Since the start of the coronavirus pandemic early last year, scientists all over the world are still trying to better understand SARS-CoV-2, the virus that causes COVID-19. Although the more commonly known symptoms involve respiratory issues, there have been other long term problems observed in recovered patients. These consist of heart issues, fatigue, and neurological issues such as loss of taste and smell and “brain fog”.
To better understand this, Dr. Tariq Rana and a team of researchers at the UC San Diego School of Medicine are using stem cells to create lung and brain organoids to better understand how the virus interacts with the various organ systems and to better develop therapies that block infection. Organoids are 3D models made of cells that can be used to analyze certain features of the human organ being modeled. Although they are far from perfect replicas, they can be used to study physical structure and other characteristics.
The team’s lung and brain organoids produced molecules ACE2 and TMPRSS2, which sit like doorknobs on the outer surfaces of cells. SARS-CoV-2 is able to use these doorknobs to enter cells and establish infection.
Dr. Rana and his team then developed a pseudovirus, a noninfectious version of SARS-CoV-2, and attached a fluorescent label, allowing them to measure how effectively the virus binds in human lung and brain organoids as well as to evaluate the cells’ response. The team was surprised to see an approximately 10-fold higher SARS-CoV-2 infection in lung organoids compared to brain organoids. Additionally, treatment with TMPRSS2 inhibitors reduced infection levels in both organoids.
Besides differences in infection levels, the lung and brain organoids also differed in their responses to the virus. Infected lung organoids pumped out molecules intended to summon help from the immune system while infected brain organoids upped their production of molecules that plays a fundamental role in pathogen recognition and activation of the body’s own immune defenses.
In a news release from UC San Diego Health, Dr. Rana elaborates on the results of his study.
“We’re finding that SARS-CoV-2 doesn’t infect the entire body in the same way. In different cell types, the virus triggers the expression of different genes, and we see different outcomes.”
The next steps for Rana and his team is to develop SARS-CoV-2 inhibitors and test out how well they work in organoid models derived from people of a variety of racial and ethnic backgrounds that represent California’s diverse population. To carry out this research, CIRM awarded Dr. Rana a grant of $250,000, which is part of the $5 million in emergency funding for COVID-19 research that CIRM authorized at the beginning of the pandemic.
All this month we are using our blog and social media to highlight a new chapter in CIRM’s life, thanks to the voters approving Proposition 14. We are looking back at what we have done since we were created in 2004, and also looking forward to the future. Today we focus on groundbreaking CIRM funded research related to COVID-19 that was recently published.
It’s been almost a year since the world started hearing about SARS-CoV-2, the virus that causes COVID-19. In our minds, the pandemic has felt like an eternity, but scientists are still discovering new things about how the virus works and if genetics might play a role in the severity of the virus. One population study found that people who have ApoE4, a gene type that has been found to increase the risk of developing Alzheimer’s, had higher rates of severe COVID-19 and hospitalizations.
It is this interesting observation that led to important findings of a study funded by two CIRM awards ($7.4M grantand $250K grant) and conducted by Dr. Yanhong Shi at City of Hope and co-led by Dr. Vaithilingaraja Arumugaswami, a member of the UCLA Broad Stem Cell Research Center. The team found that the same gene that increases the risk for Alzheimer’s disease can increase the susceptibility and severity of COVID-19.
At the beginning of the study, the team was interested in the connection between SARS-CoV-2 and its effect on the brain. Due to the fact that patients typically lose their sense of taste and smell, the team theorized that there was an underlying neurological effect of the virus.
The team first created neurons and astrocytes. Neurons are cells that function as the basic working unit of the brain and astrocytes provide support to them. The neurons and astrocytes were generated from induced pluripotent stem cells (iPSCs), which are a kind of stem cell that can become virtually any type of cell and can be created by “reprogramming” the skin cells of patients. The newly created neurons and astrocytes were then infected with SARS-CoV-2 and it was found that they were susceptible to infection.
Next, the team used iPSCs to create brain organoids, which are 3D models that mimic certain features of the human brain. They were able to create two different organoid models: one that contained astrocytes and one without them. They infected both brain organoid types with the virus and discovered that those with astrocytes boosted SARS-CoV-2 infection in the brain model.
