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UC San Diego Health Sciences

Category: Research

— Research

My So-Called Pandemic Life

How the COVID-19 pandemic turned out to be a major training experience for one graduate student-researcher

— By Gabriela Goldberg

The thought of another day looking at a blank screen made me want to rip my hair out. We were one month into the COVID-19 lockdown, and after cleaning out my incubator of cells and brain organoids, and cleaning my mouse cages, I was tasked with writing a grant proposal. I had two months until the deadline. But there I was, one month in, and I had nothing.

It was difficult to stay motivated. Before our labs closed down, I had finally gotten the hang of culturing brain organoids, and I was getting promising data for my thesis project. I was in the third year of my PhD program — the year where you’re told you will be the most productive and get the majority of your data before the infamous fourth-year slump. I didn’t expect to spend this productive year at home baking sourdough bread and brewing kombucha while procrastinating writing a grant.

Staring at the blank screen wasn’t working, and I knew I needed help. I reached out to my classmate, Margaret, and she came up with a plan to stay focused.

The next morning, I hopped on a Zoom call with Margaret, and she said, “Got your coffee? Ok, let’s write.”

I minimized the Zoom window so she was in a small box in the corner of my screen while we wrote together, following a productivity hack known as the Pomodoro Technique. It was quiet for 25 minutes. When the bell rang for our break, we chatted while we sipped our coffee until the next bell signaled us to get back to work.

After several morning coffee Zoom calls with Margaret, I finished writing the grant with a couple of days to spare. It was the first time I had felt accomplished since the lockdown started. Although I later found out that the grant didn’t get funded, it was a major training experience for me. My experience writing it during the beginning of the COVID-19 pandemic changed how I tackle obstacles in my PhD journey. Now, I’m better at managing my time, and I’m not afraid to ask for help when I need it.

Looking back, the third year of my PhD was a very productive year both at and away from the bench.

Gabriela Goldberg is now a fourth-year student in the Biomedical Sciences Graduate Program at UC San Diego School of Medicine. Goldberg is completing her thesis research in the laboratory of Alysson Muotri, PhD, where she uses brain organoids — small “mini-brains” in a dish derived from stem cells — to study how brain cells interact during development.

— Research

A ROOM OF ONE’S OWN

A physician-scientist recalls how his team quickly got a specialized facility up and running so researchers could work with live coronavirus, speeding the search for new treatments and preventions

— By Aaron Carlin, MD, PhD

My goal as a physician-scientist is to ask clinically important questions, conduct experiments in the laboratory to answer those questions, and translate those research concepts back to the bedside to help patients.

But when COVID-19 exploded, there was nothing but questions. How does this virus hurt people? How can we treat it? How can we prevent it?

I wanted to help answer these questions and so did the UC San Diego research community. Many of these questions couldn’t be answered without performing experiments using infectious SARS-CoV-2 in a biosafety level 3 (BSL-3) facility.
Combining specialized engineering with fastidious work practices, a BSL-3 allows research on important, highly pathogenic organisms to be done in a manner that is safe for both the researchers and for the community.

The UC San Diego BSL-3 became operational in April 2020, and we immediately developed a research program focused on SARS-CoV-2 and other emerging viruses. Together, with a small group of dedicated investigators that includes Davey Smith, MD; Ben Croker, PhD; Sandra Leibel, PhD, and Alex Clark, PhD, we worked tirelessly over two months to develop and optimize the protocols that allow us to conduct leading-edge research on SARS-CoV-2 pathogenesis, diagnosis, treatment and immunity.

Our COVID-19 BSL-3 lab now performs experiments with infectious SARS-CoV-2 for labs across the campus and the San Diego research community. This gives groups without experience working with pathogenic viruses the ability to perform critical proof-of-concept testing of their new COVID-19 rapid diagnostics, vaccines and treatments, in addition to experiments that increase our understanding of the virus and its pathogenesis. Some of these discoveries, like our identification of heparan sulfate as an attachment factor for SARS-CoV-2, have led to novel therapeutic approaches to treating this disease, while others may become the diagnostic, treatment and vaccination approaches of the future.

Sometimes the worst events bring out the best in us. I am thankful for the generosity of many within the UC San Diego community that have contributed to the BSL-3 and for the dedication of our biosafety staff. I am amazed at the cross-disciplinary collaborations that have developed during this pandemic at UC San Diego and their potential to make ground-breaking discoveries.

“When I go to work, my five-year-old daughter asks me, “Are you going to the BSL-3 today to fight COVID-19?” I tell her proudly that I am. But, more importantly, I hope that someday soon children won’t have to think about pandemics or viruses.”

