CIRM Board Awards $15.8 Million to Four Translational Research Projects

Last week, the CIRM Board approved $32.92 million in awards directed towards four new clinical trials in vision related diseases and Parkinson’s Disease.

In addition to these awards, the Board also approved investing $15.80 million in four awards in the Translational Research program. The goal of this program is to help promising projects complete the testing needed to begin talking to the US Food and Drug Administration (FDA) about holding a clinical trial.

Before we go into more specific details of each one of these awards, here is a table summarizing these four new projects:

ApplicationTitleInstitutionAward Amount
TRAN1 11536Ex Vivo Gene Editing of Human Hematopoietic Stem Cells for the Treatment of X-Linked Hyper IgM Syndrome  UCLA $4,896,628
TRAN1 11555BCMA/CS1 Bispecific CAR-T Cell Therapy to Prevent Antigen Escape in Multiple Myeloma  UCLA $3,176,805
TRAN1 11544 Neural Stem cell-mediated oncolytic immunotherapy for ovarian cancer  City of Hope $2,873,262
TRAN1 11611Development of a human stem cell-derived inhibitory neuron therapeutic for the treatment of chronic focal epilepsyNeurona Therapeutics$4,848,750
Dr. Caroline Kuo, UCLA

$4.89 million was awarded to Dr. Caroline Kuo at UCLA to pursue a gene therapy approach for X-Linked Hyper IgM Syndrome (X-HIM).

X-HIM is a hereditary immune disorder observed predominantly in males in which there are abnormal levels of different types of antibodies in the body.  Antibodies are also known as Immunoglobulin (Ig) and they combat infections by attaching to germs and other foreign substances, marking them for destruction.  In infants with X-HIM, there are normal or high levels of antibody IgM but low levels of antibodies IgG, IgA, and IgE.  The low level of these antibodies make it difficult to fight off infection, resulting in frequent pneumonia, sinus infections, ear infections, and parasitic infections.  Additionally, these infants have an increased risk of cancerous growths. 

The gene therapy approach Dr. Kuo is continuing to develop involves using CRISPR/Cas9 technology to modify human blood stem cells with a functional version of the gene necessary for normal levels of antibody production.  The ultimate goal would be to take a patient’s own blood stem cells, modify them with the corrected gene, and reintroduce them back into the patient.

CIRM has previously funded Dr. Kuo’s earlier work related to developing this gene therapy approach for XHIM.

Dr. Yvonne Chen, UCLA

$3.17 million was awarded to Dr. Yvonne Chen at UCLA to develop a CAR-T cell therapy for multiple myeloma (MM).

MM is a type of blood cancer that forms in the plasma cell, a type of white blood cell that is found in the bone marrow.  An estimated 32,110 people in the United States will be diagnosed with MM in 2019 alone.  Several treatment options are available to patients with MM, but there is no curative therapy.

The therapy that Dr. Chen is developing will consist of a genetically-modified version of the patient’s own T cells, which are an immune system cell that can destroy foreign or abnormal cells.  The T cells will be modified with a protein called a chimeric antigen receptor (CAR) that will recognize BCMA and CS1, two different markers found on the surface of MM cells.  These modified T cells (CAR-T cells) are then infused into the patient, where they are expected to detect and destroy BCMA and CS1 expressing MM cells.

Dr. Chen is using CAR-T cells that can detect two different markers in a separate clinical trial that you can read about in a previous blog post.

Dr. Karen Aboody, City of Hope

$2.87 million was awarded to Dr. Karen Aboody at City of Hope to develop an immunotherapy delivered via neural stem cells (NSCs) for treatment of ovarian cancer.

Ovarian cancer affects approximately 22,000 women per year in the United States alone.  Most ovarian cancer patients eventually develop resistance to chemotherapy, leading to cancer progression and death, highlighting the need for treatment of recurring ovarian cancer.

The therapy that Dr. Aboody is developing will use an established line of NSCs to deliver a virus that specifically targets these tumor cells.  Once the virus has entered the tumor cell, it will continuously replicate until the cell is destroyed.  The additional copies of the virus will then go on to target neighboring tumor cells.  This process could potentially stimulate the body’s own immune response to fight off the cancer cells as well.

