An enzyme inhibitor developed in the UC Davis laboratory of Bruce Hammock and tested in mice by a team of international researchers shows promise that it could lead to a drug to prevent or reduce the disabilities associated with the neurodevelopmental disorders of autism and schizophrenia.
“We discovered that soluble epoxide hydrolase (sEH) plays a key role in inflammation associated with neurodevelopmental disorders. Inhibiting that enzyme stops the inflammation and the development of autism-like and schizophrenia-like symptoms in animal models,” said collaborator Kenji Hashimoto, a professor with the Chiba University Center for Forensic Mental Health, Japan. The scientists found higher levels of sEH in a key region of the brain—the prefrontal cortex of juvenile offspring-- after maternal immune activation (MIA).
“Mothers who have MIA, which results from severe stress in that region of the brain, have an increased occurrence of neurodevelopment disorders in their offspring,” Hashimoto explained. “In our study, the sEH enzyme increased dramatically in a key brain region of mice pups from mothers with MIA.”
The research, published today (March 18) in the Proceedings of the National Academy of Sciences (PNAS), is the work of 14 researchers from Chiba University Center for Forensic Mental Health; the Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, in Wako, Saitama, Japan; and the Hammock laboratory.
Research in Mice Pups
By inhibiting sEH, the researchers reversed cognitive and social interaction deficiencies in the mice pups. They hypothesize that this is due to increasing natural chemicals, which prevent brain inflammation. In people, this could reduce the disabilities associated with autism, such as anxiety, gastrointestinal disturbances and epilepsy.
“The same chemical and biochemical markers behaved as predicted in human stem cells,” said Hammock, a distinguished professor who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center.
Earlier studies have indicated a genetic disposition to the disorders. The team also studied postmortem brain samples from autism patients that confirmed the alterations.
“In the case of both autism and schizophrenia, the epidemiology suggests that both genetics and environment are contributing factors,” said neuroscientist and associate professor Amy Ramsey of the Department of Pharmacology and Toxicology, University of Toronto, who was not involved in the study. “In both cases, maternal infection is a risk factor that might tip the scales for a fetus with a genetic vulnerability. This study is important because it shows that their drug can effectively prevent some of the negative outcomes that occur with prenatal infections. While there are many studies that must be done to ensure its safe use in pregnant women, it could mitigate the neurological impacts of infection during pregnancy.”
Neuroscientist Lawrence David, professor and chair of the School of Public Health, University of Albany, N.Y., who was not involved in the research, said that the study might lead to “an important therapeutic intervention for neurodevelopment disorders.”
Might Be Important Therapeutic Invervention
“There is increasing evidence that maternal immune activation activities (MIA) during fetal development can lead to aberrant neurobehaviors, including autistic-like activities,” said Lawrence, who studies neuroimmunology and immunotoxicology. The study “suggests that enzymatic control of fatty acid metabolism is implicated in neuroinflammation associated with schizophrenia and autism spectrum disorders. The expression of Ephx2 giving rise to soluble epoxide hydrolase (sEH) influences production of fatty acid metabolites, which elevate inflammation in the experimental model of mice after MIA; the sEH inhibitor TPPU (N-[1-(1-oxopropyl)-4-piperidinyl]-N'-[4-(trifluoromethoxy)phenyl)-urea) was postnatally used to improved behaviors. Analysis of cadaver brains from individuals with ASD also expressed increased sEH. Fatty acid metabolites have been known to affect fetal development, especially that of the brain; therefore, TPPU might be an important therapeutic intervention for neurodevelopmental disorders.”
Molecular bioscientist Isaac Pessah of the UC Davis School of Veterinary Medicine, distinguished professor and associate dean of research and graduate education in the Department of Molecular Biosciences, described the findings as “significant” and called for more detailed and expanded studies.
“There is mounting evidence that inappropriate maternal immune responses during pregnancy to infection contributes elevated risk to autism spectrum disorder, at least in a fraction of cases,” Pessah said. “The most significant findings reported here is that a commonly used mouse model of immune-triggered behavioral deficits mimicking some of the core symptoms in autistic children can be suppressed by inhibiting a novel biochemical target, soluble epoxide hydrolase; a target not previously explored as a target for therapeutic intervention to treat ASDs. These findings provide a rational basis for more detailed and expanded studies in mice carrying mutations implicated in ASDs to determine whether the therapeutic benefits of soluble epoxide hydrolase inhibitor(s) observed in this study are more generalizable.”