Aaron Carlin, MD, PhD, is an assistant professor of medicine at UC San Diego School of Medicine. The Carlin Lab studies the genetic interplay between viruses and human cells and the factors that determine whether the invader or the host wins.

— Research

AIR APPARENT

How aerosols have contributed to the silent spread of COVID-19 around the globe

— By Kimberly Prather, PhD

Over the course of the COVID-19 pandemic, it became clear that the predominant way people were becoming infected was through air transmission — and this was not being acknowledged. As an atmospheric chemist who has spent my entire career studying aerosols, I know first-hand how far aerosols can float through the air. I became deeply concerned and thus have spent much of the past year focusing on communicating the latest scientific evidence about the major role of aerosol transmission in silently spreading SARS-CoV-2 around the globe.

During a “normal” year, my research at UC San Diego focuses on understanding how aerosols — microscopic airborne particles — affect our atmosphere, climate and human health. I am particularly interested in bioaerosols and pathogens that get ejected from the ocean in coastal regions. Sorting out the impacts of aerosols in field studies is challenging, so my colleagues and I have transferred the full complexity of the ocean and atmosphere into the lab at Scripps Institution of Oceanography using a large wave channel. This unique approach to isolating the ocean/atmosphere system allows us to study how physical, chemical and biological processes in the ocean affect the composition of marine aerosols and their ability to seed marine clouds over 71 percent of the Earth, which strongly impacts our climate.

Throughout the pandemic, I have been deeply concerned that public health agencies, including the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC), were too narrowly focusing their guidance on protecting against large respiratory droplets. This resulted in an emphasis on advising people to clean surfaces, something now labeled as “hygiene theater.”

Changing this “droplet dogma” has required an intense international grassroots effort imploring the medical community to update their longstanding picture of the transmission modes of respiratory viruses, and at the very least to apply the precautionary principle to better protect health care workers and those at high-risk.
Decades of scientific research have shown that large droplets fall within six feet. Aerosols float. In fact, they can travel thousands of miles around the globe. The only way to explain the thousands of documented superspreader events is by including aerosol transmission. The vast majority of outbreaks have occurred indoors — in places like churches, cruise ships, gyms, nursing facilities and bars.

These outbreaks all have one thing in common: all of those who were infected shared the same indoor air. Similar to the way cigarette smoke builds up and spreads across a room, it only takes one person infected with COVID-19 to expose everyone in poorly ventilated indoor spaces.

Over the past year, I have co-authored several high-profile publications on aerosol transmission along with other aerosol and medical experts, including UC San Diego’s Robert “Chip” Schooley, MD. In The Lancet, for example, we outlined 10 lines of evidence supporting the airborne transmission of SARS-CoV-2 as the predominant pathway. I have done more than 1,000 media interviews on this topic. In addition, I’ve spent significant time advising government officials at local and federal levels on how to safely re-open, encouraging them to focus on cleaning the air. I have also worked closely with a group of UC San Diego experts to help the San Diego Unified School District safely reopen schools.

“And I’ve had conversations with numerous high-ranking officials, including Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, to alert them to the importance of acknowledging the role of aerosol transmission.”

And I’ve had conversations with numerous high-ranking officials, including Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, to alert them to the importance of acknowledging the role of aerosol transmission.

Our work to fully understand the role of aerosol transmission is just getting started. It is highly likely that SARS-CoV-2 is not the only respiratory virus that is spread through aerosols. A retrospective analysis of the transmission pathways for other respiratory viruses is already underway.

I am encouraged that we are starting to see our communication efforts pay off. WHO and CDC have updated their guidance. I am proud of the impact this international group of determined scientists has had in turning our understanding of COVID transmission around.

Once the role of aerosol transmission is clearly acknowledged globally, then we know what steps to take to help end this pandemic. Efforts need to focus on enhancing ventilation and filtration to improve air quality indoors where most infections occur. The long-term benefits of having cleaner indoor air in homes, schools and businesses are enormous. They extend well beyond this pandemic and can improve public health for generations to come.

Kimberly Prather, PhD, is a Distinguished Chair in Atmospheric Chemistry at US San Diego, where she holds a joint appointment at Scripps Institution of Oceanography and the Department of Chemistry and Biochemistry. She also serves as director of the National Science Foundation’s Center for Aerosol Impacts on Chemistry of the Environment.

— Research

History Repeats

Future pandemics are inevitable. We must prepare now.