Dr. Cory Nicholas, Neurona Therapeutics

$4.85 million was awarded to Dr. Cory Nicholas at Neurona Therapeutics to develop a treatment for epilepsy.

Epilepsy affects more than 3 million people in the United States with about 150,000 newly diagnosed cases in the US every year. It results in persistent, difficult to manage, or uncontrollable seizures that can be disabling and significantly impair quality of life. Unfortunately, anti-epileptic drugs fail to manage the disease in a large portion of people with epilepsy. Approximately one-third of epilepsy patients are considered to be drug-resistant, meaning that they do not adequately respond to at least two anti-epileptic drugs.

The therapy that Dr. Nicholas is developing will derive interneurons from human embryonic stem cells (hESCs). These newly derived interneurons would then be delivered to the brain via injection whereby the new cells are able to help regulate aberrant brain activity and potentially eliminate or significantly reduce the occurrence of seizures.

CIRM has previously funded the early stage development of this approach via a comprehensive grant and discovery grant.

How stem cells know the right way to make a heart . And what goes wrong when they don’t

Gladstone scientists Deepak Srivastava (left), Yvanka De Soysa (center), and Casey Gifford (right) publish a complete catalog of the cells involved in heart development.

The invention of GPS navigation systems has made finding your way around so much easier, providing simple instructions on how to get from point A to point B. Now, a new study shows that our bodies have their own internal navigation system that helps stem cells know where to go, and when, in order to build a human heart. And the study also shows what can go wrong when even a few cells fail to follow directions.

In this CIRM-supported study, a team of researchers at the Gladstone Institutes in San Francisco, used a new technique called single cell RNA sequencing to study what happens in a developing heart. Single cell RNA sequencing basically takes a snapshot photo of all the gene activity in a single cell at one precise moment. Using this the researchers were able to follow the activity of tens of thousands of cells as a human heart was being formed.

In a story in Science and Research Technology News, Casey Gifford, a senior author on the study, said this approach helps pinpoint genetic variants that might be causing problems.

“This sequencing technique allowed us to see all the different types of cells present at various stages of heart development and helped us identify which genes are activated and suppressed along the way. We were not only able to uncover the existence of unknown cell types, but we also gained a better understanding of the function and behavior of individual cells—information we could never access before.”

Then they partnered with a team at Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg which ran a computational analysis to identify which genes were involved in creating different cell types. This highlighted one specific gene, called Hand2, that controls the activity of thousands of other genes. They found that a lack of Hand2 in mice led to an inability to form one of the heart’s chambers, which in turn led to impaired blood flow to the lungs. The embryo was creating the cells needed to form the chamber, but not a critical pathway that would allow those cells to get where they were needed when they were needed.

Gifford says this has given us a deeper insight into how cells are formed, knowledge we didn’t have before.

“Single-cell technologies can inform us about how organs form in ways we couldn’t understand before and can provide the underlying cause of disease associated with genetic variations. We revealed subtle differences in very, very small subsets of cells that actually have catastrophic consequences and could easily have been overlooked in the past. This is the first step toward devising new therapies.”

These therapies are needed to help treat congenital heart defects, which are the most common and deadly birth defects. There are more than 2.5 million Americans with these defects. Deepak Srivastava, President of Gladstone and the leader of the study, said the knowledge gained in this study could help developed strategies to help address that.

“We’re beginning to see the long-term consequences in adults, and right now, we don’t really have any way to treat them. My hope is that if we can understand the genetic causes and the cell types affected, we could potentially intervene soon after birth to prevent the worsening of their state over time.

The study is published in the journal Nature.

CIRM Board Approves $19.7 Million in Awards for Translational Research Program

In addition to approving funding for breast cancer related brain metastases last week, the CIRM Board also approved an additional $19.7 million geared towards our translational research program. The goal of this program is to help promising projects complete the testing needed to begin talking to the US Food and Drug Administration (FDA) about holding a clinical trial.

Before getting into the details of each project, here is a table with a brief synopsis of the awards:

TRAN1 – 11532

Illustration of a healthy eye vs eye with AMD

$3.73 million was awarded to Dr. Mark Humayun at USC to develop a novel therapeutic product capable of slowing the progression of age-related macular degeneration (AMD).

