UC Davis distinguished professor Bruce Hammock, who researches how to control acute and neuropathic pain, recently received an “outstanding achievement” award from the Eicosanoid Research Foundation at its international meeting in Puerto Vallarta, Mexico.
His work on the enzyme, soluble epoxide hydrolase and its inhibitors, spans nearly 50 years of research. Human clinical trials of the Davis compounds aimed at controlling pain are expected to begin in 2018.
“The achievement award is lovely and probably the only thing I will ever own from Tiffany Jewelers,” quipped Hammock, who holds a joint appointment with the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center.
Hammock drew appreciation and applause from his colleagues following his plenary lecture on “Control of Acute and Neuropathic Pain by Inhibiting the Hydrolysis of Epoxy Fatty Acid Chemical Mediators: Path to the Clinic.”
In his talk, Hammock traced the history of his work to 1969 in the laboratory of UC Berkeley Professor John Casida. Hammock, where he was a graduate student and later a postdoctoral fellow. At the time, Hammock was researching insect developmental biology and green insecticides when he and colleague Sarjeet Gill (now a UC Riverside professor) discovered the target enzyme in mammals that regulates epoxy fatty acids.
“The work led to the discovery that many regulatory molecules are controlled as much by degradation and biosynthesis,” Hammock said. “The epoxy fatty acids control blood pressure, fibrosis, immunity, tissue growth, pain and inflammation to name a few processes.”
Since then, his laboratory has published almost 900 peer-reviewed papers in the epoxide hydrolase field.
“For many years Sarjeet and I were alone in studying this enzyme and pathway but now its importance is well recognized in mammalian biology with over 17,000 peer reviewed papers in the area,” Hammock said. “The importance of this pathway is now clear.”
Hammock collaborates with scientists worldwide, including UC Davis professors Aldrin Gomes, physiology; Fawaz Haj, nutrition; Robert Weiss, nephrology; Kent Pinkerton, pediatrics; Alan Buckpitt and Pam Lein, School of Veterinary Medicine; Niipavan Chiamvimonvat, cardiology, and Nicholas Kenyon, pulmonology.
“It is always important to realize that the most significant translational science we do in the university is fundamental science,” said Hammock, a native of Little Rock, Ark., who began his academic studies at Louisiana State University, Baton Rouge, where he received his bachelor's degree in entomology. “The epoxide hydrolase work is a great example going from developmental biology in butterflies to blood pressure and pain in man. However, the extreme and poorly treated pain that I observed as a medical officer in a burn clinic in the Army, is a major driver for me to translate this knowledge to help patients with severe pain. Hopefully, we can start human clinical trials next year.”
“One of the leaders in the lipid field--Bill Lands--stated that 'If the science is not fun, it should not be done.' Certainly, the discovery of a new biochemical pathway that regulates so much of human biology is interesting, and the science to get there is grand fun. A great personal pleasure from this work has been the wonderful scientists that I have collaborated with. They have taught me a lot about diverse fields, and many have become treasured friends.”
EicOsis, a Davis company that he founded, is working to move inhibitors of the soluble epoxide hydrolase into the clinic. They have been funded by the National Institutes of Health (NIH) Program to move the inhibitors into human trials targeting chronic or neuropathic pain with a non-opiate analgesic. In parallel. they are developing a drug to treat a commonly fatal pain condition in horses called laminitis as well as arthritic pain in dogs and cats.
Hammock's longtime collaborator, Dipak Panigrahy, a physician and assistant professor of pathology at Harvard Medical School and a researcher with Harvard's Center for Vascular Biology Research, praised his “incredible commitment to science and medicine with extraordinary outside-the-box reasoning.”
“His keen intellect and reasoning, ability to communicate complex ideas, and dedication to teaching the next generation of scientists is unparalleled,” Panigrahy said, adding “Bruce is kind, compassionate, inspiring and also a loving husband and father to three incredible kids.”
Panigrahy cited Hammock's many accomplishments that led to the Eicosanoid award. “Bruce pioneered the first class of pharmaceuticals to directly address the cytochrome P450 (CYP) pathway of arachidonic acid metabolism. These soluble epoxide hydrolase (sEH) inhibitors are powerful pharmacological tools to raise EET levels. They are being evaluated in clinical trials for cardiovascular diseases and are being considered for long-term use in diabetes, stroke, cerebral ischemia, dyslipidemia, pain, immunological conditions, eye diseases, neurological diseases, renal disease, organ damage, vascular remodeling, atherosclerosis, ischemia-reperfusion, lung disease (chronic obstructive pulmonary diseases-COPD), graft stenosis, cancer, and other medical conditions.”
