Creating a New Model for Diversity in Scientific and Medical Research

Nature Cell Biology cover

The global pandemic has highlighted many of the inequities in our health care system, with the virus hitting communities of color the hardest. That has led to calls for greater diversity, equity and inclusion at every level of scientific research and, ultimately, of medical care. A recently released article in the journal Nature Cell Biology, calls for “new models for basic and disease research that reflect diverse ancestral backgrounds and sex and ensure that diverse populations are included among donors and research participants.”

The authors of the article are Dr. Maria T. Millan, CIRM’s President & CEO; Rick Horwitz Senior Advisor and Executive Director, Emeritus, Allen Institute for Cell Science; Dr. Ekemini Riley, President, Coalition for Aligning Science; and Dr. Ruwanthi N. Gunawardane, Executive Director of the Allen Institute for Cell Science.

Dr. Maria Millan, CIRM’s President & CEO, says we need to make these issues a part of everything we do. “At CIRM we have incorporated the principles of promoting diversity, equity and inclusion in our research funding programs, education programs and future programs. We believe this is essential to ensure that the therapies our support helps advance will reach all patients in need and in particular communities that are disproportionately affected and/or under-served.”

The article highlights how, in addition to cultural, environmental, and socioeconomic factors, genetic factors also appear to play a role in the way disease affects different people. For example, 50 percent of people in South Asia have genetic traits that increases their risk for severe COVID-19, in contrast only 16 percent of Europeans have those traits.

But while some studies have shown how African American men are at greater risk for prostate cancer than white men, most of the research in this and other areas has been done on white populations of European ancestry. Efforts are already underway to change these disparities. For example, the National Institutes of Health (NIH) has sponsored the All of Us Research Program, which is inviting one million people across the U.S. to help build one of the most diverse health databases in history.

The article in Nature Cell Biology stresses the need to account for diversity at the individual molecular, cellular and tissue level. The authors make the point that diversity in those taking part in clinical trials is essential, but equally essential is that diverse biology is accounted for in the scientific work that leads to the development of potential therapies in order to increase the likelihood of success.

That’s why the authors of the article say: “If we are to truly understand human biology, address health disparities, and personalize our treatments, we need to go beyond our important, ongoing efforts in addressing diversity and inclusion in the workforce and the delivery of healthcare. We need to improve the data we generate by including diverse populations among donors and research participants. This will require new models and tools for basic and disease research that more closely reflect the diversity of human tissues, across diverse donor backgrounds.”

“Greater diversity in biological studies is not only the right thing to do, it is crucial to helping researchers make new discoveries that benefit everyone,” said Ru Gunawardane, Executive Director of the Allen Institute for Cell Science.

To do this they propose creating “a suite” of research cells, such as human induced pluripotent stem cell (hiPSC) lines from a diverse group of individuals to reflect the racial, ethnic and gender composition of the population. Human iPSCs are cells taken from any tissue (usually skin or blood) from a child or adult that have been genetically modified to behave like an embryonic stem cell. As the name implies, these cells are pluripotent, which means that they can become any type of adult cell.

CIRM has already created one version of what this suite would look like, through its iPSC Repository, a collection of more than 2,600 hiPSCs from individuals of diverse ancestries, including African, Hispanic, Native American, East and South Asian, and European. The Allen Institute for Cell Science also has a collection that could serve as a model for this kind of repository. Its collection of over 50 hiPSC

lines have been thoroughly analyzed on both a genomic and biological level and could also be broken down to include diversity in donor ethnicity and sex.

Currently researchers use cells from different lines and often follow very different procedures in using them, making it hard to compare results from one study to another. Having a diverse and well defined collection of research cells and cell models that are created by standardized procedures, could make it easier to compare results from different studies and share knowledge within the scientific community. By incorporating diversity in the very early stages of scientific research, the scientists and therapy developers gain a more complete picture of the biology disease and potential treatments.  

Stem Cell Agency Board Invests in Therapy Targeting Deadly Blood Cancers

Dr. Ezra Cohen, photo courtesy UCSD

Hematologic malignancies are cancers that affect the blood, bone marrow and lymph nodes and include different forms of leukemia and lymphoma. Current treatments can be effective, but in those patients that do not respond, there are few treatment options. Today, the governing Board of the California Institute for Regenerative Medicine (CIRM) approved investing $4.1 million in a therapy aimed at helping patients who have failed standard therapy.

Dr. Ezra Cohen, at the University of California San Diego, and Oncternal Therapeutics are targeting a protein called ROR1 that is found in B cell malignancies, such as leukemias and lymphomas, and solid tumors such as breast, lung and colon. They are using a molecule called a chimeric antigen receptor (CAR) that can enable a patient’s own T cells, an important part of the immune system, to target and kill their cancer cells. These cells are derived from a related approach with an antibody therapy that targets ROR1-binding medication called Cirmtuzumab, also created with CIRM support. This CAR-T product is designed to recognize and kill cancer stem cells that express ROR1.

