June 7, 2022
By Neelanjana Gautam
In 2020, an estimated 5.8 million Americans aged 65 years or older had Alzheimer’s disease. This number may well hover around 14 million by 2060, according to the Centers for Disease Control and Prevention. Years of research led by UC Davis Professor John Voss may play an important role in treating Alzheimer’s and other protein misfolding diseases that occur in the brain.
Voss, a professor in the Department of Biochemistry and Molecular Medicine, is developing a unique approach to treating such protein misfolding diseases by using paramagnetic molecules to diagnose and monitor the disease conditions. His contributions in this field led to the launch of ParaMag Biosciences, a company which recently executed license agreements to access foundational intellectual property and commercialize new technologies developed at the UC Davis.
Voss has been working in the area of structural biology, specializing in protein dynamics and assembly, since he joined UC Davis in 1998. In 2017, Voss received the Science Translation and Innovative Research (STAIRTM) Grant offered by Venture Catalyst – within the Innovation and Technology Commercialization division of the UC Davis Office of Research. The award afforded Voss and his team the opportunity to demonstrate early proof-of-concept and gain access entrepreneurial and technology commercialization support resources to advance the innovation.
Understanding Protein Misfolding
When proteins lose the native structure either by mutation or environmental effects, they are typically identified and cleared by the cell. However, elevated levels of misfolded proteins —accumulating either by increased production or decreased clearance — can lead to disease. In the disease pathway, oxidative stress and associated inflammation in response to aggregates of misfolded proteins act as critical mediators of cell death. Protein misfolding can lead to not only Alzheimer’s, but several disorders, including neurodegenerative and skeletal muscle diseases such as Parkinson’s and Huntington’s diseases.
Voss’ research has been primarily focused on protein structure and dynamics. He studies molecular switching in proteins, as well as protein folding and assembly. Voss explains that intrinsically disordered or misfolded proteins don’t necessarily retain a single well-defined architecture or structure. “Instead, they move around a lot and tend to aggregate or misfold, and therefore are much harder to pin down,” he said.
Voss has been particularly interested in these types of proteins to understand how they work with their high levels of intrinsic disorder. “We can get a lot of information by looking at how things move and how much order disorder they have,” said Voss.
Novel Approach to Treating Alzheimer’s Disease
The goal was then to design a mechanism that can enter cells and prevent the toxic event of protein misfolding. To carry out this work, Voss and his team have developed a tool called Electron Paramagnetic Resonance (EPR) spectroscopy, which introduces “spin probes” –– unique paramagnetic molecules with unpaired electrons –– that can bind on to these misfolded proteins and report on their dynamics and degree of aggregation.
Collaborative studies with Lee-way Jin of the UC Davis Alzheimer’s Disease Center led to the observation that these spin probes carry some unique properties, such as, they can deliver potent antioxidant activity in a catalytic manner. Based on this observation, Voss embarked on designing spin probe agents that can assemble around the neurotoxic proteins and reduce their toxicity in cells.
Another key property of the innovation results from the ability of the agents to generate contrast in magnetic resonance imaging (MRI), which then can be used as a diagnostic tool and understand the course of treatment. “We use this approach to address problems in several biological systems, including those related to cardiovascular and neurodegenerative diseases,” said Voss. “Unlike available imaging methods, the MRI contrast does not involve metals, eliminates radiation exposure to the patient, and is less expensive — enabling greater patient access,” said Voss.
Voss used the STAIR grant to get access to imaging instrumentation, collected specimens from animals as well as from patients in the UC Davis Alzheimer’s Disease Center, and used them to validate the hypothesis that these paramagnetic molecules can be used in a diagnostic manner.
They performed in vivo tests to synthesize and demonstrate the effectiveness of nine novel small molecules, co-invented by Ruiwu Liu, a research professor in the School of Medicine. They also conducted lead optimization studies of therapeutic activities and used imaging instrumentation to better correlate the contrast signal with identifiable brain structures.
Voss’ laboratory has engineered a series of proprietary spin-labeled agents that preferentially bind to aggregates of misfolded proteins and provide neuronal protection from toxic effects of amyloid-beta. These molecules have been termed paramagnetic amyloid ligands (PALs) as they are not only neuroprotective but also can be visualized in the brain with MRI. Voss’s efforts with the Davis-based ParaMag Biosciences are aiming to bring the UC-licensed PAL technology to patients.
