By Lisa Howard
UC Davis Health
See Video on YouTube (includes segment with Bruce Hammock, UC Davis distinguished professor)
Researchers at UC Davis are developing a new type of pain medication from an unusual source — tarantula venom.
The project is part of the NIH Helping to End Addiction Long-Term (HEAL) Initiative, aimed at ending opioid addiction and creating non-addictive therapies to treat pain.
Vladimir Yarov-Yarovoy, a professor of physiology and membrane biology, and Heike Wulff, a professor of pharmacology, are leading the 20-person team using computational biology to turn a poisonous peptide into one that can relieve pain. Peptides are smaller versions of proteins.
“Spiders and scorpions have millions of years of evolution optimizing peptide, protein and small-molecule poisons in their venom, which we can take advantage of,” said Bruce Hammock, a distinguished professor of entomology, who is working on the new pain reliever. “The same venoms that can cause pain and neurological dysfunction can also help nerves work better and reduce pain.”
Approximately 20 percent of adults in the U.S., around 50 million, are affected by chronic pain. About 11 million are affected by high-impact chronic pain, defined as pain that lasts three months or longer and restricts a significant activity, like being unable to work outside the home, go to school or do household chores.
A few non-opioid medications are available to help those with chronic pain, and complementary or integrative health approaches can help. In general, though, people with chronic pain have limited options for pain relief.
“For strong pain, drugs like ibuprofen or aspirin are just not strong enough. Opioids are strong enough, but they have the problem of tolerance development and addiction,” said Wulff.
Opioid addiction and misuse in the United States surged in recent years, leading to a significant health crisis. In 2019, nearly 50,000 people in the United States died from opioid-involved overdoses.
“What we need are new medications, new therapies with improved risk profiles,” said David Copenhaver, a member of the team and director of Cancer Pain Management and Supportive Care at UC Davis Health. “There's been a push to develop other, better, safer, less addictive — or zero addictive — medication and therapeutics for pain management,” said Copenhaver, who is also the associate director for the Center for Advancing Pain Relief at UC Davis.
“Channels” key to new pain reliever
To create a non-addictive but strong pain medication, the researchers are focused on pain signals traveling on sensory neurons. To stop these signals, they have targeted a particular type of protein “channel” found on the cell membranes of neurons and muscles.
These channels, called voltage-gated sodium channels, play a crucial role in generating signals to nerves and muscles.
Nine different types of these channels have been identified in humans. The sodium symbol is Na, so the voltage-gated channels are referred to as Nav1.1 through Nav1.9.
The Nav1.7 channel is the one that interests pain scientists the most because it is a key source of pain transmission.
That's where the tarantula venom comes in. A peptide — a type of protein — found in the venom of the Peruvian green velvet tarantula blocks Nav1.7, preventing it from transmitting signals, including those for pain.
“The promise of a Nav1.7 inhibitor is that we would have something that is as effective as an opioid, but not addictive,” said Wulff, who specializes in preclinical therapeutics development targeting ion channels.
The challenge with the protein in the tarantula venom is that it doesn't just block Nav1.7 channels in the sensory nerves. In its natural form, the peptide blocks all Nav1.7 channels, including those in the muscles and the brain, meaning that it could cause terrible side effects.
Engineering a non-toxic protein
To solve this problem, the researchers are using an approach known as “toxineering.” They are trying to engineer — modify — the toxin in the venom to block pain signals but not create unwanted side effects.
To do this, they are using a computer program developed by the University of Washington called Rosetta. The complex modeling software lets the team create many different iterations of the tarantula peptide, which they can then synthesize and test in the lab.
“Using the Rosetta software, we can take a natural peptide and then redesign it and make it into a therapeutic,” said Yarov-Yarovoy, an expert in computational structural modeling of peptide toxins. “Our lead peptides already show efficacy at the level of morphine, but without the side effects of opioids.”
Their preliminary results are extremely promising, but a lot of work remains to be done. The potential therapeutic candidates will need to be tested in animals, and if found safe, carefully tested in humans. The researchers estimate any new medication is at least five years away.