“In addition, Dr. Hammock's laboratory has demonstrated that epoxides of omega 3 or fish oil fatty acids are more potent than EETs in many assays, Panigrahy said. “Importantly, Dr, Hammock's studies are providing insight into the outcome of dramatically increasing omega 3 lipids in the U.S. diet."
Hammock, a member of the National Academy of Sciences and the National Academy of Inventors, has led a team of more than 40 scientists and students with what program manager Cindy McReynolds describes as “unprecedented research with a multidisciplinary, integrated approach to research focused on insect biology, mammalian enzymology, and analytical chemistry.” He has produced more than 1000 publications on a wide range of topics in entomology, biochemistry, analytical and environmental chemistry in high quality journals. The laboratory has generated more than 80 patents.
The Hammock lab is the home of the UC Davis/National Institute of Environmental Health Sciences Superfund Research and Training Program. Lab alumni total more than 65 graduates, who now hold positions of distinction in academia, industry and government. The list also includes more than 300 postdoctoral fellows.
The historical research funding base is diverse and includes long-term grants from NIH, National Science Foundation, U.S. Department of Agriculture, Department of Defense, UC Mosquito Research Program and many private and research foundation contracts and grants.
Make that a scientist who knows about soluble epoxide hydrolase, and a physician who knows about acute kidney injury (AKI), formerly called acute renal failure.
"It makes my brain hurt (reading it)," commented a colleague who is neither.
However, it's an important research paper published in the current edition of Proceedings of the National Academy of Sciences and it's co-authored by a distinguished UC Davis professor trained as an entomologist: Bruce Hammock, who holds a joint appointment with the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center.
The gist of it: newly published research by an international team of scientists, headed by the Jun-Yan Liu lab of Tongji University, Shanghai, China, and the Bruce Hammock lab at UC Davis, may provide promising therapeutic strategies for those suffering from acute kidney injury (AKI), formerly called acute renal failure. Access PNAS article.
“The soluble epoxide hydrolase or sEH degrades chemically stable fatty acid epoxides,” explained Hammock. “But sometimes it can be useful to block the function of sEH, so that beneficial fatty acid epoxides, like those from omega-3 and omega-6 fatty acids, are not degraded. These fatty acid epoxides have been found to protect the kidney, reduce inflammation, inflammatory pain, and even chronic or neuropathic pain.”
In general, the epoxides of docosahexaenoic acid (DHA) from fish oil make the soluble epoxide hydrolase inhibitors even more effective, the Hammock lab has found. “However, in this case, the fish oil seemed to be deleterious rather than beneficial when combined with the sEH inhibitors with kidney injury,” Hammock said. This was unexpected and the investigators caution that fish oil may not always have beneficial effects.
Professor Jun-Yan Liu, a former postgraduate researcher and assistant project scientist in the Hammock lab, related that the lipid mediators that preserve the kidney in AKI are termed EETs. “Their levels can be changed by altering their degradation or biosynthesis with selective inhibitors. This increase in EET resulted in anticipated decreases in the plasma level of creatinine and urea nitrogen—both biomarkers for kidney injury.” He added that they are looking forward to the epoxide hydrolase inhibitors finishing phase I clinical trials in humans so they can be evaluated for preventing or treating AKI.
Specifically, the researchers discovered that a 14(15)-EET mitigated kidney injury and prolonged life, while another epoxide, 19(20)-EDP from fish oil, exacerbated the kidney injury and shortened life. “We found that epoxides of docosahexaenoic acid (DHA) and DHA-enriched fish oil worsened kidney injury prophylactically and therapeutically in multiple animal models of AKI,” wrote Liu, pointing out that fish oil has proven beneficial in a number of other investigations.
Statistics show that “the incidence of AKI in hospitalized patients increased dramatically from 4.9 percent in 1983 to 20 percent in 2012,” the researchers wrote in their paper. “The mortality from AKI is greater than 50 percent; worldwide, approximately 2 million people die of AKI every year. Therefore, novel, safe and effective approaches are urgently needed to prevent and treat AKI.”