AJ Cheline, UC Davis Office of Research, 530-752-1101, email@example.com
Heather Siefkes, assistant professor of pediatric critical care at UC Davis Children’s Hospital, and founder of the startup NeoPOSE, signed a letter of agreement for the exclusive rights to commercialize a new technology developed at UC Davis that could improve the detection of congenital heart defects in newborns.
According to the Centers for Disease Control, roughly 7,200 babies in the United States are born with a critical congenital heart defect (CCHD) every year. The condition is life-threatening and prevents the heart from circulating blood effectively throughout the body.
The current approach to screening for these defects uses pulse oximetry. The non-invasive, painless and low-cost test measures oxygen saturation in blood as an indicator of how well oxygen is supplied to tissues through the body. All states now require the screening. Siefkes herself helped get legislation passed in Oregon — testifying in support of the screen as legislation was being considered.
“The mandate by states was a tremendous step forward to help screen, but unfortunately, an estimated 15 percent of critical congenital heart defects still go undetected,” said Siefkes. “And, when it comes to such heart defects, the timeline for detection is critical.”
Siefkes personal clinical experience bolsters her motivation to continue to improve detection. She recalls one event in particular when a two-week-old baby came to the emergency room very sick.
“It was clear that the baby had a heart defect that was not detected by the oximeter test,” she said. “The late diagnosis contributed to the unfortunate death of the baby and lit a fire in me to explore research to prevent such tragedies from happening again.”
“Pulse oximetry is good at catching defects that cause poor oxygenation of the blood flow, for example, when the pathway from heart to lung and back to heart is interrupted,” she said. “But conditions that obstruct blood flow to the body, such as coarctation of the aorta, are only detected about one-third of the time by oxygen saturation screening.” Coarctation of the aorta, or narrowing of the aorta vessel, is one of the most common critical heart defects.
To address the gap, Siefkes looked to enhance the current screening tool, knowing it could be the quickest path to clinical acceptance.
Pulse oximetry can also be used to quantify blood flow to pick up abnormalities caused by obstructions to flow to the body, but the variability in the data over time makes that impractical to interpret and apply in a clinical setting. As a practicing clinician, Siefkes knew the data would need to be processed in a manner that would make it clear and actionable.
Siefkes enlisted the help of graduate students, and Professors Chen-Nee Chuah and Satyan Lakshminrusimha to develop a screening algorithm that combines non-invasive measurements of perfusion, oxygenation and waveform characteristics.
In 2019, the team received a Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) award and a National Center for Advancing Translational Sciences (NCATS) grant to conduct a clinical study at six hospitals. The objective was to develop a machine learning/artificial intelligence model to identify the perfusion (blood flow) value that can predict CCHD.
In 2020, Siefkes received internal funding through a proof-of-concept grant from the Venture Catalyst Data, Informatics and Application Launch (DIAL) program. The program provides grants up to $20,000 to advance research and innovations with commercial potential.
The team has enrolled 300 patients to date and looks to complete enrollment this fall. Once the study is complete, the team will conduct a follow-up study to validate the algorithms developed during the initial study.
Local startup licensing technology from UC Davis aims to reduce energy costs and environmental impact
The University of California, Davis and RePurpose Energy, a clean energy startup, have executed a licensing agreement for an innovative system that repurposes batteries from electric cars to use as energy storage systems with various applications, like solar power. The license, negotiated by InnovationAccess, the university’s office for technology transfer, provides RePurpose access to commercialize the technology developed at UC Davis.
As battery technology has advanced, its use has expanded into many applications, with a particular impact on the increased adoption of electric vehicles. Over the last ten years, battery powered electric cars have increased dramatically, reaching 3.2 million in 2020.
With this rapid growth comes an imminent challenge — how to dispose of all of those batteries that need to be replaced. Over time, batteries lose their storage capacity and require special methods for disposal due to their toxic components. For electric vehicles that begins when batteries lose 25 to 30 percent of their charge capacity, often occurring after five to ten years of use.
Jae Wan Park, professor Mechanical and Aerospace Engineering at UC Davis looked at this from a different perspective, one of opportunity.