Autism in the United States
The Center for Disease Control and Prevention (CDC) estimates that 1 in 68 children in the United States have autism, commonly diagnosed around age 3. It is four times more common in boys than girls. CDC defines autism spectrum disorder as a “developmental disability that can cause significant social, communication and behavioral challenges.” The disorder impairs the ability to communicate and interact.
Approximately 3.5 million people or 1.2 percent of the population in the United States are diagnosed with schizophrenia, one of the leading causes of disability, according to the Schizophrenia and Related Disorders Alliance of America (SARDAA). Scores more go unreported. Approximately three-quarters of persons with schizophrenia develop the illness between 16 and 25 years of age. Statistics also show that between one-third and one half of all homeless adults have schizophrenia, and 50 percent of people diagnosed have received no treatment. Among the symptoms: delusions, hallucinations, disorganized speech, disorganized or catatonic behavior, and obsessive-compulsive disorders, such as hoarding, according to SARDAA.
Promising Prophylactic or Theraputic Target
In their research paper, titled “Key Role of Soluble Epoxide Hydrolase in the Neurodevelopmental Disorders of Offspring After Maternal Immune Activation,” the scientists described sEH as “a promising prophylactic or therapeutic target for neurodevelopmental disorders in offspring after MIA.”
First author Min Ma and second Qian Ren of the Hashimoto lab conducted the animal and biochemical work, while chemists Jun Yang and Sung Hee Hwang of the Hammock lab performed the chemistry and analytical chemistry. Takeo Yoshikawa, a team leader with the RIKEN's Molecular Psychiatry Laboratory, performed measurements of gene expression in the neurospheres from iPSC (induced pluripotent stem cells) from schizophrenia patients and postmortem brain samples from autism patients.
Hashimoto described the international collaboration as “exciting and productive.” This is their third PNAS paper in a series leading to endoplasmic reticulum stress. “We report discovery of a biochemical axis that leads to multiple neurological disorders, including depression, Parkinson's disease, schizophrenia, autism spectrum disorders and similar diseases,” he said.
First Human Trials
William Schmidt, vice president of clinical development at EicOsis, a Davis-based company developing inhibitors to sEH to treat unmet medical needs in humans and companion animals, said the company is developing a first-in-class therapy for neuropathic and inflammatory pain. “EicOsis is in the process of finalizing our first human trials on the inhibitors of the soluble epoxide hydrolase, originally reported from UC Davis,” Schmidt said. “We are targeting the compounds as opioid replacements to treat peripheral neuropathic pain. It is exciting that the same compound series may be used to prevent or treat diseases of the central nervous system.”
Several grants from the National Institutes of Health, awarded to Hammock, supported the research. Hammock praised the many collaborators and students he has worked with on the project. “This work illustrates the value of research universities in bringing together the diverse talent needed to address complex problems,” Hammock said. “It also illustrates the value of fundamental science. This autism research can be traced directly to the fundamental question of how caterpillars turn into butterflies.”
Now working solely on research to benefit humankind, Hammock began his career in insect science at UC Berkeley where he investigated how epoxide hydrolase degrades a caterpillar's juvenile hormone. The process leads to metamorphosis from the larval stage to the adult insect. Hammock then wondered "Does the enzyme occur in plants? Does it occur in mammals?"
It does, and particularly as a soluble epoxide hydrolase in mammals.
"Science is full of surprises," said Hammock, who founded EicOsis to help human patients conquer pain without opioids. "We need to remember that the concept, the clinical target, and even the chemical structure, came from asking how caterpillars turn into butterflies."
