Microscopic images of human stem cell–derived airway tissue models with cell nuclei (blue) and SARS-CoV-2 virus infected cells (green); tissue exposed to cigarette smoke (right) had 2 to 3 times more infected cells than non-exposed tissue (left). Image Credit: UCLA Broad Stem Cell Research Center/Cell Stem Cell
In the middle of a pandemic, stress can run really high and you might be tempted to light up a cigarette to decompress from the world around you. However, a CIRM-funded study revealed that you might want to think twice before lighting up.
It is already known that cigarette smoke is one of the most common causes of lung diseases, including lung cancer, but Dr. Brigitte Gomperts and Vaithilingaraja Arumugaswami at UCLA have pinpointed how smoking cigarettes may worsen infection by SARS-CoV-2, the virus that causes COVID-19, in the airways of the lungs.
The team used airway stem cells from the lungs of healthy non-smoking donors to create a tissue model that replicates the way that airways behave and function in humans. The researchers then exposed these newly created airways to cigarette smoke to mimic the effects of smoking.
Next, the team infected the airway tissue exposed with cigarette smoke with SARS-CoV-2 and also infected tissue not exposed to cigarette smoke. In the tissue model exposed to smoke, the researchers saw between two and three times more infected cells.
The UCLA team determined that smoking resulted in more severe SARS-CoV-2 infection. This was due to the smoke blocking the activity of immune system messenger proteins called interferons, which play an important role in the body’s early immune response. They trigger infected cells to produce proteins to attack the virus, summon additional support from the immune system, and alert uninfected cells to prepare to fight the virus. Cigarette smoke is known to reduce the interferon response in the airways.
In a UCLA news release, Dr. Gomperts explains the results with a simple analogy.
“If you think of the airways like the high walls that protect a castle, smoking cigarettes is like creating holes in these walls. Smoking reduces the natural defenses and that allows the virus to set in.”
The hope is that these findings will help researchers better understand COVID-19 risks for smokers and could inform the development of new therapeutic strategies to help reduce smokers’ chances of developing severe disease.
The full results to this study were published in Cell Stem Cell.
When people ask me what I do at CIRM I sometimes half-jokingly tell them that I’m the official translator: I take complex science and turn it into everyday English. That’s important. The taxpayers of California have a right to know how their money is being spent and how it might benefit them. But that message can be even more effective when it comes from the scientists themselves.
Recently we asked some of the scientists we are funding to do research into COVID-19 to record what’s called an “elevator pitch”. This is where they prepare an explanation of their work that is in ordinary English and is quite short, short enough to say it to someone as you ride in an elevator. Hence the name.
It sounds easy enough. But it’s not. When you are used to talking in the language of science day in and day out, suddenly switching codes to talk about your work in plain English can take some practice. Also, you have spent years, often decades, on this work and to have to explain it in around one minute is no easy thing.
But our researchers rose to the challenge. Here’s some examples of just how well they did.
Too many acronyms? Not to worry. It is all perfectly clear in the news release we just sent out about this.
A new collaboration between the California Institute for Regenerative Medicine (CIRM) and the Chan Zuckerberg Initiative (CZI) will advance scientific efforts to respond to the COVID-19 pandemic by collaborating on disseminating single-cell research that scientists can use to better understand the SARS-CoV-2 virus and help develop treatments and cures.
CIRM and CZI have signed a Memorandum of Understanding (MOU) that will combine CIRM’s infrastructure and data collection and analysis tools with CZI’s technology expertise. It will enable CIRM researchers studying COVID-19 to easily share their data with the broader research community via CZI’s cellxgene tool, which allows scientists to explore and visualize measurements of how the virus impacts cell function at a single-cell level. CZI recently launched a new version of cellxgene and is supporting the single-cell biology community by sharing COVID-19 data, compiled by the global Human Cell Atlas effort and other related efforts, in an interactive and scalable way.
