Parinaz Fozouni was on winter break when she first heard about a new coronavirus outbreak in Wuhan, China. She was eager to get back to the lab—she realized that her work on HIV detection could apply to coronavirus.
As an MD/PhD student at UC San Francisco (UCSF), she had been studying HIV in the lab of Melanie Ott, MD, PhD, at Gladstone Institutes since 2016. When she first started working with HIV, she quickly became frustrated with the testing techniques that were available.
“HIV is an RNA virus but we don’t have any good detection tools to directly detect RNA,” explains Fozouni. “To test for the virus, we have to convert everything from RNA to DNA and then detect it in the DNA. This requires time and expensive lab equipment.” Fozouni wanted to find a way to simply and directly detect RNA without any additional manipulations or bulky equipment.
In late 2016, Jennifer Doudna, PhD, gave a talk at Gladstone about a newly discovered CRISPR protein called Cas13. Cas13 recognizes specific RNA sequences, and Fozouni realized it could be used to develop a test to detect viral RNA. A collaboration was formed between Gladstone and UC Berkeley to create an HIV self-testing device that people could use in their own homes to directly detect HIV in their blood.
Like HIV, coronaviruses are also RNA viruses and a widely deployable diagnostic tool was urgently needed due to the scope of the outbreak. “When the team and I realized that the coronavirus was becoming an issue globally and that testing was a major issue, we knew that our RNA detection system would be a logical fit to help the crisis,” explains Fozouni.
Fozouni and the team, which includes UC Berkeley bioengineer Dan Fletcher, started talking about pivoting their work in January 2020, and in February started doing their first experiments, well before offices in the US began shutting down, and well before the shelter-in-place order in California. They’re accelerating their work with the hope of applying for FDA approval later this year.
Creating 3D Lung Models
Along with Fozouni, other virologists at Gladstone found that their research projects naturally translated to studying SARS-CoV-2, the virus responsible for COVID-19. Nathan Meyers, PhD, a staff scientist also working in Ott’s lab, came to Gladstone with an interest in studying the liver, and focused originally on hepatitis C. From this, he helped spearhead the use of lung organoids in collaboration with the lab of Todd McDevitt, PhD.
Organoids are tiny 3D structures that recapitulate many features and functions of the organs found in the body. Gladstone scientists have been using this cutting-edge technology to study a variety of diseases, ranging from motor neuron diseases to heart disease.
“The beauty of organoids is that we can create them from patient cells,” explains Meyers. “Since the cells that we use to create these structures come from humans and resemble what happens in humans, they bring us one step closer to knowing the impact on patient biology.”
Ultimately, Meyers and the research team are looking to see how SARS-CoV-2 damages lung tissues and they hope to identify targets that could lead to drug discovery.
For Meyers, his work has only gotten busier. “Some people are getting antsy working from home but that hasn’t been the issue for me.” While Meyers is going into the lab a bit less, only to perform essential experiments, the work continues at home—analyzing data, planning for the next round of experiments—and some nights doesn’t end until he goes to sleep. “My main concern right now is work/life balance,” says Meyers. “I have two small kids and I want to make sure I make time for them so they don’t get too stir crazy.”
Coronavirus and the Heart
Virologists pivoting their work to focus on COVID-19 seems like a natural fit, but at Gladstone, more than just virologists are switching gears. Juan Pérez-Bermejo, PhD, has been studying heart disease in the lab of Bruce Conklin, MD, since he started as a graduate student at UCSF in 2012.
“Basically, I’ve been studying why some people are more susceptible to developing heart disease than others,” says Pérez-Bermejo. In this work, Pérez-Bermejo uses stem cells to test the impact of different treatments and genetic backgrounds of individuals.
Earlier this year, Pérez-Bermejo was independently reading about how doctors in China were reporting a number of COVID-19 patients with heart damage. This information intrigued Pérez-Bermejo and later that day, he received a text from his mentor Bruce Conklin asking if he could talk.
“Bruce never texts me but I already knew what he was going to say,” explains Pérez-Bermejo. Just as Pérez-Bermejo expected, Conklin suggested that they pivot their work and dive into studying heart disease in COVID-19 patients.
“Around 10 to 15 percent of COVID-19 patients will get heart damage,” says Serah Kang, PhD, a postdoc in Todd McDevitt’s lab. “Doctors saw that even patients with healthy hearts were suffering from heart damage. So, there is clearly something unusual going on when patients experience heart damage from a lung disease,” says Kang.
This realization inspired a collaboration between the labs of Todd McDevitt and Bruce Conklin to further study the implications of COVID-19 on the heart.
Conklin’s team is studying how the virus damages the function of heart cells. Normally, they’d used cells cultured in 2-dimensions for this research but by teaming up with McDevitt’s lab, they’re able to get a bigger picture of what’s going on.
