Of the more than 30 million cases of COVID-19 in the United States, 547,000 people have died. They are not numbers: they represent family, friends, co-workers, colleagues, neighbors and acquaintances who have succumbed to this tragic disease.
And today Dr. Rochelle Walensky, director of the Centers for Disease Control and Prevention (CDC) warns of another surge. Our nation, she says, shows a seven-day average of about 57,000 new COVID-19 cases per day, a 7 percent increase over the last week.
A burning question: Why do some COVID-19 patients recover and some don't?
The laboratory of UC Davis distinguished professor Bruce Hammock, who holds joint appointments with the Department of Entomology and the UC Davis Comprehensive Cancer Center, may have just pinpointed why.
The team of eight UC researchers, primarily from the Hammock lab, found that four compounds in the blood of COVID-19 patients are highly associated with the disease. Their paper, “Plasma Linoleate Diols Are Potential Biomarkers for Severe COVID-19 Infections,” is published as open access in the current edition of Frontiers in Physiology.
ARDS, characterized by fluid build-up in the lungs, is the second leading cause of death in COVID-19 patients, next to viral pneumonia, according to the National Center for Biotechnology Information.
“Different outcomes from COVID-19 infections are both terrifying from a human health perspective and fascinating from a research perspective,” said UC Davis lead author and doctoral candidate Cindy McReynolds of the Hammock lab. “Our data provide an important clue to help determine what impacts the severity of COVID-19 outcomes. Initially, we focused on the immune response and cytokine profile as important drivers in severity, but considering what we now know from our study and others in the field, lipid mediators may be the missing link to answering questions such as why some people are asymptomatic while others die, or why some disease resolves quickly while others suffer from long-haul COVID.”
“The hypothesis advanced in this paper is that because the leukotoxins have been associated with serious illness and death in humans and dogs and the symptoms are those of adult respiratory distress syndrome, these compounds are biomarkers of pulmonary involvement in COVID-19,” Hammock said. “We also think that it is the conversion of leukotoxin to the toxic leukotoxin diol that causes pulmonary and perivascular edema and this could be leading to the respiratory complications.”
“So the leukotoxins and leukotoxin diols,” Hammock said, “are indicators of respiratory problems in COVID-19 patients as plasma biomarkers. They also present a pathway for reducing ARDS in COVID-19 if we could inhibit the soluble epoxide hydrolase, a key regulatory enzyme involved in the metabolism of immune resolving fatty acids.”
The UC Davis scientists used clinical data collected from six patients with laboratory-confirmed SARS-CoV-2 infection and admitted to the UC Davis Medical Center, Sacramento, and 44 healthy samples carefully chosen from the healthy control arm of a recently completed clinical study.
The Hammock lab's 50-year research on soluble epoxide hydrolase (sEH) and its inhibitors led the professor to found and direct EicOsis Human Health, a Davis-based company that is developing a potent soluble epoxide hydrolase inhibitor for pain relief. Epoxy fatty acids control blood pressure, fibrosis, immunity, tissue growth, depression, pain, inflammation and other processes.
But more recently, the Hammock lab has turned its attention to using sEH as a means to resolve inflammation associated with COVID-19 and the fibrosis that can follow.
The paper is the work of Hammock, McReynolds and Jun Yang (corresponding author) of the Department of Entomology and Nematology and EicOsis Human Health; Irene Cortes-Puch of the Department of Entomology and Nematology, EicOsis Human Health, and the Department of Internal Medicine's Division of Pulmonary Critical Care and Sleep Medicine; Resmi Ravindran and Imran Khan of the Department of Pathology and Laboratory Medicine; Bruce G. Hammock of UC Davis Department of Veterinary Medicine, Aquatic Health; and Pei-an Betty Shih of the UC San Diego Department of Psychiatry.
See the news story on the Department of Entomology and Nematology website at https://bit.ly/3lSWbwf
Yes, that's UC Davis distinguished professor Bruce Hammock "resting" in a hammock on the UC Davis campus.
But as his family, friends, students and colleagues can testify, the indefatigable professor, inventor, researcher, scientist, author, CEO and athlete does not rest...much less rest in a hammock!
Cindy McReynolds of the Hammock lab, a UC Davis doctoral student in pharmacology/toxicology, coaxed him to pose for that image when some of the Hammock lab folks were heading across campus (before the coronavirus pandemic precautions).