— By Davey Smith , MD, MAS

As 2019 turned into 2020, my husband and I took my parents on their dream vacation: a cruise around New Zealand and Australia. At the same time, a new virus, eventually designated SARS-CoV-2, was breaking out in China, causing a new disease that would be called COVID-19.

By the second week of the cruise, I was eager to get home. Despite reports that it was “contained,” the virus in China still clearly raged. In the modern era of travel, a respiratory virus cannot be contained. Indeed, cases of SARS-CoV-2 had already been reported in Italy and Seattle and in other cruise ships sailing the Pacific. It was on its way everywhere.

Thankfully, my family and I remained healthy. At the time, there were no known, effective treatments specific to COVID-19 and, of course, no vaccines. I had already lived through one pandemic. I knew there were challenges ahead. I knew we would need science to save us. In 1996, when I started my internship and residency at UC San Diego Health, hospitals were filled with patients dying of AIDS, the end-stage of HIV infection.

“Every shift began at the nurses’ station where I would ask if any of my patients had died overnight.”

But before my residency ended in 2000, many of my patients were leaving their hospital beds and going home because scientists, including several at UC San Diego, had developed antiviral medications that prevented HIV from ravaging their immune systems. Today, people with HIV who have access to these medications and are able to take them regularly can lead long, happy lives.

Two decades later in July 2020, the SARS-CoV-2 virus was in full swing in San Diego. Hospitals were filled with patients suffering from COVID-19, and I was back on the hospital wards that were once filled with HIV patients, an infectious disease physician caring for them.

I was putting in long hours, often for days on end, to keep my patients alive. And I was again thinking we needed science to save us. And, we needed to be better prepared for the next pandemic, which would inevitably come.

SCIENCE
SAVES LIVES

Action was needed. We set up international trials to study new vaccines and treatments for COVID-19, such as the ACTIV-2 study, which opened in August 2020. We found effective therapies, vaccines and testing methods and implemented them for our community by setting up large-scale testing, vaccine and treatment centers. We also worked with other regional health care providers. These efforts undoubtedly saved thousands of lives, yet they were all aimed at ending the current crisis. If we want to avoid history repeating itself, perhaps in even more devastating terms, preparations must be made now for the next pandemic, whatever its cause.

PLANNING
FOR PREVENTION

In October 2020, we began outlining the structure of a new institute at UC San Diego. The Pandemic Response to Emerging Pathogens, Antimicrobial Resistance and Equity (PREPARE) Institute is now poised to become a global leader in preparing for, responding to and thwarting pandemics. By connecting interdisciplinary scientists from UC San Diego and other local scientific partners, including the J. Craig Venter Institute, the La Jolla Institute of Immunology, the Sanford Burnham Prebys and Scripps Research, the PREPARE Institute will provide much-needed infrastructure and personnel to respond rapidly to future pathogens.

Effective collaboration across departments, divisions and institutions will equip the PREPARE Institute to rapidly translate lab discoveries to the clinical/patient interface where they can help stem epidemics before they consume our lives.

Together, we can leverage collective knowledge and innovation to reduce the impact of pandemics. Our members are experts in surveillance, proactive therapeutics and vaccine research, health behaviors and public policy. We are gearing up to defend against any infectious disease vector — bacteria, viruses, parasites, fungi or yet-to-be-discovered pathogens.

This is a massive undertaking; public and private support are critical. Whether you are a scientist, CEO, community member or philanthropist, you can help the PREPARE Institute redefine how pandemics are managed. Your knowledge, your innovation and your voice may save countless lives. For information about membership, services or gifts, please email prepare@ucsd.edu.

Davey Smith, MD, MAS, is the chief of the Division of Infectious Diseases and Global Public Health and professor of medicine at UC San Diego School of Medicine.

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— A Letter from David A. Brenner, MD

Life Became a Laboratory

Life is change. It’s about adapting to new situations and circumstances that ensure not just survival, but a presumably better, stronger future.

Viruses are especially good at this, mutating constantly and continuously, often at dizzying rates, for billions of years.

The coronavirus known as Severe Acute Respiratory Syndrome Coronavirus 2 of the genus Betacoronavirus, or slightly more colloquially, SARS-CoV-2, isn’t new at this game of life. It likely existed in other forms in other animals before jumping species, but it was new to us.

Now, we are painfully familiar. The unexpected debut of SARS-CoV-2 in late-2019 and the pandemic that followed have provoked all manner of subsequent change in all manner of ways. Like the virus and its variants, life as we knew it will never be the same.

