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.
Long time passing
Where have all the flowers gone?
Long time ago
Where have all the flowers gone?
Girls have picked them every one
When will they ever learn?
When will they ever learn?"
The late folksinger and social activist Pete Seeger (1919-2014) sounded many alarms, but a recent article in the New York Times Magazine struck a different but somewhat similar chord: the declining population of insects worldwide.
Brooke Jarvis's piece on "The Insect Apocalypse Is Here," published Nov. 27, should be required reading.
Basically: Where have all the insects gone? What does it mean? Why haven't we noticed? And what are we going to do about it?
Well, butterfly guru/entomologist Art Shapiro, distinguished emeritus professor of evolution and ecology at the University of California, Davis, has noticed. Shapiro has monitored butterfly population trends on a transect across central California for 46 years and maintains a research website at http://butterfly.ucdavis.edu/. The 10 sites stretch from the Sacramento River Delta through the Sacramento Valley and Sierra Nevada mountains to the high desert of the Western Great Basin. Shapiro visits his sites every two weeks "to record what's out" from spring to fall. The largest and oldest database in North America, it was recently cited by British conservation biologist Chris Thomas in a worldwide study of insect biomass.
In her article, Jarvis related: "In October, an entomologist sent me an email with the subject line, “Holy [expletive]!” and an attachment: a study just out from Proceedings of the National Academy of Sciences that he labeled, “Krefeld comes to Puerto Rico.” (See news article on Krefeld's "Insect Armageddon.")
That entomologist was Art Shapiro.
Pesticides, loss of habitat, diseases, climate change, and human encroachment--and more--are some of the reasons why our global population of insects is dwindling.
Shapiro, who engaged in a 90-minute conversation with author Jarvis (and suggested topics and interviews for the piece), is quoted as having one of the few long-term data sets about insect abundance in the United States.
"In 1972, he began walking transects in the Central Valley and the Sierras, counting butterflies," Jarvis wrote. "He planned to do a study on how short-term weather variations affected butterfly populations. But the longer he sampled, the more valuable his data became, offering a signal through the noise of seasonal ups and downs. 'And so here I am in Year 46,' he said, nearly half a century of spending five days a week, from late spring to the end of autumn, observing butterflies. In that time he has watched overall numbers decline and seen some species that used to be everywhere — even species that 'everyone regarded as a junk species' only a few decades ago — all but disappear. Shapiro believes that Krefeld-level declines are likely to be happening all over the globe. 'But, of course, I don't cover the entire globe,' he added. 'I cover I-80.'"
Jarvis quotes plant ecologist Hans de Kroon of Radboud University, the Netherlands, as characterizing the life of many modern insects as trying to survive from one dwindling oasis to the next but with “a desert in between, and at worst it's a poisonous desert.”
Why should we care? As Jarvis succinctly points out: "Insects are the vital pollinators and recyclers of ecosystems and the base of food webs everywhere."
Now the concern should not only be "Where have all the insects gone?" but "What are we going to do about it?"
It was billed as the second annual Butterfly Summit, hosted last Saturday by Annie's Annuals and Perennials in Richmond.
But a yellow-faced bumble bee, Bombus vosnesenskii, foraging on Anchusa azurea (a member of the borage family), apparently didn't like the focus on butterflies.
Butterfly Summit? How about a Bumble Bee Summit?
For several minutes, we watched this industrious bumble bee zip in and out of the Anchusa. It zig-zagged between a Delphinium Cobalt Dreams and a Linaria triornithophora, Three-Birds Flying.
With her heavy load of orange pollen, she appeared to be bogged down, perhaps too heavy to fly?
We remember National Public Radio running a piece on "Heavy Loads of Pollen May Shift Flight Plans of the Bumble Bee," which aired in August of 2015. NPR's Nell Greenfieldboyce drew attention to research by biologist Andrew Mountcastle of Harvard University, work published in the Proceedings of the National Academy of Sciences.
"Despite what you may have heard, bumble bees do not defy the laws of physics when they fly," Greenfieldboyce related.
Fact is, they just fly differently than airplanes. "They flap their wings, and their wings bend and twist as they flap them," Mountcastle told her. He said that when bumble bees carry a pollen load, rather than a nectar load, "they are more stable, but less maneuverable in flight."
Bottom line: bumble bees are very good at flying, even when they're loaded with cargo (pollen).
The Hammock lab and the Guodong Zhang lab at the University of Massachusetts published exciting research today (April 30) in the Proceedings of the National Academy of Sciences that involves hope for patients with obesity-enhanced colon cancer.
Their research showed that inhibiting an enzyme, soluble epoxide hydrolase--discovered in the Hammock lab--may reduce the risk of obesity-enhanced colon cancer and may offer a therapeutic target to block and treat colonic inflammation.