AMD is an eye disease that causes severe vision impairment, resulting in the inability to read, drive, recognize faces, and blindness if left untreated.  It is the leading cause of vision loss in the U.S. and currently affects over 2 million Americans.  By the year 2050, it is projected that the number of affected individuals will more than double to over 5 million.  A layer of cells in the back of the eye called the retinal pigment epithelium (RPE) provide support to photoreceptors (PRs), specialized cells that play an important role in our ability to process images.  The dysfunction and/or loss of RPE cells plays a critical role in the loss of PRs and hence the vision problems observed in AMD.  One form of AMD is known as dry AMD (dAMD) and accounts for about 90% of all AMD cases.

The approach that Dr. Humayun is developing will use a biologic product produced by human embryonic stem cells (hESCs). This material will be injected into the eye of patients with early development of dAMD, supporting the survival of photoreceptors in the affected retina.

TRAN1 – 11579

Illustration depicting the role neuronal relays play in muscle sensation

$6.23 million was awarded to Dr. Mark Tuszynski at UCSD to develop a neural stem cell therapy for spinal cord injury (SCI).

According to data from the National Spinal Cord Injury Statistical Center, as of 2018, SCI affects an estimated 288,000 people in the United States alone, with about 17,700 new cases each year. There are currently no effective therapies for SCI. Many people suffer SCI in early adulthood, leading to life-long disability and suffering, extensive treatment needs and extremely high lifetime costs of health care.

The approach that Dr. Tuszynski is developing will use hESCs to create neural stem cells (NSCs).  These newly created NSCs would then be grafted at the site of injury of those with SCI.  In preclinical studies, the NSCs have been shown to support the formation of neuronal relays at the site of SCI.  The neuronal relays allow the sensory neurons in the brain to communicate with the motor neurons in the spinal cord to re-establish muscle control and movement.

TRAN1 – 11548

Graphic depicting the challenges of traumatic brain injury (TBI)

$4.83 million was awarded to Dr. Brian Cummings at UC Irvine to develop a neural stem cell therapy for traumatic brain injury (TBI).

TBI is caused by a bump, blow, or jolt to the head that disrupts the normal function of the brain, resulting in emotional, mental, movement, and memory problems. There are 1.7 million people in the United States experiencing a TBI that leads to hospitalization each year. Since there are no effective treatments, TBI is one of the most critical unmet medical needs based on the total number of those affected and on a cost basis.

The approach that Dr. Cummings is developing will also use hESCs to create NSCs.  These newly created NSCs would be integrated with injured tissue in patients and have the ability to turn into the three main cell types in the brain; neurons, astrocytes, and oligodendrocytes.  This would allow for TBI patients to potentially see improvements in issues related to memory, movement, and anxiety, increasing independence and lessening patient care needs.

TRAN1 – 11628

Illustration depicting the brain damage that occurs under hypoxic-ischemic conditions

$4.96 million was awarded to Dr. Evan Snyder at Sanford Burnham Prebys to develop a neural stem cell therapy for perinatal hypoxic-ischemic brain injury (HII).

HII occurs when there is a lack of oxygen flow to the brain.  A newborn infant’s body can compensate for brief periods of depleted oxygen, but if this lasts too long, brain tissue is destroyed, which can cause many issues such as developmental delay and motor impairment.  Current treatment for this condition is whole-body hypothermia (HT), which consists of significantly reducing body temperature to interrupt brain injury.  However, this is not very effective in severe cases of HII. 

The approach that Dr. Snyder is developing will use an established neural stem cell (NSC) line.   These NSCs would be injected and potentially used alongside HT treatment to increase protection from brain injury.

The stem cell conference where even the smartest people learn something

A packed house for the opening keynote address at ISSCR 2019

At first glance, a scientific conference is not the place you would think about going to learn about how to run a political or any other kind of campaign. But then the ISSCR Annual Meeting is not your average conference. And that’s why CIRM is there and has been going to these events for as long as we have been around.

For those who don’t know, ISSCR is the International Society for Stem Cell Research. It’s the global industry representative for the field of stem cell research. It’s where all the leading figures in the field get together every year to chart the progress in research.

