Coronavirus

Could a common herb help in the fight against COVID-19 and other inflammatory diseases?

/ Esteban Cortez / 1 Comment

THIS BLOG IS ALSO AVAILABLE AS AN AUDIO CAST

The culinary herb rosemary is commonly used in our kitchens to season an array of dishes, and is also considered a good source for vitamins and minerals.  

Rosemary is also valued for its medicinal properties, and has traditionally been used to help alleviate muscle pain, boost the immune and circulatory system, as well as many other health benefits. 

Now, scientists at Scripps Research have found evidence that a compound contained in rosemary could be a two-pronged weapon against the SARS-CoV-2 coronavirus that causes COVID-19.  

The research was partly funded by the California Institute for Regenerative Medicine (CIRM). 

Published in the journal Antioxidants, the study found that the compound, carnosic acid, can block the interaction between the SARS-CoV-2 outer “spike” protein and the receptor protein, ACE2, which the virus uses to gain entry to cells. 

“We think that carnosic acid, or some optimized derivative, is worth investigating as a potentially cheap, safe, and effective treatment for COVID-19 and some other inflammation-related disorders,” says study senior author Dr. Stuart Lipton of Scripps Research. 

The team also reviewed prior studies and presented new evidence that carnosic acid could inhibit a powerful inflammatory pathway that is active in severe COVID-19, as well as in other diseases including Alzheimer’s.   

They also proposed that this effect could be beneficial in treating the post-COVID syndrome known as “long COVID” whose reported symptoms include cognitive difficulties often described as “brain fog.” 

While the research is preliminary, the researchers propose that carnosic acid has this antiviral effect because it is converted to its active form by the inflammation and oxidation found at sites of infection. In that active form, they suggest, the compound modifies the ACE2 receptor for SARS-CoV-2—making the receptor impregnable to the virus and thereby blocking infection. 

Lipton and his colleagues are now working with Scripps Research chemists to synthesize and test more potent derivatives of carnosic acid with improved drug characteristics for potential use in inflammation-related disorders. 

The full study was co-authored by Takumi Satoh of the Tokyo University of Technology; and by Dorit Trudler, Chang-ki Oh and Stuart Lipton of Scripps Research. Read the source news release here. 

Disclaimer: This research is still in its early phase and there is no suggestion that sprinkling rosemary on everything you eat could help prevent or fight COVID-19. For the latest guidance on COVID-19, see the official CDC website. 

Bridges Scholar Spotlight: Samira Alwahabi

/ Katie Sharify / Leave a comment

THIS BLOG IS ALSO AVAILABLE AS AN AUDIO CAST

For more than a decade, CIRM has funded a number of educational and research training programs to give students the opportunity to explore stem cell science. One such project, the Bridges to Stem Cell Research program, helps train future generation of scientists by preparing undergraduate and master’s students from several California universities for careers in stem cell research.

Last summer, the Pacific Division of AAAS organized a ‘Moving on from COVID-19’ virtual forum specifically focused on students of science presenting their future career and research plans through 3-5 minute descriptive videos. 

Samira Alwahabi, a Bridges scholar and undergraduate student majoring in Biological Sciences at California State University, Fullerton was one of the many participants who submitted a video detailing their current work and future aspirations. Alwahabi is a CIRM intern conducting research in the Kuo lab at the Stanford University School of Medicine where she focuses on the identification and characterization of human distal lung stem cells as well as the effects of the novel SARS-CoV-2 virus on the human distal lung through the use of organoids. Her video, which you can watch below, was recognized for “Best Video Submission by an Undergraduate Student.” 

We reached out to Samira to congratulate her and she shared a few words with us about her experience with the Bridges program:

I am very grateful to the CSUF Bridges to Stem Cell Research program for giving me the opportunity to pursue research in the Kuo Lab at Stanford University. The past 11 months have been nothing less than exceptional! I have learned more than I could have even imagined and have been able to really solidify my future career goals through hands-on practice and interactions with professionals at all levels in the field of medical research. The CIRM Bridges program has allowed me to better understand how medical advancements are made and helped to further strengthen my interest in medicine. My future career goals include a career in medicine as a physician, where I will be able to use my research experience to better understand medical innovations that translate into improved quality of care for my patients. 

Congratulations Samira!

