- Author: Kathy Keatley Garvey
Entomologist Marlin Rice, a past president of the Entomological Society of America (ESA), penned the piece, titled "Bruce D. Hammock: Science Should Be Fun!"
Wrote Rice: "Bruce D. Hammock is widely known for his groundbreaking research in insect physiology, toxicology, pharmacology, and experimental therapeutics. Early contributions were in fundamental regulatory biology, development of both small molecules and recombinant viruses as environmentally friendly pesticides, and the application of accelerator mass spectrometry to biological science. His laboratory pioneered the use of immunoassay for the analysis of human and environmental exposure to pesticides and other contaminants.His laboratory provides graduate training that is diverse in disciplines and research areas. He recently formed a company, EicOsis, to develop an orally active non-addictive drug for inflammatory and neuropathic pain for humans and companion animals."
Hammock, who joined the UC Davis faculty in 1980 from UC Riverside, has directed the UC Davis Superfund Research Program (funded by the National Institutes of Health's National Institute of Environmental Health Sciences) for nearly four decades. He is a member of the National Academy of Sciences, and a fellow of the National Academy of Inventors and ESA.
A native of Little Rock, Ark., Bruce received his bachelor's degree in entomology (with minors in zoology and chemistry) magna cum laude from Louisiana State University, Baton Rouge, in 1969. He received his doctorate in entomology-toxicology from UC Berkeley in 1973 with John Casida at UC Berkeley. Hammock served as a public health medical officer with the U.S. Army Academy of Health Science, San Antonio, and as a postdoctoral fellow at the Rockefeller Foundation, Department of Biology, Northwestern University, Evanston, Ill.
Read the feature story here.
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(Editor's Note: Thanks to Lisa Junker, ESA's director of publications, communications and marketing, who reached out to "our publishers at Oxford" to grant free community access to this feature story in American Entomologist)
- Author: Kathy Keatley Garvey
DAVIS--Newly published research in the Proceedings of the National Academy of Sciences (PNAS) indicates that a drug discovered and developed in the laboratory of Bruce Hammock,UC Davis Department of Entomology and Nematology, may have a major role in preventing and treating llnesses associated with obesity.
More than 43 percent of adults in the United States are obese, according to the Center for Disease Control and Prevention (CDC). Obesity increases the risk of coronary artery disease, stroke, type 2 diabetes, and certain kinds of cancer.
The drug, a soluble epoxide hydrolase (sEH) inhibitor, appears to regulate “obesity-induced intestinal barrier dysfunction and bacterial translocation,” the 12-member team of researchers from UC Davis, University of Massachusetts and University of Michigan discovered. The same non-opioid drug is being investigated in human clinical safety trials in Texas to see if it blocks chronic pain associated with diseases such as spinal cord injury, diabetes and inflammatory bowel disease.
The research, funded by multiple federal grants, is titled “Soluble Epoxide Hydrolase Is an Endogenous Regulator of Obesity-Induced Intestinal Barrier Dysfunction and Bacterial Translocation.”
“Obesity usually causes the loss of tight junctions and leaky gut,” said first author Yuxin Wang, a postdoctoral researcher who joined the Hammock lab in 2019 from the Department of Food Sciences, University of Massachusetts, Amherst. “In normal conditions, the gut mucosal barrier is like a defender to protect us from the ‘dirty things' in the lumen, such as bacteria and endotoxin. For obese individuals, the defender loses some function and leads to more ‘bad things' going into the circulation system, causing systemic or other organ disorders.”
Although intestinal dysfunction and other problems enhancing bacterial translocation underlies many human diseases, “the mechanisms remain largely unknown,” said Wang, who holds a doctorate in biochemistry and molecular biology from the Chinese Academy of Sciences. “What we found is sEH inhibition can repair the defender function (barrier function), decrease the ‘bad things' going into the blood (bacteria translocation), and reduce inflammation of fat.”
“Our research shows that sEH is a novel endogenous regulator of obesity-induced intestinal barrier dysfunction and bacterial translocation,” said corresponding author Guodong Zhang, a former researcher in the Hammock lab and now with the Food Science Department and Molecular and Cellular Biology Graduate Program at the University of Massachusetts. “To date, the underlying mechanisms for obesity-induced intestinal barrier dysfunction remain poorly understood. Therefore, our finding provides a novel conceptual approach to target barrier dysfunction and its resulting disorders with clinical/transitional importance.”
