It's Veterans' Day, and after paying tribute to the military veterans (my ancestors have fought in all of our nation's wars, dating back to the American Revolution--and my other half is a U.S. Air Force veteran), I slip out the back door to our pollinator garden to see where the insect action is.
Honey bees and a sole carpenter bee are buzzing on the African blue basil; Gulf Fritillaries are nectaring on the Mexican sunflower (Tithonia); and a cabbage white butterfly is sipping nectar from the Lantana.
But the passionflower vine (Passiflora) steals the show. A Gulf Fritillary has just eclosed from a chrysalis that resembles a thick wad of gum chewed up and spit out and left to mummify; several male Gulf Frits are fluttering around in search of females; and the offspring of previous reunions are crawling on the stems and munching what's left of the leaves.
Overhead, the California scrub jays glance down, as if trying to decide on their luncheon menu: a fat juicy caterpillar or the bird seed scattered in the feeder.
Their choice is clear. They forsake the fat juicy caterpillars for the bird seed. Tomorrow morning, however, there will be several caterpillars missing in action.
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.”
The distinguished professor, known for his expertise in chemistry, toxicology, biochemistry and entomology, meshes all four sciences in his 50-year research on acute and neuropathic pain in humans and companion animals. It all began with his basic research on how caterpillars become butterflies, research that led to key discoveries about chronic pain.
But back to the reunion.
illed as “Biochemistry and Society: Celebrating the Career of Professor Bruce Hammock,” the three-day event drew Hammock lab alumni from throughout the United States, as well as Egypt, Spain, China, Australia, New Zealand, Germany, Sweden, Canada and the Czech Republic.
“It was really special and I will treasure that weekend always,” said Hammock, who trained scientists at UC Riverside for five years before joining the UC Davis faculty in 1980. He currently holds a joint appointment with the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center. He has directed the UC Davis Superfund Program, funded by the National Institutes of Health's National Institute of Environmental Health (NIH/NIEHS), for 31 years.
Hammock's colleagues, and former postdoctoral fellows, graduate and undergraduate students and visiting scholars arrived at the lab reunion with their spouses--as well as their scientific posters for display and discussion. The posters covered everything from ground-breaking research in prestigious journals to a humorous look at his annual water balloon battles in front of Briggs Hall.
The scientists dined at the UC Davis Conference Center, the Buehler Alumni Center and the Stonegate Country Club; shared months, years and decades of memories; and toasted, roasted and gifted their mentor. Hammock, in turn, toasted, roasted and gifted them.
“We had a blast,” recalled organizer Shirley Gee, a former research toxicologist and manager of the Hammock lab for 31 years. She retired in June 2016 after 40 years of service with the university.
“I have had a vision of this event to honor Bruce for many years now, and it was such a thrill to see it come together,” she said. “Reconnecting in person with all the alumni and their families was more rewarding than I could have imagined, but even more importantly was the thrill of watching alumni reconnect with each other! There were a lot of tears in the house. Many people I think were surprised by how the years melted away when they began reacquainting. I think that speaks to the environment that Bruce created that led to many strong personal and professional bonds.”
Gee credited her seven-member committee—former Hammock students Keith Wing, Jim Ottea, Tom Sparks, Babak Borhan, Qing Li; postdoctoral fellow and “academic grandson” Kin Sing Stephen Lee, a former student of Babak Borhan; and colleague Sarjeet Gill, now a distinguished professor at UC Riverside, with greatly contributing to the success of the one-of-a-kind celebration.
Hammock has studied the enzyme system and its inhibitors ever since. His lab has generated more than 80 patents, 300 postdoctoral fellows, and more than 65 graduates, who now hold positions of distinction in academia, industry and government. He recently formed a Davis-based company, EicOsis, to develop an orally active non-addictive drug for inflammatory and neuropathic pain for human beings and companion animals. Human clinical trials are scheduled to begin in 2019. Several seed-fund grants and a NIH/NINDS (National Institute of Neurological Disorders and Stroke) Blueprint Development Grant support EicOsis.
