The grant, “Food Quality in Egypt: Screening for Contamination with Pesticides using Innovative VHH Antibody-Based Assays and Biosensors,” was one of 15 collaborative projects selected for funding by the U.S.-Egypt Science and Technology Joint Board. The grants foster research collaboration between Egyptian and U.S. scientists.
“Zagazig is one of the world's premier agricultural institutions,” said Hammock, a distinguished professor who holds a joint appointment with the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center. “I am thrilled to have this support to expand our long collaboration with Zagazig. This is very practical work with potentially profound outcomes on reducing exposure of consumers and workers to pesticides. We are using a very sophisticated new antibody technology to allow on site monitoring of potentially dangerous pesticides.”
“Our postdoctoral scientist Natalia Vasylieva is the star on the project,” Hammock said, “but it encompasses our entire immunoassay group. We have a long-term collaboration with Zagazig University.”
The grants are funded by the National Academies of Sciences, and the Egyptian Science and Technology Development Fund. Reviewers evaluated the proposals' scientific and technical merit, relevance to program objectives, capabilities of partner institutions and individuals, nature of collaboration, and cost-effectiveness. The board funded less than 12 percent of the eligible proposals.
“Immunoassay (ELISA) is an alternative and complimentary analytical method to instrumental techniques like liquid or gas chromatography,” said Vasylieva, who leads the immunoassay group in the Hammock lab. A native of the Ukraine, she received her master's degree from Taras Shevchenko National University of Kyiv, Ukraine, and her doctorate from National Institute of Applied Sciences in France. Joining the Hammock lab in May 2013, she focuses her research on development of nanobodies as neutralizing agents for small molecule poisoning, as well as use of nanobodies as therapeutics.
“ELISA is also considered cheaper method,” said Vasylieva. “Particularly, ELISA is economically interesting when relatively large set of samples have to be analyzed. This is usually the case in the environmental monitoring for contamination and human exposure studies.”
The Hammock lab, which has extensive experience in development of immunoassays, extends the field by developing new formats of the immunoassays by developing new reagents. “In particular, we develop new type of antibodies, called nanobodies or VHH (from variable heavy domain from heavy chain only antibodies) that naturally occur in camelids and sharks,” Vasylieva said. “These antibodies have all the affinity properties of conventional (polyclonal and monoclonal) antibodies, but also have unique properties, like small size (1/10th of the size of conventional antibodies), high thermal stability, resilience to organic solvents and high refolding capacity. These properties make them particularly suitable for use in portable devices for environmental and human exposure monitoring.”
A large amount of pesticide is used in Egypt,” she said. “So far, only limited amount of information is available about environmental contamination and human exposure to those pesticides. In these few publications available, levels of pesticide in the food appears to be over the allowed limits.”
In their abstract, the researchers explained that long-term application of pesticides has resulted in contamination of food in Egypt. “Continuous exposure to pesticides is usually associated with infertility, birth defects, endocrine disruption, neurological disorders and cancer in humans. Worldwide reliance on chemical pesticides in agriculture remains an essential component for high food production. According to the Egyptian Agricultural Pesticide Committee, the amount of pesticides imported and used for agricultural production has more than doubled from 2005 to 2012. However, only a few studies have been published on this subject over the past 10 years and they show high levels of pesticides in a variety of food products.”
“Food monitoring studies in Egypt have been primarily limited to analysis of organochlorides, organophosphates, and carbamate insecticides,” the researchers noted in their abstract. “Research and monitoring of other pesticide groups is a relatively new subject, and a knowledge gap still remains. With this study, we propose to assess the safety of food available on the Egyptian market and develop tools for fast and low-cost contamination screening. Our long-term goal is to contribute to a healthier Egypt by raising awareness about food chemical safety and to provide simple tools for researchers and stakeholders to screen the food products for compliance with regulatory policies. We hypothesize that human exposure to toxic chemicals through contaminated food (domestic and imported) has increased due to excessive application of pesticides in order to face nutrition needs.”
They defined three specific goals of the project:
- To screen Egyptian domestic and imported food samples for pyrethroid insecticide residues, a major group of insecticides used today, using immunoassays;
- To develop new reagents and immunoassays for detecting diamide insecticides, a group of pesticides whose use is rapidly growing, and
- To develop tools for fast and low-cost food contamination screening in the environment with minimal technical support.