But it’s more than just the science that gets discussed. One of the panels kicking off this year’s conference was on ‘Why is it Important to Communicate with Policy Makers, the Media and the Public?” It was a wide-ranging discussion on the importance of learning the best ways for the scientific community to explain what it is they do, why they do it, and why people should care.

Sean Morrison

Sean Morrison, a former President of ISSCR, talked about his experience trying to pass a bill in Michigan that would enable scientists to do embryonic stem cell research. At the time CIRM was spending millions of dollars funding scientists in California to create new lines of embryonic stem cells; in Michigan anyone doing the same could be sent to prison for a year. He said the opposition ran a fear-based campaign, lying about the impact the bill would have, that it would enable scientists to create half man-half cow creatures (no, really) or human clones. Learning to counter those without descending to their level was challenging, but ultimately Morrison was successful in overcoming opposition and getting the bill passed.

Sally Temple

Sally Temple, of the Neural Stem Cell Institute, talked about testifying to a Congressional committee about the importance of fetal tissue research and faced a barrage of hostile questions that misrepresented the science and distorted her views. In contrast Republicans on the committee had invited a group that opposed all fetal tissue research and fed them a bunch of softball questions; the answers the group gave not only had no scientific validity, they were just plain wrong. Fortunately, Temple says she had done a lot of preparation (including watching two hours Congressional hearings on C-SPAN to understand how these hearings worked) and had her answers ready. Even so she said one of the big lessons she stressed is the need to listen to what others are saying and respond in ways that address their fears and don’t just dismiss them.

Other presenters talked about their struggles with different issues and different audiences but similar experiences; how do you communicate clearly and effectively. The answer is actually pretty simple. You talk to people in a way they understand with language they understand. Not with dense scientific jargon. Not with reams of data. Just by telling simple stories that illustrate what you did and who it helped or might help.

The power of ISSCR is that it can bring together a roomful of brilliant scientists from all over the world who want to learn about these things, who want to be better communicators. They know that much of the money for scientific research comes from governments or state agencies, that this is public money, and that if the public is going to continue to support this research it needs to know how that money is being spent.

That’s a message CIRM has been promoting for years. We know that communicating with the public is not an option, it’s a responsibility. That’s why, at a time when the very notion of science sometimes seems to be under attack, and the idea of public funding for that science is certainly under threat, having meetings like this that brings researchers together and gives them access to new tools is vital. The tools they can “get” at ISSCR are ones they might never learn in the lab, but they are tools that might just mean they get the money needed to do the work they want to.

Testing a drug is safe before you give it to a pregnant woman

Pregnant woman holding medicine.

When a doctor gives you a medication you like to think that it’s safe, that it has been tested to make sure it will do you some good or, at the very least, won’t do you any harm. That’s particularly true when the patient is a pregnant woman. You hope the medication won’t harm her or her unborn child. Now scientists in Switzerland have found a new way to do that that is faster and easier than previous methods, and it uses cell cultures instead of animals.

Right now, drugs that are intended for use in pregnant women have to undergo some pretty rigorous testing before they are approved. This involves lots of tests in the lab, and then in animals such as rats and rabbits. It’s time consuming, costly, and not always accurate because animals never quite mimic what happens in people.

In the past researchers tested new medications in the lab on so-called “embryoid bodies”. These are three-dimensional clumps of cells developed from embryonic stem cells from mice. The problem is that even when tested in this way the cells don’t always reflect what happens to a medication as it passes through the body. For example, some medications can seem fine on the surface but after they pass through the liver can take on toxic qualities. 

So, scientists at ETH Zurich in Basel, Switzerland, developed a better way to test for toxicity.

They took a cell-culture chip and created several compartments on it, in some they placed the embryoid bodies and in others they put microtissue samples from human livers.  The different compartments were connected so that fluid flowed freely from the embryoid bodies to the liver and vice versa.

In a news release, Julia Boos, a lead author of the study, says this better reflects what happens to a medication exposed to a human metabolism.