ABSTRACT, PNAS Paper, "Key Role of Soluble Epoxide Hydrolase in the Neurodevelopmental Disorders of Offspring After Maternal Immune Activation"
“Maternal infection during pregnancy increases the risk of neurodevelopmental disorders such as schizophrenia and autism spectrum disorder (ASD) in offspring. In rodents, maternal immune activation (MIA) yields offspring with schizophrenia- and ASD-like behavioral abnormalities. Soluble epoxide hydrolase (sEH) plays a key role in inflammation associated with neurodevelopmental disorders. Here we found higher levels of sEH in the prefrontal cortex (PFC) of juvenile offspring after MIA. Oxylipin analysis showed decreased levels of epoxy-fatty acids in the PFC of juvenile offspring after MIA, supporting increased activity of sEH in the PFC of juvenile offspring. Furthermore, the expression of sEH (or EPHX2) mRNA in iPSC-derived neurospheres from schizophrenia patients with the 22q11.2 deletion was higher than that of healthy controls. Moreover, the expression of EPHX2 mRNA in the postmortem brain samples (Brodmann area 9 and 40) from ASD patients was higher than that of controls. Treatment of TPPU (a potent sEH inhibitor) into juvenile offspring from P28 to P56 could prevent cognitive deficits and loss of parvalbumin (PV)-immunoreactivity in the medial PFC of adult offspring after MIA. In addition, dosing of TPPU to pregnant mothers from E5 to P21 could prevent cognitive deficits, and social interaction deficits and PV-immunoreactivity in the mPFC of juvenile offspring after MIA. These findings suggest that increased activity of sEH in the PFC plays a key role in the etiology of neurodevelopmental disorders in offspring after MIA. Therefore, sEH would represent a promising prophylactic or therapeutic target for neurodevelopmental disorders in offspring after MIA.”
Related Research Published in PNAS
- Soluble Epoxide Hydrolase Plays a Key Role in the Pathogenesis of Parkinson's Disease
- Gene Deficiency and Pharmacological Inhibition of Soluble Epoxide Hydrolase Confers Resilience to Repeated Social Defeat Stress
Should auld acquaintance be forgot,
and never brought to mind?
No, they won't—at least not for Bruce Hammock, a distinguished professor at the University of California, Davis, and the hundreds of scientists he's trained over an academic career spanning more than four decades at UC Davis and UC Riverside.
Looking back over 2018, Hammock remembers fondly the weekend that 100 of his former laboratory alumni from 10 countries traveled to Davis to honor his work, reunite, collaborate, and reminiscence.
Billed as “Biochemistry and Society: Celebrating the Career of Professor Bruce Hammock,” the three-day event drew Hammock lab alumni from throughout the United States, as well as Egypt, Spain, China, Australia, New Zealand, Germany, Sweden, Canada and the Czech Republic.
“It was really special and I will treasure that weekend always,” said Hammock, who trained scientists at UC Riverside for five years before joining the UC Davis faculty in 1980. He currently holds a joint appointment with the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center. He has directed the UC Davis Superfund Program, funded by the National Institutes of Health's National Institute of Environmental Health (NIH/NIEHS), for 31 years.
The distinguished professor, known for his expertise in chemistry, toxicology, biochemistry and entomology, meshes all four sciences in his 50-year research on acute and neuropathic pain in humans and companion animals. It all began with his basic research on how caterpillars become butterflies, research that led to key discoveries about chronic pain.
Since then, his lab has generated more than 80 patents, 300 postdoctoral fellows, and more than 65 graduates, who now hold positions of distinction in academia, industry and government.
Hammock's colleagues, and former postdoctoral fellows, graduate and undergraduate students and visiting scholars arrived at the lab reunion with their spouses--as well as their scientific posters for display and discussion. The posters covered everything from ground-breaking research in prestigious journals to a humorous look at his annual water balloon battles in front of Briggs Hall.
The scientists dined at the UC Davis Conference Center, the Buehler Alumni Center and the Stonegate Country Club; shared months, years and decades of memories; and toasted, roasted and gifted their mentor. Hammock, in turn, toasted, roasted and gifted them.
“We had a blast,” recalled organizer Shirley Gee, a former research toxicologist and manager of the Hammock lab for 31 years. She retired in June 2016 after 40 years of service with the university.
