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.”
From basic science to applied science.
From studying insects to helping humankind.
The ovarian cancer research published today in the Proceedings for the National Academy of Science (PNAS) can be traced back, in part, to a former graduate student at UC Berkeley trying to answer some basic questions on how a caterpillar becomes a butterfly.
In investigating those basic questions, that graduate student, Bruce Hammock, and fellow graduate student Sarjeet Gill, co-discovered a soluble epoxide hydrolase (sEH). Both scientists are now distinguished professors in the UC system: Hammock, a distinguished professor at UC Davis, and Gill, a distinguished professor at UC Riverside.
For the past 50 years, Hammock has been studying sEH inhibitors, leading to drugs that target such diseases as diabetes, hypertension (heart disease), Alzheimer's disease, and cancer. 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.
But back to the research published today in PNAS.
Did you know that chemotherapy kills cancer cells, but that the debris of dead and dying cells can lead to inflammation and the surge of more cancerous cells?
The research is the work of a 13-member team from Harvard Medical School/Beth Israel Deaconess Medical Center (BIDMC), UC Davis, Institute of Systems Biology of Seattle, and Emory University School of Medicine of Atlanta. They tested the compound on mice models.
Lead author Allison Gartung of Harvard Medical School/BIDMC described the research as a “novel approach to suppressing therapy-induced tumor growth and recurrence. To prevent tumor-recurrence after therapy, it will be critical to neutralize the inherent tumor-promoting activity of therapy-generated debris,” she said. "Our results indicate that a dual COX-2/sEH inhibitor may offer a novel alternative to protect the body from a debris-mediated inflammatory response.”
Gartung said that the study confirms that chemotherapy-killed ovarian cancer cells “induce surrounding immune cells called macrophages to release a surge of cytokines and lipid mediators that create an optimal environment for tumors to survive and grow.
Hammock, who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center, lamented that “Chemotherapy and surgery, the mainstays of conventional cancer treatment, can act as double-edged swords. It is tragic that the very treatments used to cure cancer are helping it to survive and grow."
Chemist Sung Hee Hwang of the Hammock lab developed the compound, known as PTUPB, for the study. “The dual inhibitor here follows earlier work we did with it, blocking breast and lung tumors in mice,” Hammock said. “PTUPB is already being clinically evaluated for its therapeutic properties in other diseases.” Chemist Jun Yang of the Hammock lab did the mass spectrometry, showing how stabilization of lipid mediators reduces cancer growth and metastasis.
Lead researcher Dipak Panigrahy, a former Harvard physician turned full-time researcher, described chemotherapy and surgery “as our best tools for front-line cancer therapy, but chemotherapy and surgery create cell debris that can stimulate inflammation, angiogenesis, and metastasis. Thus, the very treatment used by oncologists to try to cure cancer is also helping it survive and grow. Overcoming the dilemma of debris-induced tumor progression is critical if we are to prevent tumor recurrence of treatment-resistance tumors which lead to cancer therapy failure.”
The tumor cell debris generates a “cytokine surge” that can result in a perfect storm for cancer progression. “The dual inhibitor acts as a surge protector,” Panigrahy said.
Panigrahy, who led angiogenesis and cancer animal modeling in the laboratory of Judah Folkman, a leading cancer research laboratory, based the debris model on his mother's chemotherapy treatments, and dedicated the research to his mother and “all other women who lost their lives to ovarian cancer.” American Cancer Society statistics show that among women, ovarian cancer ranks fifth in cancer deaths. A woman's risk of ovarian cancer is about 1 in 78; every year more than 14,000 die from the disease.
“Traditional cancer therapy sets up a dilemma,” Panigrahy commented. “Yes, we need to kill cancer cells but the inevitable byproduct of successfully doing so also stimulates tumor regrowth and progression. The more tumor cells you kill, the more inflammation you create, which can inadvertently stimulate the growth of surviving tumor cells. Overcoming the dilemma of debris-induced tumor progression is paramount if we are to prevent tumor recurrence of treatment-resistant tumors – the major reason for failure of cancer therapy. Our studies potentially pave the path for a new strategy for the prevention and treatment of chemotherapy-induced resistance with potential to translate to the clinic. If successful, this approach may also allow us to reduce the toxic activity of current treatment regimens.”
“The collaborative work in this paper not only defines a common problem with current cancer therapy, but it actually offers a potential solution to reduce metastasis and tumor growth following therapy,” said Primo Lara Jr., director of the UC Davis Comprehensive Cancer Center and associate director of Translational Research. “I am pleased that our Center was involved in this exciting project and we hope we can be involved in translating this basic research to the clinic.”
Panigrahy said that non-steroidal anti-inflammatory drugs (NSAIDs), which include aspirin and ibuprofen, reduce pain, fever and inflammation “bit may have severe side effects including stomach and brain bleeding as well as severe cardiovascular and kidney toxicity. They also do not specifically enhance clearing of debris.”