Corresponding author Hammock, a distinguished UC Davis professor who holds a joint appointment with the Department of Entomology and Nematology and the Comprehensive Cancer Center, praised Zhang's “amazing record while he was a postgraduate at UC Davis, and now in Food Science Department at the University of Massachusetts, where he recently received tenure.”
Zhang mentored two co-authors of the paper: Yuxin and Weicang Wang, both formerly of the Department of Food Science, University of Massachusetts and now with the Hammock lab.
“I feel so lucky that Yuxin and Weicang have joined my laboratory,” Hammock said. “The drugs studied in this PNAS paper are now in human clinical trials and on a path to replace opioid analgesics for pain treatment. I hope the continuing work of Guodong, Weicang and Yuxin will evaluate them as treatments for a variety of inflammatory bowel diseases.”
Andreas Baumler, professor and vice chair of research in the UC Davis Department of Medical Microbiology and Immunology, who was not affiliated with the study, said: “Obesity-induced gut leakage and bacterial translocation can be ameliorated by targeting microbes with antibiotics, suggesting that the microbiota contributes to disease. However, the work by Zhang and co-workers suggest that rather than targeting the microbes themselves, obesity-induced gut leakage and bacterial translocation can be normalized by silencing a host enzyme, which identifies host metabolism as an alternative therapeutic target.”
In addition to Hammock, Zhang, Yuxin and her husband Weicang, the other eight co-authors on the team are:
- Jun Yang, Sung Hee Hwang, and Debin Wan of the Hammock lab, UC Davis Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center
- Kin Sing Stephen Lee, formerly of the Hammock lab, and Maris Cinelli, both of the Department of Pharmacology and Toxicology, Michigan State University, Lansing
- Katherine Sanidad and Hang Xiao, Department of Food Science and the Molecular and Cellular Biology Graduate Program, University of Massachusetts, Amherst
- Daeyoung Kim, Department of Mathematics and Statistics, University of Massachusetts, Amherst
The abstract: “Intestinal barrier dysfunction, which leads to translocation of bacteria or toxic bacterial products from the gut into bloodstream and results in systemic inflammation, is a key pathogenic factor in many human diseases. However, the molecular mechanisms leading to intestinal barrier defects are not well understood, and there are currently no available therapeutic approaches to target intestinal barrier function. Here we show that soluble epoxide hydrolase (sEH) is an endogenous regulator of obesity-induced intestinal barrier dysfunction. We find that sEH is overexpressed in the colons of obese mice. In addition, pharmacologic inhibition or genetic ablation of sEH abolishes obesity-induced gut leakage, translocation of endotoxin lipopolysaccharide or bacteria, and bacterial invasion-induced adipose inflammation. Furthermore, systematic treatment with sEH-produced lipid metabolites, dihydroxyeicosatrienoic acids, induces bacterial translocation and colonic inflammation in mice. The actions of sEH are mediated by gut bacteria-dependent mechanisms, since inhibition or genetic ablation of sEH fails to attenuate obesity-induced gut leakage and adipose inflammation in mice lacking gut bacteria. Overall, these results support that sEH is a potential therapeutic target for obesity-induced intestinal barrier dysfunction, and that sEH inhibitors, which have been evaluated in human clinical trials targeting other human disorders, could be promising agents for prevention and/or treatment.”
The research was funded by grants from the National Institute of Food and Agriculture, U.S. Department of Food and Agriculture (USDA); National Cancer Institute; USDA Hatch Grant; National Institute of Environmental Health Sciences (NIEHS) Superfund Research Program; and a National Science Foundation.
According to the CDC, many of obesity-related conditions that lead to diseases are preventable. In 2008, the estimated annual medical cost of obesity in the United States tallied $147 billion. The medical cost for obese individuals averaged $1,429 higher than those of normal weight.
Contact: Bruce Hammock, bdhammock@ucdavis.edu
- Author: Kathy Keatley Garvey
Dr. Panigrahy is an assistant professor of pathology, Beth Israel Deaconess Medical Center, Harvard Medical School.