Hammock, described at the lab reunion as a “genius,” collaborates with scientists worldwide in what's been described as “unprecedented research with a multidisciplinary, integrated approach to research focused on insect biology, mammalian enzymology, and analytical chemistry.” He has authored more than 1000 publications on a wide range of topics in entomology, biochemistry, analytical and environmental chemistry in high quality journals, and has been cited more than 54,000 times. In the epoxide hydrolase field, the Hammock laboratory has published almost 900 peer-reviewed papers.
Tom Sparks, who was Hammock's first graduate student at UC Riverside, chronicled Hammock's career and recalled humorous anecdotes from his early professorship at UC Riverside. A former professor at Louisiana State University, and now a research fellow in Discovery Research at Dow AgroSciences (now Corteva Agriscience, Indianapolis, Sparks praised Hammock's intellect and curiosity. “For Bruce, it was all about the journey, looking around and operative at the interface between entomology, biochemistry and chemistry.”
Gill, along with University of Utah emeritus professor Glenn Prestwich and UC Davis research scientist Karen Wagner also delivered presentations, fondly recalling their shared time and science with Hammock.
Keith Wing, who was Hammock's second graduate student at UC Riverside/Davis, served as emcee at the lab reunion. A former senior research associate at DuPont and Rohm and Haas and current consultant, Wing said “Bruce has inspired many hundreds of developing scientists. For myself and many others, he was able to see what we could become as scientists and social contributors before we could see it ourselves."
Others commented that they learned this from Hammock: “We explore the unexpected and get to do things that don't work” and “Design things to fail; when they don't fail follow along.”
Hammock, the crowd agreed, seems to follow baseball legend Yogi Berra's sage advice: “If you come to a fork in the road, take it.”
Gill praised Hammock's “impact on human health, environmental health” as well as his love of the outdoors—from kayaking to mountain climbing.
Numerous alumni lauded Hammock's sense of humor. One scientist quoted Albert Einstein as saying “Creativity is intelligence having fun” and added “Bruce is always having fun.”
Among the other comments:
- “I never heard him speak a cross word.”
- "He treats everyone with respect.”
- "Bruce loves science and he loves people.”
- "He never heard a crazy idea.”
- "What Bruce does—he delivers the future.”
- "Bruce has a lot of determination and can approach difficult problems from multiple angles.”
- "Bruce values strong relationships with friends he has made over the years”
A native of Little Rock, Ark., Hammock received his bachelor of science degree, magna cum laude, in 1969 from Louisiana State University, Baton Rouge, where he majored in entomology and minored in zoology and chemistry. Then it was off to UC Berkeley, for his doctorate in entomology/toxicology in 1973, and postdoctoral fellowship.
It was at UC Berkeley where he met and married his wife, Lassie, who had just entered the doctoral program in plant physiology. They married in 1972 and then “the Army called me up,” Hammock remembers.
Hammock served as a public health medical officer/first lieutenant with the U.S. Army Academy of Health Science in San Antonio, Texas; and then did more postdoctoral research at the Rockefeller Foundation, Department of Biology, Northwestern University, Evanston. Ill.
Hammock then joined the faculty of the Division of Toxicology and Physiology, UC Riverside Department of Entomology in 1975 before heading for UC Davis in 1980 to accept a joint-faculty appointment in toxicology and entomology.
Bruce and Lassie reared three children: Tom, Bruce and Frances. “Frances and her husband, Adrian, teach math at UC San Diego; Bruce is on the UC Davis School of Veterinary Medicine faculty; and Tom, a graduate of the American Film Institute Conservatory, makes movies,” Hammock said, adding that he and Lassie appeared in one of the movies that Tom directed: "The Last Survivors."
Highly honored by his peers, Hammock is a fellow of the National Academy of Inventors, which honors academic invention and encourages translations of inventions to benefit society. He is a member of the U.S. National Academy of Sciences, a fellow of the Entomological Society of America, and the recipient of scores of awards, including the Bernard B. Brodie Award in Drug Metabolism, sponsored by the America Society for Pharmacology and Experimental Therapeutics; and the first McGiff Memorial Awardee in Lipid Biochemistry.
Hammock told the crowd at the reunion that he began his career studying insect science but switched to human research after encountering “all the suffering involved in acute and neuropathic pain.”
His insect science research centered around how a key enzyme, epoxide hydrolase, degrades a caterpillar's juvenile hormone, leading to metamorphosis from the larval stage to the adult insect. He then wondered "Does the enzyme occur in plants? Does it occur in mammals?" It does, and particularly as a soluble epoxide hydrolase in mammals.