“We’re the first to directly combine liver and embryonic cells in a body-on-a-chip approach. Metabolites created by the liver cells – including metabolites that are stable for just a few minutes – can thus act directly on the embryonic cells. In contrast to tests on mice, in our test, the substances are metabolised by human liver cells – in other words, just as they would be in the human body when the medication is administered.”

To see if this worked in practice the researchers tested their approach on the chemotherapy drug cyclophosphamide, which is turned into a toxic substance after passing through the liver.

They compared results from testing cyclophosphamide with the new liver/embryoid body method to the older method. They found the new approach was far more sensitive and determined that a 400 percent lower concentration of cyclophosphamide was enough to pose a toxic threat.

The team now hope to refine the test even further so it can one day, hopefully, be applied to drug development on a large scale.

Their findings are published in the journal Advanced Science

Stem cell model reveals deeper understanding into “ALS resilient” neurons

A descriptive illustration of Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s Disease. Courtesy of ALS Foundation website.

Understanding the basic biology of how a cell functions can be crucial to being able to better understand a disease and unlock a potential approach for a treatment. Stem cells are unique in that they give scientists the opportunity to create a controlled environment of cells that might be otherwise difficult to study. Dr. Eva Hedlund and a team of researchers at the Karolinska Institute in Sweden utilize a stem cell model approach to uncover findings related to Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s Disease.

ALS is a progressive neurodegenerative disease that destroys motor neurons, a type of nerve cell, that are important for voluntary muscle movement. When motor neurons can no longer send signals to the muscles, the muscles begin to deteriorate, a process formally known as atrophy. The progressive atrophy leads to muscle paralysis, including those in the legs and feet, arms and hands, and those that control swallowing and breathing. It affects about 30,000 people in the United States alone, with 5,000 new cases diagnosed each year. There is currently no cure.

In a previous study, researchers at the Karolinska Institute were able to successfully create oculomotor neurons from embryonic stem cells. For reasons not yet fully understood, oculomotor neurons are “ALS resilient” and can survive all stages of the disease.

In the current study, published in Stem Cell Reports, Dr. Hedlund and her team found that the oculomotor neurons they generated appeared more resilient to ALS-like degeneration when compared to spinal cord motor neurons, something commonly observed in humans. Furthermore, they discovered that their “ALS resilient” neurons generated from stem cells activate a survival-enhancing signal known as Akt, which is common in oculomotor neurons in humans and could explain their resilience. These results could potentially aid in identifying genetic targets for treatments protecting sensitive neurons from the disease.

In a press release, Dr. Hedlund is quoted as saying,

“This cell culture system can help identify new genes contributing to the resilience in oculomotor neurons that could be used in gene therapy to strengthen sensitive motor neurons.”

CIRM is currently funding two clinical trials for ALS, one of which is being conducted by Cedars-Sinai Medical Center and the other by Brainstorm Cell Therapeutics. The latter of the trials is currently recruiting patients and information on how to enroll can be found here.

One year later, spinal cord therapy still looks promising

Jake Javier – participant in the SCIStar study

The beginning of a clinical trial, particularly the first time a new therapy is being tested in people, is often a time of equal parts anticipation and nervousness. Anticipation, because you have been working to this point for many years. Nervousness, because you have never tested this in people before and even though you have done years of study to show it is probably safe, until you try it in people you never really know.

That’s why the latest results from the CIRM-funded SCiStar Study, a clinical trial for spinal cord injury, are so encouraging. The results show that, one year after being treated, all the patients are doing well, none have experienced any serious side effects, and most have experienced impressive gains in movement, mobility and strength.

Ed Wirth, Chief Medical Officer at BioTime

In a news release Ed Wirth,  BioTIme’s Chief Medical Officer, said they were encouraged by what they saw:

“We believe the primary goals of the SCiStar Study, which were to observe the safety of OPC1 in cervical spinal cord injury patients as well as other important metrics including related to the optimal timing of OPC1 injection, tolerability of the immunosuppression regimen, engraftment of OPC1 cells, and rates of motor recovery observed among different study subpopulations, have all been successfully achieved.”

The study involved transplanting what the researchers called AST-OPC1 cells into patients who have suffered recent injuries that have left them paralyzed from the neck down.  AST-OPC1 are oligodendrocyte progenitor cells, which develop into cells that support and protect nerve cells in the central nervous system, the area damaged in spinal cord injury. It’s hoped the treatment will restore connections at the injury site, allowing patients to regain some movement and feeling.