This is a late-stage preclinical project so the goal is to show they can produce enough high-quality cells to treat patients, as well as complete other regulatory measures needed for them to apply to the US Food and Drug Administration (FDA) for permission to test the therapy in a clinical trial in people.

If given the go-ahead by the FDA the therapy will target patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL) and acute lymphoblastic leukemia (ALL).  

“CAR-T cell therapies represent a transformational advance in the treatment of hematologic malignancies,” says Dr. Maria T. Millan, CIRM’s President and CEO. “This approach addresses the need to develop new therapies for patients whose cancers are resistant to standard chemotherapies, who have few therapeutic options and a very poor chance or recovery.”

Type 1 diabetes therapy gets go-ahead for clinical trial

ViaCyte’s implantable cell-based therapy for type 1 diabetes

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Taking even the most promising therapy and moving it out of the lab and into people is an incredibly complex process and usually requires a great team. Now, two great teams have paired up to do just that with a therapy for type 1 diabetes (T1D). ViaCyte and CRISPR Therapeutics have put their heads together and developed an approach that has just been given clearance by Health Canada to start a clinical trial.

Regular readers of this blog know that CIRM has been a big supporter of ViaCyte for many years, investing more than $72 million in nine different awards. They have developed an implantable device containing embryonic stem cells that develop into pancreatic progenitor cells, which are precursors to the islet cells destroyed by T1D. The hope is that when this device is transplanted under a patient’s skin, the progenitor cells will develop into mature insulin-secreting cells that can properly regulate the glucose levels in a patient’s blood.

One of the challenges in earlier testing was developing a cell-based therapy that could evade the immune system, so that people didn’t need to have their immune system suppressed to prevent it attacking and destroying the cells. This particular implantable version sprang out of an early stage award we made to ViaCyte (DISC2-10591). ViaCyte and CRISPR Therapeutics helped with the design of the therapeutic called VCTX210.

In a news release, Michael Yang, the President and CEO of ViaCyte, said getting approval for the trial was a major milestone: “Being first into the clinic with a gene-edited, immune-evasive cell therapy to treat patients with type 1 diabetes is breaking new ground as it sets a path to potentially broadening the treatable population by eliminating the need for immunosuppression with implanted cell therapies. This approach builds on previous accomplishments by both companies and represents a major step forward for the field as we strive to provide a functional cure for this devastating disease.”

The clinical trial, which will be carried out in Canada, is to test the safety of the therapy, whether it creates any kind of reaction after being implanted in the body, and how well it does in evading the patient’s immune system. In October our podcast – Talking ‘Bout (re)Generation – highlighted work in T1D and included an interview with Dr. Manasi Jaiman, ViaCyte’s Vice President for Clinical Development. Here’s an excerpt from that podcast.

Dr. Manasi Jaimin, ViaCyte VP Clinical development

Sweating bullets and other stories from the front line

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When the COVID-19 pandemic hit and the 2020 election became one of the most contentious in living history it suddenly made trying to get a proposition on the ballot in California a lot harder. That meant the fate of Proposition 14, a ballot initiative refunding CIRM, California’s Stem Cell Agency, was in doubt. And if the agency went down, then a vital source of future funding for scientific research that could change and even save lives would also disappear.

It was a pretty nerve-racking time for all of us involved. We waited day after day after day after day before the election was finally called. Happily, it was in our favor. But only just!

In this podcast we talk to two of the key figures in this saga. Melissa King and Maria Bonneville. Melissa was part of the team that helped secure the votes needed to pass Proposition 14, and Maria helped keep CIRM on track to cope with whatever the outcome of the election was. 

I hope you enjoy this latest episode of our podcast ‘Talking ‘Bout (re)Generation.’

A year unlike any other – a look back at one year post Prop 14

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State flag of California

2020 was, by any standards, a pretty wacky year. Pandemic. Political convulsions. And a huge amount of uncertainty as to the funding of life-saving therapies at CIRM. Happily those all turned out OK. We got vaccines to take care of COVID. The election was won fair and square (seriously). And Proposition 14 was approved by the voters of California, re-funding your favorite state Stem Cell Agency.

But for a while, quite a while, there was uncertainty surrounding our future. For a start, once the pandemic lockdown kicked in it was impossible for people to go out and collect the signatures needed to place Proposition 14 on the November ballot. So the organizers of the campaign reached out online, using petitions that people could print out and sign and mail in.