“I have had a vision of this event to honor Bruce for many years now, and it was such a thrill to see it come together,” she said. “Reconnecting in person with all the alumni and their families was more rewarding than I could have imagined, but even more importantly was the thrill of watching alumni reconnect with each other! There were a lot of tears in the house. Many people I think were surprised by how the years melted away when they began reacquainting. I think that speaks to the environment that Bruce created that led to many strong personal and professional bonds.”
Gee credited her seven-member committee—former Hammock students Keith Wing, Jim Ottea, Tom Sparks, Babak Borhan, Qing Li; postdoctoral fellow and “academic grandson” Kin Sing Stephen Lee, a former student of Babak Borhan; and colleague Sarjeet Gill, now a distinguished professor at UC Riverside, with greatly contributing to the success of the one-of-a-kind celebration.
As graduate students, and Hammock and Gill worked together in the John Casida lab at UC Berkeley and later in Larry Gilbert's lab where they co-discovered the enzyme, soluble epoxide hydrolase. Hammock remembers researching juvenile hormones and what's involved in "how caterpillars became butterflies."
Hammock has studied the enzyme system and its inhibitors ever since. He recently formed a Davis-based company, EicOsis, to develop an orally active non-addictive drug for inflammatory and neuropathic pain for human beings and companion animals. Human clinical trials are scheduled to begin in 2019. Several seed-fund grants and a NIH/NINDS (National Institute of Neurological Disorders and Stroke) Blueprint Development Grant support EicOsis.
Hammock, described at the lab reunion as a “genius,” collaborates with scientists worldwide in what's been described as “unprecedented research with a multidisciplinary, integrated approach to research focused on insect biology, mammalian enzymology, and analytical chemistry.” He has authored more than 1000 publications on a wide range of topics in entomology, biochemistry, analytical and environmental chemistry in high quality journals, and has been cited more than 54,000 times. In the epoxide hydrolase field, the Hammock laboratory has published almost 900 peer-reviewed papers.
Tom Sparks, who was Hammock's first graduate student at UC Riverside, chronicled Hammock's career and recalled humorous anecdotes from his early professorship at UC Riverside. A former professor at Louisiana State University, and now a research fellow in Discovery Research at Dow AgroSciences (now Corteva Agriscience, Indianapolis, Sparks praised Hammock's intellect and curiosity. “For Bruce, it was all about the journey, looking around and operative at the interface between entomology, biochemistry and chemistry.”
Gill, along with University of Utah emeritus professor Glenn Prestwich and UC Davis research scientist Karen Wagner also delivered presentations, fondly recalling their shared time and science with Hammock.
Keith Wing, who was Hammock's second graduate student at UC Riverside/Davis, served as emcee at the lab reunion. A former senior research associate at DuPont and Rohm and Haas and current consultant, Wing said “Bruce has inspired many hundreds of developing scientists. For myself and many others, he was able to see what we could become as scientists and social contributors before we could see it ourselves."
Qing Li, a professor in the University of Hawaii's Department of Molecular Biosciences and Bioengineering College of Tropical Agriculture and Human Resources who received his doctorate from UC Davis, studying with major professors Bruce Hammock and James Seiber, said that "Bruce is an eminent scientist and a great mentor. Many of us have benefited from his effective mentorship. Back in 1990, after he signed my dissertation, he shook my hand, and then he asked me to tape-record it and give him the recordings -- a great 'homework' assignment and good practices for me."
Others commented that they learned this from Hammock: “We explore the unexpected and get to do things that don't work” and “Design things to fail; when they don't fail follow along.”
Hammock, the crowd agreed, seems to follow baseball legend Yogi Berra's sage advice: “If you come to a fork in the road, take it.”
Gill praised Hammock's “impact on human health, environmental health” as well as his love of the outdoors—from kayaking to mountain climbing.
Numerous alumni lauded Hammock's sense of humor. One scientist quoted Albert Einstein as saying “Creativity is intelligence having fun” and added “Bruce is always having fun.”
Among the other comments:
- “I never heard him speak a cross word.”
- "He treats everyone with respect.”
- "Bruce loves science and he loves people.”
- "He never heard a crazy idea.”
- "What Bruce does—he delivers the future.”