“We are pleased to be able to enter into this partnership with CZI,” said Dr. Maria T. Millan, CIRM’s President & CEO. “This MOU will allow us to leverage our respective investments in genomics science in the fight against COVID-19. CIRM has a long-standing commitment to generation and sharing of sequencing and genomic data from a wide variety of projects. That’s why we created the CIRM genomics award and invested in the Stem Cell Hub at the University of California, Santa Cruz, which will process the large complex datasets in this collaboration.”
“Quickly sharing scientific data about COVID-19 is vital for researchers to build on each other’s work and accelerate progress towards understanding and treating a complex disease,” said CZI Single-Cell Biology Program Officer Jonah Cool. “We’re excited to partner with CIRM to help more researchers efficiently share and analyze single-cell data through CZI’s cellxgene platform.”
In March 2020, the CIRM Board approved $5 million in emergency funding to target COVID-19. To date, CIRM has funded 17 projects, some of which are studying how the SARS-CoV-2 virus impacts cell function at the single-cell level.
Three of CIRM’s early-stage COVID-19 research projects will plan to participate in this collaborative partnership by sharing data and analysis on cellxgene.
Dr. Evan Snyder and his team at Sanford Burnham Prebys Medical Discovery Institute are using induced pluripotent stem cells (iPSCs), a type of stem cell that can be created by reprogramming skin or blood cells, to create lung organoids. These lung organoids will then be infected with the novel coronavirus in order to test two drug candidates for treating the virus.
Dr. Brigitte Gomperts at UCLA is studying a lung organoid model made from human stem cells in order to identify drugs that can reduce the number of infected cells and prevent damage in the lungs of patients with COVID-19.
Dr. Justin Ichida at the University of Southern California is trying to determine if a drug called a kinase inhibitor can protect stem cells in the lungs and other organs, which the novel coronavirus selectively infects and kills.
“Cumulative data into how SARS-CoV-2 affects people is so powerful to fight the COVID-19 pandemic,” said Stephen Lin, PhD, the Senior CIRM Science Officer who helped develop the MOU. “We are grateful that the researchers are committed to sharing their genomic data with other researchers to help advance the field and improve our understanding of the virus.”
CZI also supports five distinct projects studying how COVID-19 progresses in patients at the level of individual cells and tissues. This work will generate some of the first single-cell biology datasets from donors infected by SARS-CoV-2 and provide critical insights into how the virus infects humans, which cell types are involved, and how the disease progresses. All data generated by these grants will quickly be made available to the scientific community via open access datasets and portals, including CZI’s cellxgene tool.
Don’t you love it when someone does your job for you and does it so well you have no need to add anything to it! Doesn’t happen very often – sad to say – but this week our friends at UCLA wrote a great article describing the work they are doing to target COVID-19. Best of all, all the work described is funded by CIRM. So read, and enjoy.
Two scientists in a lab at the UCLA Broad Stem Cell Research Center
By Tiare Dunlap, UCLA
As the COVID-19 pandemic rages on, UCLA researchers are rising to the occasion by channeling their specialized expertise to seek new and creative ways to reduce the spread of the virus and save lives. Using years’ — or even decades’ — worth of knowledge they’ve acquired studying other diseases and biological processes, many of them have shifted their focus to the novel coronavirus, and they’re collaborating across disciplines as they work toward new diagnostic tests, treatments and vaccines.
“As a result of the pandemic, everyone on campus is committed to finding ways that their unique expertise can help out,” said Dr. Brigitte Gomperts, professor and vice chair of research in pediatric hematology-oncology and pulmonary medicine at the David Geffen School of Medicine at UCLA and a member of the UCLA Children’s Discovery and Innovation Institute. “So many of my colleagues have repurposed their labs to work on the virus. It’s very seldom that you have one thing that everybody’s working on, and it has been truly inspiring to see how everyone has come together to try and solve this.”
Here’s a look at five projects in which UCLA scientists are using stem cells — which can self-replicate and give rise to all cell types — to take on COVID-19.