His topic is "Pro-Resolution Lipid Mediators in the Resolution of Cancer," said Hammock, who holds a joint appointment with the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center.
The abstract: "For decades, cancer therapy has focused on killing cancer cells, from broad cytotoxic therapy to the inhibition of specific molecular pathways. However, cytotoxic cancer therapy may inherently be a double-edged sword as apoptotic tumor cells ('debris') may stimulate inflammation and tumor growth via a pro-inflammatory ‘cytokine storm'. Environmental carcinogens (e.g. Aflatoxin B1) can also generate debris which may stimulate inflammation and tumor dormancy escape. This is clinically relevant as 30-90% of humans harbor dormant tumors."
"To stimulate the natural debris-clearing process which would eliminate this source of tumor stimulation, we utilized endogenous specialized pro-resolving mediators (SPMs), specifically maresins, which are biosynthesized by human macrophages from endogenous docosahexaenoic acid. Additionally, novel COX-2/sEH inhibitors (e.g. PTUPB) can stimulate inflammation resolution more potently than either COX-2 or sEH inhibition alone by stabilizing epoxy-eicosanoids, promoting the formation of pro-resolving mediators such as lipoxins, and activating anti- inflammatory cytokine programs. In dramatic contrast to conventional anti-inflammatories, pro-resolving lipid mediators clear debris and counter-regulate a series of pro-inflammatory cytokines. We demonstrate that the resolution of inflammation represents a novel modality in cancer treatment by enhancing endogenous clearance of tumor cell debris and counter- regulating pro-tumorigenic cytokines."
Earlier this year, a collaborative research paper authored by Hammock, Panigrahy and colleagues won the Editor's Pick of the Journal of Investigation for the month of July. The paper, “Preoperative Stimulation of Resolution and Inflammation Blockade Eradicates Micrometastases,” relates how blocking inflammation and/or activating the resolution of inflamation before surgery can eradicate small tumors and promote long-term survival in experimental cancer modes. (See news story.)
Dipak was accepted into medical school at Boston University at age 17. He trained in surgery with Dr. Roger Jenkins, who performed the first liver transplant in New England. Over the past decade, Dr. Panigrahy led angiogenesis and cancer animal modeling in the Judah Folkman laboratory. He joined the Beth Israel Deaconess Medical Center in 2013, and in 2014 was appointed assistant professor of pathology and currently has a laboratory in the Center for Vascular Biology Research.
For more information on the seminar, contact Hammock Lab account manager Gregory Zebouni at gzebouni@ucdavis.edu or (530) 752-8465.
- Author: Kathy Keatley Garvey
Leal, a distinguished professor in the Department of Molecular and Cellular Biology and a former chair of the Department of Entomology (now the Department of Entomology and Nematology) is one of 168 distinguished academic inventors who will be inducted April 10 at NAI's ninth annual meeting in Phoenix. The only other UC Davis recipient: Cristina Davis, the Warren and Leta Geidt Endowed Professor and Chair, Department of Mechanical and Aerospace Engineering
“I am humbled by this honor,” said Leal, who was nominated by UC Davis chancellor emerita Linda Katehi, an NIA fellow inducted in 2012. “To express my sentiment I have to paraphrase my predecessor as president of the International Society of Chemical Ecology, late Professor Thomas Hartmann, who said in our meeting in Prague in 1996: ‘In academia, students, postdocs, and other associates do most of the work and professors received the honors.' I look forward to opportunities to support NAI's mission of promoting innovation and celebrating invention.”
Katehi, now of Texas A&M, where she is a distinguished TEES (Engineering Experiment Station) chair and professor, Department of Electrical and Computer Engineering, praised Leal's “novel, sustainable and continued contributions to the field of entomology and for their greater implications in molecular and cellular biology and the understanding of disease and prevention.” Leal holds 28 Japanese and two U.S. patents.
Leal is the second faculty member affiliated with the Department of Entomology to be selected an NIA fellow. Distinguished professor Bruce Hammock, who holds a joint appointment with the Department of Entomology and the UC Davis Comprehensive Cancer Center, received the honor in 2014. (See news story.)
