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
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)
The Multistate Research Fund supports agricultural innovation and sustainability by providing federal funds to collaborative research projects led by State Agricultural Experiment Stations and land-grant universities. These projects bring together scientists, Extension educators, and other university, federal, and industry partners to tackle high-priority regional or national issues in agriculture, a spokesman said.
Under the category, “Researchers studied chemical cues that mediate interactions among plants, pests, and predators,” UC Davis (Karban) is credited with identifying “the sagebrush cues that trigger resistance against chewing herbivores” and also finding that “plant cue effectiveness is affected by the geographic proximity of the source of the cue.”
Under the category, “Researchers used chemical ecology to protect pollinators from pesticides and disease,” UC Davis (Vannette) is credited with identifying “floral chemistry traits and microbial communities that affect the patterns or preferences of hummingbirds, honey bees, and carpenter bees.”
Professor Karban, an international authority on plant communication, is the author of the landmark book, Plant Sensing and Communication (University of Chicago Press).
Karban has researched plant communication in sagebrush (Artemisia tridentata) on the east side of the Sierra since 1995. His groundbreaking research on plant communication among kin, published in February 2013 in the Proceedings of the Royal Society B: Biological Sciences, drew international attention. In that study, Karban and his co-researchers found that kin have distinct advantages when it comes to plant communication, just as “the ability of many animals to recognize kin has allowed them to evolve diverse cooperative behaviors.”
Karban is a fellow of Ecological Society of America and the American Association for the Advancement of Science (AAAS). Michael Pollan featured him in the Dec. 23-30, 2013 edition of The New Yorker: “The Intelligent Plant: Scientists Debate a New Way of Understanding Plants."
Vannette, an assistant professor who joined the UC Davis Department of Entomology and Nematology in 2015 after serving as a postdoctoral fellow at Stanford University's biology department, seeks to unlock the mysteries of flower microbes: how do plants protect against them, and can bees benefit from them?
The Vannette lab is a team of entomologists, microbiologists, chemical ecologists, and community ecologists trying to understand how microbial communities affect plants and insects (sometimes other organisms too). “We often study microbial communities in flowers, on insects or in soil,” according to her website. “We rely on natural history observations, and use techniques from chemical ecology, microbial ecology and community ecology. In some cases, we study applied problems with an immediate application including pathogen control or how to support pollinators. Other questions may not have an immediate application but are nonetheless grounded in theory and will contribute to basic knowledge and conservation (e.g. how can dispersal differences among organisms affect patterns of abundance or biodiversity?).
All plants are colonized by microorganisms that influence plant traits and interactions with other species, including insects that consume or pollinate plants, Vannette explains. “I am interested in the basic and applied aspects of microbial contributions to the interaction between plants and insects. I also use these systems to answer basic ecological questions, such as what mechanisms influence plant biodiversity and trait evolution.”
“Much of the work in my lab focuses on how microorganisms affect plant defense against herbivores and plant attraction to pollinators. For example, we are interested in understanding the microbial drivers of soil health, which can influence plant attractiveness to herbivores and the plant's ability to tolerate or defend against damage by herbivores. In addition, we are working to examine how microorganisms modify flower attractiveness to pollinators. This may have relevance in agricultural systems to improve plant and pollinator health.”
Vannette, who holds a doctorate in ecology and evolutionary biology (2011) from the University of Michigan, was selected a UC Davis Hellman Fellow in 2018.
Her recent research grants include two from the National Science Federation (NSF). One is a five-year Faculty Early Career Development (CAREER) Program award, titled “Nectar Chemistry and Ecological and Evolutionary Tradeoffs in Plant Adaptation to Microbes and Pollinators.” The other is a three-year collaborative grant, “The Brood Cell Microbiome of Solitary Bees: Origin, Diversity, Function, and Vulnerability.”
Entomological offerings will be showcased at the 107th annual UC Davis Picnic Day, themed "Discovering Silver Linings," to take place virtually on Saturday, April 17.
Silver linings promise to grace this family-oriented event, billed as informative, educational and entertaining.
Picnic Day officials have released the schedule of events that includes entomological exhibits and talks from the UC Davis Department of Entomology and Nematology, Bohart Museum of Entomology and the UC Davis Graduate Student Association.