- "Bruce has a lot of determination and can approach difficult problems from multiple angles.”
- "Bruce values strong relationships with friends he has made over the years”
A native of Little Rock, Ark., Hammock received his bachelor of science degree, magna cum laude, in 1969 from Louisiana State University, Baton Rouge, where he majored in entomology and minored in zoology and chemistry. Then it was off to UC Berkeley, for his doctorate in entomology/toxicology in 1973, and postdoctoral fellowship.
It was at UC Berkeley where he met and married his wife, Lassie, who had just entered the doctoral program in plant physiology. They married in 1972 and then “the Army called me up,” Hammock remembers.
Hammock served as a public health medical officer/first lieutenant with the U.S. Army Academy of Health Science in San Antonio, Texas; and then did more postdoctoral research at the Rockefeller Foundation, Department of Biology, Northwestern University, Evanston. Ill.
Hammock then joined the faculty of the Division of Toxicology and Physiology, UC Riverside Department of Entomology in 1975 before heading for UC Davis in 1980 to accept a joint-faculty appointment in toxicology and entomology.
Bruce and Lassie reared three children: Tom, Bruce and Frances. “Frances and her husband, Adrian, teach math at UC San Diego; Bruce is on the UC Davis School of Veterinary Medicine faculty; and Tom, a graduate of the American Film Institute Conservatory, makes movies,” Hammock said, adding that he and Lassie appeared in one of the movies that Tom directed: "The Last Survivors."
Highly honored by his peers, 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 scores of awards, including the Bernard B. Brodie Award in Drug Metabolism, sponsored by the America Society for Pharmacology and Experimental Therapeutics; and the first McGiff Memorial Awardee in Lipid Biochemistry.
Hammock told the crowd at the reunion that he began his career studying insect science but switched to human research after encountering “all the suffering involved in acute and neuropathic pain.”
His insect science research centered around how a key enzyme, epoxide hydrolase, degrades a caterpillar's juvenile hormone, leading to metamorphosis from the larval stage to the adult insect. He then wondered "Does the enzyme occur in plants? Does it occur in mammals?" It does, and particularly as a soluble epoxide hydrolase in mammals.
“It is always important to realize that the most significant translational science we do in the university is fundamental science,” said Hammock. “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.”
And it all began with him asking how caterpillars turn into butterflies.
"Science is full of surprises," the distinguished UC Davis professor said. "We need to remember that the concept, the clinical target, and even the chemical structure came from asking how caterpillars turn into butterflies."
“All my life I've known my feet didn't have the strength and capability of most of the people I knew,” she recalled.
In high school, she began experiencing severe pain. Her family physician diagnosed her as having “growing pains.”
It wasn't until after she'd retired from her 34-year career as an elementary school teacher in Concord that a neurologist correctly diagnosed her—and her brother--as having peripheral neuropathy, a disease that afflicts more than 30 million people in the United States alone. Specifically, she and her brother inherited Hereditary Sensory Autonomic Neuropathy or HSAN.
Anderson's journey to learn more about peripheral neuropathy and to help others led her to co-found the Western Neuropathy Association (WNA) in Auburn in 1998, and serve as its president for the last two decades.
Her 20-year journey of hope recently led to the University of California, Davis, where distinguished professor Bruce Hammock is researching an enzyme aimed at controlling acute and neuropathic pain.
Anderson and WNA treasurer Darrell O'Sullivan, a former lab manager at the UC Davis Medical Center, recently visited the Hammock lab to present a $5000 check from the association to EicOsis, the Davis company that Hammock founded to move inhibitors of the soluble epoxide hydrolase into human clinical trials.
“We raised the money through $2,500 from our budget, and from voluntary donations from members and friends,” she said. “One member donated $1000 and asked it to be matched.”
“It was heartwarming to receive a $5000 check from this dedicated, grass-roots group,” said Hammock, whose research on the compounds spans nearly 50 years. “We are touched.”
Anderson and O'Sullivan toured Hammock's lab in Briggs Hall, UC Davis Department of Entomology and Nematology, and discussed his research and the WNA mission and goals.