And now we're delighted to see that Hammock, internationally recognized for his work in alleviating inflammatory and neuropathic pain in humans and companion animals--and known as the founder of the field of environmental immunoassays--is the recipient of the prestigious Lifetime Achievement Award in Innovation, part of the 2020 Chancellor's Innovation Awards.
An honor well-deserved!
The annual campuswide award honors researchers who have made a long-term positive impact on the lives of others and who inspire other innovators. It is one of several awards announced June 15 in a program managed by the Office of Research. (See recipients.)
“Research universities like UC Davis play a critical role in advancing innovative solutions for the global community that not only stimulate our economy but create a better quality of life,” said Chancellor Gary S. May in a news release. “The recipients of this year's awards demonstrate the impact of reaching beyond what is expected to deliver game-changing innovations that address some of the world's most critical issues.”
Hammock, who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center, co-discovered a human enzyme termed Soluble Epoxide Hydrolase (sEH), a key regulatory enzyme involved in the metabolism of fatty acids. It regulates a new class of natural chemical mediators, which in turn regulates inflammation, blood pressure and pain. Hammock and his lab have been involved in enzyme research for more than 50 years.
UC Davis recently licensed certain patents exclusively to EicOsis that support the underlying technology.
Hammock traces the history of his enzyme research to 1969 to his graduate student days in the John Casida laboratory, UC Berkeley. 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.
“My research 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, depression, pain and inflammation to name a few processes.”
The National Institute on Drug Abuse awarded a $15 million HEAL grant (Helping to End Addiction Long-term Initiative) to EicOsis in 2019 to support human clinical trials of a novel compound that has been found effective for the treatment of pain in preclinical animal studies.
In 2019, Hammock received a $6 million “outstanding investigator” federal grant for his innovative and visionary environmental health research. His pioneering work on inflammation not only extends to alleviating chronic pain, but to targeting inflammation involved in cancer, cardiovascular diseases, diabetes and other health issues.
EicOsis won the Sacramento Region Innovation Award in the Medical and Health category in 2019.
More recently, Hammock has turned his attention to using sEH as a means to control the deadly cytokine storm associated with COVID-19.
A member of the UC Davis faculty since 1980, Hammock 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, supporting scores of pre- and postdoctoral scholars in interdisciplinary research in 5 different colleges and graduate groups on campus. He is a fellow of the National Academy of Inventors and the National Academy of Sciences, and the Entomological Society of America. He is the recipient of scores of awards, including the first McGiff Memorial Awardee in Lipid Biochemistry; and the Bernard B. Brodie Award in Drug Metabolism, sponsored by the America Society for Pharmacology and Experimental Therapeutics. At UC Davis he received the Distinguished Teaching Award and the Faculty Research Lectureship.
He has authored or co-authored more than 1,200 peer-reviewed publications and holds more than 95 patents in agriculture, environmental science and medicinal chemistry.
Hammock is known for his expertise in chemistry, toxicology, biochemistry and entomology. Earlier in his career, he founded the field of environmental immunoassay, using antibodies and biosensors to monitor food and environmental safety, and human exposure to pesticides. His groundbreaking research in insect physiology, toxicology led to his development of the first recombinant virus for insect control.
As director of the UC Davis Superfund Research Program, he pioneered trans-disciplinary research across campus, engaging faculty in multiple colleges and schools “to transform the way we treat diseases in multiple species.”
A native of Little Rock, Ark., Hammock 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. 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.
In the Army, Hammock served as a medical officer at Fort Sam, Houston, and what he saw--severely burned people in terrible pain--made a lasting impression on him and steered him toward helping humankind.
The rest, as they say, is history: "his story" that is drawing worldwide attention.
So begins Marlin Rice, author and a past president of the Entomological Society of America (ESA), in his wonderful and comprehensive piece in the current edition of ESA's American Entomologist about the legendary Bruce Hammock.
His story begins in Arkansas.
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.
The headline says it well: "Bruce D. Hammock: Science Should Be Fun."
Hammock describes his Tom Sawyer-like childhood in Little Rock, where he wandered the woods and collected animals.
Rice asked him: "What was your favorite thing to collect?"
"I just liked interested creatures," Hammock told him. "I had a pet 'coon, pet deer, pet 'possums named Sears and Roebuck. The two 'possums had stolen some hot dogs at a Boy Scout jamboree and were trying to make their escape. This guy was going to kill them, so I took them home."
"I found Willy—his mom had been killed by hunters—in a tree stump and bottle-raised him with an old toothless bulldog, and he would ride around on her back. Raccoons and dogs are natural enemies. If an [unfamiliar] dog would growl at him, Willy would try to kill it, so he was not popular."