It worked. But even after getting all the signatures needed they faced problems such as how do you campaign to get something passed, when the normal channels are not available. The answer is you get very creative very quickly.

Bob Klein

Bob Klein, the driving force behind both Proposition 71 (the 2004 ballot initiative that created CIRM) and Proposition 14, says it was challenging:

“It was a real adventure. It’s always hard, you have a complicated message about stem cells and genetics and therapy and it’s always a challenge to get a million signatures for a ballot initiative but in the middle of a pandemic where we had to shut down the signature gathering at grocery stores and street corners, where we had to go to petitions that had to be sent to voters and get them to fill them out properly and send them back. And of course the state went into an economic recoil because of the pandemic and people were worried about the money.”

Challenging absolutely, but ultimately successful. On November 13, ten days after the election, Prop 14 was declared the winner.

As our President and CEO, Dr. Maria Millan says, we went from an agency getting ready to close its doors to one ramping up for a whole new adventure.

“We faced many challenges in 2020. CIRM’s continued existence was hinging on the passage of a new bond initiative and we began the year uncertain if it would even make it on the ballot.  We had a plan in place to wind down and close operations should additional funding not materialize.  During the unrest and challenges brought by 2020, and functioning in a virtual format, we retained our core group of talented individuals who were able to mobilize our emergency covid research funding round, continue to advance our important research programs and clinical trials and initiate the process of strategic planning in the event that CIRM was reauthorized through a new bond initiative. Fortunately, we planned for success and Proposition 14 passed against all odds!”

“When California said “Yes,” the CIRM team was positioned to launch the next Era of CIRM! We have recruited top talent to grow the team and have developed a new strategic plan and evolved our mission:  Accelerating world-class science to deliver transformative regenerative medicine treatments to a diverse California and worldwide in an equitable manner.” 

And since that close call we have been very busy. In the last year we have hired 16 new employees, everyone from a new General Counsel to the Director of Finance, and more are on the way as we ramp up our ability to turn our new vision into a reality.

We have also been working hard to ensure we could continue to fund groundbreaking research from the early-stage Discovery work, to testing therapies in patients in clinical trials. Altogether our Board has approved almost $250 million in 56 new awards since December 2020. That includes:

Clinical – $84M (9 awards)

Translational – $15M (3 awards)

Discovery – $13M (11 awards)

Education – $138M (33 awards)

We have also enrolled more than 360 new patients in clinical trials that we fund or that are being carried out in the CIRM Alpha Stem Cell Clinic network.

This is a good start, but we know we have a lot more work to do in the coming years.

The last year has flown by and brought more than its fair share of challenges. But the CIRM team has shown that it can rise to those, in person and remotely, and meet them head on. We are already looking forward to 2022. We’ve got a lot of work to do.

Promising new approach for people with epilepsy

Image courtesy Epilepsy.com

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A new therapeutic approach, supported by CIRM, that blocks the signals in the brain that can cause epilepsy has been given permission by the US Food and Drug Administration (FDA) to be tested in a clinical trial.

Nearly 3.5 million Americans suffer from some form of epilepsy. It can affect people in different ways from stiff muscles or staring spells, to violent shaking and loss of consciousness. The impact it has on people’s lives extends far beyond the condition itself. People who suffer from epilepsy experience a higher frequency of depression and other mood disorders, social isolation, challenges in school and with living independently, higher unemployment, limitations on driving, and higher risk of early death.

Medications can help control the seizures in some people, but around one-third of patients don’t respond to those drugs. The alternative is surgery, which is invasive and can cause damage to delicate brain tissue.

Now Neurona Therapeutics has developed an approach, called NRTX-1001, that turns stem cells into interneurons, a kind of nerve cell in the brain. These cells secrete chemical messengers, called GABA inhibitory neurotransmitters, that help rebalance the misfiring electrical signals in the brain and hopefully eliminate or reduce the seizures.

Cory Nicholas, PhD, Neuron’s Therapeutics co-founder and CEO, said getting the go-ahead from the FDA for a clinical trial is a key milestone for the company. “Neurona’s accomplishments are a testament to longstanding support from CIRM. CIRM has supported the NRTX-1001 program from bench to bedside, dating back to early research in the Neurona founders’ laboratories at the University of California, San Francisco to the recent IND-enabling studies conducted at Neurona. It’s an exciting time for the field of regenerative medicine and is gratifying to see the NRTX-1001 neuronal cell therapy now cleared by the FDA to enter clinical testing in people who have drug resistant temporal lobe epilepsy. We are thankful to CIRM for their support of this important work that has the potential to provide seizure-freedom for patients who currently have limited treatment options.”