Overall, the scientists aim to develop innovative immunoassays and biosensors empowering scientists and engaged Egyptian communities to collect analytical data to address environmental chemical concerns. “We will do this by adapting and refining technologies to improve assay performance, reliability and field portability,” they wrote. “The knowledge gained from this research will provide insight into human exposure to agricultural pesticides in Egypt and will raise the Egyptian population's awareness of food quality.”
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. Hammock, who holds a doctorate in entomology/toxicology from UC Berkeley, served as a public health medical officer at the U.S. Army Academy of Health Science in San Antonio, Texas; a postdoctorate fellow in entomology/toxicology at UC Berkeley; and a postdoctoral fellow in biochemistry with the Rockefeller Foundation, Northwestern University, Evanston, Ill., before joining the UC Davis faculty in 1980.
Science intrigues her, fulfills her, and propels her.
Rand, who is drawing widespread recognition for her work with omega-6 fatty acids as a postdoctoral researcher in Bruce Hammock's biological analytical lab at UC Davis, says science is both “exciting and rewarding.”
“Science and chemistry were my two favorite subjects in school,” said Rand, who was born in Bermuda but grew up in Nova Scotia, Canada. “I had excellent teachers that really fueled my interest. It was their enthusiasm. I remember my eighth grade math teacher leaping up on a table to get her point across about the Pythagorean theorem, and my 11th grade chemistry teacher used memorable metaphors to explain challenging concepts. Both my parents were biologists, and growing up in Eastern Canada we went on many outdoor trips. The combination of motivational teachers and exploring the natural world fueled my interest to continue in science professionally.”
Rand thinks of science “as a way to connect with the world in many ways, by working to understand it better, collaborating with a network of scientists, and communicating science to the public. Science matters because of its diversity: it heals, transforms, innovates, and understands, all of which globally shape our world.”
Rand, who holds a bachelor of science degree in chemistry from Mount Allison University, Canada and a doctorate in environmental chemistry at the University of Toronto, joined the Hammock lab in 2013 and was named a fellow on the Oncogenic Signals and Chromosome Biology T32 Training Grant, Department of Microbiology and Molecular Genetics.
In the Hammock lab, Rand studies omega-6 fatty acids, or technically, “the regulation of cancer angiogenesis from the metabolism of epoxy omega-6 fatty acids.”
How does Amy Rand explain to the average layperson what she does?
"Amy took on one of the most demanding projects in the laboratory in asking how a group of natural compounds regulate angiogenesis," said Hammock, a distinguished professor of entomology who holds a joint appointment with the UC Davis Department of Entomology and the UC Davis Comprehensive Cancer Center.
In April of 2016, Rand drew international accolades when she received a prestigious career development award from the American Association for Cancer Research—the two-year $100,000 Judah Folkman Fellowship for Angiogenesis Research. She won the highly competitive international award for her proposal, “Regulation of Cancer Angiogenesis from the Metabolism of Epoxy Omega-6 Fats.”
Cancer researchers praised her for her potential as a future leader in the field of angiogenesis research.
“We're so proud of her,” said Hammock, who 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.
Hammock and Rand collaborate with Harvard Medical School professor Dipak Panigrahy, former researcher in the Hammock lab and a fellow in the late Professor Judah Folkman's angiogenesis research lab. Folkman, the father of angiogenesis research, is best known for pioneering the concept of blocking angiogenesis or the development of blood vessels, to control cancer growth. "This concept has resulted in a number of anti-cancer drugs and has had a major impact on cancer treatment,” Hammock said. “Of course blood vessel development is also critical for survival."
Looking back, Rand related that her Ph.D research “focused on our exposure to fluorinated commercial materials, their resulting metabolism, and how the metabolites might affect our health. While my Ph.D training was heavily focused on analytical chemistry and metabolic characterization, I wanted more formal training on the biological and biochemical mechanisms associated with disease. I've always been interested in research that combines chemistry and biology to enhance our understanding of human health.”