Young Tom went on to become an Eagle Scout and graduate from Louisiana State University. "I liked football, but I was not good at it," he recalled. "But I was upset with the football craziness in Arkansas, so I thought I could go to LSU and get away from it, but I ended up living underneath the football stadium."
In the Army, he served as a medical officer at Fort Sam, Houston, and what he saw--severely burned people in terrible pain--made a lasting impression on him. Today he's deeply involved in his research at UC Davis and the company he founded, EicOsis, in 2011 to alleviate pain in humans and companion animals.
Of EicOsis, he told Rice: "It's actually three companies: human health, equine health, and companion animal health. The human health goal is moving the drug into the clinic to treat human neuropathic pain. In dogs and cats and horses, it turns out that non-steroidals, like aspirin, are so much more toxic. If you give your dog some non-steroidals, you're saying you want your dog to be pain-free for a year, but you know you're killing it. Some non-steroidals are so toxic to non-primates that there's a real opportunity to get epoxide hydrolase to the clinic."
Excerpts from the article:
- Little did we know: While in Warsaw to attend a scientific meeting, Professor Hammock was arrested in Poland on suspicion of being a spy and spent six hours in jail.
- What does he look for in researchers hoping to join his lab? "Curiosity. And then there's this: If science is not fun, then it shouldn't be done. And if they enjoy science then they probably will be successful."
- Why did he leave UC Riverside for UC Davis? "Smog. [But] I absolutely loved Riverside. At the time, it was the largest entomology department in the world. It was just wonderful. And it was in the desert and I loved the desert. And I like rattlesnakes, and there is no shortage of rattlesnakes. They're not very pettable, but they're interesting. I've been bitten a lot of times by non-poisonous snakes. I thought I was fast, but snakes were faster. So I never kept a rattlesnake more than a few hours."
- His parents? His father was a postal worker and his mother sold World Book encyclopedias "and was convinced that if you bought World Book, you would be brilliant."
Indeed, Bruce Hammock's career is incredible--incredibly focused, superlative and kind. But he also has a finely honed sense of humor. Who else would launch an annual water balloon battle? He started it in 1980 on the Briggs Hall lawn, just outside his office. It's now called the Bruce Hammock Lab Water Balloon Battle or "Bruce's Big Balloon Battle at Briggs."
"A few years ago, we had the management officer in biochemistry upset because she thought it was unseemly for the university," Hammock told Rice. "Last year, somebody called the police on us, and the police came, and the guy took off his gun belt and joined us. [Laughs.] That was fun!"
So is science. Or it ought to be.
Some Related Links:
- Bruce Hammock and EicOsis, Innovator of the Year
- Bruce Hammock Receives $6 Million Grant
- Bruce Hammock Water Balloon Battle: 15 Minutes of Aim
- Research Could Lead to Drug to Prevent or Reduce Autism, Schizophrenia
- Hammock Lab Union Draws 100 Scientists from 10 Countries
- Bruce Hammock: Scientist Extraordinaire
And now, the company he founded, EicOsis LLC, to develop a non-opiate drug to relieve inflammatory pain in companion animals and target chronic neuropathic pain in humans and horses, can 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. (See more information on YouTube (the EicOsis award presentation starts at 1:05.)
“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.”
A member of the UC Davis faculty since 1980, Hammock received his doctorate in entomology and toxicology from UC Berkeley, where he studied insect science. He now devotes his research to human health.
What many people do not know, however, is that he began his career studying how caterpillars turn into butterflies.
That morphed into human health research.
“The work led to the discovery that many regulatory molecules are controlled as much by degradation and biosynthesis,” Hammock related. “The epoxy fatty acids control blood pressure, fibrosis, immunity, tissue growth, pain and inflammation to name a few processes.”
Fast forward to today.
An enzyme inhibitor developed in the Hammock lab 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.
What the Inhibitor Did
"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).
The news embargo lifted today (March 18) on their research, to appear in the Proceedings of the National Academy of Sciences (PNAS). (Link will be here: https://www.pnas.org/cgi/doi/10.1073/pnas.1819234116.) It's 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.
Reversed Cognitive and Sciatl Interaction Deficiencies
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.
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.”
“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.
Autism: 1 of 68 Children
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.
Schizophrenia: 1.2 Percent of Population
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.
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.
Exciting and Productive
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.
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.”