Using lung organoids as models to test possible treatments
Dr. Brigitte Gomperts
Gomperts has spent years perfecting methods for creating stem cell–derived three-dimensional lung organoids. Now, she’s using those organoids to study how SARS-CoV-2, the virus that causes COVID-19, affects lung tissue and to rapidly screen thousands of prospective treatments. Because the organoids are grown from human cells and reflect the cell types and architecture of the lungs, they can offer unprecedented insights into how the virus infects and damages the organ.
Gomperts is collaborating with UCLA colleagues Vaithilingaraja Arumugaswami, a virologist, and Robert Damoiseaux, an expert in molecular screening. Their goal is to find an existing therapy that could be used to reduce the spread of infection and associated damage in the lungs.
“We’re starting with drugs that have already been tested in humans because our goal is to find a therapy that can treat patients with COVID-19 as soon as possible,” Gomperts said. Read more.
Repurposing a cancer therapy
Dr. Vaithi Arumugaswami: Photo courtesy UCLA
Vaithilingaraja Arumugaswami, associate professor of molecular and medical pharmacology at the Geffen School of Medicine
In addition to collaborating with Gomperts, Arumugaswami and Damoiseaux identified the cancer drug Berzosertib as a possible treatment for COVID-19 after screening 430 drug candidates. The drug, which is currently being tested in clinical trials for cancer, works by blocking a DNA repair process that is exploited by solid cancers and the SARS-CoV-2 virus, and the UCLA scientists found that it is very effective at limiting viral replication and cell death.
“Clinical trials have shown that Berzosertib blocks the DNA repair pathway in cancer cells, but has no effects on normal, healthy cells,” Arumugaswami said.
Now, Arumugaswami and Gustavo Garcia Jr., a staff research associate, are testing Berzosertib and additional drug combinations on lung organoids developed in Gomperts’ lab and stem cell–derived heart cells infected with SARS-CoV-2. They suspect that if the drug is administered soon after diagnosis, it could limit the spread of infection and prevent complications. Read more.
Studying the immune response to the virus
Dr. Gay Crooks
Dr. Gay Crooks, professor of pathology and laboratory medicine and of pediatrics at the Geffen School of Medicine, and co-director of the Broad Stem Cell Research Center; and Dr. Christopher Seet,
assistant professor of hematology-oncology at the Geffen School of Medicine
Crooks and Seet are using stem cells to model how immune cells recognize and fight the virus in a lab dish. To do that, they’re infecting blood-forming stem cells — which can give rise to all blood and immune cells — from healthy donors with parts of the SARS-CoV-2 virus and then coaxing the stem cells to produce immune cells called dendritic cells. Dendritic cells devour viral proteins, chop them up into pieces and then present those pieces to other immune cells called T cells to provoke a response.
By studying that process, Crooks and Seet hope to identify which parts of the virus provoke the strongest T-cell responses. Developing an effective vaccine for SARS-CoV-2 will require a deep understanding of how the immune system responds to the virus, and this work could be an important step in that direction, giving researchers and clinicians a way to gauge the effectiveness of possible vaccines.
“When we started developing this project some years ago, we had no idea it would be so useful for studying a viral infection — any viral infection,” Crooks said. “It was only because we already had these tools in place that we could spring into action so fast.” Read more.
Developing a booster that could help a vaccine last longer
A COVID-19 vaccine will need to provide long-term protection from infection. But how long a vaccine protects from infection isn’t solely dependent on the vaccine.
The human body relies on long-living immune cells called T memory stem cells that guard against pathogens such as viruses and bacteria that the body has encountered before. Unfortunately, the body’s capacity to form T memory stem cells decreases with age. So no matter how well designed a vaccine is, older adults who don’t have enough of a response from T memory stem cells will not be protected long-term.
To address that issue, Li is developing an injectable biomaterial vaccine booster that will stimulate the formation of T memory stem cells. The booster is made up of engineered materials that release chemical messengers to stimulate the production of T memory stem cells. When combined with an eventual SARS-CoV-2 vaccine, they would prompt the body to produce immune cells primed to recognize and eliminate the virus over the long term.