Says Weiss: “Because AKI has no specific effective therapy and treatment is merely supportive frequently requiring hemodialysis any new treatment or therapeutic paradigm would be welcome in the nephrology community and has the potential to improve the lives of many patients with AKI."
Kidney injury expert Alan Parrish of the University of Missouri's School of Medicine, Columbia, also not involved in the research, called the findings “significant.”
“The collaborative studies between Dr. Liu's and Hammock's group are an elegant, and timely, contribution to our understanding of acute kidney injury (AKI),” said Parrish, vice chair for education and director of Graduate Studies for Medical Pharmacology at the medical school. “AKI has potentially devastating short-term consequences - high mortality - as well as the detrimental long-term impact on renal function. Importantly, specific interventions to treat AKI in patients have not yet been identified. These results are significant in that they provide a unique mechanistic insight into pathways targeted by soluble epoxide hydrolase inhibitors that attenuate AKI, providing a powerful rationale for future clinical trials in AKI patients.”
Bruce Hammock knows well the tragedy of AKI and its terrible toll. "When I was in a burn unit in the U.S. Army, many patients faced their last few hours with sepsis and AKI. I have had my mom and cousin die of acute renal failure. It is not all that rare, and there is not much a doctor can do now except watch. Dialysis normally comes too late--and dialysis comes with its own problems."
The paper is the work of scientists led by Jun-Yan Liu from the Center for the Nephrology and Metabolomics and Division of Nephrology and Rheumatology, Tongji University School of Medicine, Shanghai, China: Bing-Qing Deng, Ying Luo, Xin Kang, Chang-Bin Li, Jian Huang, Da-Yong Hu, Ming-Yu Wu, and Ai Peng; and Hammock and his lab researchers Jun Yang, Christophe Morrisseau, Kin Sing Stephen Lee at UC Davis.
"For humans, we are supported by the National Institutes of Health Blueprint Program to take this through Human Phase I," Hammock says. "We hope to be in Phase 1 next year. We are looking for support for Phase II. Once Phase 1 is finished, there should be an IND that can be referenced for physician-initiated trials. We are looking for angel or venture funding for similar FDA trials in horses and companion animals.”
“The epoxy fatty acids and sHE inhibitors block ER stress," Hammock says. "Thus, they should help with a number of disorders that arise from ER stress. We are first targeting neuropathic pain in humans and inflammatory pain in horses and companion animals.”
The intellectual property status? “Some licensed by the University of California to EicOsis LLC (a company founded by Hammock, the CEO) and others are EicOsis patents.”
Licensing? “Licensed exclusively to EicOsis, but EicOsis is interested in partnerships or sublicenses for specific indications.”
Access PNAS article
Hammock lab: http://www.biopestlab.ucdavis.edu/Epoxide_Hydrolase/
Bruce Hammock, distinguished professor at the University of California, Davis, who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center, annually hosts a water balloon battle for his lab members and staff.
It amounts to 15 minutes of aim (not fame) and it takes place on the Briggs Hall lawn, off Kleiber Hall Drive. Only 15 minutes? That's how fast the water warriors can toss 2000 water balloons.
Researcher Christophe Morisseau, who organizes the annual funfest, says this year's event will take place at 3 p.m., Friday, July 21.
Hammock's lab and staff are international. They're from Canada, Ukraine, France, China, Sweden, Japan, Germany, Korea, Uruguay and the Netherlands, besides the United States. They are post docs, researchers, graduate students, visiting scholars, visiting graduate students, visiting summer students, short-term visiting scholars and student interns.
They will fill 2000 water balloons, place them in plastic tubs, and at 3 p.m., they begin. But just when you think it's all over, it's not. Any water remaining in the buckets will be splashed on unsuspecting water warriors.
Hammock launched the annual event in 2003 as a form of camaraderie and as a means of rewarding the lab members for their hard work. Other professors and their labs are invited to join in.
After the 15 minutes of aim, it's clean-up time. The water warriors leave refreshed (especially in triple-digit temperatures) and the thirsty lawn isn't as thirsty.