“While these batteries can no longer meet the needs to power the vehicle, they still have plenty of energy capacity to service other applications,” said Park. “We see an opportunity not only to reduce the environmental impact of batteries, but to also offer more affordable clean energy solutions.”
Park, who had been researching fuel cell technology for over a decade, turned his attention to exploring different applications. He noticed a parallel trend happening in the industry with the rapid deployment of solar panels. In 2011, he purchased a used battery on eBay and retrofitted it to test the idea at his home with a solar panel system.
After almost a decade of researching and innovating, Park received a grant from the California Energy Commission to install energy storage in a microgrid at the Robert Mondavi Institute Winery using retired electric vehicle batteries paired with a solar panel system. This allowed his team to prove a scaled up, 300kw commercial system.
One of the biggest challenges was quantifying the used batteries’ state of health and balancing the capacity of each unit for optimal efficiency and safety. Initially the team labored through a three-hour process of discharging and then recharging each battery, but they quickly realized the need for a more efficient approach. Over time, they developed a better method that measures the response to an electrical pulse and uses machine-learning algorithms to determine the state of health in less than 15 seconds.
In 2018, Park decided to commercialize this idea and founded RePurpose Energy with his graduate students Ryan Barr and Joseph Lacap, who have become COO and CTO, respectively. To do so, he enlisted the help of the UC Davis Venture Catalyst team.
“I recall the realization that the entire team was comprised of engineers without a firm grasp on what needed to be done to make this commercially viable,” Park said. “We were pleased to be connected with the resources through Venture Catalyst to guide us in the right direction and help get us started.”
The team quickly began to receive attention, winning the grand prize in the 2019 Big Ideas contest supported by the University of California Office of the President as well as a $12,500 award from the UC Davis Big Bang! Business Competition. More recently, the U.S. Green Building Council selected RePurpose as one of the top 10 green building products for 2021.
The company is now engaged in validating a 1.2-megawatt system in an industrial complex in Sacramento thanks to a $3 million grant from the California Energy Commission. The need for such reserves in power is growing with the increased power outages in Northern California due to wildfire risk, especially in industrial applications with refrigerated goods.
“We are always thrilled to see companies like RePurpose bring innovations from UC Davis to the market that address important needs in our society,” said Bill Tucker, interim associate vice chancellor for Innovation and Technology Commercialization. “That connection between entrepreneurship and innovation is critical to helping our regional economy flourish.”
Soheil Ghiasi, a professor in the UC Davis Department of Electrical and Computer Engineering, has launched a startup, Storx Technologies, to commercialize a noninvasive pulse oximeter that can measure a baby’s blood oxygen saturation while it is still in the womb. His innovation may lead to safer deliveries and enable new fetal research.
Since he joined the UC Davis faculty in 2004, Ghiasi’s main focus has been application-specific embedded computers.
“These are computers that don’t look like computers,” said Ghiasi. “They are pretty much everywhere. Some are in low-end devices like toys or coffeemakers. But some have high-end, mission-critical requirements, and are integrated into military applications, airplanes or medical devices.”
He became interested in fetal monitoring technology after his daughter was born. During her delivery, the readings on the fetal monitors, which measure heart rate and uterine contractions, fell into a gray zone, indicating possible low oxygen levels. Inadequate oxygen supply to the fetus can result in hypoxic brain injury, and can lead to disabilities or death.
“Some patterns are obviously alarming so doctors do an emergency C-section,” said Ghiasi. “And some patterns show there isn’t a problem. But there’s a gray area in the middle, which is referred to as ‘non-reassuring’ fetal heart rate traces. ”
Because of his daughter’s non-reassuring heart rate, she was delivered via C-section. Both mother and daughter were fine, but the major abdominal surgery meant a long recovery for his wife.
Afterwards, Ghiasi learned that non-reassuring fetal heart traces are not uncommon during delivery. He also learned that in the United States, C-sections account for almost a third of all births — a rate higher than most developed countries — without resulting in better health outcomes for mothers and babies.
“I was new to this. I did some research and connected with colleagues at UC Davis Health who work on the obstetric side as well as those working with animal models. There’s a large body of research about fetal oxygen levels,” said Ghiasi.