Rand encourages students to follow their dreams, to pursue what interests them, “if they're able, regardless the subject. I wouldn't be where I am without balancing science with other parts of my life, like performing music during graduate school, which allowed me to come back to the lab with fresh inspiration for next steps. But we need to motivate people, especially minorities, to continue in science, because people from different backgrounds and experiences are necessary for creating a collective mind that does effective scientific research and innovation.”
When she started her postdoctoral research, moving across the continent to Davis, she knew few people. “Within a short time, I fell into a great community of people at the local climbing gym, that have sparked many outdoor adventures - climbing, backpacking, swimming, and skiing - over the past 3 years. Living in Northern California has been a real treat!”
She also has a soft spot for entomology. “Growing up, I used to swim insects to shore if I found them floating far from it - I was alarmed to see them nearly drowning, and did my part to help. That might have been what initiated my future role as lifeguard and swimmer.”
Hammock says his own long-term interest in nature and biology “was fostered by a wonderful scoutmaster who thought kids should be wandering in the woods, and a great biology teacher who provided a microscope to me in high school and said 'go discover.' The move to entomology was further stimulated when I realized that the big cause of human suffering in the world was starvation caused in part by insects eating crops. It was also stimulated by realizing that insect-borne diseases dwarf cancer, heart disease, etc., in terms of human suffering. It is hard to know where science leads.”
As for where science leads, Rand has just accepted a position as assistant professor of organic toxicology in the chemistry department, Carleton University in Ontario. She starts her position Sept. 1.
“We really hate to lose her,” Hammock said, “but we're happy for her; this is a really nice position. And, we'll still be collaborating.”
"I hope we collaborate for the next 80 years or so," he quipped.
Earlier research by the Judah Folkman laboratory of Harvard Medical School showed that cutting off blood vessels that feed a cancerous tumor can stop its growth.
The seven-member research team—five from the Bruce Hammock laboratory of UC Davis—“characterized a novel lipid signaling molecule that can change fundamental biological processes involved in our health and disease,” said lead author and researcher Amy Rand. “We've found that a novel product derived from the metabolism of omega-6 fatty acids stimulates angiogenesis, which may contribute to enhanced tumor growth by providing tumors with oxygen and nutrients.”
“As a highly regulated process, angiogenesis is critical for wound healing and development, but many diseases result in unregulated angiogenesis, including cancer,” explained Rand, a postdoctoral fellow in the lab of Bruce Hammock, a distinguished professor who holds a joint appointment with UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center. “We may be able to control angiogenesis to stimulate wound healing when necessary, but also block tumor growth in patients. Diseases that rely on angiogenesis may be able to be treated in part by changes in dietary lipid exposure or by controlling levels of these metabolites through enzyme inhibitors that block their formation.”
The research, published April 10 in the Proceedings of the Natural Academy of Sciences (PNAS), explains, in part, why inhibiting the soluble epoxide hydrolase (sEH) in some systems is angiogenic whereas combining sEH inhibition with the inhibition of cyclooxygenase (COX) enzymes is dramatically antiangiogenic, which in turn may suppress tumor growth.
“There's uncertainty regarding the link between unsaturated fats and cancer, due to ongoing conflicts between scientific studies and insufficient data,” Rand said. “Because of this, there is a major gap in our understanding of how these essential dietary fats affect our health. We used tools to detect and characterize unknown metabolites from omega-6 unsaturated fats and determined their effect on angiogenesis, to address at least a small part of this uncertainty by focusing on how these fats contribute to cancer tumor growth.”
Hammock, who holds a joint appointment in the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center, said the research, titled “Cyclooxygenase-Derived Proangiogenic Metabolites of Epoxyeicosatrienoic Acids
Holds long term hope for cancer patients and those afflicted with heart, eye and other diseases. The team also included Christophe Morisseau, Bogdan Barnych, and Kin Sing Stephen Lee all of the UC Davis Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center; Tomas Cajka of the UC Davis Genome Center; and Dipak Panigraphy of Harvard Medical School. Lee is now an assistant professor at Michigan State University.
“Pro and anti-angiogenic therapy can potentially help millions of people worldwide in various diseases such as heart, ulcers, eye and cancer as first demonstrated by Dr. Judah Folkman and his colleagues,” said Panigraphy, formerly of the Hammock lab and now with the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, and the school's Department of Pathology.