COVID is a real pain in the ear

/ Kevin McCormack / 6 Comments

THIS BLOG IS ALSO AVAILABLE AS AN AUDIO CAST

The more you learn about COVID-19 the more there is to dislike about it. The global death toll from the virus is now more than five million and for those who survive there can be long-term health consequences. We know COVID can attack the lungs, heart and brain. Now we are learning it can also mess up your ears causing hearing problems, ringing in the ear (tinnitus) and leave you dizzy.

Viral infections are a known cause of hearing loss and other kinds of infection. That’s why, before the pandemic started, Dr. Konstantina Stantovic at Massachusetts Eye and Ear and Dr. Lee Gherke at MIT had been studying how and why things like measles, mumps and hepatitis affected people’s hearing. After COVID hit they heard reports of patients experiencing sudden hearing loss and other problems, so they decided to take a closer look.

They took cells from ten patients who had all experienced some hearing or ear-related problems after testing positive for COVID and, using the iPSC method, turned those cells into the kind found in the inner ear including hair cells, supporting cells, nerve fibers, and Schwann cells.  

They then compared those to cells from patients who had similar hearing issues but who had not been infected with COVID. They found that the hair and Schwann cells both had proteins the virus can use to infect cells. That’s important because hair cells help with balance and the Schwann cells play a protective role for neuronal axons, which help different nerve cells in the brain communicate with each other.

In contrast, some of the other cells in the inner ear didn’t have those proteins and so were protected from COVID.

In a news release Dr. Stankovic says it’s not known how many people infected with COVID experienced hearing issues. “Initially this was because routine testing was not readily available for patients who were diagnosed with COVID, and also, when patients were having more life-threatening complications, they weren’t paying much attention to whether their hearing was reduced or whether they had tinnitus. We still don’t know what the incidence is, but our findings really call for increased attention to audio vestibular symptoms in people with Covid exposure.”

The doctors are not sure how the virus gets into the inner ear but speculate that it may enter through the Eustachian tube, that’s a small passageway that connects your throat to your middle ear. When you sneeze, swallow, or yawn, your Eustachian tubes open, preventing air pressure and fluid from building up inside your ear. They think that might allow particles from the nose to spread to the ear.

The study is published in the journal Communications Medicine.

CIRM has funded 17 different projects targeting COVID-19, several of which are still active.

Beware of misleading headlines and claims

/ Kevin McCormack / Leave a comment

THIS BLOG IS ALSO AVAILABLE AS AN AUDIO CAST

Coronavirus particles, illustration.

When the COVID pandemic broke out researchers all over the world scrambled to find new approaches to tackling the virus. Some of these, such as the vaccines, proved remarkably effective. Others, such as the anti-parasite medication ivermectin or the anti-malaria drug chloroquine, were not only not helpful, they were sometimes harmful.

Part of the problem was the understandable desire to find something, anything that would protect people from the virus. But another part of the problem was that even with research that was based on solid science, the reporting of that research in the media sometimes tilted towards hype rather than hard evidence.

A new study in the journal Stem Cell Reports takes a look at the explosion of research targeting COVID. They highlighted the lack of rigor that sometimes accompanied that research, and the lack of regulation that allowed some predatory clinics to offer stem cell “therapies” that had never been tested in people let alone shown to be either safe or effective.

Dr. Leigh Turner, from the University of California Irvine and a co-author of the study, warned against studies that were cutting ethical and scientific corners. “Scientists, regulators, and policymakers must guard against the proliferation of poorly designed, underpowered, and duplicative studies that are launched with undue haste because of the pandemic, but are unlikely to provide convincing, clinically meaningful safety and efficacy data.”

The researchers cited an earlier study (by UC Davis’ Dr. Paul Knoepfler and Dr. Mina Kim) that looked at 70 clinical trials involving cell-based treatments for COVID-19. Drs. Knoepfler and Kim found that most were small, involving around 50 patients, and only 22.8% were randomized, double-blinded, and controlled experiments. They say even if these produced promising results they would have to be tested in much larger numbers to be of real benefit.

Another issue that Turner and his team highlighted was the hype that sometimes accompanied this work, citing news releases that over-hyped findings and failed to mention study limitations to gain more media coverage.

In a news release Dr. Laertis Ikonomou, of the University at Buffalo and a co-author of the study, said over-hyping treatments is nothing new but that it seemed to become even more common during COVID.

“Therefore, it is even more important to communicate promising developments in COVID-19-related science and clinical management [responsibly]. Key features of good communication are an accurate understanding of new findings, including study limitations and avoidance of sensationalist language.”