We are changed and changing, often in ways that have made us wiser, stronger and better. Nowhere is that more evident than in the response of faculty, students and staff at UC San Diego, who pivoted their attentions, expertise, talents and resources to confronting and combatting this highly infectious, often deadly virus festooned with trademark spikes of protein on its surface.

The scope of these efforts and contributions are astounding, from helping pin down the virus’ origins in China, Europe and North America to parsing the threat of aerosolization and understanding the critical performance of neutralizing antibodies.

While much of society necessarily shut down, research at UC San Diego continued, affected but unabashed, even expanding in some cases. For example, we built from scratch a new biosafety level 3 lab capable of handling highly infectious pathogens and pop-up labs for measuring viral loads in patients. We created high-throughput systems to process daily thousands of COVID-19 test samples, including wastewater from our buildings, and to sequence and analyze all viral genomes. We developed a cellphone-based technology to alert users when someone close to them had tested positive.

Researchers shifted priorities, moving robots and equipment around to create new programs in a matter of days when the norm is more often measured in years. It was hard, often exasperating, work. A working scientist might get only one scheduled day in the lab each week, part of vital and exacting safety protocols. It might be only enough time to do a bit of “wet work,” then go home to analyze the data. Zoom calls multiplied like, well, viruses. People grumbled, but they carried on and important work was done.

Perhaps nowhere was the depth and breadth of our expertise more obvious than in our participation in three of the four first and biggest clinical trials for a COVID-19 vaccine: Moderna, AstraZeneca and Johnson & Johnson. UC San Diego Health scientists and the thousands of San Diegans who volunteered in these trials were players in the development of these vaccines. With critical help from the Altman Clinical and Translational Research Institute, they moved the needle. We have learned a lot. We have earned a lot: To date more than $30 million in new grants specifically funding COVID-19-related projects, with more in the works. And from these lessons and efforts, we prepare to change even more with an aptly named project called PREPARE, which will bring together people, programs and infrastructure to be ready for pandemics to come.

“When you are finished changing, you are finished”

— Ben Franklin

The pandemic changed everything, but not our research mission to make the world a better, healthier place. That remains unchanged and our work unfinished.

Sincerely, Signature of David A. Brenner David A. Brenner Vice Chancellor, UC San Diego Health Sciences

Decenber 10, 2021

— Research

Tested & Testing

A synergistic effort that helped keep the UC San Diego campus, local schools and community safe.

By Heather Buschman, PhD

Concern for his pregnant wife and soon-to-be-born twin girls prompted one scientist’s obsession with COVID-19 testing,
ultimately leading to a collaborative effort that helped keep the UC San Diego campus, local schools and community safe, and made numerous research projects possible.

Spring

2020

Expecting twin girls, Gene Yeo and Corina Antal thought it would be fun and meaningful to hold their baby shower on International Women’s Day.

The couple was “beyond excited,” but also anxious. They were expecting not just identical twins, but monoamniotic-monochorionic (MoMo) twins, which means the fetuses shared a single placenta and amniotic sac. It’s an extremely rare type of pregnancy, occurring in just one in 60,000 pregnancies. Pregnancies with MoMo twins are considered very high-risk because of heightened dangers of umbilical cord entanglement.

That much Yeo and Antal knew. Now, a new danger loomed.

The baby shower was March 8, 2020. Earlier that week, California Governor Gavin Newsom had declared a state of emergency due to the spread of a novel coronavirus that had only recently been formally named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the cause of coronavirus disease-2019, or COVID-19.

At their baby shower, Yeo and Antal prudently asked everyone to wash their hands as they arrived. Guests laughed at the novelty of elbow bumping instead of hugging or shaking hands, still becoming accustomed to the new public health recommendation intended to help prevent the spread of COVID-19.

Over the next few days, the first local community case would be reported in San Diego County, the World Health Organization would officially declare a COVID-19 pandemic and schools throughout San Diego County would close.

“As scientists, we were not only reading all the studies we could find on MoMo twins, but now we were also learning all we could about COVID-19,”

said Yeo, PhD, a professor of cellular and molecular medicine at UC San Diego School of Medicine. Antal, PhD, is a postdoctoral researcher at Salk Institute for Biological Studies.

Yeo leads a research team focused on RNA, how cells translate the genetic material into proteins, how these processes are regulated and how they can go wrong in diseases like adult-onset muscular dystrophy and ALS. But the COVID-19 pandemic was a crisis of global proportions, and Yeo felt he needed to do something, to help make the world safer for his growing family.