“It is always important to realize that the most significant translational science we do in the university is fundamental science,” said Hammock. “The extreme and poorly treated pain that I observed as a medical officer in a burn clinic in the Army, is a major driver for me to translate this knowledge to help patients with severe pain.”
And it all began with him asking how caterpillars turn into butterflies.
"Science is full of surprises," the distinguished UC Davis professor said. "We need to remember that the concept, the clinical target, and even the chemical structure came from asking how caterpillars turn into butterflies."
We walked into our little pollinator garden in Vacaville, Calif., this afternoon to cut a few tropical milkweed stems to feed the indoor caterpillars, and there, hidden beneath a leaf, was a tiny caterpillar.
Well, hello, there! Aren't you a little late? The monarchs have been overwintering along coastal California for a couple of months. Your parents did not get the memo.
This uncharacteristic weather we're having--autumn temperatures soaring into the 70s here in recent weeks--means the milkweed is still growing and the caterpillars are, too.
We've pruned all of the tropical milkweed down to the ground except for one plant that's still flowering. We're keeping it. Food is scarce for the honey bees, syrphid flies and other pollinators.
Meanwhile, Tiny Caterpillar is a new addition to our indoor habitat. Ours is just a small-scale conservation project of rearing and releasing monarchs to help boost the declining monarch population. So far this season, our total is 54. That's 54 that may have been eaten by birds or consumed inside-and-out by parasitoids such as the tachinid flies, which lay their eggs inside the caterpillars or chrysalids. Overall, about 2 or 3 percent of the monarchs make it all the way through their life cycle, from egg to caterpillar to chrysalis to adult, scientists estimate.
Here are the basics of how we rear them, but all Monarch Moms and Monarch Dads do it differently.
- Grow milkweed species, the host plant of the monarchs. We have four different species in our pollinator garden:
--Asclepias fascicularis, narrowleafed milkweed
--Asclepias speciosa, broadleaf milkweed
--Asclepias tuberosa, a Midwest favorite
--Asclepias curassavica, tropical milkweed
- In addition to milkweed, plant other nectar-producing plants for your monarchs and other pollinators. The monarch favorites, at least in our yard, include Mexican sunflower (Tithonia), an annual that grows here from April through November (in fact it's still blooming), butterfly bush (Buddleia), and Lantana.
- When you see caterpillars on the milkweed, you'll need to protect them from predators, such as birds, tachinid flies and wasps by bringing them indoors. Add water to a heavy, narrow-necked, flat-bottomed bottle (we use Patron tequila bottles, compliments of our friends). Tuck the milkweed stems, with the 'cats still on the stems, in the tequila bottle. Then place the bottle in a meshed, zippered butterfly habitat, such as the ones from the Bohart Museum of Entomology. You can also buy meshed, zippered laundry bags from stores.
- Be sure to keep the milkweed fresh. Mist it lightly, and add new milkweed daily. Clean the frass from the bottom of the habitat.
- Watch caterpillars eat their fill and then pupate. You'll see the jade-green chrysalids, rimmed in gold, hanging from the top of the habitat.
- When the monarchs eclose, wait for their wings to dry before releasing them. We usually release them after four or five hours--if it's not cold or rainy. Food? They usually won't eat for 24 hours. If the weather is inclement and we can't release them right away, we feed them. We dip a cotton ball into a mixture of honey and water, and place it on a tray, along with a fresh flower or a slice of fruit, such as cantaloupe or watermelon. Some folks feed them a sugar and water mixture. Some use sports drinks such as Gatorade. Mona Miller, administrator of the Facebook page, Raising Butterflies and Moths for Conservation, tells how to feed monarchs on her YouTube channel. She uses 2 tablespoons of water (heated) and 1/2 teaspoon of raw organic honey (more amino acids and protein). She cools the mixture and places in a colorful cap lid (yellow, red, orange).
- When it's time to release a monarch, we just unzip the container. Sometimes we gently cradle the monarch, and then open our hands and watch it go. Some monarchs take off immediately. Others linger on our hands or head for a nearby plant.