The team then decided to further study the effects of ApoE4 on susceptibility to SARS-CoV-2. They did this by generating neurons from iPSCs “reprogrammed” from the cells of an Alzheimer’s patient. Because the iPSCs were derived from an Alzheimer’s patient, they contained ApoE4. Using gene editing, the team modified some of the ApoE4 iPSCs created so that they contained ApoE3, which is a gene type considered neutral. The ApoE3 and ApoE4 iPSCs were then used to generate neurons and astrocytes.
The results were astounding. The ApoE4 neurons and astrocytes both showed a higher susceptibility to SARS-CoV-2 infection in comparison to the ApoE3 neurons and astrocytes. Moreover, while the virus caused damage to both ApoE3 and ApoE4 neurons, it appeared to have a slightly more severe effect on ApoE4 neurons and a much more severe effect on ApoE4 astrocytes compared to ApoE3 neurons and astrocytes.
“Our study provides a causal link between the Alzheimer’s disease risk factor ApoE4 and COVID-19 and explains why some (e.g. ApoE4 carriers) but not all COVID-19 patients exhibit neurological manifestations” says Dr. Shi. “Understanding how risk factors for neurodegenerative diseases impact COVID-19 susceptibility and severity will help us to better cope with COVID-19 and its potential long-term effects in different patient populations.”
In the last part of the study, the researchers tested to see if the antiviral drug remdesivir inhibits virus infection in neurons and astrocytes. They discovered that the drug was able to successfully reduce the viral level in astrocytes and prevent cell death. For neurons, it was able to rescue them from steadily losing their function and even dying.
The team says that the next steps to build on their findings is to continue studying the effects of the virus and better understand the role of ApoE4 in the brains of people who have COVID-19. Many people that developed COVID-19 have recovered, but long-term neurological effects such as severe headaches are still being seen months after.
“COVID-19 is a complex disease, and we are beginning to understand the risk factors involved in the manifestation of the severe form of the disease” says Dr. Arumugaswami. “Our cell-based study provides possible explanation to why individuals with Alzheimer’s’ disease are at increased risk of developing COVID-19.”
All this month we are using our blog and social media to highlight a new chapter in CIRM’s life, thanks to the people of California approving Proposition 14. We are looking back at what we have done since we were created in 2004, and also looking forward to the future.
The news that effective vaccines have been developed to help fight COVID-19 was a truly bright spot at the end of a very dark year. But it will be months, in some countries years, before we have enough vaccines to protect everyone. That’s why it’s so important to keep pushing for more effective ways to help people who get infected with the virus.
One of those ways is in a clinical study that CIRM is funding with City of Hope’s Dr. John Zaia. Dr. Zaia and his team, in partnership with the Translational Genomics Research Institute (TGen) in Flagstaff, Arizona, are using something called convalescent plasma to try and help people who have contracted the virus. Here’s the website they have created for the study.
Plasma is a part of our blood that carries proteins, called antibodies, that help defend our bodies against viral infections. When a patient recovers from COVID-19, their blood plasma contains antibodies against the virus. The hope is that those antibodies can now be used as a potential treatment for COVID-19 to help people who are newly infected.
For the study to succeed they’ll first need people who have recovered from the virus to donate blood. That’s particularly appropriate in January because this is National Volunteer Blood Donor Month.
The team has three elements to their approach:
A rapid-response screening program to screen potential COVID-19 convalescent plasma donors, particularly in underserved communities.
A laboratory center that can analyze the anti-SARS-CoV-2 antibodies properties in COVID-19 convalescent plasma.
An analysis of the clinical course of the disease in COVID-19 patients to identify whether antibody properties correlate with clinical benefit of COVID-19 convalescent plasma.
There’s reason to believe this approach might work. A study published this week in the New England Journal of Medicine, found that blood plasma from people who have recovered from COVID-19 can help older adults and prevent them from getting seriously ill with the virus if they get the plasma within a few days of becoming infected.
We are used to thinking of blood donations as being used to help people after surgery or who have been in an accident. In this study the donations serve another purpose, but one that is no less important. The World Health Organization describes blood as “the most precious gift that anyone can give to another person — the gift of life. A decision to donate your blood can save a life, or even several if your blood is separated into its components — red cells, platelets and plasma.”