A few days after the baby shower, Yeo logged into Slack, where many other local researchers were also eager to help.

With their own research programs paused, conferences cancelled, lab teams working remotely and a lot of leading-edge technology shut down and gathering dust, these bored, anxious, smart people were keen to use their time and talents to at least help blunt the coming waves of COVID-19 cases.

What started as a small online discussion for local researchers — a support group of sorts — exploded into a round-the-clock frenzy of activity. Within a few months, nearly 1,000 scientists were sharing information, forming research collaborations, offering available research reagents, technology, sourcing materials and volunteers. (The community later became screencovid.info.)

1000 Scientists Sharing Information

At the time, SARS-CoV-2 was not yet highly prevalent in San Diego. The main and pressing concern was personal protective equipment (PPE) for health care workers. Sudden, high demand worldwide for surgical masks, N95 respirators, paper gowns and gloves produced alarming shortages.

In California, health systems had some wiggle room to shore up supply chains and implement emergency plans, but in places like New York City, hit by one of the first and worst surges of cases in the U.S., some health care workers were forced to repeatedly reuse masks, or even wear trash bags instead of medical-grade gowns. The Slack community of San Diego scientists zeroed in on the PPE problem with unprecedented clarity and cooperation. Yeo helped facilitate that effort, but he had other worries too.

“Personally, I was terrified. Here’s the beginnings of a pandemic and my wife is pregnant, right smack in the middle of it. I was very worried about her and the babies.”

— Gene Yeo

“Due to the difficulty of the pregnancy, we had to go to the hospital often for checkups. I was worried about people around us being masked, about our physicians and nurses getting masks and about getting tested. All of that made me push for more testing for everyone.”

But in this moment, COVID-19 testing capacity was very limited. Until late-February, nasal swabs collected from patients in the U.S. suspected of having COVID-19 needed to be shipped to the Centers for Disease Control and Prevention (CDC) in Atlanta for testing. Getting results took days. Eventually, the U.S. Food and Drug Administration (FDA) allowed hospital laboratories that meet federal regulations for clinical diagnostic testing (CLIA certification) to develop their own in-house tests for COVID-19. That included UC San Diego Health’s Center for Advanced Laboratory Medicine, which ramped up quickly. In mid-March, UC San Diego Health was performing just 20 COVID-19 tests per day; a month or so later, it was performing thousands daily, a rate that continues.

With severely limited supplies, instrumentation and staffing, most testing labs prioritized patients with symptoms of COVID-19, but emerging data suggested the coronavirus was also being spread by asymptomatic people — those who carried and spread the virus without any signs of illness.

“At that time, I wished we had had a better idea of how prevalent the virus was in the community,” Yeo said.

“I knew I’d sleep better if we knew that people, even those without symptoms, were being regularly tested and that those testing positive were being appropriately isolated and treated. That’s what they were doing in Singapore, China, Taiwan and other places. But here we had this silent spread.”

— Gene Yeo

Yeo reached out to a friend and colleague who also knows RNA, Rob Knight. Knight had pioneered the use of bacteria-specific RNA as a “barcode” to read what’s living in a mixed sample, whether soil, ocean water, human stool or just about anything. Over the past decade, he and his team figured out how to scale up the approach. Now, in a global effort known as the Earth Microbiome Project, researchers worldwide are cataloging which bacteria and viruses live where, and determining how the makeup of each of those unique communities, called microbiomes, influence human and environmental health.


The lab of Rob Knight, PhD,

(left) re-deployed staff and resources to help build the EXCITE testing platform, screen wastewater from campus buildings for the presence of SARS-CoV-2 and test surfaces for the virus.




Knight was sheltering in place at home with his partner, a bioinformatician, and their eight-year-old daughter, struggling to balance two work and one school Zooms simultaneously, in a small house not intended for it.
Knight is originally from New Zealand, a country known for handling the COVID-19 pandemic differently — and very successfully. Yet even early on, he recognized that his home country’s ability to enforce stricter lockdowns and the advantage of being an island made his family’s situation a bit different than the one he faced in the U.S. Because the COVID-19 case rate was always low in New Zealand, they didn’t need to invest in as much technology to solve the problem.

“It’s the difference between setting your toast on fire, in which case you just need a cup of water to put it out, versus your whole house is on fire and you need a fire truck,” said Knight, PhD, professor at UC San Diego School of Medicine and Jacobs School of Engineering and director of the Center for Microbiome Innovation.

“So we decided to build the fire truck.”

Yeo and Knight Slack-messaged and emailed everyone they could think of in San Diego to ask how many thermal cyclers they had.

