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
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.”
What do you get?
An epic battle during the 15th annual Bruce Hammock Lab Water Balloon Battle on the Briggs Hall lawn at the University of California, Davis.
Who won? It was not distinguished professor Bruce Hammock, who holds a joint appointment with the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center.
It was undergraduate student Andrew Kisin of the lab of Aldrin Gomes, UC Davis Department of Neurobiology, Physiology and Behavior.
Hammock, clutching three water balloons, didn't stand a chance as Kisin raced toward him with a container full of water. The rest is history. Drenched history.
The annual battle amounts to 15 minutes, or "15 Minutes of Aim." That's how long it takes for the some 40 participants to toss 2,000 water balloons. Currently 28 researchers--from the United Staes, China, France, Ukraine, Lebanon, Japan and Korea--work in the Hammock lab. They include postdoctoral scholars, researchers, graduate students, visiting scholars, visiting graduate students, visiting summer students, short-term visiting scholars and student interns.
Trained as a entomologist, chemist and toxicologist--and who now focuses his research on human health, Bruce Hammock is known for his work on using natural chemical mediators to control inflammation and intractable pain. He co-discovered the soluble epoxide hydrolase, and many of his more than 1100 publications and patents are on the P450 branch of the arachidonate cascade where the soluble epoxide hydrolase (sEH) degrades natural analgesic and anti-inflammatory compounds.
Kisin, a second-year UC Davis student from San Jose, just enrolled at UC Davis a week ago. Majoring in biological sciences, he joined the Gomes lab to study "the effects of drugs such as ibuprofin on organs and may also study how proteasomes contribute to aging."
The annual event is open to all UC Davis personnel and their families. They fill the balloons, toss them and clean up the remnants--and then look forward to next year's battle.
Odds are that you won't find many water warriors like Bruce Hammock, whose credentials rival noted academicians worldwide. A native of Little Rock, Ark., who holds a doctorate from UC Berkeley, Bruce joined the UC Davis faculty in 1980. He is the founding director (1987-present) of the UC Davis NIEHS (National Institute of Environmental Health Sciences) Superfund Research Program and is a founding member (1990-present) of the UC Davis Comprehensive Cancer Center. He has directed the UC Davis NIH/NIEHS Combined Analytical Laboratory for 25 years.
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 is the first McGiff Memorial Awardee in Lipid Biochemistry. The Eicosanoid Research Foundation recently honored him for work on oxidized lipids.
But on one day in July--for 15 minutes--Bruce Hammock turns from academician to water warrior. And yes, he's excels at that, too! See what happened to his doctoral student Cindy McReynolds in one of the photos below.
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.