That plasma could help in developing more effective treatments against the virus. Because until we have enough vaccines for everyone, we are still going to need as much help as we can get in fighting COVID-19. The recent surge in cases throughout the US and Europe are a reminder that this virus is far from under control. We have already lost far too many people. So, if you have recently recovered from the virus, or know someone who has, consider donating blood to this study. It could prove to be a lifesaver.
For more information about the study and how you can be part of it, click here.
As the worldwide coronavirus pandemic rages on, scientists are trying to better understand SARS-CoV-2, the virus that causes COVID-19, and the effects that it may have beyond those most commonly observed in the lungs. A CIRM-funded project at UCLA, co-led by Vaithilingaraja Arumugaswami, Ph.D. and Arjun Deb, M.D. discovered that SARS-CoV-2 can cause organ failure in the heart, kidney, spleen, and other vital organs of mice.
Mouse models are used to better understand the effects that a disease can have on humans. SARS-CoV-2 relies on a protein named ACE2 to infect humans. However, the virus doesn’t recognize the mouse version of the ACE2 protein, so healthy mice exposed to the SARS-CoV-2 virus don’t get sick.
To address this, past experiments by other research teams have genetically engineered mice to have the human version of the ACE2 protein in their lungs. These teams then infected the mice, through the nose, with the SARS-CoV-2 virus. Although this process led to viral infection in the mice and caused pneumonia, they don’t get as broad a range of other symptoms as humans do.
Previous research in humans has suggested that SARS-CoV-2 can circulate through the bloodstream to reach multiple organs. To evaluate this further, the UCLA researchers genetically engineered mice to have the human version of the ACE2 protein in the heart and other vital organs. They then infected half of the mice by injecting SARS-CoV-2 into their bloodstreams and compared them to mice that were not infected. The UCLA team tracked overall health and analyzed how levels of certain genes and proteins in the mice changed.
Within seven days, all of the mice infected with the virus had stopped eating, were completely inactive, and had lost an average of about 20% of their body weight. The genetically engineered mice that had not been infected with the virus did not lose a significant amount of weight. Furthermore, the infected mice had altered levels of immune cells, swelling of the heart tissue, and deterioration of the spleen. All of these are symptoms that have been observed in people who are critically ill with COVID-19.
What’s even more surprising is that the UCLA team also found that genes that help cells generate energy were shut off in the heart, kidney, spleen and lungs of the infected mice. The study also revealed that some changes were long-lasting throughout the organs in mice with SARS-CoV-2. Not only were genes turned off in some cells, the virus made epigenetic changes, which are chemical alterations to the structure of DNA that can cause more lasting effects. This might help explain why some people that have contracted COVID-19 have symptoms for weeks or months after they no longer have traces of the virus in their body.
In a UCLA press release, Dr. Deb discusses the importance and significance of their findings.
“This mouse model is a really powerful tool for studying SARS-CoV-2 in a living system. Understanding how this virus can hijack our cells might eventually lead to new ways to prevent or treat the organ failure that can accompany COVID-19 in humans.”
The full results of this study were published in JCI Insight.
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.
To try and boost sales during the pandemic many businesses are offering two-for-one deals; buy one product get another free. Well, that might also be the case with a flu shot; get one jab and get protection from two viruses.
A new study offers an intriguing – though not yet certain – suggestion that getting a flu shot could not only reduce your risk of getting the flu, but also help reduce your risk of contracting the coronavirus. If it’s true it would be a wonderful tool for health professionals hoping to head of a twindemic of flu and COVID-19 this winter. It would also be a pretty sweet deal for the rest of us.
Researchers at Radboud University Medical Center in the Netherlands looked through their hospital’s database and compared people who got a flu shot during the previous year with people who didn’t. They found that people who got the vaccine were 39 percent less likely to have tested positive for the coronavirus than people who didn’t get the vaccine.
Now, there are a bunch of caveats about this study (published in the preprint journal MedRxiv) one of which is that it wasn’t peer reviewed. Another is that people who get flu shots might just be more health conscious than people who don’t, which means they might also be more aware of the need to wear a mask, social distance, wash their hands etc.