In a news release Dr. Nicholas said the timing was perfect. “This milestone is especially rewarding and timely given that November is Epilepsy Awareness Month. NRTX-1001 is a new type of inhibitory cell therapy that is targeted to the focal seizure onset region in the brain and, in a single treatment, has the potential to significantly improve the lives of people living with focal epilepsy.”

In animal models NRTX-1001 produced freedom from seizures in more than two-thirds of the treated group, compared to just 5 percent of the untreated group. It also resulted in reduced tissue damage in the seizure-affected area of the brain.

The clinical trial will initially target people affected by mesial temporal lobe epilepsy (MTLE) where seizures often begin in a structure called the hippocampus. MTLE is the most common type of focal epilepsy.

CIRM has invested almost $6.67 million in funding three stages of this project, from the early Discovery work to this latest late-stage preclinical work, highlighting our commitment to doing all we can to advance the most promising science from the bench to the bedside.

COVID is a real pain in the ear

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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

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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.

A hair raising tale

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For many men, losing their hair is not just something that happens with age, it’s traumatic. A survey of men from the UK, France, Germany, Italy and Spain found that more than 70% of men who reported losing their hair said it was an important feature of their image, and 62% agreed that hair loss could affect self-esteem. So, while a scientist who comes up with a way to prevent hair loss may not win a Nobel Prize, they will certainly get the undying gratitude of millions of men, and some women, around the world.

Now a team at Northwestern Medicine may just have found some clues as to why it happens, and some clues on how to stop it.

As we age our hair follicles go through a cycle of growth and death. As older hairs die there are stem cells in the hair follicles that produce new, replacement hair follicle cells. In this study, which was done in older male mice, the researchers found that as the mice age the stem cells in the hair start to lose the stickiness that helps them remain in the hair follicles. Without that stickiness they drift outside of the protective environment and can’t survive.

As Dr. Rui Yi, lead author of the study says in a news release; no hair stem cells, no hair replacements. “The result is fewer and fewer stem cells in the hair follicle to produce hair. This results in thinning hair and ultimately baldness during aging.”

Happily, the team also discovered two genes that seem to play a key role in generating the stickiness the cells need to stay in the follicle. They are now trying to reinstate those genes to see if that can reverse hair loss.

While this was done in mice the researchers say there are a lot of similarities between mice and humans in hair and stem cells.

One can only hope.

The study is published in the journal Nature Aging.

A step forward in finding a treatment for a deadly neurological disorder

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MRI section of a brain affected by ALS with the front section of the brain highlighted

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a nasty disease that steadily attacks nerve cells in the brain and spinal cord. It’s pretty much always fatal within a few years. As if that wasn’t bad enough, ALS also can overlap with a condition called frontotemporal dementia (ALS/FTD). Together these conditions cause devastating symptoms of muscle weakness along with changes in memory, behavior and personality.

Now researchers at Cambridge University in the UK have managed to grow groups of cells called “mini-brains” that mimic ALS/FTD and could lead to new approaches to treating this deadly combination.

We have written about these mini-brains before. Basically, they are created, using the iPSC method, that takes skin or blood cells from a patient with a particular condition, in this case ALS/FTD, and turns them into the kind of nerve cells in the brain affected by the disease. Because they came from someone who had ALS/FTD they display many of the characteristics of the disease and this gives researchers a great tool to study the condition.

This kind of approach has been done before and given researchers a glimpse into what is happening in the brains of people with ALS/FTD. But in the past those cells were in a kind of clump, and it wasn’t possible to get enough nutrients to the cells in the middle of the clump for the mini-brain to survive for long.

What is different about the Cambridge team is that they were able to create these mini-brains using thin, slices of cells. That meant all the cells could get enough nutrients to survive a long time, giving the team a better model to understand what is happening in ALS/FTD.

In a news release, Dr András Lakatos, the senior author of the study, said: “Neurodegenerative diseases are very complex disorders that can affect many different cell types and how these cells interact at different times as the diseases progress.

“To come close to capturing this complexity, we need models that are more long-lived and replicate the composition of those human brain cell populations in which disturbances typically occur, and this is what our approach offers. Not only can we see what may happen early on in the disease – long before a patient might experience any symptoms – but we can also begin to see how the disturbances change over time in each cell.”

Thanks to these longer-lived cells the team were able to see changes in the mini-brains at a very early stage, including damage to DNA and cell stress, changes that affected other cells which play a role in muscle movements and behavior.

Because the cells developed using the iPSC method are from a patient with ALS/FTD, the researchers were able to use them to screen many different medications to see if any had potential as a therapy. They identified one, GSK2606414, that seemed to help in reducing the build-up of toxic proteins, reduced cell stress and the loss of nerve cells.

The team acknowledge that these results are promising but also preliminary and will require much more research to verify them.

CIRM has funded three clinical trials targeting ALS. You can read about that work here.