“What Vladimir has put together is really fantastic because no one scientist could have any hope of tackling a project that is this hard,” Hammock said about the 20-person team. “But having a collection of people makes it fun and exciting, and I think it gives us a real chance at relieving pain.”
Additional team members include Karen Wagner, Jon T. Sack, Theanne Griffith, Scott Fishmann, Hai Nguyen, Daniel J. Tancredi, Nieng Yan, William Schmidt, Andre Ghetti, Neil Castle, Michael Pennington, Phuong Tran Nguyen, Brandon Harris, Diego Lopez Mateos, Robert Stewart and Parashar Thapa.
The tarantula venom research at UC Davis is funded by a $1.5 million grant from NIH initiative Helping to End Addiction Long-Term (HEAL). FOA Number: RFA-NS-19-010
Lisa Howard, Health News Office
UC Davis Health
4900 Broadway, Suite 1200
Sacramento, CA 95820
The Staff Assembly will honor her and other award recipients at a ceremony in late summer or early fall, said Tasha Burr and Danielle Kehler, co-chairs of the Citations of Excellence Committee. McReynolds will receive a $1500 check.
“Our nominee, a 10-year UC Davis employee and longtime scientist with a master's degree in pharmacology and a bachelor's degree in animal science, excels at program management, research administration, and research itself,” wrote nominators Bruce Hammock, forensic entomologist Robert Kimsey and communications specialist Kathy Keatley Garvey.
“She was the lead author of research that may be ‘the missing link' as to why some COVID-19 patients recover and some don't,” they wrote. “Her innovative work on a blood plasma biomarker discovered in hospitalized COVID-19 patients may not only predict the severity of adult respiratory distress syndrome but further research may lead to inhibiting its progression. She initiated the collaborative research to test specialized pro‑resolving mediators (SPM) for their therapeutic potential against COVID-19 in a preclinical model at Rutgers University. This ongoing study is expected to provide ‘proof-of-concept' for a novel treatment to COVID-19.”
The trio pointed out that “her expertise includes grants management (applying and budgeting), organizing program outreach, coordinating training grants for trainees funded by a multi-million national grant, and mentoring students, whether in the lab or in the classroom. Our nominee goes above and beyond what is expected of her. Her supervisor says she is ‘the most amazing person I've ever met. For her entire career at UC Davis, she has been a phenomenal asset to the laboratory and campus. In her role in the laboratory, she oversees an accountant who handles the complex budget problems of the federally funded UC Davis Superfund Program Project. This multi-college, multi-principal investigator program has essentially five separate NIH grants, each of which itself is multi-departmental and multi-college supported by three cores.”
In addition, McReynolds also helped establish a community research program on human and environmental health in Northern California with the Yurok Indian Tribe, and a research translation program with several state agencies to identify STEM opportunities between UC Davis and surrounding communities.
Coordinated National Meeting
Hammock, who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center and for nearly four decades has directed the UC Davis Superfund Research Program (funded by the National Institutes of Health's National Institute of Environmental Health Sciences) noted that in 2019-20, McReynolds coordinated the national meeting of the Superfund Programs with multiple state and federal agencies. “She played an integral and critical role in submitting a competing renewal for years 30-35 of the program. This massive effort involved integrating multiple budgets across campus and coordinating with NIH, the campus research office, and multiple colleges.”
“On all of these projects, her knowledge of accounting and grantsmanship, coupled with her personal skills (always congenial and eager to help) proved critical,” Hammock said. “She was involved even to the point of editing specific objectives to make the projects more integrated, which relied on her knowledge as a scientist as well.” This was on top of being office manager for the large Hammock research laboratory involving a team of multiple disciplines.
“During this time, she served as both the lab manager and the accountant/business manager, replacing a retiree,” Hammock noted.
The nominators pointed out that McReynolds is a doctoral candidate (now PhD graduate), wife, mother of two, and a community volunteer. Known for sharing her scientific expertise, she organized a “Science Day” with UC Davis and Davis primary schools; organized speakers for “Meet a Scientist”; judged Davis science fairs; helped struggling high school students with their science projects; and coached the Davis Youth Robotics Team.