Here's a quick list:
Bohart Museum of Entomology
Bohart associate Greg Kareofelas, Bohart Museum associate and naturalist, has created a pre-recorded video on the Gulf Fritillary butterfly, Agraulis vanillae. These orange-reddish butterflies have silver-spangled underwings, are glorious. Kareofelas will showcase them and show you how to rear them, which is what he did last year during the pandemic. It's on YouTube at https://www.youtube.com/watch?v=OR3WwE7mbrA.
Entomologist Jeff Smith, the volunteer curator of the Lepidoptera collection at the Bohart, will present a live Zoom event from 1 to 2 p.m. on Saturday on mimicry in Lepidoptera (moths and butterflies). "I will briefly mention camouflage," Smith says, "and spend most of the time on mimicry for defense--mimics of toxic or distasteful species, mimicry using odors or sounds, mimics of snakes or spiders, and mimics of non-food materials such as bird feces."
To connect, access https://ucdavis.zoom.us/j/92841203978?pwd=ay91SUpFZnl5MEdnVmlzOUxmMFFZQT09
Zoom Meeting ID: 928 4120 3978
Zoom Passcode: 160485
"People who want to submit their questions to Jeff or request to see certain species from the collection can email their requests to email@example.com with Picnic Day in the subject," says Tabatha Yang, the Bohart Museum's education and outreach coordinator. "We won't have the time or capacity to access the collection during the event for any requests. Instead, we will pull the items that are requested or relevant to the talk and have those prepared to show. Of course we may not be able to honor everyone's request, but we will do our best."
The Bohart Museum, located in Room 1124 of the Academic Surge Building on Crocker Lane (the museum is closed now due to the pandemic), is directed by Lynn Kimsey, UC Davis professor of entomology. It houses nearly eight million insect specimens, plus a year-around gift shop and a live "petting zoo," comprised of Madagascar hissing cockroaches, stick insects and tarantulas.
Department of Entomology and Nematology
Live Zoom session with questions and answers, from 10 to 11 a.m. with Cooperative Extension specialist IanGrettenberger, assistant professor,UC Davis Department of Entomology and Nematology. A downloadable worksheet will be available.
Livestream on Zoom, 11 a.m. to 12 noon
Viewers can watch American cockroaches from a Briggs Hall colony race to victory.
Bug Doctor Booth
This is a live Zoom session from 12 noon to 3 p.m., with questions and answers. Folks can ask questions about insects and spiders.
Landscaping with Native Plants to Support Local Pollinators
This is a live Zoom session from 1 to 2 p.m. with question and answers, with community ecologist Rachel Vannette, assistant professor, talking about using landscaping with native plants to support local pollinators.
Zoom Meeting ID: 980 2830 2647
Zoom Passcode: 078510
EGSA T-Shirt Sales
The video will focus on Entomology Graduate Student Association (EGSA) T-shirts, masks and stickers. Order items here.
Can Plants Communicate?
A pre-recorded video by Professor Richard Karban, UC Davis Department of Entomology and Nematology, an expert on plant communication. The video is at https://youtu.be/xOXSqy05EO0
What Are Nematodes?
A pre-recorded video on "The Wonderful World of Nematodes" by nematologist Steve Nadler, professor and chair, UC Davis Department of Entomology and Nematology
Ants of Davis
A pre-recorded video by ant lab of Professor Phil Ward, UC Davis Department of Entomology and Nematology. Graduate students in the Ward lab will talk about their ant research.
A downloadable coloring sheet will be available.
Entomology at UC Davis
This will include links to all of the department-based KQED videos and a downloadable coloring sheet.
Professor Sharon Lawler, UC Davis Department of Entomology and Nematology, offers a pre-recorded video, adapted from her live lil' swimmers exhibit. She will display water striders, dragonflies and damselflies and discuss their biology.
Can Bumble Bees Take the Heat?
A downloadable PDF from the lab of pollination ecologist Neal Williams, UC Davis Department of Entomology and Nematology, about climate change and native species.
Fly Fishers of Davis
A pre-recorded video about the Davis Fly Fishers Club.
UC Statewide Integrated Pest Management Program
A downloadable worksheet will be offered.
Fight the Bite
Folks can learn about local vector control in this pre-recorded/reposted video from the Sacramento-Yolo Mosquito Control District.
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