“We had this crazy plan to bring them all together in one spot to run tests,”

— Gene Yeo

“And then Louise chimed in on Slack and said that she not only had the instruments, she’d been miniaturizing the COVID test and it’s all in her lab, just one floor up from mine.”

Thermal cyclers and PCR:

How SARS-CoV-2 is detected.

Louise C. Laurent, MD/PhD
Vice-Chair for Translational Research and Director of Perinatal Research for the Department of Obstetrics, Gynecology, and Reproductive Sciences

At the time, Louise Laurent already had what sounds like multiple jobs:

As a perinatologist, she cares for women with high-risk pregnancies. She runs a research lab focused on understanding the molecular mechanisms involved in human development and looks for molecular clues that could help predict or diagnose pregnancy complications. She’s also a mother of four: two in high school and two in college.

“I’ve long been interested in the process of fetal development, labor and birth — something we all go through, yet we don’t understand all that well. Women’s reproductive health has always been a little bit of a second-priority type of thing when it comes to research and funding,” said Laurent, MD, PhD, professor of obstetrics, gynecology and reproductive sciences, vice chair for translational research and co-director of the Center for Perinatal Discovery at UC San Diego School of Medicine

The due date for Yeo and Antal’s twins was fast approaching. At one of the couple’s hospital visits, they were pleasantly surprised to see Laurent, the on-call perinatologist, walk into the room. She went over the monitoring and birth plan with them.

“It was so funny to suddenly see this person that I’d been talking to professionally by email about thermal cyclers, here to help us take care of our twins, too,”

— Gene Yeo

In early April, Antal was admitted to Jacobs Medical Center at UC San Diego Health for observation.

On April 14, at 32 weeks gestation and via Cesarean section, Antal and Yeo welcomed their MoMo twins, Emilleen and Emabelle, who each weighed approximately three pounds.

Monoamniotic

Despite their umbilical cords being knotted together, there were no critical complications at birth. But because both twins were high-risk and born a bit prematurely, the girls were admitted to the neonatal intensive care unit (NICU) for observation. Yeo and Antal visited their “California burritos,” as they called them, in the NICU every day, masks on.
“I always looked around just to make sure that all the nurses and doctors had their masks on as well,” Yeo said.

“And it was scary, and almost surreal, that we just had these fragile babies in the middle of what felt, at times, like an apocalypse.”

Between NICU visits, the quest to test helped Yeo channel his anxious energy. RNA is a notoriously finicky molecule that easily degrades. Yeo, Knight, Laurent and their teams countered with experience and resources.

Knight’s lab had something most academic labs do not: Automated lab machinery that can extract RNA from many distinct samples simultaneously. Laurent’s lab was already running concurrent qPCR tests on RNA as molecular clues to predict pregnancy complications and working out how to miniaturize the process so they could run even more tests with fewer materials. Yeo’s lab had experience with computational biology. They introduced an information management system to keep track of samples, experiments and data.

“We glued all the pieces together, and had an idea of how we could track samples all the way through the workflow from extraction to qPCR to result,” Yeo said. “But the problem was still that we’re not virologists or epidemiologists.”

Yeo, Knight and Laurent teamed up with Slack community members Kristian Andersen, PhD, whose lab at nearby Scripps Research was known for using genomics and computational biology to investigate emerging infectious diseases, such as Zika and Ebola, and Lauge Farnaes, MD, PhD, assistant medical director at Rady Children’s Institute for Genomic Medicine.
The team set up an experiment: A drive-through site near Rady Children’s Hospital-San Diego, where they could collect nasopharyngeal swabs from study participants, all of whom were invited health care workers and firefighters.

In the first two months, the team screened more than 10,000 participants, mostly asymptomatic, and found that an average of two participants per every 1,000 carried SARS-CoV-2. In addition to looking for the virus itself (sign of an active infection), the researchers tested participants who hadn’t been diagnosed with COVID-19 to see if they had antibodies against the virus (a sign of a past infection), to better gauge the extent to which SARS-CoV-2 was spreading undetected.

Summer

2020

In mid-May, Emilleen and Emabelle were ready to graduate from the NICU.

“When we finally got home, it’s probably an understatement to say that I was a bit distracted by them,” Yeo said. “There were so many meetings, even when I was chairing a session or giving a talk, where one of the babies was screaming and I had to go grab her and hold her before I could continue.

“There were so many times I had to text Rob and Louise to say that I couldn’t make a meeting, but they have kids too, so they get it. Everyone has been so understanding. I even learned to delegate, to give more freedom and independence to the people in my lab, and they’ve done amazingly well.”