Highly honored by his peers (but a target at the annual water balloon battle), Hammock is a fellow of the National Academy of Inventors, which honors academic invention and encourages translations of inventions to benefit society. He is a member of the U.S. National Academy of Sciences, a fellow of the Entomological Society of America, and the recipient of the Bernard B. Brodie Award in Drug Metabolism, sponsored by the America Society for Pharmacology and Experimental Therapeutics. He directs the campuswide Superfund Research Program, National Institutes of Health Biotechnology Training Program, and the National Institute of Environmental Health Sciences (NIEHS) Combined Analytical Laboratory.
Art Shapiro, distinguished professor of evolution and ecology at the University of California, Davis, figured it was too rainy and too cold to head over to West Sacramento to look for the first cabbage white butterfly of the year, so he walked around campus Thursday.
And he found it.
Shapiro nabbed the cabbage white butterfly, Pieris rapae, at 1:56 p.m., Thursday, Jan. 19 in the student gardens near the Solano Park Apartments.
He again won the annual Butterfly-for-a-Beer contest, which he launched in 1972 as part of his long-term studies of butterfly life cycles and climate.
The contest rules indicate that the first person who finds the first cabbage white butterfly of the year in the three-county area of Yolo, Solano and Sacramento receives a pitcher of beer or its equivalent.
Shapiro, who has been defeated only four times in the contest (and all by UC Davis graduate students) said this was the first find on the campus.
“Earlier today I was asked when P. rapae would come out, given the very wet January this year. I replied that when it stopped raining. we'd probably get into tule fog…and that would take us into February for any decent butterfly weather.”
Jan. 19 dawned with a “a cold, unstable air mass overhead,” Shapiro recalled, describing it as “an ideal convective day, with showers and thundershowers popping up.”
With the ground and the vegetation sopping wet, he figured this would not a “potential rapae day.”
“When I got out of class at noon it was bright and sunny, clear overhead but with cumulus building to the west over the Coast Range. It felt warm and I might have gone to West Sacramento, but decided by the time I got there it would have clouded over and perhaps even be raining. So I got lunch and then walked over to the student gardens near the Solano Park Apartments just to gather host plant for my rapae culture--yes, I'm mass-rearing the bugs for photoperiod studies, and have some 100 live ones in a refrigerator."
“It remained sunny and got quite warm—55 or 56, I'd say," Shapiro related. "The vegetation was indeed sopping wet. At 12:59 I saw—a rapae. It was sitting quietly, wings folded, on a cultivated Brassica. It had not opened its wings to body-bask, that is, warm the body by exposure to incoming solar radiation. If it had, it almost certainly would have flown and, being netless, I would have lost it. Instead it just sat there as I picked it off the plant. I always carry one glasseine envelope in my eyeglass case. Into the envelope it went. It's a winter-phenotype male and, I imagine, had just emerged this morning and not yet flown.”
“This is the second year in a row that the first rapae was found in a garden rather than one of the conventional ‘warm pockets,' Shapiro noted. “What does it all mean?”
Davis resident Cindy McReynolds, program manager of the Bruce Hammock lab, UC Davis Department of Entomology and Nematology, spotted some cabbage white butterfly chrysalids in her garden two weeks ago. "They were on the cabbage when I was removing the vegetation."
Colleague/collaborator Matthew Forister, McMinn professor of biology at the University of Nevada, Reno (his major professor was Shapiro), said that Shapiro's find was right on time. "You couldn't have hit closer to the trend line if you'd tried," he told him, sending him the illustration below. "This year in red," he pointed out, noting that "the slope has not changed from last year."
The cabbage white was not the only butterfly Shapiro found on Jan. 19. He also noticed a “fresh-looking female West Coast Lady, Vanessa annabella, nectaring at a crucifer in the same garden—first one of those this year too, but it's a hibernator.”
Shapiro launched the "Beer-for-a-Butterfly" contest in 1972 to draw attention to Pieris rapae and its first flight. “Since 1972, the first flight has varied from Jan. 1 to Feb. 22, averaging about Jan. 20.” The butterfly is emerging earlier and earlier as the regional climate has warmed, said Shapiro, who researches biological responses to climate change. "The cabbage white is now emerging a week or so earlier on average than it did 30 years ago here."
The professor, a fellow of the American Association for the Advancement of Science, the Royal Entomological Society and the California Academy of Sciences, said the cabbage white butterfly inhabits vacant lots, fields and gardens where its host plants, weedy mustards, grow.
Shapiro teaches his students well. The other winners were his own graduate students: Adam Porter defeated him in 1983; and Sherri Graves and Rick VanBuskirk each won in the late 1990s.