But that doesn’t mean this study is wrong. Two recent studies (in the journal Vaccines and the Journal of Medical Virology) also found similar findings, that people over the age of 65 who got a flu shot had a lower risk of getting COVID-19. That’s particularly important for that age group as they are the ones most likely to experience life-threatening complications from COVID-19.
But what could explain getting a two-fer from one vaccine? Well, there’s a growing body of research that points to something called “trained innate immunity”. Our bodies have two different kinds of immune system, adaptive and innate. Vaccines activate the adaptive system, causing it to develop antibodies to attack and kill a virus. But there’s also evidence these same vaccines could trigger our innate immune system to help fight off infections. So, a flu vaccine could boost your adaptive immunity against the flu, but also kick in the innate immunity against the coronavirus.
In an article in Scientific American, Ellen Foxman, an immunobiologist and clinical pathologist at the Yale School of Medicine, says that might be the case here: “There is evidence from the literature that trained immunity does exist and can offer broad protection, in unexpected ways, against other pathogens besides what the vaccine was designed against.”
The researchers in the Netherlands wanted to see if there was any evidence that what they saw in their hospital had any basis in fact. So, they devised a simple experiment. They took blood cells from healthy individuals and exposed some of the cells to the flu vaccine. After six days they exposed all the cells to the SARS-CoV-2, the virus that causes COVID-19.
Compared to the untreated cells, the cells that had been exposed to the flu vaccine produced more virus-fighting immune molecules called cytokines. These can attack the virus and help protect people early on, resulting in a milder, less dangerous infection.
All in all it’s encouraging evidence that a flu shot might help protect you against the coronavirus. And at the very least it will reduce your risk of the flu, and if there’s one thing you definitely don’t want this year it’s having to battle two life-threatening viruses at the same time.
The development of organoid modeling has significantly expanded our understanding of human organs and the diseases that can affect them. For those unfamiliar with the term, an organoid is a miniaturized, simplified version of an organ produced that is also three dimensional.
Recently, scientists from the University of Cambridge and the Korea Advanced Institute Science and Technology (KAIST) were able to develop ‘mini lungs’ from donated tissue and use them to uncover the mechanisms behind the new coronavirus infection and the early immune response in the lungs.
SARS-CoV-2, the name of the coronavirus that causes COVID-19, first appears in the alveoli, which are tiny air sacs in the lungs that take up the oxygen we breathe and exchange it with carbon dioxide.
To better understand how SARS-CoV-2 infects the lungs and causes COVID-19, the team used donated tissue to extract a specific type of lung cell. They then reprogrammed these cells to an earlier stem cell-like state and used them to grow the lung organoids.
The team then infected the ‘mini lungs’ with a strain of SARS-CoV-2 taken from a patient in South Korea who was diagnosed with COVID-19 after traveling to Wuhan, China.
Within the newly infected lung organoids, the team observed that the virus began to replicate rapidly, reaching full cellular infection in just six hours. Replication allows the virus to spread the infection throughout the body to other cells and tissue. The infected cells also began to produce interferons, which are proteins that act as warning signals to healthy cells, telling them to activate their antiviral defenses. After two days, the interferons triggered an immune response and the cells started fighting back against infection. Two and a half days after infection, some of the alveolar cells began to disintegrate, leading to cell death and damage to the lung tissue.
In a news release, Dr. Joo-Hyeon Lee, co-senior author of this study, elaborates on how he hopes this study can help more vulnerable sections of the population.
“We hope to use our technique to grow these 3D models from cells of patients who are particularly vulnerable to infection, such as the elderly or people with diseased lungs, and find out what happens to their tissue.”
CIRM has funded two discovery stage research projects that use lung organoids to look at potential treatments for COVID-19. One is being conducted by Dr. Brigitte Gomperts at UCLA and the other by Dr. Evan Snyder at the Sanford Burnham Prebys Medical Discovery Institute.
I love maps; I still have auto club maps of various parts of the country in my car. But, to tell the truth, those maps just don’t have as much information as I can get by typing in an address on my cell phone. Technological advances in global positioning systems, cellular service, data gathering and storage, etc. have made my beloved paper maps a bit of a relic.