“She balances her multiple difficult tasks with skill, efficiency and good humor,” the nominators wrote. “She is always eager to help, even to transporting a colleague's newly eclosed, out-of-season monarch butterfly to an overwintering site in Santa Cruz!”
'Brilliant Researcher and Wonderful Instructor'
Kimsey praised her work in teaching and mentoring students in his animal biology classes. “She has not only made their time and efforts highly productive in the research arena, but provides effective counseling on their career trajectories, how to balance personal life, kids and family with university life,” Kimsey said. “She is not only a brilliant researcher, a wonderful instructor for undergraduates that enter the laboratory, but is a dedicated and caring mentor. Her principal investigator has stated that she is possibly the most amazing person he has ever met. I very certainly concur in all regards.”
McReynolds, who received her doctorate in pharmacology and toxicology in June, initially sought a career as a veterinarian. She received her bachelor's degree in animal science from UC Davis in 1999, and her master's degree in animal science from Washington State University, Pullman, in 2001.
“After receiving a master's degree in animal science, I quickly realized that I had an interest and passion for understanding the roles of nutrition and environment on disease outcomes in both human and animal health,” McReynolds related. “Instead of continuing my research career in animal science, I left to gain experience in development therapeutics for humans and animals. My work in understanding the role of bioactive lipid mediators began in 2006 when I joined Arete Therapeutics, South San Francisco, as project manager to advance soluble epoxide inhibitors through clinical trials for treating hypertension. After leaving Arete, I joined Dr. Hammock's laboratory as a research administrator where I gained important experience in project management, budgeting and grants administration. Once my children were old enough to accommodate the often-inconsistent schedule of laboratory work, I continued my career goals of becoming a PhD scientist.”
McReynolds traced her interest in scientific research to her “formative years in a small town in western Kentucky, cataloging observations of animals in a notebook.”
Understanding the Roles of Lipid Mediators
McReynolds has studied the biological activity of lipid mediators for the past 12 years. “My current efforts focus on understanding the roles of lipid mediators in inflammation especially relating to pain and degenerative disease,” said McReynolds, who is a member of the American Society for Pharmacology and Experimental Therapeutics and the American Chemical Society. “My research focuses on developing tools for use in in vitro and in vivo knockout studies to understand their role in inflammation with a focus on mechanism of pharmacokinetics.”
McReynolds said her “career aspirations are to lead collaborative research programs that will use science to improve overall health outcomes by developing disruptive treatment or diagnostic capabilities to predict early responders/nonresponders to therapies,” she said, adding that “I approach problems and challenges now, not with a pass/fail approach, but with an understanding of how to address the problem at hand.”
“In my career, I strive to make significant contributions in advancing science to understand disease so that there are better treatment options for everyone; I strive to provide encouragement to women struggling to balance a family and career, to lead by example that it is possible to be a mom and scientist; I strive to motivate others, as I have been motivated by my mentors, that their fears are not too big to prevent them from reaching their goals; I strive to create a positive, collaborative work environment. Ultimately, I strive to share my enthusiasm for science and learning as well as unique background to advance a basic understanding of biology that will benefit global health outcomes for all.”
The Staff Assembly's annual awards program provides recognition for individual staff and staff teams “who have demonstrated outstanding achievement that go above and beyond the requirements outlined in their position descriptions.” Staff Assembly presents Individual awards in the categories of innovation, research, service, supervision and teaching; and team awards for project or program staff, office staff, or other similar groups.
In announcing the Horizon Team Award on June 8, the Royal Society of Chemistry (RSC) applauded the 47 worldwide collaborators “for the development of multidimensional click chemistry, a next-generation click-technology that extends perfect bond creation into the three-dimensional world, opening doors to new frontiers in biomedicine, materials science, and beyond.” (See list of winners. See Horizon Team award winners)
K. Barry Sharpless of the Scripps Research Institute in La Jolla, who won the 2001 Nobel Prize for Sharpless epoxidation, led the team. “His magic is like the click- chemistry he invented,” said Hammock, who holds a joint appointment with the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center.
