CIRM-funded study shows how cigarette smoke can worsen COVID-19 infection in the airways

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.

One shot, two benefits!

Doctor preparing an influenza vaccine for a patient.

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.

Want to help us solve a mystery?

Patient that has recovered from Covid-19 donating blood plasma. Photo courtesy Science Photo

Convalescent plasma has been in the news a lot lately as a potential treatment for people infected with the coronavirus. In August the US Food and Drug Administration (FDA) granted emergency use authorization (EUA) to use these products based on preliminary data that suggested it might help people battling COVID. But there are still a lot of unanswered questions about this approach.

And that’s where you come in.

Plasma is a component of blood that carries proteins called antibodies that are usually involved in defending our bodies against viral infections.  We also know that blood plasma from patients that have recovered from COVID-19, referred to as convalescent plasma, contain antibodies against the virus that can be used as a potential treatment for COVID-19. 

That’s the theory, but the reality is that there are still a lot we don’t know, basic questions such as does it really work, how does it work, does it work for everyone or just some patients? A clinical  grant includes testing the plasma in COVID-19 Positive patients that CIRM is funding with City of Hope, UC Irvine and Translational Genomics Research Institute (TGen) hopes to answer those questions. 

The first step is getting the plasma from people who have recovered from COVID and then testing it to make sure it’s safe and to identify what blood type it is, so you can match that blood type with the person receiving it.

But plasma doesn’t contain just one kind of antibody, there are many antibodies and each one works in a slightly different way. For example, two antibodies, IGM and IGG, target in on the spike protein on the coronavirus. The goal is to block that spike and prevent the virus from spreading throughout the body. IGM has up to 10 ‘arms’ and so has the potential to bind multiple copies of the spike, whereas IGG has only 2 arms, but lasts longer. Both IGM and IGG also come in many different flavors, allowing them to bind to many different parts of the spike, some being more protective than others.

That’s one of the things that this trial is trying to find out. And you can help them do that. The trial needs volunteers, volunteers to donate the plasma and volunteers to try the therapy.

The team is evaluating changes that occur before and after plasma treatment.  Many recipients have no immediate response, a few get dramatically better, and some continue to have symptoms long after discharge from the hospital.  These so-called “long-haulers” can have debilitating problems, months after becoming infected. The study hopes to evaluate these variable responses to plasma treatment.

But more people are needed if we are to truly understand what works best. We need people who are newly infected, those being treated with plasma, and those that have recovered from the virus.

We are particularly interested in recruiting people from the Black and Latinx communities, groups that are often underserved when it comes to access to medical care.

The team has created a website to make it easy to find out more about the clinical trial, and to see if you are a good candidate to be part of it, either as a donor or recipient.

Lives are at stake and time is short so join us, help us find answers to the most pressing medical issue of our times. It’s a chance to do something that might benefit your family, your friends and your community.

‘Mini lung’ model shows scientists early stages of new coronavirus infection

Representative image of three-dimensional human lung alveolar organoid showing alveolar stem cell marker, HTII-280 (red) and SARS-CoV-2 entry protein, ACE2 (green)
Image Credit: Jeonghwan Youk, Taewoo Kim, and Seon Pyo Hong

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.”

The complete study was published in Cell Stem Cell.

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.

An Atlas of the Human Heart that May Guide Development of New Therapies

By Lisa Kadyk, PhD. CIRM Senior Science Officer

Illustration of a man’s heart – Courtesy Science Photo

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.

Battling COVID and turning back the clock on stem cell funding

Coronavirus

Battling the virus that causes COVID-19 is something that is top of everyone’s mind right now. That’s why CIRM is funding 17 different projects targeting the virus. But one of the most valuable tools in helping develop vaccines against a wide variety of diseases in the past is now coming under threat. We’ll talk about both issues in a live broadcast we’re holding on Wednesday, October 14th at noon (PDT).

That date is significant because it’s Stem Cell Awareness Day and we thought it appropriate to host a meeting looking at two of the most important issues facing the field.

The first part of the event will focus on the 17 projects that CIRM is funding that target COVID-19. This includes three clinical trials aiming to treat people who have been infected with the virus and are experiencing some of the more severe effects, such as damaged lungs.

We’ll also look at some of the earlier stage research that includes:

  • Work to help develop a vaccine
  • Using muscle stem cells to help repair damage to the diaphragm in patients who have spent an extended period on a ventilator
  • Boosting immune system cells to help fight the virus

The second part of the event will look at ways that funding for stem cell research at the federal level is once again coming into question. The federal government has already imposed new restrictions on funding for fetal tissue research, and now there are efforts in Congress to restrict funding for embryonic stem cell research.

The impacts could be significant. Fetal tissue has been used for decades to help develop some of the most important vaccines used today including rubella, chickenpox, hepatitis A, and shingles. They have also been used to make approved drugs against diseases including hemophilia, rheumatoid arthritis, and cystic fibrosis.

We’ll look at some of the reasons why we are seeing these potential restrictions on the medical research and what impact they could have on the ability to develop new treatments for the coronavirus and other deadly diseases.