With current fetal monitors, the health of a baby is inferred from her heartrate and mother’s uterine contractions, but the baby’s exact level of oxygen is not known. Ghiasi began to think about a non-invasive way to determine the fetal blood oxygen levels in utero, rather than solely relying on cardiac patterns, to know when a fetus was truly in distress and in need of delivery by C-section.
He pictured something similar to a pulse oximeter, the inexpensive devices that are widely used in healthcare and can be clipped onto a finger, earlobe, or even toe to measure blood oxygen saturation.
“When blood is not oxygenated it looks darker, and when it’s oxygenated it looks redder. The pulse oximeter shines light and registers how much of the light is absorbed. Then, it performs some color analysis to compute the fraction of red blood cells that carry oxygen,” explained Ghiasi.
Developing a noninvasive fetal monitor
In fall 2018, Ghiasi received a $1.2 million grant from the National Science Foundation to work on improving fetal monitoring.
Along with Daniel D. Fong, a Ph.D. student in his lab, Ghiasi designed a noninvasive transabdominal fetal oximeter that transmits near-infrared light through the mother’s abdomen.
The small amount of tissue-diffused light is sensed on the maternal abdomen; the measurements are subsequently analyzed to remove the contributions of mother’s tissue layers and to infer measurements that are strictly due to the fetal tissue. Such measurements are then utilized, similar to conventional pulse oximeters, to compute the baby’s blood oxygen saturation.
They also worked with Herman Hedriana and Aijun Wang at UC Davis Health; Andre Knoesen, Vivek Srinivasan and Weijian Yang at UC Davis; Michael G. Ross at UCLA; and M. Austin Johnson, previously at UC Davis Health and now at the University of Utah.
“Through collaboration with all of these colleagues we were able to successfully test our innovation in animal models,” said Ghiasi
Next up is testing the novel fetal monitoring system with humans.
“We have approval to test patients who are at least 36 weeks pregnant and are coming in for routine checks. If that goes well, the next phase will be to test this during labor. That would be the ultimate application,” said Ghiasi. Read more >
AJ Cheline, UC Davis Office of Research, 530-752-1101, firstname.lastname@example.org
Soheil Ghiasi, Department of Electrical and Computer Engineering, 530- 752-0836, email@example.com
Verndari Inc., a biopharmaceutical company, announced today (April 29) that it will begin preclinical testing this week at the University of California, Davis, Mouse Biology Program to evaluate a potential vaccine and delivery system for COVID-19.
Verndari’s VaxiPatch is a single-dose vaccination kit that uses a dermal patch with a metal microneedle array to deliver vaccines. The company states that the technology eliminates the need for refrigeration, facilitates high-volume, automated manufacturing of vaccines and can potentially be self-administered on the subject’s arm.
Sierra Biopharma, a biotechnology startup founded on intellectual property developed by researchers at the University of California, Davis, is developing a new therapeutic approach to treat autoimmune diseases.
Inventors and co-founders Robert Fairclough and Vu Trinh have set an initial focus on treating myasthenia gravis, a chronic autoimmune disease that affects 1.4 million people globally. Myasthenia gravis causes use-induced muscle fatigue and generalized muscle weakness that can result in life-altering difficulties with seeing, swallowing, talking and walking. The disease stems from a mistake made by the immune system in producing antibodies that bind to neurotransmitter receptors, triggering the immune system to destroy the folded post-synaptic muscle fiber membranes that are vital for repeated muscle contractions.
Sierra Biopharma is taking a new approach to treat the disease with an antigen-specific therapy that attacks the cause of the disease without suppressing the entire immune system. To accomplish this, the company is developing a biologic compound that not only binds to, neutralizes and clears the pathogenic antibodies, but also binds to and eliminates the memory B-cells responsible for producing more of the pathogenic antibodies.
Fairclough and Trinh recently completed the Biotech Innovation Gallery (BIG) Accelerator program led by UC Davis Venture Catalyst. The program provides leaders of UC Davis-associated biotech startups with training on how to develop an effective business model, strategies to protect intellectual property and guidance on how to pitch to potential strategic partners and investors.. The year’s program concluded with a showcase event where 22 startups, including Sierra Biopharma, pitched their value proposition to venture capitalists and biotech companies attending the annual J.P. Morgan Healthcare Conference in San Francisco.