The scientists from UC Davis also include researcher Christophe Morisseau of the Hammock lab and Seiya Kitamura, who completed his doctorate in the UC Davis Pharmacology/Toxicology Graduate Group working with Hammock and Morisseau before starting a postdoctoral position at Scripps Research Institute in La Jolla.
Morisseau described click-chemistry “as such a ubiquitous tool in multiple aspects of science that kits are sold and the chemistry utilized without even recognizing where it comes from. Many of the beautiful and informative fluorescent pictures of cells on journal covers are based on click chemistry.”
The list of the team members reads like a Who's Who of modern organic chemistry at multiple stages of their careers, Hammock noted.
Hammock said his involvement in click chemistry started when he was on sabbatical leave at UC San Diego. “Barry explained to me how one could use the SF bonds of SOF4 and related compounds to make additions one at a time and create a defined three-dimensional molecule with high precision. The potential of these reagents to design new pharmaceuticals and agricultural products was really exciting. Thus, our contribution was being there at the right time to show translation into the real world.”
“Seiya did amazing work showing the utility of this reaction,” Hammock said. “He is continuing to work with Drs. Wang and Morisseau at UC Davis on using another concept in modern medicinal chemistry called PROTAC to investigate cell biology.”
“Click-chemistry and particularly the copper-catalyzed azide-alkyne-Huisgen cycloaddition (CuAAC), has had a profound impact on drug discovery (for which it was intended),” the team wrote in the award packet. “It is now the 'go-to' technology in every corner of molecular science. The introduction of Sulfur(VI) fluoride exchange (SuFEx) in 2014 opened up a whole new world of possibilities for reliable bond-forming technology, particularly for chemical biology applications where the fugacity of sulfur-fluoride functional groups are primed for selective covalent bond formation with active protein sites.”
The team will receive a trophy and each member will receive a certificate. John Moses of the Cancer Center, Cold Spring Harbor Laboratory, New York, submitted the nomination on behalf of the team.
The RSC Horizon Prizes “highlight the most exciting, contemporary chemical science at the cutting edge of research and innovation,” according to its website. “These prizes are for teams or collaborations who are opening up new directions and possibilities in their field, through ground-breaking scientific developments."
The mission of the London-based RSC, founded in 1841, is to advance excellence in the chemical sciences. The organization includes physicians, academics, manufacturers and entrepreneurs. Dialysis inventor Thomas Graham served as its first president.
- Bruce Hammock: Lifetime Achievement Award from Chancellor
- Why Science Is Fun (feature on Bruce Hammock)
A blood plasma biomarker discovered in hospitalized COVID-19 patients may not only predict the severity of adult respiratory distress syndrome (ARDS) but further research may lead to inhibiting the progression, a team of eight University of California researchers announced today.
The UC researchers, primarily from the laboratory of UC Davis distinguished professor Bruce Hammock, 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 compounds, known as leukotoxins and leukotoxin diols, originate from linoleic acid, the body's most abundant dietary fat, said Hammock, who holds a joint appointment in the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center and directs the National Institute of Environmental Health Sciences (NEIHS) Superfund Research Program at UC Davis. “The leukotoxins (also called EpOMEs) are converted to the leukotoxin diols (also called DiHOMES) by the soluble epoxide hydrolase we work on.”
“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.”
Professor John Imig, director and eminent scholar of the Medical College of Wisconsin's Drug Discovery Center, who was not involved in the study, said: “The COVID-19 pandemic has demonstrated that coronaviruses can have deadly consequences. Lung distress is a major reason for death in COVID-19 patients infected with the coronavirus (SARS-CoV-2). The findings of McReynolds et al. identified lipids called leukotoxin diols in the blood of COVID-19 patients that could act as a biomarker for lung distress. In addition, leukotoxin diols could be responsible for lung distress in COVID-19 patients. Excitingly, this suggest that therapies to lower leukotoxin diols could treat lung distress and prevent death in COVID-19 patients.”
“The findings presented in this paper bring important attention to a role for oxylipin metabolites in COVID-19 infections,” said Professor A. Daniel Jones of Michigan State University's Department of Biochemistry and Molecular Biology and director of the university's Research Technology Facility's Mass Spectrometry and Metabolomics Core. “Most notably, metabolites known as DiHOMEs which have been previously implicated in lung inflammation show promise for their potential to predict outcomes in COVID patients and guide therapeutic, and perhaps dietary interventions beneficial to human populations.” Jones, who was not involved in the study, serves as secretary of the Metabolomics Association of North America.