You can watch the CIRM Stem Cell Awareness Day live event by going here: https://www.youtube.com/c/CIRMTV/videos at noon on Wednesday, October 14th.

Feel free to share news about this event with anyone you think might be interested.

We look forward to seeing you there.

Exploring tough questions, looking for answers

COVID-19 and social and racial injustice are two of the biggest challenges facing the US right now. This Thursday, October 8th, we are holding a conversation that explores finding answers to both.

The CIRM Alpha Stem Cell Clinic Network Symposium is going to feature presentations about advances in stem cell and regenerative research, highlighting treatments that are already in the clinic and being offered to patients.

But we’re also going to dive a little deeper into the work we support, and use it to discuss two of the most pressing issues of the day.

One of the topics being featured is research into COVID-19. To date CIRM has funded 17 different projects, including three clinical trials. We’ll talk about how these are trying to find ways to help people infected with the virus, seeing if stem cells can help restore function to organs and tissues damaged by the virus, and if we can use stem cells to help develop safe and effective vaccines.

Immediately after that we are going to use COVID-19 as a way of exploring how the people most at risk of being infected and suffering serious consequences, are also the ones most likely to be left out of the research and have most trouble accessing treatments and vaccines.

Study after study highlights how racial and ethnic minorities are underrepresented in clinical trials and disproportionately affected by debilitating diseases. We have a responsibility to change that, to ensure that the underserved are given the same opportunity to take part in clinical trials as other communities.

How do we do that, how do we change a system that has resisted change for so long, how do we overcome the mistrust that has built up in underserved communities following decades of abuse? We’ll be talking about with experts who are on the front lines of this movement.

It promises to be a lively meeting. We’d love to see you there. It’s virtual – of course – it’s open to everyone, and it’s free.

Here’s where you can register and find out more about the Symposium

Explaining COVID can be a pitch

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.

Charting a new course for stem cell research

What are the latest advances in stem cell research targeting cancer? Can stem cells help people battling COVID-19 or even help develop a vaccine to stop the virus? What are researchers and the scientific community doing to help address the unmet medical needs of underserved communities? Those are just a few of the topics being discussed at the Annual CIRM Alpha Stem Cell Clinic Network Symposium on Thursday, October 8th from 9am to 1.30pm PDT.

Like pretty nearly everything these days the symposium is going to be a virtual event, so you can watch it from the comfort of your own home on a phone or laptop. And it’s free.

The CIRM Alpha Clinics are a network of leading medical centers here in California. They specialize in delivering stem cell and gene therapies to patients. So, while many conferences look at the promise of stem cell therapies, here we deal with the reality; what’s in the clinic, what’s working, what do we need to do to help get these therapies to patients in need?

It’s a relatively short meeting, with short presentations, but that doesn’t mean it will be short on content. Some of the best stem cell researchers in the U.S. are taking part so you’ll learn an awful lot in a short time.

We’ll hear what’s being done to find therapies for

  • Rare diseases that affect children
  • Type 1 diabetes
  • HIV/AIDS
  • Glioblastoma
  • Multiple myeloma

We’ll discuss how to create a patient navigation system that can address social and economic determinants that impact patient participation? And we’ll look at ways that the Alpha Clinic Network can partner with community care givers around California to increase patient access to the latest therapies.

It’s going to be a fascinating day. And did I mention it’s free!

All you have to do is go to this Eventbrite page to register.

And feel free to share this with your family, friends or anyone you think might be interested.

We look forward to seeing you there.

Meet the people who are changing the future

Kristin MacDonald

Every so often you hear a story and your first reaction is “oh, I have to share this with someone, anyone, everyone.” That’s what happened to me the other day.

I was talking with Kristin MacDonald, an amazing woman, a fierce patient advocate and someone who took part in a CIRM-funded clinical trial to treat retinitis pigmentosa (RP). The disease had destroyed Kristin’s vision and she was hoping the therapy, pioneered by jCyte, would help her. Kristin, being a bit of a pioneer herself, was the first person to test the therapy in the U.S.

Anyway, Kristin was doing a Zoom presentation and wanted to look her best so she asked a friend to come over and do her hair and makeup. The woman she asked, was Rosie Barrero, another patient in that RP clinical trial. Not so very long ago Rosie was legally blind. Now, here she was helping do her friend’s hair and makeup. And doing it beautifully too.

That’s when you know the treatment works. At least for Rosie.

There are many other stories to be heard – from patients and patient advocates, from researchers who develop therapies to the doctors who deliver them. – at our CIRM 2020 Grantee Meeting on next Monday September 14th Tuesday & September 15th.

It’s two full days of presentations and discussions on everything from heart disease and cancer, to COVID-19, Alzheimer’s, Parkinson’s and spina bifida. Here’s a link to the Eventbrite page where you can find out more about the event and also register to be part of it.

Like pretty much everything these days it’s a virtual event so you’ll be able to join in from the comfort of your kitchen, living room, even the backyard.

And it’s free!

You can join us for all two days or just one session on one day. The choice is yours. And feel free to tell your friends or anyone else you think might be interested.

We hope to see you there.