“Realistic time frames for clinical translation are equally important as is the realization that promising interventions at preliminary stages may not always translate to proven treatments following rigorous testing.”

They also warned about clinics advertising “stem cell therapies” that were unproven and unlicensed and often involved injecting the patients’ own cells back into them. The researchers say it’s time that the FDA and other authorities cracked down on companies taking advantage of patients in this way.

“If companies and affiliated clinicians are not fined, forced to return to patients whatever profits they have made, confronted with criminal charges, subject to revocation of medical licensure, or otherwise subject to serious legal and financial consequences, it is possible that more businesses will be drawn to this space because of the profits that can be generated from selling unlicensed and unproven cell-based products in the midst of a pandemic.”

At a time when so many were dying or suffering long-term health problems as a result of COVID, it’s unconscionable that others were happy to cash in on the fear and pain to make a quick buck.

When the pandemic broke out the CIRM Board voted to approved $5 million in emergency funding to help develop new therapies to combat the virus. Altogether we funded 17 different projects including three clinical trials.

Retooling a COVID drug to boost its effectiveness

/ Kevin McCormack / 1 Comment

Coronavirus particles, illustration.

When the COVID-19 pandemic broke out scientists scrambled to find existing medications that might help counter the life-threatening elements of the virus. One of the first medications that showed real promise was remdesivir. It’s an anti-viral drug that was originally developed to target novel, emerging viruses, viruses like COVID19. It was approved for use by the Food and Drug Administration (FDA) in October 2020.

Remdesivir showed real benefits for some patients, reducing recovery time for those in the hospital, but it also had problems. It had to be delivered intravenously, meaning it could only be used in a hospital setting. And it was toxic if given in too high a dose.

In a new study – partially funded by CIRM (DISC2 COVID19-12022 $228,229) – researchers at the University of California San Diego (UCSD) found that by modifying some aspects of remdesivir they were able to make it easier to take and less toxic.

In a news release about the work Dr. Robert Schooley, a first author on the study, says we still need medications like this.

“Although vaccine development has had a major impact on the epidemic, COVID-19 has continued to spread and cause disease — especially among the unvaccinated. With the evolution of more transmissible viral variants, breakthrough cases of COVID are being seen, some of which can be severe in those with underlying conditions. The need for effective, well-tolerated antiviral drugs that can be given to patents at high risk for severe disease at early stages of the illness remains high.”

To be effective remdesivir must be activated by several enzymes in the body. It’s a complex process and explains why the drug is beneficial for some areas, such as the lung, but can be toxic to other areas, such as the liver. So, the researchers set out to overcome those problems.

The team created what are called lipid prodrugs, these are compounds that do not dissolve in water and are used to improve how a drug interacts with cells or other elements; they are often used to reduce the bad side effects of a medication. By inserting a modified form of remdesivir into this lipid prodrug, and then attaching it to an enzyme called a lipid-phosphate (which acts as a delivery system, bringing along the remdesivir prodrug combo), they were able to create an oral form of remdesivir.

Dr. Aaron Carlin, a co-first author of the study, says they were trying to create a hybrid version of the medication that would work equally well regardless of the tissue it interacted with.

“The metabolism of remdesivir is complex, which may lead to variable antiviral activity in different cell types. In contrast, these lipid-modified compounds are designed to be activated in a simple uniform manner leading to consistent antiviral activity across many cell types.”

When they tested the lipid prodrugs in animal models and human cells they found they were effective against COVID-19 in different cell types, including the liver. They are now working on further developing and testing the lipid prodrug to make sure it’s safe for people and that it can live up to their hopes of reducing the severity of COVID-19 infections and speed up recovery.

The study is published in the journal Antimicrobial Agents and Chemotherapy.

Friends, Romans, countrymen, lend me your ears – we have a podcast for you.

/ Kevin McCormack / Leave a comment
It seems like everyone, including my dog Freddie, has a podcast these days. So now we do too.

According to the Podcasthosting.org website there are some two million podcasts in the world. Make that two million and one. That’s because CIRM is launching its own podcast and doing it with one of the biggest names in biotech.

Our podcast is called – with a nod to The Who – “Talking ’bout (Re)Generation” and the first episode features our President & CEO Dr. Maria Millan interviewing Dr. Derrick Rossi, the co-founder of Moderna. Moderna, as I am sure you know, is the maker of one of the most effective vaccines against COVID.