Said Hammock: “When Walter Leal reached UC Davis, he came with the reputation of being a 'one man army in research.' This reputation was well deserved. I know of no one at UC Davis who matches Walter in taking his remarkable fundamental advances in science and translating them to increase the safety and magnitude of world food production.”
Insect Communication
Leal, an expert in insect communication investigates how insects detect odors, connect and communicate within their species; and detect host and non-host plant matter. His research, spanning three decades, targets insects that carry mosquito-borne diseases as well as agricultural pests that damage and destroy crops. He and his lab drew international attention with their discovery of the mode of action of DEET, the gold standard of insect repellents. (See the Leal lab's work on DEET in Entomology Today.)
He and his collaborators, including Nobel Laureate Dr. Kurth Wuthrich (Chemistry 2002), unravel how pheromones are carried by pheromone-binding proteins, precisely delivered to odorant receptors, and finally activated by pheromone-degrading enzymes.
That led to Leal's identification of the sex pheromones of the navel orangeworm (Amyelois transitella), a pest of almonds, figs, pomegranates and walnuts, the major hosts. This has led to practical applications of pest management techniques in the fields.
Leal, a fellow of the Entomological Society of America (ESA), "has greatly advanced scientific understanding of insect olfaction," said Joe Rominiecki, communications manager, Entomological Society of America. "He has identified and synthesized several insect pheromones, and his collaborative efforts led to the first structure of an insect pheromone-binding protein."
'Tangible Impact on Quality of Life'
“The NAI Fellows Program highlights academic inventors who have demonstrated a spirit of innovation in creating or facilitating outstanding inventions that have made a tangible impact on quality of life, economic development and the welfare of society,” said NIA director Jayde Stewart. “Election to NAI Fellow is the highest professional distinction accorded solely to academic inventors. To date, NAI Fellows hold more than 41,500 issued U.S. patents, which have generated over 11,000 licensed technologies and companies, and created more than 36 million jobs. In addition, over $1.6 trillion in revenue has been generated based on NAI Fellow discoveries.”
A native of Brazil, educated in Brazil and Japan, and fluent in Portuguese, Japanese and English, Leal received his master's degree and doctorate in Japan: his master's degree at Mie University in 1987, and his doctorate in applied biochemistry at Tsukuba University in 1990. Leal then conducted research for 10 years at Japan's National Institute of Sericultural and Entomological Science and the Japan Science and Technology Agency before joining the faculty of the UC Davis Department of Entomology in 2000. He served as chair of the department from July 2006 to February 2008.
Leal co-chaired the 2016 International Congress of Entomology meeting, "Entomology Without Borders," in Orlando, Fla., that drew the largest delegation of scientists and experts in the history of the discipline: 6682 attendees from 102 countries.
Leal served as president of the International Society of Chemical Ecology and ESA's Integrative Physiological and Molecular Insect System Section. He co-founded the Asia Pacific Association of Chemical Ecologists and played a key role in founding the Latin American Association of Chemical Ecology.
Among his many other honors, Leal is a fellow of the American Association for the Advancement of Science and the California Academy of Sciences; an honorary fellow of the Royal Entomological Society and an inductee of the Brazilian Academy of Sciences. He received a silver medal from the International Society of Chemical Ecology. Leal recently presented the Founders' Memorial Lecture at the ESA meeting in St. Louis, the first UC Davis scientist selected to do so.
“Walter is an amazing person and an amazing scientist,” said Fred Gould, distinguished professor in the Department of Entomology and Plant Pathology at North Carolina State University. “His work has opened new doors to the understanding of how insects receive and perceive odors and has saved farmers in California and Brazil more than $100 million. He's at a point where he could sit back and bask in the glory of his accomplishments, but that is not Walter. He remains as prolific as ever.”
Related Links
- Author: Kathy Keatley Garvey
EicOsis LLC, a company founded by UC Davis distinguished professor Bruce Hammock to develop a non-opiate drug to relieve inflammatory pain in companion animals and target chronic neuropathic pain in humans and horses, can now add “Sacramento Region Innovator of the Year” to its list of accomplishments.
EicOsis won the award in the medical health/biopharmaceutical category of the annual Sacramento Region Innovation Awards Program. The program “recognizes the area's vibrant innovation community—from emerging to established companies—and their breakthrough creations,” according to sponsors Stoel Rives LLP, Moss Adams LLP and the Sacramento Business Journal.