“There are medications that help the symptoms, but no cure yet,” Anderson said, adding that the Hammock discovery “may be close to a cure for some people who have pain and inflammation.”
"On behalf of EicOsis I want to thank the Western Neuropathy Association, and particularly Bev Anderson and Darryl O'Sullivan, for championing this effort," Hammock said. "Everyone at EicOsis is touched by the confidence they have put in us to develop a treatment for chronic pain. There are never guarantees in drug development, but certainly their support drives us to work hard to move this drug through FDA and on to clinical trials."
"We are, of course, working to raise support from federal agencies, venture funds and the pharmaceutical industry, but this support from Bev and her associates is heartfelt and inspiring. It illustrates what a great need there is to develop treatments for pain," Hammock said. "The fact that the support is coming from so many of the people who are suffering from pain is particularly inspiring."
"It is inspiring about how upbeat the individuals are in these organizations as they support each other and exchange approaches in dealing with pain," he pointed out. "But underlying these optimistic conversations is the reality that pain can be an overpowering factor compromising the leading a full and health life. We must find a solution to the problems of pain and neuropathy."
The clinical trials, expected to begin next year, will target chronic or neuropathic pain with a non-opiate analgesic. In parallel, Hammock and his UC Davis colleagues 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 traces the history of his work to 1969 to his graduate student days in the laboratory of UC Berkeley Professor John Casida. Hammock was researching insect developmental biology and green insecticides when he and colleague Sarjeet Gill, now a distinguished professor at UC Riverside, 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.”
Peripheral neuropathy is a complex disease. It refers to “the many conditions that involve damage to the peripheral nervous system, the vast communication network that sends signals between the central nervous system (the brain and spinal cord) and all other parts of the body,” according to the National Institute of Neurological Disorders and Stroke. “Best known are the signals to the muscles that tell them to contract, which is how we move, but there are different types of signals that help control everything from our heart and blood vessels, digestion, urination, sexual function, to our bones and immune system. The peripheral nerves are like the cables that connect the different parts of a computer or connect the Internet. When they malfunction, complex functions can grind to a halt.”
“There are over 150, some say over 200, known causes of neuropathy,” said Anderson, a resident of Colfax. “Diabetes is considered a chief cause. but chemotherapy and likely hereditary neuropathies are gaining on it.”
Although the peripheral neuropathy she has is HSAN, “there are10 or more hereditary types,” she said. “HSAN is unique in its early onset as I could have been diagnosed by kindergarten if medical science had been up to it then.” The neurologist who correctly diagnosed her told her she had “The neuropathy walk.”
“One aspect is that toes naturally go outward for better balance,” Anderson explained. “I call them my ‘outrigger toes.' With neuropathy, it usually starts with tingling like the foot is asleep and waking up and progresses into numbness. Pain of various types and intensities may follow. It boggles the mind to have feet so numb that surgery could be done on them without anesthesia but they still have pain. It depends on the amount of nerve damage.”
“There is a long list of other symptoms: sensory ones like feelings of hot or cold when the feet or hands are not hot or cold to the touch, deep itching, feeling like you are wearing a stocking or glove when you aren't, etc., motor ones like balance, and movement concerns, and autonomic ones that are internal as all internal organs are operated by peripheral nervous system. Blood pressure, kidney function, urinary tract, digestive system, sexual feelings, etc. are affected by the health of the nerves.”
Anderson noted that neuropathy “usually starts in the longest nerve which is the one that goes to the toes. When the progress gets up to the knees, it may start in the fingers and hands as that is now about the same length. However, it may also start in the hands if the injury that causes the neuropathy is in the cervical spine area initially. “
The mission of WNA, comprised of 500 members and many other attendees in California, Oregon and Nevada, is “to provide support, information and referral to people with neuropathy and to those who care about them, to inform and connect with the health care community and to support research,” Anderson said. The all-volunteer organization seeks to establish and develop support groups in as many cities as possible.
Highly honored for his work, Hammock is a member of the National Academy of Sciences and the National Academy of Inventors. He received an outstanding achievement award from the international Eicosanoid Research Foundation at its 2017 meeting in Puerto Vallarta, Mexico, where he delivered a plenary lecture on “Control of Acute and Neuropathic Pain by Inhibiting the Hydrolysis of Epoxy Fatty Acid Chemical Mediators: Path to the Clinic.”