“While the COX and sEH pathways can be targeted with drugs, their interaction is poorly understood,” Panigraphy said. “These studies by Rand et al demonstrate for the first time new specific mechanisms whereby targeting the sEH pathway can be both pro- and anti-angiogenic and has the potential to help patients with devastating diseases such as in the eye and cancer where blocking angiogenesis is desired.”
Rand, who received her doctorate in chemistry from the University of Toronto, Canada, in 2013, the same year she joined Hammock's biological analytical chemistry lab, said she's “always been interested in research that combines chemistry and biology to enhance our understanding of human health.”
Future work? “We aim to understand the direct involvement of these omega-6 fatty acid metabolites with cancer tumor growth and metastasis.”
Rand last year received the $100,000 Judah Folkman Fellowship for Angiogenesis Research from the American Association for Cancer Research. She won the highly competitive international award for her proposal, “Regulation of Cancer Angiogenesis from the Metabolism of Epoxy Omega-6 Fats.” Rand joined Hammock's biological analytical chemistry lab in 2013 and was a fellow on the Oncogenic Signals and Chromosome Biology T32 Training Grant, UC Davis Department of Microbiology and Molecular Genetics.
The late Judah Folkman (1933-2008), a Harvard Medical School professor considered the father of angiogenesis research, “is best known for pioneering the concept of blocking angiogenesis (the development of blood vessels) to control cancer growth," Hammock said. "This concept has resulted in a number of anti-cancer drugs and has had a major impact on cancer treatment. Of course, blood vessel development is also critical for survival."
Folkman discovered that cutting off the blood vessels that feed the tumor can stop cancer tumor growth. His revolutionary work has led to the discovery of a number of therapies based on inhibiting or stimulating neovascularization. Inhibitors of the sEH pathway are moving toward human trials to control neuropathic pain, but if combined with nonsteroidal anti-inflammatory drugs can block tumor growth by blocking angiogenesis. So Dr. Sung Hee Hwang combined inhibitors of both pathways into one molecule which is being investigated in cancer models at the UC Davis Cancer Center by Dr. Paul Henderson and Northwestern University Medical School by Dr. Guang-yu Yang.
Hammock 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.
This work was supported by NIEHS and the NIEHS Superfund Program; and two of Rand's grants: the Oncogenic Signals and Chromosome Biology T32 Training Grant, NIH/NIEHS; and her 2016 AACR Judah Folkman Fellowship for Angiogenesis Research.
The researchers found that a chemical inhibitor of a soluble epoxide hydrolase may be a new, innovative tool to control depression, a severe and chronic psychiatric disease that affects 350 million persons worldwide.
Soluble epoxide hydrolase, or sEH, is emerging as a therapeutic target that acts on a number of inflammatory or inflammation-linked diseases, said NIEHS grantee Bruce Hammock, who holds a joint appointment in the UC Davis Department of Entomology and Nematology, and the UC Davis Comprehensive Cancer Center.
“The research in animal models of depression suggests that sEH plays a key role in modulating inflammation, which is involved in depression,” Hammock said. “Inhibitors of sEH protect natural lipids in the brain that reduce inflammation, and neuropathic pain. Thus, these inhibitors could be potential therapeutic drugs for depression.”
NIEHS singled out the depression research as one of its four top papers of the month. It headlined the work “Anti-Inflammatory Chemical May Offer New Tool for Depression Treatment,” in its May newsletter.
“Researchers found that the sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea (TPPU), displayed rapid antidepressant effects in mice,” according to the NIEHS summary. “Researchers observed mice for depression-like behavior after repeated social stress. They found that administering TPPU reduced depression-like behaviors. Inhibiting sEH in the mice also produced resilience to the repeated stress.”
“The researchers also observed higher levels of sEH expression in key brain regions of the chronically stressed mice than in mice not subject to repeated stress,” NIEHS wrote. “They then examined postmortem human brain samples from patients with psychiatric diseases, including depression.
The work, published March 14 in the journal Proceedings of the National Academy of Sciences, drew international attention.
Other authors on the paper are Christophe Morisseau, Karen Wagner and Jun Yang, UC Davis; and Qian Ren, Min Ma, Tamaki Ishima, Ji-chun Zhang, Chun Yang, Wei Yao, Chao Dong, and Mei Han, Chiba University.