“This project is an illustration of how fundamental science leads to real world applications, in this case addressing severe pain of humans and companion animals,” said Hammock, chief executive officer of EicOsis and a UC Davis faculty member who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center. “Our success in translation has been due largely to support from a number of institutes of the National Institutes of Health and a small team of hard-working scientists.”
The ceremony, honoring the winners of the eight categories, took place Nov. 7 in the Crest Theatre, Sacramento. Judges scored the finalists on novelty, market need, economic or social impact and disruption.
“It was an honor to be awarded the Sacramento Region Innovator of the Year in Medical Health and BioPharma,” said Cindy McReynolds, senior program manager of EicOsis and a UC Davis doctoral candidate studying pharmacology and toxicology. “The companies represented were inspiring, and it is great to be a part of the innovation going on in the Sacramento region.”
“Chronic pain is an enormous emotional and economic burden for more than 100 million people in the United States alone,” said Hammock, who co-founded EicOsis in December 2011 to alleviate pain in humans and companion animals. “The extreme and poorly treated pain that I observed as a medical officer working in a burn clinic in the Army, is a major driver for me to translate my research to help patients with severe pain.”
Phase 1 human clinical trials to test the drug candidate, EC5026, a first-in-class, small molecule that potently inhibitssEH, will begin Dec. 10 in Texas. The title: "A Single-Center, Double-Blind, Placebo-Controlled, Phase 1a Single Ascending Dose Study to Investigate the Safety, Tolerability, and Pharmacokinetics of Sequential Dose Regiments of Oral EC5026 in Healthy Male and Female Subjects." Eight will participate; six with the drug candidate and two with the placebo. The technology was discovered in the Hammock lab and UC Davis has licensed patents exclusively to EicOsis.
“EC5026 is a key regulatory enzyme involved in the metabolism of membrane fatty acids,” Hammock said. "It's a novel, non-opioid and oral therapy for neuropathic and inflammatory pain. Inhibition of sEH treats pain by stabilizing natural analgesic and anti-inflammatory mediators."
The project is unique in that “there have been very few truly new types of analgesic compounds that have reached the market in the past 50 years,” Hammock said.
“The sEH enzyme is involved in regulating the activity of powerful anti-inflammatory fatty acids called EETs that are present in all cells in humans and animals,” the scientists explained in their awards application. “EETs are anti-inflammatory, analgesic, anti-hypertensive, but they are short lived molecules that are normally eliminated within seconds. By inhibiting sEH, EET levels can be increased by 4x or more and maintained at high anti-inflammatory and analgesic levels for 24 hours or longer.”
“The sEH inhibitors are very potent molecules that are designed for once daily oral dosing. They can also be administered intravenously for acute pain (e.g. equine laminitis),” they wrote. “Preclinical safety studies show that sEH inhibitors are very safe with no visible signs of toxicity at doses more than 100x higher than the therapeutic dose levels. Unlike conventional analgesics, they do not produce sedation or cognitive dysfunction and they have been shown to have no addiction liability, no adverse cardiovascular effects, and no adverse effects on the gastrointestinal tract. They can be safely co-administered with existing analgesic medications.”
Approximately 50 million Americans (20 percent of the population) suffer from chronic pain, according to the Center for Disease Control and Prevention. The annual economic toll is $560 billion, encompassing direct medical expenses, lost productivity, and disability claims. Pain research is now one of the top priorities of the National Institutes of Health (NIH).
EicOsis advancement of EC5026 into clinical trials has been funded as part of the Blueprint Neurotherapeutics Network (BPN) of the NIH Blueprint for Neuroscience Research. The BPN is a collaboration of NIH Institutes and Centers that supports innovative research on the nervous system with the goal of developing new neurotherapeutic drugs.
EicOsis (pronounced eye-cosis), derives its name from eicosanoid, “the major backbone of chemical mediators in the arachidonate cascade,” said McReynolds. “It symbolizes the epoxide group in chemistry, which is key to the anti-inflammatory chemical mediators and where the biochemical target called soluble epoxide hydrolase works.”