Hammock's career took him from UC Berkeley to the U.S. Army Academy of Health Science in San Antonio, Texas; to a Rockefeller Foundation Fellowship at Northwestern University, Evanston, Ill., and to UC Riverside, where he served as an assistant and associate professor before he joined the UC Davis faculty in 1980. He holds a joint appointment with the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Center for Cancer Research.
Hammock collaborates with scientists worldwide in unprecedented research with a multidisciplinary, integrated approach to research focused on insect biology, mammalian enzymology, and analytical chemistry. He has authored more than 1000 publications on a wide range of topics in entomology, biochemistry, analytical and environmental chemistry in high quality journals. In the epoxide hydrolase field, the Hammock laboratory has published almost 900 peer-reviewed papers.
“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.”
The Hammock laboratory is the home of the UC Davis/National Institute of Environmental Health Sciences Superfund Program. The laboratory has generated more than 80 patents, 300 postdoctoral fellows, and more than 65 graduates, who now hold positions of distinction in academia, industry and government.
“It is always important to realize that the most significant translational science we do in the university is fundamental science,” said Hammock. “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.”
Bev Anderson and fellow members of WNA hope so, too. It's been a long journey, from misdiagnosis to rays of hope to bursts of optimism.
A newly published study by a team of scientists at Chiba University, Japan and at the University of California, Davis shows that inhibiting an enzyme, the soluble epoxide hydrolase (sEH), plays a key role in curbing the inflammation associated with the development and progression of Parkinson's disease, an age-related brain disorder that affects a million Americans, mostly 60 and over.
The research, published today in the Proceedings of the National Academy of Sciences, is primarily the work of scientists in the labs of Kenji Hashimoto, a professor with the Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan, and Bruce Hammock, UC Davis distinguished professor of entomology with a joint appointment in the UC Davis Comprehensive Cancer Center.
“Our research suggests that the sEH inhibitor may prevent the progression of Parkinson's disease (PD) as well as treat patients with dementia of Lewy bodies (DLB) if the sEH inhibitor is used in early phases of patients with these disorders,” said Hashimoto, whose career spans 30 years in the development of blood biomarkers and novel therapeutic drugs and includes more than 550 publications on the topic. “Both PD and DLB are chronic and progressive movement disorders. However, the precise causes of these diseases are largely unknown.”
Statistics indicate physicians diagnose 60,000 new cases of Parkinson's disease every year in the United States. The average age of onset is 60, and is more predominant among men.
Hammock said that the work by lead author Qian Ren and his colleagues in the Hashimoto lab “shows that markers and symptoms of Parkinson's disease in whole mice and in human cells with a mutation associated with Parkinson's disease can be treated with a small druglike molecule. By establishing this causal chain of events leading to Lewy body disorders we can better predict environmental chemicals that could predispose people to Parkinson's disease and possibly even treat the disease.”
The paper, titled “Soluble Epoxide Hydrolase Plays a Key Role in the Pathogenesis of Parkinson's Disease,” is co-authored by 14 scientists, including Professor Hammock and Jun Yang and Sung Hee Hwang, all part of the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center.
“Although there are many medications available to treat symptoms in PD, these do not prevent the progression of the disease, and, to date, no agent with a disease-modifying or neuroprotective indication for PD has been approved,” said Hashimoto. “Therefore, the development of new drugs possessing disease-modifying and /or neuroprotective properties is critical.”
In research studies involving mice, the scientists found “that sEH plays a key role in the inflammation associated with PD pathogenesis and the mechanisms that lead to the disease,” Hashimoto said. “The sEH inhibitor or deletion of the sEH gene protected against MPTP-induced neurotoxicity in mouse brain.” MPTP is an acronym for methyl-4-phenyl-1, 2, 3, 6 tetrahydropyridine, a relative of cyperquat and paraquat herbicides. “Our findings indicate that sEH inhibitors or epoxy fatty acids mimics may be promising prophylactic or therapeutic drugs for alpha-synuclein-related neurodegenerative disorders.”