The COVID-19 screening study at Rady continued to hum along, boosted by a donation from philanthropists Gary and Jean Shekhter, but it wasn’t an easy or simple operation.

Volunteers and lab staff transported samples around town, from the drive-through to Yeo and Laurent’s labs on one side of UC San Diego’s La Jolla campus, to Knight’s lab on the other, to Andersen’s lab down the street.

The collection and testing process was not CLIA-certified, so any positive samples needed to be sent back to the clinical laboratory at Rady Children’s Hospital for re-testing, confirmation and communication to the participant.

“Everything we did was considered part of a research study, not a clinical diagnostic test,” Knight said. “The drive-through worked, but it wasn’t the most efficient or cost-effective process. We tweaked and optimized, learning everything there is to know about running a large-scale viral testing facility.”

Excite: Expedited COVID Identification Environment

In early July, COVID-19 cases surged in San Diego and the drive-through site closed down so staff could be redeployed to patient care. But soon after, the team’s original dream of “everything in one place” was realized, and a new COVID-19 testing facility was born: Expedited COVID IdenTification Environment, or EXCITE.

The Department of Pathology at UC San Diego School of Medicine had two small laboratory spaces they had been reserving for new faculty, but with hiring and onboarding delayed due to the pandemic, the empty space was offered to EXCITE.

Laurent submitted the paperwork to extend an existing CLIA license, previously granted to the Biochemical Genetics Lab in the Department of Pediatrics, to include EXCITE in late-August; approval came September 4. Eleven days later, the team completed clinical validation of their COVID-19 qPCR test.

EXCITE runs COVID-19 tests in a mostly-automated assembly line, from intake to RNA extraction to qPCR and detection. Samples to be tested are barcoded so technicians don’t handle private patient information. Everything is tracked by the laboratory information management system and, depending on the source, test results are reported directly to patients’ electronic medical records or the physician leading a partner program. All positive results are also reported to San Diego County’s public health office.

A bonus is redundancy. The lab runs COVID-19 tests on a different platform than the Center for Advanced Laboratory Medicine at UC San Diego Health, which Yeo says helps safeguard against shortages. If one site is down for some reason, the campus will still have the other.

Laurent says one of the upsides of the pandemic has been the opportunity to work with so many different people. Before EXCITE, she had worked with Knight on a few small projects to study changes in the gut microbiome during pregnancy. Yeo’s research lab is in the same building as hers.

“But it’s a lot different when you actually have to start a lab with someone — buy equipment, hire people and all that,” she laughs. Yeo calls the group his “COVID buddies.”

“We routinely run about 3,000 tests a day without really breaking a sweat and we could double that without too much trouble if we had to.”

— Louise Laurent, MD, PHD

Fall

2020

3000 Tests per Day

“We routinely run about 3,000 tests a day without really breaking a sweat,” Laurent said, “and we could double that without too much trouble if we had to.”

While the Center for Advanced Laboratory Medicine at UC San Diego Health continued to be the health system’s primary testing facility for tens of thousands of staff, patients and other community members, EXCITE played an integral role in UC San Diego’s Return to Learn program, a science-informed approach that allowed the university to continue to offer on-campus housing and in-person classes and research opportunities throughout the pandemic. Largely because EXCITE could provide regular asymptomatic testing of all students, staff and faculty, the university hosted approximately 10,000 students on campus in the fall of 2020, maintaining a positivity rate of less than 1 percent, generally 10 to 15-fold lower than the surrounding community.

But even Return to Learn didn’t max out EXCITE’s testing capacity. Testing services were soon extended to local fire departments and schools.

“I’m proud that we’re serving populations that weren’t necessarily the first priority in the pandemic — children, students, frontline workers,” Laurent said.

“We’re serving a need that might not otherwise have been served.”

Laurent and team quickly kicked EXCITE into high gear, managing 20 people working two shifts, seven days a week.

Winter

2020

On December 15, the first COVID-19 vaccines arrived in San Diego, going first to health care workers and COVID-19 testing and research lab staff.

“After nine months of relentless bad news, the announcement that a vaccine was developed faster than for any virus before was an amazing piece of good news — even leading some to think the pandemic would be over soon,” Knight said.