Similarly, technological advances have enabled scientists to begin making maps of human tissues and organs at a level of detail that was previously unimaginable. Hundreds of thousands of single cells can be profiled in parallel, examining expression of RNA and proteins. These data, in combination with new three-dimensional spatial analysis techniques and sophisticated computational algorithms, allow high resolution mapping of all the cells in a given tissue or organ.
Given these new capabilities, an international “Human Cell Atlas Consortium” published a white paper in 2017 outlining plans and strategies to build comprehensive reference maps of all human cells, organ by organ. The intent of building such an atlas is to give a much better understanding of the biology and physiology of normal human tissues, as well as to give new insights into the nature of diseases affecting those tissues and to point the way to developing new therapies.
One example of this new breed of cartography was published September 24 in the journal Nature, in a paper called simply “Cells of the Human Heart”. This tour-de-force effort was led by scientists from Harvard Medical School, the Wellcome Sanger Institute, the Max Delbruck Center for Molecular Medicine in Berlin and Imperial College, London. These teams and their collaborators analyzed about 500,000 cells from six different regions of the healthy adult human heart, using post-mortem organs from 14 donors. They examined RNA and protein expression and mapped the distribution of different types of cells in each region of the heart. In addition, they made comparisons of male and female hearts, and identified cells expressing genes known to be associated with different types of heart disease.
One of the take-home messages from this study is that there is a lot of cellular complexity in the heart – with 11 major cell types (examples include atrial and ventricular cardiomyocytes, fibroblasts and smooth muscle cells), as well as multiple subpopulations within each of those types. Also notable is the different distribution of cells between the atria (which are at the top of the heart and receive the blood) and ventricles (which are on the bottom of the heart and pump blood out): on average, close to half of the cells in the ventricles are cardiomyocytes, whereas only a third of the cells in the atria are cardiomyocytes. Finally, there is a significantly higher percentage of cardiomyocytes in the ventricles of women (56%) than in the ventricles of men (47%). The authors speculate that this latter difference might explain the higher volume of blood pumped per beat in women and lower rates of cardiovascular disease.
The authors gave a few examples of how their data can be used for a better understanding of heart disease. For example, they identified a specific subpopulation of cardiomyocytes that expresses genes associated with atrial fibrillation, suggesting that the defect may be associated with those cells. Similarly, they found that a specific neuronal cell type expresses genes that are associated with a particular ventricular dysfunction associated with heart failure. In addition, the authors identified which cells in the heart express the highest levels of the SARS-CoV-2 receptor, ACE2, including pericytes, fibroblasts and cardiomyocytes.
Now that these data are accessible for exploration at www.heartcellatlas.org, I have no doubt that many scientific explorers will begin to navigate to a more complete understanding of both the healthy and diseased heart, and ultimately to new treatments for heart disease.
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
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, 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
In late March the CIRM Board approved $5 million in emergency funding for COVID-19 research. The idea was to support great ideas from California’s researchers, some of which had already been tested for different conditions, and see if they could help in finding treatments or a vaccine for the coronavirus.
Less than a month later we were funding a clinical trial and two other projects, one that targeted a special kind of immune system cell that has the potential to fight the virus.
Researchers use stem cells to model the immune response to COVID-19
By Tiare Dunlap
Cities across the United States are opening back up, but we’re still a long way from making the COVID-19 pandemic history. To truly accomplish that, we need to have a vaccine that can stop the spread of infection.
But to develop an effective vaccine, we need to understand how the immune system responds to SARS-CoV-2, the virus that causes COVID-19.
Vaccines work by imitating infection. They expose a person’s immune system to a weakened version or component of the virus they are intended to protect against. This essentially prepares the immune system to fight the virus ahead of time, so that if a person is exposed to the real virus, their immune system can quickly recognize the enemy and fight the infection. Vaccines need to contain the right parts of the virus to provoke a strong immune response and create long-term protection.
Most of the vaccines in development for SARS CoV-2 are using part of the virus to provoke the immune system to produce proteins called antibodies that neutralize the virus. Another way a vaccine could create protection against the virus is by activating the T cells of the immune system.