Robert Higgins, emeritus professor of neuropathology at the UC Davis School of Veterinary Medicine, said: "I find it exciting that Ren and colleagues illustrate a promising path to a drug to prevent the progression of Parkinson's disease. It is impressive how far this work has come since we collaborated with Shirley Gee and the Hammock laboratory on developing a sheep model of Parkinson's disease in the early 1980s."
Neurosurgeon Cesar Borlongan of Morsani College of Medicine, University of South Florida, who was not involved in the study, praised the findings as advancing “our understanding of how Parkinson's disease evolves.” Describing Parkinson's disease as “a devastating brain disorder that mostly affects the aging population,” he said: “There is no cure, only relief from symptoms which include tremors, muscle rigidity, slurred speech, and freezing of gait.”
“While we know that a certain group of brain cells that produce dopamine are selectively destroyed in Parkinson's patients, what triggers this brain cell death remains poorly understood,” said Borlongan, a distinguished professor and vice chair for Research, Department of Neurosurgery and Brain Repair. “In their paper, the authors observed that a protein called soluble epoxide hydrolase (sEH) may be key to the demise of the brain dopamine cells. In small and large animal models of Parkinson's disease, and further confirmed in a group of PD patients, this protein is highly elevated in specific regions of the brain implicated in dopamine cell death.”
Borlongan pointed out that “Equally compelling evidence demonstrated that using a drug that inhibits sEH can reduce brain inflammation and levels of sEH and effectively lessen PD-associated toxicity in the animal models of the disease. Clinical trials of sEH inhibitors in heart and lung disease have been ongoing over the last decade, and may facilitate the entry of these drugs for PD. These results advance our understanding of how PD may evolve, but also point to its novel treatment.”
Qing Li, a professor in the Department of Molecular Biosciences and Bioengineering, College of Tropical Agriculture and Human Resources, University of Hawaii at Mānoa, who also was not involved in the study, called Parkinson's disease “a devastating neurodegenerative disorder that affects patients and caregivers alike with a significant economic burden in the United States and worldwide.”
This basic research drew support from several grants from Japan, including the Strategic Research Program for Brain Sciences, and at UC Davis, grants funded by the National Institute of Health's Institute of Environmental Health Sciences (NIH/NIEHS), and the NIEHS Superfund Program.
Hammock, a member of the National Academy of Sciences and the National Academy of Inventors, has directed the NIH/NIEH Superfund Program for more than 30 years.
Hammock said the soluble epoxide hydrolase inhibitors that inhibit the soluble epoxide hydrolase will soon enter human clinical trials supported by the NIH-NINDS Blueprint Program (NIH's Health's National Institute of Neurological Disorders and Stroke). “These drugs could provide relief for patients with a wide variety of inflammatory diseases,” he said.
The Hammock laboratory has published nearly 900 peer-reviewed papers on the sEH enzyme, discovered while Hammock and Sarjeet Gill (now of UC Riverside) were researching insect developmental biology and green insecticides at UC Berkeley. The work, begun in 1969, led to the discovery that many regulatory molecules are controlled as much by degradation as by biosynthesis, Hammock said. These epoxy fatty acid chemical mediators control blood pressure, fibrosis, immunity, tissue growth, and pain and inflammation.
To date, journals have published more than 17,000 peer-reviewed papers on the sEH enzyme and its inhibitors. Hammock credits the NIEHS for supporting his research in this area since the 1970s.
A Davis-based company, EicOsis, is developing inhibitors to sEH
to treat unmet medical needs in humans and animals. The company recently received a multi-million dollar grant from the NIH/NINDS Blueprint Program to move sEH inhibitors through phase I human clinical trials. “We are developing a non-opiate analgesic to treat the chronic pain often associated with diabetes,” said William Schmidt, vice president of clinical development at EicOsis. “Once we have investigational new drug status from the Food and Drug Administration and have finished our phase I trial, physicians will be able initiate their own trials with the EicOsis compound on Parkinson's disease and other Lewy body disorders.”
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.
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.
The National Institute of Environmental Health Sciences, National Institutes of Health, funded the research.
Highly honored by his peers, 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.