In the interview Dr. Rossi talks about his early days as a postdoc at Stanford – supported by CIRM – and the career arc that led him to help create the company behind the vaccine, and what his plans are for the future. It’s a fun, chatty, lively interview; one you can listen to in the car, at home or wherever you listen to your podcasts.

We want the podcast to be fun for your ear holes and interesting and engaging for your brain. We’re going to be talking to scientists and researchers, doctors and nurses, patients and patient advocates and anyone else we think has something worth listening to.

We have other episodes planned and will share those with you in the near future. In the meantime, if you have any ideas or individuals you think would make a good subject for a podcast let us know, we are always happy to hear from you.

In the meantime, enjoy the show.

CIRM funding helps identify potential COVID-19 treatment

/ Yimy Villa / 1 Comment
The steps of the virus growth cycle that can be targeted with therapies: The virus enters a host cell (1), the virus’s genetic instructions are released, taking over cellular machinery (2), the virus is replicated within the cell (3) and copies of the virus exit the cell in search of new host cells to infect (4). Drugs like berzosertib might disrupt steps 2 and 3.  Image credit: Marc Roseboro/California NanoSytems Institute at UCLA

During the global pandemic, many researchers have responded to the needs of patients severely afflicted with COVID-19 by repurposing existing therapies being developed to treat patients.  CIRM responded immediately to the pandemic and to researchers wanting to help by providing $5 million in emergency funding for COVID-19 related projects. 

One of these grants ($349,999), awarded to Dr. Vaithilingaraja Arumugaswami at UCLA, has aided a study that has singled out a compound that shows promise for treating SARS-CoV-2, the virus that causes COVID-19.

In the spirit of banding together to help patients severely affected by COVID-19, the project was a collaboration among scientists from UCLA and other universities in California, Delaware and Germany, as well as a German pharmaceutical company.

The compound is named berzosertib and is licensed by the company Merck KGaA in Darmstadt, Germany.  Prior to the pandemic, it was developed for potential use, in combination with chemotherapy, as a possible treatment for small-cell lung cancer, ovarian cancer, and other types of solid tumors.

The team screened 430 drugs from among the approximately 200,000 compounds in CNSI’s Molecular Screening Shared Resource libraries before zeroing in on berzosertib as the most promising candidate.  They limited their search to compounds that either had been approved, or are already in the process of being evaluated, for safety in humans.

In a press release from UCLA, Dr. Arumugawami explains the rationale behind screening a potential drug candidate.

“That way, the compounds have cleared the first regulatory hurdle and could be deployed for further clinical trials on COVID-19 faster than drugs that have not been tested in humans.”

The researchers, led by Dr. Arumugaswami and Dr. Robert Damoiseaux from UCLA, conducted a series of experiments using different cell types in lab dishes to look at how effective the compound was at blocking SARS-CoV-2 from replicating.  Unlike other approaches which attack the virus directly, targeting replication could help better address the ability of the virus to mutate. 

For this study, the team used cells from the kidney, heart and lungs, all of which are organs that the virus is known to attack. The researchers pretreated cells with berzosertib, exposed the cells to SARS-CoV-2, allowed 48 hours for infection to set in, and then evaluated the results.

The team found that the compound consistently stalled SARS-CoV-2 replication without damaging the cells. The scientists also tested the drug against SARS and MERS, both of which are other types of coronaviruses that triggered deadly outbreaks earlier in the 2000s. They found that it was effective in stopping the replication of those viruses as well.

In the same press release from UCLA, Dr. Damoiseaux expressed optimism for what these findings could mean as a potential treatment.

“This is a chance to actually find a drug that might be broader in spectrum, which could also help fight coronaviruses that are yet to come.”

The next steps for this research would be to explore the mechanism through which the compound blocks coronavirus replication.  Understanding this and conducting preclinical studies are both necessary before the compound could be tested in clinical trials for COVID-19.

The full results of this study were published in Cell Reports.

The study’s co-corresponding author is Ulrich Betz of Merck KGaA, Darmstadt, Germany; the company also provided partial funding and clinical-grade berzosertib for the research. Other co-authors are from UCLA, Cedars-Sinai Medical Center, UC Irvine, University of Delaware, the Leibniz Institute for Experimental Virology in Germany, Heidelberg University in Germany and Scripps Research Institute.

In addition to CIRM, the study was also funded by CNSI, the Broad Stem Cell Research Center, the David Geffen School of Medicine at UCLA, the National Eye Institute, and the Bill and Melinda Gates Foundation.