T cells specifically “recognize” virus-infected cells, and these kinds of responses may be especially important for providing long-term protection against the virus. One challenge for researchers is that they have only had a few months to study how the immune system protects against SARS CoV-2, and in particular, which parts of the virus provoke the best T-cell responses.
For years, they have been perfecting an innovative technology that uses blood-forming stem cells — which can give rise to all types of blood and immune cells — to produce a rare and powerful subset of immune cells called type 1 dendritic cells. Type 1 dendritic cells play an essential role in the immune response by devouring foreign proteins, termed antigens, from virus-infected cells and then chopping them into fragments. Dendritic cells then use these protein fragments to trigger T cells to mount an immune response.
Using this technology, Crooks and Seet are working to pinpoint which specific parts of the SARS-CoV-2 virus provoke the strongest T-cell responses.
Building long-lasting immunity
“We know from a lot of research into other viral infections and also in cancer immunotherapy, that T-cell responses are really important for long-lasting immunity,” said Seet, an assistant professor of hematology-oncology at the David Geffen School of Medicine at UCLA. “And so this approach will allow us to better characterize the T-cell response to SARS-CoV-2 and focus vaccine and therapeutic development on those parts of the virus that induce strong T-cell immunity.”
Crooks’ and Seet’s project uses blood-forming stem cells taken from healthy donors and infected with a virus containing antigens from SARS-CoV-2. They then direct these stem cells to produce large numbers of type 1 dendritic cells using a new method developed by Seet and Suwen Li, a graduate student in Crooks’ lab. Both Seet and Li are graduates of the UCLA Broad Stem Cell Research Center’s training program.
“The dendritic cells we are able to make using this process are really good at chopping up viral antigens and eliciting strong immune responses from T cells,” said Crooks, a professor of pathology and laboratory medicine and of pediatrics at the medical school and co-director of the UCLA Broad Stem Cell Research Center.
When type 1 dendritic cells chop up viral antigens into fragments, they present these fragments on their cell surfaces to T cells. Our bodies produce millions and millions of T cells each day, each with its own unique antigen receptor, however only a few will have a receptor capable of recognizing a specific antigen from a virus.
When a T cell with the right receptor recognizes a viral antigen on a dendritic cell as foreign and dangerous, it sets off a chain of events that activates multiple parts of the immune system to attack cells infected with the virus. This includes clonal expansion, the process by which each responding T cell produces a large number of identical cells, called clones, which are all capable of recognizing the antigen.
“Most of those T cells will go off and fight the infection by killing cells infected with the virus,” said Seet, who, like Crooks, is also a member of the UCLA Jonsson Comprehensive Cancer Center. “However, a small subset of those cells become memory T cells — long-lived T cells that remain in the body for years and protect from future infection by rapidly generating a robust T-cell response if the virus returns. It’s immune memory.”
Producing extremely rare immune cells
This process has historically been particularly challenging to model in the lab, because type 1 dendritic cells are extremely rare — they make up less than 0.1% of cells found in the blood. Now, with this new stem cell technology, Crooks and Seet can produce large numbers of these dendritic cells from blood stem cells donated by healthy people, introduce them to parts of the virus, then see how T cells taken from the blood can respond in the lab. This process can be repeated over and over using cells taken from a wide range of healthy people.
“The benefit is we can do this very quickly without the need for an actual vaccine trial, so we can very rapidly figure out in the lab which parts of the virus induce the best T-cell responses across many individuals,” Seet said.
The resulting data could be used to inform the development of new vaccines for COVID-19 that improve T-cell responses. And the data about which viral antigens are most important to the T cells could also be used to monitor the effectiveness of existing vaccine candidates, and an individual’s immune status to the virus.
“There are dozens of vaccine candidates in development right now, with three or four of them already in clinical trials,” Seet said. “We all hope one or more will be effective at producing immediate and long-lasting immunity. But as there is so much we don’t know about this new virus, we’re still going to need to really dig in to understand how our immune systems can best protect us from infection.”
Supporting basic research into our body’s own processes that can inform new strategies to fight disease is central to the mission of the Broad Stem Cell Research Center.
“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. “And it was only because we already had these tools in place that we could spring into action so fast.”