Vaccine optimism helped blunt the disappointment of the holiday season. None of EXCITE’s leadership was able to see extended family: Yeo’s parents live in Singapore, Laurent’s in Kansas and Knight’s in New Zealand. One of Laurent’s daughters was unable to come home from college in Canada for fear she wouldn’t be able to return to school. Knight’s daughter hadn’t touched another child in nine months. Yeo and Antal celebrated Emilleen and Emabelle’s first Christmas quietly at home, just the four of them, opening presents with their extended family over Zoom.

Then Came the Variants

On December 29, an EXCITE technician spotted the tell-tale “S dropout” in a test sample. The team drove the sample over to Scripps Research, where Andersen’s lab labored through the night to sequence the full genome of the virus in the sample. They confirmed the first known case of the B.1.1.7 variant in California. It was a local man in his 30s who had not recently traveled, indicating the variant was already spreading in the community.

“It’s not random chance that we were the first to detect B.1.1.7 in California. It wasn’t because it wasn’t anywhere else. It’s because we were looking for it,”

Knight said, “and because we already had highly trained EXCITE staff, sequencing built into our workflow thanks to close collaboration with Scripps Research, support from our own research lab members, as well as the cooperation of many campus administrative units that quickly turned around the various approvals we needed to be able to do this work with patient samples, between two different organizations.”

Spring

2021

More than a year into the COVID-19 pandemic, EXCITE has evolved into not just a high-throughput clinical testing lab, but also a research hub.

“We’re available to any researcher in San Diego who has a question about the virus that we can help answer through testing and sequencing. For example, how long does the virus survive on surfaces? What kills it? How does it evolve under certain conditions?” Laurent said.

Despite increasing vaccination rates, Laurent said it’s still critically important to understand where the virus lurks, who is most likely affected and how best to deploy resources.

“There are still many areas of San Diego, and the country, that are disproportionately affected by COVID-19 and experience a number of barriers to health care, testing and vaccination. We need to overcome these to reduce health disparities.”

To that end, Laurent is involved in two projects supported by Rapid Acceleration of Diagnostics (RADx) grants from the National Institutes of Health. One study seeks to maximize COVID-19 testing among pregnant women and children in an area of San Diego near the U.S.-Mexico border with the highest local incidence of COVID-19. In the other, a team is working to enhance asymptomatic COVID-19 testing capabilities at three regional community health centers in San Diego County.

Milestones:

In April 2021, Gene Yeo and Corina Antal celebrated Emilleen and Emabelle’s first birthday the same way they had all previous holidays. The four of them stayed home, Zooming with family. At one year old, the twin girls still hadn’t met their grandparents in person.

Sequencing Remains a High Priority

“We’re furiously trying to expand sequencing of positive samples so we can build phylogenetic trees — maps that help us track how the virus is evolving and when and where new variants of concern may be emerging,” Knight said.

“Fortunately, especially compared to one year ago, we have more funding and more equipment, and we are expanding sequencing capabilities rapidly.”

Sequencing SARS-CoV-2 samples also allows researchers to explore some interesting questions. For example, UC San Diego researchers are sequencing samples from patients with severe cases of COVID-19 in the intensive care unit to see if the viruses infecting them differ genetically from those causing milder disease in other people.

Another UC San Diego team is working with EXCITE to sequence SARS-CoV-2 samples repeatedly collected from the same patient over time. The patient has a blood cancer and has undergone chemotherapy, leaving him with next to no immune cells. For months, the patient has continuously tested positive for COVID-19 because his body has no way to get rid of the virus. As his physicians work to get him well enough to resume chemotherapy, researchers are sequencing his samples to keep tabs on how the virus may mutate as it replicates without restraint.

“It was hard at first, but as more testing happened and we were more reassured that the right behaviors were being adopted in our community, we realized that we’re going to be fine. The girls are thriving now.”

— Gene Yeo, PhD

On April 12, most of San Diego’s children — including Laurent’s — were finally given the option to return to in-person learning. They had been attending school remotely via Zoom for 13 months. The same week, Yeo and Antal celebrated Emilleen and Emabelle’s first birthday the same way they had all previous holidays. The four of them stayed home, Zooming with family. At one year old, the twin girls still haven’t met their grandparents in person.

“It was hard at first, but as more testing happened and we were more reassured that the right behaviors were being adopted in our community, we realized that we’re going to be fine. The girls are thriving now,” said Yeo.

If there’s a silver lining to the pandemic, Yeo said it’s that he was able to  be home all year, rather than traveling around the world giving talks, something he used to do almost on a weekly basis.

“Instead, I’ve had this once-in-a-lifetime opportunity to work with some amazing colleagues, to help keep people safe during a crisis and, most importantly, to learn how to be a father.”

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