“Gladstone is in a pretty unique position,” says Sarah Rockwood, a research assistant in the lab of Todd McDevitt. Rockwood completed her undergraduate degree at UC Berkeley in 2019 but wanted to continue working in a lab before she made a decision about pursuing an MD/PhD degree. Her work in the lab has focused on creating 3D models using cardiac microtissues in order to understand heart development and disease. This technology is similar to the lung organoids that Nathan Meyers is working with.
“We already had stem cell–derived heart tissues set up with the express purpose of modeling heart function and disease,” explains Rockwood. This technology allows scientists to understand how the virus affects multiple kinds of cells in the heart and the interactions between them.
McDevitt’s team then started talking with Bruce Conklin’s lab, which focuses on genetic diseases and therapies, about collaborating in order to learn more about specifically what’s happening in heart cells with the virus.
“I’ve always felt that science is collaborative...but this is a whole new level. Scientists and institutions are working together and breaking down walls, across fields and countries.”
“Is the virus able to directly infect the heart or is the damage more of a response to infection in other tissues?” This is just one of the questions that the team is looking into.
“Doing my old research wasn’t an option,” says Gokul Ramadoss, a graduate student working in the lab of Bruce Conklin. “My decision was really, do I stay home and try to figure out what I can do from there, or do I come into the lab to work on this? For me, that was an easy decision.”
Ramadoss brings experience with CRISPR-based screening. In a CRISPR screen, scientists use gene-editing tools to manipulate thousands of different genes and observe which manipulations have a desired effect on cells. The team is applying this screening to the heart. If they can uncover alterations that make heart cells less vulnerable to being infected by the virus or dying, they hope this might point to treatments that could protect the heart from damage.
Volunteering to Study COVID-19
While most people are working from home during this time, some Gladstone scientists have volunteered to go into the lab to study coronavirus, rather than stay at home, analyze data, and write papers or grants.
“There was a shared sentiment among the lab,” explains Kang. “we weren’t sure how our expertise could be used or what particular projects would be helpful, but we wanted to contribute in some way.”
Gladstone has essentially shut down its offices, with only essential personnel allowed to enter. Anyone who comes into the building has to sign a daily attestation that they will abide by the physical distancing protocol, which includes wearing face masks, and that they are not experiencing any COVID-19 related symptoms. Lab meetings have moved online, and strict schedules have been developed so only a limited number of people are in the lab and building at a given time. The cardio team has a dedicated Slack channel where they plan experiments and share reports and papers relevant to their work in the lab.
Still, traveling in and out of the office, even with all these precautions, can cause unease, especially among friends and family.
“I try not to tell my family that I go to the lab too much,” says Pérez-Bermejo, who is a native of Spain. “My family is back in Europe and they’re seeing the worst of this pandemic, so I spare them the details.”
Rockwood shares that she initially wanted to volunteer at UCSF and help bring people in who were potentially infected. She ultimately decided that this was too high of a risk and didn’t want to expose her family, with whom she lives, to that level of threat. But her desire to be helpful in the pandemic was strong, so she opted to continue her work at Gladstone. Seeing everyone come together to help in the midst of the crisis continues to motivate her.
“This is exactly the kind of situation that I’ve been training for. For me, this is exactly where I’m supposed to be.”
“I’ve always felt that science is collaborative—and Gladstone is a really special place in that regard, with a lot of interaction and collaboration across different groups,” says Rockwood. “But this is a whole new level. Scientists and institutions are working together and breaking down walls, across fields and countries.”
Organized to Pivot
Gladstone is a relatively small organization, less than 500 people total. The small size and organizational structure, with little red tape, and quick decision-making, has been an asset in the midst of this crisis. It’s made it easy for scientists to shift their focus, create new collaborations, and mobilize to attack the pandemic. Gladstone also has a wide breadth of knowledge and experience within its walls. Virologists are working alongside data scientists, neurologists, cardiovascular and gene-editing experts. Collaboration was part of everyday life before COVID-19 hit.
“Gladstone is a small organization,” says Ramadoss. “You pass people in the halls, see them at happy hours, or research presentations. So, working closely with all these different people from different labs, it felt pretty seamless for us.” Instead of trying to get to know the team and make the collaboration work, researchers could focus on the hard part—the science itself.
Gladstone has a history of risk-taking that has made it perfectly suited to address the COVID-19 pandemic. The Gladstone Institute of Virology and Immunology was created in 1991 in response to the HIV epidemic. And over the years, as other viral outbreaks have happened, the institute has delved into this work, gaining insights with broad applications.
“We’re applying a lot of lessons that have been learned over the years,” says Fozouni. “Not just from HIV, but Zika, and other viruses.”
As for Fozouni, her training has placed her in a unique position. Her career thus far, both in medicine and research, has been devoted to becoming someone who can help in a viral pandemic. “I became interested in viruses as a kid when I read about the Ebola outbreaks and the scientists who were responsible for identifying the virus,” says Fozouni. “This is exactly the kind of situation that I’ve been training for. For me, this is exactly where I’m supposed to be.”