“We are exploring all options to translate PTUPB to cancer patients especially in combination with current cancer therapies such as chemotherapy, radiation, immunotherapy, or surgery which either directly or indirectly may generate tumor cell debris,” Panigrahy said. “Our next step is to investigate whether our findings are consistent with clinical studies involving human cancer.”
Said Hammock: "We have a series of papers largely in PNAS, with the Panigrahy group showing first our soluble epoxide hydrolase inhibitors block tumor growth and metastasis when used with omega3 fish oils or with COX inhibitors and the role for these compounds in regulating a number of mediators of cancer growth."
And to think this all began with a young graduate student at UC Berkeley studying how caterpillars become 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."
The Bohart Museum Society hosted the Bohart Museum of Entomology's 24th annual pre-Halloween party on Saturday, Oct. 27 at the University of California, Davis, billing it as “They Come From Within" and promising a “haunting night full of frights and delights."
You can thank the emerald cockroach wasp or jewel wasp (Ampulex compressa), an entomophagous parasite, for that! It is known for its unusual reproductive behavior, in which it stings a cockroach and then uses it as a host for its larvae, eating it alive.
That was the critter depicted on the invitation.
UC Davis entomology undergraduate student and talented artist Karissa Merritt created the much-applauded, wasp-inspired invitation. "For this year's Bohart Halloween party invite, I set out to create an original--fake--movie poster, inspired by old B-movies such as 'Them' and 'Invasion of the Saucer Men,'" she explained. "I really wanted the invitations to grab people's attention with the bright colors, and grotesque horror as a giant jewel wasp--based on Ampulex compressa--emerges from a living man's chest."
It did. It also grabbed the attention of UC Davis entomology doctoral candidate Charlotte Herbert Alberts, who studies Asilidae (Assassin flies) with her major professor, Lynn Kimsey, director of the Bohart Museum and professor of entomology. "I made my costume to honor Karissa's incredible drawing of the invitation," said Charlotte, who anticipates receiving her Ph.D in 2020. Her husband, George, dressed as Dracula. Their Brittany Spaniel, Westley, declined to wear a dinosaur costume and came as himself.
At the entrance, assorted mustaches and masks commanded a table. A sign urged people to "write a name tag, yet disguise yourself if you aren't in costume." (With the addition: "I know it doesn't make sense; just humor us.")
Among those coming as themselves were entomologist Jeff Smith, who curates the butterfly and moth collection; his wife, Cathy; and Bohart associate and naturalist-photographer Greg Kareofelas.
Senior museum scientist Steve Heydon wore an orange jumpsuit lettered with "Department of Corrections" while his wife, Anita, came dressed as a police officer, complete with badge and handcuffs.
Forensic entomologist Robert "Bob" Kimsey, husband of Lynn Kimsey, donned his traditional ghillie suit.
Bohart Museum director Lynn Kimsey cut a 72nd anniversary cake, a red-velvet, chocolate-frosted cake decorated with--what else?--bugs! After all, the Bohart Museum houses some 8 million specimens, plus a live "petting zoo" of Madagascar hissing cockroaches, walking sticks, tarantulas and praying mantids, as well an insect-themed gift shop.
Meanwhile evolutionary ecologist Scott Carroll, at 6'11", towered over everyone. "I can pick him out in a crowd," quipped his wife, entomologist Jenella Loye.
(See tomorrow's Bug Squad blog for more Halloween images, including the pinata breaking game. The pinata? A replica of a monarch chrysalis.)
It starts out slow.
Beginning in the spring (and sometimes year-around in some locales) Gulf Fritillaries (Agraulis vanillae) lay their eggs on their host plant, the passionflower vine (Passiflora).
They deposit their eggs on the tendrils, on the leaves, and sometimes on the fence, wall or door where the passionflower vine climbs.
When fall approaches and the Gulf Frits are still laying eggs, you won't recognize your vine. It is skeletonized. The caterpillars, incredible shredding machines, have devoured all the leaves, leaving nothing but scarred sticks. And the 'cats are now gobbling up the remaining fruit. Hungry, hungry caterpillars!
Your plant, now incognito, looks like it should be in the Federal Witness Protection Program--and you have to defend yourself for "being a bad gardener."
But that's why we plant the Passiflora: for the Gulf Frits.
"No plant wants to be eaten," wisely observes Bruce Hammock, a UC Davis distinguished professor with a joint appointment in the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center. "They all have defenses. They do not like insects, fungi, cows or even vegetarians that eat them."
At the time, Professor Hammock was talking to a reporter about toxic plants, and how we have bred many poisons out of plants or learned to not eat the most toxic parts. "In some cases, we like the taste of the poisons: cinnamon, potato, parsley, and mustard," Hammock told him.
In the case of the passionflower vine, aka Scraped Skinny Stick, it probably wishes (if plants could wish) and wonders (if plants could wonder) "Why am I so attractive?" and "Where are all the birds, wasps and other predators of caterpillars when I need them?"