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.
Lipid metabolism researcher Ameer Taha of the UC Davis Department of Food Science and Technology pointed out that linoleic acid is an essential fatty acid present in only small amounts in our evolutionary diets. “In addition to nutritional and structural roles of linoleate, minor linoleate metabolites including the leukotoxin diols (also known as DiHOMEs) regulate a number functions including body temperature, cardiac health and vascular permeability. This study cautions that now with dietary linoleate levels at an all-time high, in periods of high stress as with COVID-19, these regulatory functions may become detrimental.”
The paper is the work of Hammock, McReynolds and Jun Yang 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.
“This study resulted from an exciting collaboration with Imran Khan and Angela Haczku of the UC Davis School of Medicine to identify potential biomarkers for differentiating the severity of COVID-19 diseases,” said Yang, the corresponding author.
The research drew financial support from several National Institutes of Health agencies: National Institute of Environmental Health Sciences (NIEHS) Superfund Research Program and R35 grant, National Institute of General Medical Sciences (NIGMS),and the National Institute of Mental Health (NIMH).
- EicOsis: Developing a New Approach to Treat Pain
- Bruce Hammock: Lifetime Achievement Award from the Chancellor
- Cindy McReynolds Receives Major NIH Training Grant
- Cancer Team's Research Paper Named Journal of Clinical Investigation's Editor's Pick (Includes Bruce Hammock and Jun Yang)
- Bruce Hammock at firstname.lastname@example.org
- Cindy McReynolds at email@example.com or firstname.lastname@example.org
- Jun Yang at email@example.com
The American Entomologist announced the award in a recent edition.
Bonning serves as the Davies, Fischer and Eckes Eminent Scholar Chair and director of the Center for Arthropod Management Technologies (CAMTech), a National Science Foundation Industry/University Cooperative Research Center.
A 1990-1994 postdoctoral research associate in the Bruce Hammock lab, where she researched genetic engineering and optimization of baculovirus insecticides, Bonning is the third Hammock lab recipient of the prestigious PBT award. Hammock, now a UC Davis distinguished professor who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center, won the award in 1998, the second year of its presentation. Thomas Sparks, Hammock's first graduate student, received it in 2018.
“During the course of her career, Dr. Bonning has made significant advances in (1) fundamental understanding of stink bug digestive physiology, (2) the genetic optimization of baculovirus insecticides, (3) novel approaches for the development of insect resistant transgenic plants,” wrote the nominating team, which included Hammock.
“We were together for a year in Oxford, making the first recombinant baculoviruses," Hammock related. Following her postdoctoral appointments at the Natural Environment Research Council Institute of Virology in Oxford, UK and at UC Davis, Bonning joined the faculty at Iowa State University, serving from 1994 to 2017 when she accepted her current position in Florida.
"Her husband, Jeff Beetham, got his PhD. with me in biochemistry," Hammock said, "and worked on recombinant baculovirus pesticides and cloned and expressed the human soluble epoxide hydrolase, among other projects.”
Recalling the years they were at UC Davis, Hammock commented that he, Bonning and Beethan and the late Sean Duffey (1943-1997) "and crew used to run 5 to 7 miles four times a week." At the time of his death, Duffey was serving as vice chair of the entomology department.
The PBT award is based on research contributions, quality and originality of research; quality of publications; evaluation by colleagues peers and constituents;impact of research findings on the understanding of the subject; participation and leadership in honor and professional societies; and awards, honors and special recognitions.
Chemical ecologist Walter Leal, UC Davis distinguished professor, Department of Molecular and Cellular Biology, and a former chair of the entomology department, received the PBT award in 2008. The list of previous award winners is here.
The 7000-member Entomological Society of America, founded in 1889, is comprised of educators, extension personnel, consultants, students, researchers, and scientists from agricultural departments, health agencies, private industries, colleges and universities, and state and federal governments.