Co-first authors Weicang Wang and Jianan Zhang of the Zhang lab, and Jun Yang of the Hammock lab/UC Davis Comprehensive Cancer Center, noted that 30 percent of Americans are obese, and these individuals have a 30 to 60 percent higher risk of developing colon cancer. It is the third most common cancer and the second leading cause of cancer-related deaths in the United States. Colon inflammation is an early symptom of cancer.
“But to date, the mechanisms by which obesity increases cancer risks are not well understood, and there are few effective strategies to prevent obesity-enhanced colon cancer," said Zhang, a former postdoctoral researcher in the Hammock lab and now an assistant professor of food science at UMass where he focuses his research on prevention of colonic inflammation (inflammatory bowel disease) and colon cancer. "Our study showed that soluble epoxide hydrolase and its metabolites are over-expressed in colon of obese mice. In addition, we found that pharmacological inhibition or genetic deletion of soluble epoxide hydrolase (sEH) abolishes obesity-induced inflammation and activation of pro-tumorigenic pathways in colon. These results showed that sEH is an essential enzyme involved in obesity-enhanced colonic inflammation and potentially colon cancer, and pharmacological inhibitors of sEH could be novel agents for prevention of these diseases.”
In the study, the 18-member team investigated the roles of sEH in obesity-induced colonic inflammation, which included using two different sEH inhibitors and a knockout mouse genetically modified not to produce sEH. Results proved similar in all cases.
They further conducted another study in both lean and obese mice with experimentally induced colon inflammation and used molecular analyses to follow a pathway called Wnt. About 90 percent of sporadic colorectal cancers have activating mutations within the Wnt pathway. The team found that obesity increases activation of Wnt signaling in the colon, but it can be abolished by the two different inhibitors and the knockout.
“The sEH inhibitor blocked obesity-induced colon inflammation,” said Hammock. “This worked even for mice on high fat diets.”
“Colon inflammation is highly associated with a variety of diseases and the inflammation often progresses to colon cancer,” Hammock said. “Weicang Wang, Guodong Zhang and co-workers have done a meticulous job investigating the biologically active fats including fatty acid diols that are associated with the inflammation. By blocking the production of these diols they were able to block the inflammation.”
“The study was an exciting discovery from lipidomics technique,” said co-first author Jun Yang. “The consistent results from pharmacologic inhibition and genetic knockout (KO) as well as the signaling pathway mechanistic studies all support sEH as a potential treatment for obesity-induced colon inflammation."
Co-author Jun-Yan Liu is already collecting human samples to extend the study, and Hammock pointed out that they hope that the soluble epoxide hydrolase inhibitor will be in human clinical trials this year.
This work, titled “Lipidomic Profiling Reveals Soluble Epoxide Hydrolase as a Therapeutic Target of Obesity-Induced Colonic Inflammation,” drew grant support from the USDA's National Institute for Food and Agriculture; National Institutes of Health's National Institute of Environmental Health Sciences (NIH/NIEHS); NIEHS Superfund Research Program, and the National Natural Science Foundation of China.
The five UC Davis researchers—Bruce Hammock, Jun Yang, Jia Sun, and Sung Hee Hwang and Debin Wan—are all with the Hammock lab/UC Davis Comprehensive Cancer Center.
The UMass researchers, in addition to those listed above: Yuxin Wang, Wiepeng Qi, Haixia Yang, and Professor Yeonhwa Park, Department of Food Science, Katherine Sanidad, Food Science and Molecular and Cellular Biology Graduate Program, and Professor Daeyoung Kim of the Department of Mathematics and Statistics.
Hammock, a member of the National Academy of Sciences and the National Academy of Inventors, directs two major UC Davis programs; the Superfund Program financed by the National Institute of Environmental Health's National Institute of Environmental Health Sciences (NIH-NIEHS); and the NIH Biotechnology Training Program. He began his career reseaching insect pests but switched to human health issues.
To date, the Hammock laboratory has published almost 900 peer-reviewed papers on the sEH enzyme, discovered while Hammock and Sarjeet Gill (now of UC Riverside) were researching insect developmental biology and green insecticides at UC Berkeley. The work, begun in 1969, led to the discovery that many regulatory molecules are controlled as much by degradation as by biosynthesis, Hammock said. These epoxy fatty acid chemical mediators control blood pressure, fibrosis, immunity, tissue growth, and pain and inflammation.
For many years Gill and Hammock were alone in studying this enzyme but today its importance is well recognized in mammalian biology, with more than 17,000 peer-reviewed papers in the area. Hammock credits the NIEHS for supporting research in this area since the 1970s.
A Davis-based company, EicOsis, has received a large grant from the U.S. National Institutes of Health to move inhibitors to the clinic to treat diabetic neuropathic pain. “We are developing a non-opiate analgesic to treat the chronic pain often associated with diabetes and hope to be in human trials over the next 12 months,” said William Schmidt, vice president of clinical development at EicOsis.