spray photo http://18.104.22.168/news/images/culexquinquefasciatuspnas.jpg(Kathy Keatley Garvey, UC Davis Department of Entomology)
PNAS paper (PDF)
Science article (March 2008) referred to by James Miller