“It was amazing to be surrounded by so many fantastic biotech startups from UC Davis,” said Fairclough, an emeritus associate professor in the UC Davis Department of Neurology. “We were able to pitch our research to so many VCs and companies and they provided us with great insight and guidance in how best to proceed with the company’s development.”
Sierra Biopharma is now scaling up production of the therapeutic biologic and plans to complete the proof of concept and preclinical work in the next six months. The company has accepted an invitation to participate in the 2020 Science2Startup showcase event — a forum for top scientists from around the world to present their ideas and interact with leading investors and executives in the Boston biotechnology hub.
Christian Nansen, an associate professor in the UC Davis Department of Entomology and Nematology, has launched a startup, Spectral Analytix, to apply machine vision and machine learning to the classification and sorting of seeds and insects.
“The idea is to combine machine vision, robotics and machine learning so you have an automatic eye, an automated arm and an automated brain,” said Nansen. “If you automate those three components you end up with a system that can automatically classify or sort whatever you are working with.”
For the machine “vision,” Nansen works with hyperspectral cameras, which collect data at very high spectral resolution. “The camera on your phone divides light into three wavelengths—red, blue and green,” said Nansen. “You can think of it like a cake with three layers—for each pixel you have three values. With a hyperspectral camera you have 250 bands, so the ‘cake’ now has 250 layers.”
Hyperspectral imaging is used for a wide variety of applications, from mining to surveillance to investigating works of art. Paired with machine learning, hyperspectral imaging is widely used in food processing and recycling industries for sorting.
Several aspects of crop breeding and commercialization of crop seeds involve inspection and quality control.
“Often, these inspection and control measures are time consuming and rely on highly trained technicians. They may also be associated with consistency challenges due to human error. So, replacing them with automated procedures can improve such inspection and control measures and also enable people to focus on other tasks that involve higher levels of complexity,” said Nansen.
EicOsis LLC, a UC Davis-enabled startup, announced yesterday (Oct. 15) it has been awarded a $15 million grant from the National Institute on Drug Abuse (NIDA) to support human clinical trials of a non-opioid pain therapy.
The technology of the lead compounds was developed at UC Davis in the lab of Professor Bruce Hammock. Hammock co-founded EicOsis (pronounced eye-co-sis) in 2011 to provide a new analgesic solution for neuropathic pain management without the side effects of opioids and other standard pain therapies. The patented technology of the lead compounds developed by Hammock were licensed exclusively to EicOsis from UC Davis.
Hammock, who joined the UC Davis faculty in 1980, is a distinguished UC Davis professor and holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center.
Delix Therapeutics, founded by David Olson, an assistant professor in the Department of Chemistry and the Department of Biochemistry and Molecular Medicine, is investigating whether neural plasticity–promoting drugs can lead to new treatments for depression, anxiety and related disorders.
Atrophy of neurons in the prefrontal cortex of the brain is known to play a key role in depression and related diseases. The known antidepressant properties of ketamine, a dissociative anesthetic, may stem from its ability to promote neural plasticity–enabling neurons in the prefrontal cortex to rewire their connections.
In 2018, Olson and his team demonstrated that a wide range of psychedelic drugs, including well-known compounds such as LSD and MDMA (commonly called Ecstasy), increase the number of neuronal branches, the density of small protrusions on these branches (dendritic spines) and the number of connections between neurons. Rats treated with a single dose of DMT (N,N-Dimethyltryptamine), a psychedelic compound found in Amazonian herbal tea known as ayahuasca, showed an increase in the number of dendritic spines, similar to that seen with ketamine treatment. Their work was published in the journal Cell Reports.
While drawbacks of using compounds such as LSD and MDMA as therapeutics include their hallucinogenic and psychostimulant effects, in a significant development Olson and his team discovered how to decouple the beneficial effects of neuroplasticity-promoting compounds from the unwanted hallucinogenic side effects.
This discovery could potentially open doors for the development of novel drugs to treat mood and anxiety disorders. Olson and his team have proposed the term psychoplastogen to describe this new class of “plasticity-promoting” compounds.
The company is investigating several distinct novel chemical scaffolds and molecules capable of promoting plasticity in order to develop safer and more effective alternatives to treat depression and related disorders.