- After you release each batch of monarchs, clean the container with soapy water and a little bleach.
Some excellent resources to get you started and keep you going:
- Xerces Society: Monarchs for Conservation and Project Milkweed
- The Beautiful Monarch, Facebook page administered by Holli Webb Hearn
- Raising Butterflies and Moths for Conservation, Facebook page administered by Mona Miller
Bruce Hammock, UC Davis distinguished professor of entomology who holds a joint appointment with the UC Davis Comprehensive Cancer Center, is fond of saying that in his many talks.
"Science is full of surprises."
His research clearly shows that basic science can lead to surprising findings.
A recently published news story, "From Caterpillars to Kidney Disease: Surprise Discoveries in Basic Science," on the Medical College of Wisconsin website chronicles how Hammock's basic research on caterpillars--how caterpillars become butterflies--led to key discoveries about chronic pain, including diabetic pain.
As an aside, Hammock suggested to communication specialist Karri Stock that the story could include a photo of a caterpillar and a butterfly, and did I have one?
I did, thanks to the Gulf Fritillary (Agraulis vanillae) population explosion on our passionflower vine (Passiflora). A caterpillar was doing what caterpillars do. Then two butterflies came along and started doing what males and females do. The three-in-one photo illustrates the article, along with a photo of Hammock and collaborator John Imig, professor of pharmacology and toxicology at the Medical College of Wisconsin, Milwaukee.
The gist of the news story is that Imig received a $2.3 million grant from the National Institute of Diabetes and Digestive and Kidney Diseases "to investigate the development of a drug to treat type 2 diabetes and metabolic syndrome."
"But what we didn't tell you is that this translational grant is all thanks to some caterpillars in California and decades of research," Stock wrote. "It's a tale of pure curiosity with a great lesson for budding scientists and the public alike: You can't always predict where basic science discoveries will lead."
She related how, more than 40 years ago, a young entomologist in California named Bruce Hammock found a key enzyme (epoxide hydrolase or EH) in the metamorphosis of caterpillars into butterflies. "The enzyme degrades a caterpillar's juvenile hormone, allowing it to move from the larval stage into an adult insect. Early in his career, Dr. Hammock found that if he exploited this EH and prevented larvae from becoming adults, he had on his hands an effective genetically engineered insecticide."
Then came the basic science and fundamental questions that Hammock asked. "Does the enzyme occur in plants? Does it occur in mammals?"
"And it turns out that it does, particularly as soluble epoxide hydrolase (sEH) in mammals, including mice and humans, and its distribution suggested it was involved in regulatory biology," Stock wrote. She went on to detail the collaboration of Hammock and Imig. Read the entire MCW story here.
Hammock's work has drawn national and international attention. Groundbreaking neuropathic pain research emanating from the Hammock lab made Discover magazine's Top 100 Science Stories of 2015 ranking among the Top 15 in the medicine/genetics category.
The UC Davis research was singled out for its “Endoplasmic Reticulum Stress in the Peripheral Nervous System is a Significant Driver of Neuropathic Pain,” published in July 2015 in the Proceedings of the National Academy of Sciences. (See UC Davis news story).
Highly honored by his peers, Hammock is a fellow of the National Academy of Inventors, which honors academic invention and encourages translations of inventions to benefit society. He is a member of the U.S. National Academy of Sciences, a fellow of the Entomological Society of America, and the recipient of the Bernard B. Brodie Award in Drug Metabolism, sponsored by the America Society for Pharmacology and Experimental Therapeutics. He directs the campuswide Superfund Research Program, National Institutes of Health Biotechnology Training Program, and the National Institute of Environmental Health Sciences (NIEHS) Combined Analytical Laboratory.
A native of Little Rock, Ark., Bruce earned a bachelor's degree in entomology from Louisiana State University in 1969 and his doctorate in entomology/toxicology from UC Berkeley in 1973, and then accepted a Rockefeller Postdoctoral Fellowship at Northwestern University. Hammock served as a member of the UC Riverside faculty for six years before joining UC Davis in 1980. In addition to maintaining a vigorous research program, Hammock teaches, mentors students, works with visiting scholars and enjoys rock climbing and kayaking.
And if you get a chance to hear him speak about his research, he's likely to say: "Science is full of surprises."
Because it is.