“I consider it my responsibility as a scientist and an engineer to translate scientific findings into applications to help people and the community,” Li said. Read more.
Invariant natural killer T cells, or iNKT cells, are the special forces of the immune system. They’re extremely powerful and can immediately recognize and respond to many different intruders, from infections to cancer.
Yang is testing whether iNKT cells would make a particularly effective treatment for COVID-19 because they have the capacity to kill virally infected cells, offer protection from reinfection and rein in the excessive inflammation caused by a hyperactive immune response to the virus, which is thought to be a major cause of tissue damage and death in people with the disease.
One catch, though, is that iNKT cells are incredibly scarce: One drop of human blood contains around 10 million blood cells but only around 10 iNKT cells. That’s where Yang’s research comes in. Over the past several years, she has developed a method for generating large numbers of iNKT cells from blood-forming stem cells. While that work was aimed at creating a treatment for cancer, Yang’s lab has adapted its work over the past few months to test how effective stem cell–derived iNKT cells could be in fighting COVID-19. With her colleagues, she has been studying how the cells work in fighting the disease in models of SARS-CoV-2 infection that are grown from human kidney and lung cells.
“My lab has been developing an iNKT cell therapy for cancer for years,” Yang said. “This means a big part of the work is already done. We are repurposing a potential therapy that is very far along in development to treat COVID-19.” Read more.
“Our center is proud to join CIRM in supporting these researchers as they adapt projects that have spent years in development to meet the urgent need for therapies and vaccines for COVID-19,” said Dr. Owen Witte, founding director of the UCLA Broad Stem Cell Research Center. “This moment highlights the importance of funding scientific research so that we may have the foundational knowledge to meet new challenges as they arise.” Crooks, Gomperts, Seet and Yang are all members of the UCLA Jonsson Comprehensive Cancer Center. Damoiseaux is a professor of molecular and medical pharmacology and director of the Molecular Shared Resource Center at the California NanoSystems Institute at UCLA
Dr. Brigitte Gomperts (left) and Dr. Gay Crooks (right), UCLA Image Credit: UCLA Broad Stem Cell Center
This past Friday, the CIRM Board approved funding for its first clinical study for COVID-19. In addition to this, the Board also approved two discovery stage research projects, which support promising new technologies that could be translated to enable broad use and improve patient care. Before we go into more detail, the two awards are summarized in the table below:
The discovery grant for $150,000 was given to Dr. Gay Crooks at UCLA to study how specific immune cells called T cells respond to COVID-19. The goal of this is to inform the development of vaccines and therapies that harness T cells to fight the virus. Typically, vaccine research involves studying the immune response using cells taken from infected people. However, Dr. Crooks and her team are taking T cells from healthy people and using them to mount strong immune responses to parts of the virus in the lab. They will then study the T cells’ responses in order to better understand how T cells recognize and eliminate the virus.
This method uses blood forming stem cells and then converts them into specialized immune cells called dendritic cells, which are able to devour proteins from viruses and chop them into fragments, triggering an immune response to the virus.
In a press release from UCLA, Dr. Crooks says that, “The dendritic cells we are able to make using this process are really good at chopping up the virus, and therefore eliciting a strong immune response”
The discovery grant for $149,998 was given to Dr. Brigitte Gomberts at UCLA to study a lung organoid model made from human stem cells in order to identify drugs that can reduce the number of infected cells and prevent damage in the lungs of patients with COVID-19. Dr. Gomberts will be testing drugs that have been approved by the U.S. Food and Drug Administration (FDA) for other purposes or have been found to be safe in humans in early clinical trials. This increases the likelihood that if a successful drug is found, it can be approved more rapidly for widespread use.
In the same press release from UCLA, Dr. Gomberts discusses the potential drugs they are evaluating.
“We’re starting with drugs that have already been tested in humans because our goal is to find a therapy that can treat patients with COVID-19 as soon as possible.”
The Stem Cellar 