A word from our Chair, several in fact

/ Kevin McCormack / 2 Comments

In 2005, the New Oxford American Dictionary named “podcast” its word of the year. At the time a podcast was something many had heard of but not that many actually tuned in to. My how times have changed. Now there are some two million podcasts to chose from, at least according to the New York Times, and who am I to question them.

Yesterday, in the same New York Times, TV writer Margaret Lyons, wrote about how the pandemic helped turn her from TV to podcasts: “Much in the way I grew to prefer an old-fashioned phone call to a video chat, podcasts, not television, became my go-to medium in quarantine. With their shorter lead times and intimate production values, they felt more immediate and more relevant than ever before.”

I mention this because an old colleague of ours at CIRM, Neil Littman, has just launched his own podcast and the first guest on it was Jonathan Thomas, Chair of the CIRM Board. Their conversation ranged from CIRM’s past to the future of the regenerative field as a whole, with a few interesting diversions along the way. It’s fun listening. And as Margaret Lyons said it might be more immediate and more relevant than ever before.

Scientists look at how the lung and brain respond differently to SARS-CoV-2 infection

/ Yimy Villa / 1 Comment
UC San Diego School of Medicine researchers found approximately 10-fold higher SARS-CoV-2 infection (green) in lung organoids (left), compared to brain organoids (right). Image courtesy of UCSD Health

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.

The full results of this study can be found in Stem Cell Reports.

Charting a course for the future

/ Kevin McCormack / 1 Comment
A new home for stem cell research?

Have you ever been at a party where someone says “hey, I’ve got a good idea” and then before you know it everyone in the room is adding to it with ideas and suggestions of their own and suddenly you find yourself with 27 pages of notes, all of them really great ideas. No, me neither. At least, not until yesterday when we held the first meeting of our Scientific Strategy Advisory Panel.

This is a group that was set up as part of Proposition 14, the ballot initiative that refunded CIRM last November (thanks again everyone who voted for that). The idea was to create a panel of world class scientists and regulatory experts to help guide and advise our Board on how to advance our mission. It’s a pretty impressive group too. You can see who is on the SSAP here.  

The meeting involved some CIRM grantees talking a little about their work but mostly highlighting problems or obstacles they considered key issues for the future of the field as a whole. And that’s where the ideas and suggestions really started flowing hard and fast.

It started out innocently enough with Dr. Amander Clark of UCLA talking about some of the needs for Discovery or basic research. She advocated for a consortium approach (this quickly became a theme for many other experts) with researchers collaborating and sharing data and findings to help move the field along.

She also called for greater diversity in research, including collecting diverse cell samples at the basic research level, so that if a program advanced to later stages the findings would be relevant to a wide cross section of society rather than just a narrow group.

Dr. Clark also said that as well as supporting research into neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, there needed to be a greater emphasis on neurological conditions such as autism, bipolar disorder and other mental health problems.

(CIRM is already committed to both increasing diversity at all levels of research and expanding mental health research so this was welcome confirmation we are on the right track).

Dr. Mike McCun called for CIRM to take a leadership role in funding fetal tissue research, things the federal government can’t or won’t support, saying this could really help in developing an understanding of prenatal diseases.

Dr. Christine Mummery, President of ISSCR, advocated for support for early embryo research to deepen our understanding of early human development and also help with issues of infertility.

Then the ideas started coming really fast:

  • There’s a need for knowledge networks to share information in real-time not months later after results are published.
  • We need standardization across the field to make it easier to compare study results.
  • We need automation to reduce inconsistency in things like feeding and growing cells, manufacturing cells etc.
  • Equitable access to CRISPR gene-editing treatments, particularly for underserved communities and for rare diseases where big pharmaceutical companies are less likely to invest the money needed to develop a treatment.
  • Do a better job of developing combination therapies – involving stem cells and more traditional medications.

One idea that seemed to generate a lot of enthusiasm – perhaps as much due to the name that Patrik Brundin of the Van Andel Institute gave it – was the creation of a CIRM Hotel California, a place where researchers could go to learn new techniques, to share ideas, to collaborate and maybe take a nice cold drink by the pool (OK, I just made that last bit up to see if you were paying attention).

The meeting was remarkable not just for the flood of ideas, but also for its sense of collegiality.  Peter Marks, the director of the Food and Drug Administration’s Center for Biologics Evaluation and Research (FDA-CBER) captured that sense perfectly when he said the point of everyone working together, collaborating, sharing information and data, is to get these projects over the finish line. The more we work together, the more we will succeed.