Shapiro, who is in the field more than 200 days of the year, monitoring butterflies of central California, knows where to find the cabbage whites. He has collected many of his winners in mustard patches near railroad tracks in West Sacramento, Yolo County. Over the last seven years, five of the winners came from West Sacramento; one in Davis, Yolo County; and one in Suisun, Solano County.
Coincidentally, Shapiro caught the 2013 and 2009 winners on President Obama's Inauguration Day. This year he missed President Trump's Inauguration Day by a day.
Shapiro maintains a research website on butterflies, where he records the population trends. He and artist Tim Manolis co-authored A Field Guide to Butterflies of the San Francisco Bay and Sacramento Valley Regions, published in 2007 by the University of California Press.
He marveled at how a caterpillar turns into a butterfly and said that "science is full of surprises." One of the surprises: his basic research on insects led to a drug for blocking hypertension and neuropathic pain.
Now add Alzheimer's to that list.
This week Hammock announced that a drug developed in his lab yields hope for the prevention of Alzheimer's, a severe and chronic psychiatric disease that affects more than 350 million people worldwide.
Researchers at the Huazhong University of Science and Technology, Wuhan China, used the drug developed at UC Davis to show that the neurofibrillary pathology of an Alzheimer's disease-related protein could be dramatically reduced. Their work was published in December in the Journal of Huazhong University of Science and Technology.
“They further demonstrated the mechanism of action of the UC Davis drug in blocking the oxidative stress-driven phosphorylation events associated with Alzheimer's disease,” Hammock said. The UC Davis drug stabilizes natural anti-inflammatory mediators by inhibiting an enzyme called soluble epoxide hydrolase (sEH) discovered at UC Davis and recently spotlighted in the Proceedings of the National Academy of Sciences and the National Institutes of Health's PubMed.
“I was thrilled to see this paper on tau phosphorylation from Huazhong University shows that our drug could block a key event and a key enzyme called GSK-3 beta thought critical in the development of Alzheimer's disease,” said Hammock, who holds a joint appointment in the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center.
“We were planning to do this study, but having another laboratory do it with our compound was even better,” he said. “Since our publication last year in PNAS that showed UC Davis soluble epoxide hydrolase inhibitors both prevented and reversed depression, we have been excited about trying to block the development of Alzheimer's disease.”
The PNAS paper, “Gene Deficiency and Pharmacological Inhibition of Soluble Epoxide Hydrolase Confers Resilience to Repeated Social Defeat Stress,” was co-authored by a 13-member research team led by Hammock and Kenji Hashimoto of Chiba University Center's Division of Clinical Neuroscience, Japan. They found that sEH plays a key role in the pathophysiology of depression, and that epoxy fatty acids, their mimics, as well as sEH inhibitors could be potential therapeutic or prophylactic drugs for depression and several other disorders of the central nervous system. Co-authors of the paper included Hammock lab researchers Christophe Morisseau, Jun Yang and Karen Wagner. The National Institute of Environmental Health Sciences, National Institutes of Health, funded the research.
Hammock credited several UC Davis colleagues for their work leading to the publications. Research from the labs of Liang Zhang and Qing Li at the University of Hawaii--Qing is a former UC Davis doctoral student--pointed out some of the mechanisms involved in cognitive decline which associate professor Aldrin Gomes of the UC Davis Department of Neurobiology, Physiology and Behavior and Fawaz Haj of the UC Davis Department of Nutrition “have shown to be blocked by the natural metabolites stabilized by the UC Davis drugs,” Hammock said.
One of the Hammock lab drugs is moving toward human clinical trials for neuropathic pain through a Davis-based company, EicOsis, LLC, and the financial support of the Blueprint Program through NIH's National Institute of Neurological Disorders and Stroke. Hammock founded the company to develop inhibitors to the soluble epoxide hydrolase, a key regulatory enzyme involved in the metabolism of fatty acids, to treat unmet medical needs in human and animals.
“The clinical back-up candidate at EicOsis penetrates the blood brain barrier and should be a perfect compound to test if this class of chemistry can prevent cognitive decline and Alzheimer's disease,” Hammock said.
Meanwhile, I'm still thinking about that seminar, "From Butterflies to Blood Pressure and Beyond."
Alzheimer's, a cruel disease characterized by progressive memory loss, language problems and unpredictable behavior issues.