Altogether 25 patients were involved. Three, in Cohort 1, were given injections of just two million OPC1 cells. This was to ensure the approach was safe and wouldn’t endanger patients. The remaining 22, in Cohorts 2-5, were given between 10 and 20 million cells. One year after the last patient was treated the results show:

  • MRI scans show no evidence of adverse changes in any of the 25 SCiStar study subjects.
    • No SCiStar study subjects had worsening of neurological function post-injection
    • At 12 months, 95% (21/22) of patients in Cohorts 2-5 recovered at least one motor level on at least one side and 32% (7/22) of these subjects recovered two or more motor levels on at least one side. 
    • No patient saw decreased motor function following administration of OPC1 and all either retained for 12 months the motor function recovery seen through 6 months or experienced further motor function recovery from 6 to 12 months.
    • All three subjects in Cohort 1 and 95% (21/22) of those in Cohorts 2 to 5 have MRI scans at 12 months consistent with the formation of a tissue matrix at the injury site. This is encouraging evidence the OPC1 cells have engrafted at the injury site and helped to prevent cavitation, a destructive process that occurs within the spinal cord following spinal cord injuries, and typically results in permanent loss of motor and sensory function.

“We appreciate the support of the California Institute for Regenerative Medicine, the world’s largest institution dedicated to bringing the future of cellular medicine closer to reality, whose generous grant funding to date of $14.3 million has helped advance the clinical development of our OPC1 program and generate these encouraging clinical results in patients with traumatic spinal cord injuries.”

BioTime is now planning to meet with the Food and Drug Administration (FDA) later this year to discuss next steps for the therapy. Soon as we know the outcome of those talks, we’ll share them with you.

First patient treated for colon cancer using reprogrammed adult cells

Dr. Sandip Patel (left) and Dr. Dan Kaufman (center) of UC San Diego School of Medicine enjoy a light-hearted moment before Derek Ruff (right) receives the first treatment for cancer using human-induced pluripotent stem cells (hiPSCs). Photo courtesy of UC San Diego Health.

For patients battling cancer for the first time, it can be quite a draining and grueling process. Many treatments are successful and patients go into remission. However, there are instances where the cancer returns in a much more aggressive form. Unfortunately, this was the case for Derek Ruff.

After being in remission for ten years, Derek’s cancer returned as Stage IV colon cancer, meaning that the cancer has spread from the colon to distant organs and tissues. According to statistics from Fight Colorectal Cancer, colorectal cancer is the 2nd leading cause of cancer death among men and women combined in the United States. 1 in 20 people will be diagnosed with colorectal cancer in their lifetime and it is estimated that there will be 140,250 new cases in 2019 alone. Fortunately, Derek was able to enroll in a groundbreaking clinical trial to combat his cancer.

In February 2019, as part of a clinical trial at the Moores Cancer Center at UC San Diego Health in collaboration with Fate Therapeutics, Derek became the first patient in the world to be treated for cancer with human-induced pluripotent stem cells (hiPSCs). hiPSCs are human adult cells, such as those found on the skin, that are reprogrammed into stem cells with the ability to turn into virtually any kind of cell. In this trial, hiPSCs were reprogrammed into natural killer (NK) cells, which are specialized immune cells that are very effective at killing cancer cells, and are aimed at treating Derek’s colon cancer.

A video clip from ABC 10 News San Diego features an interview with Derek and the groundbreaking work being done.

In a public release, Dr. Dan Kaufman, one of the lead investigators of this trial at UC San Diego School of Medicine, was quoted as saying,

“This is a landmark accomplishment for the field of stem cell-based medicine and cancer immunotherapy. This clinical trial represents the first use of cells produced from human induced pluripotent stem cells to better treat and fight cancer.”

In the past, CIRM has given Dr. Kaufman funding related to the development of NK cells. One was a $1.9 million grant for developing a different type of NK cell from hiPSCs, which could also potentially treat patients with lethal cancers. The second grant was a $4.7 million grant for developing NK cells from human embryonic stem cells (hESCs) to potentially treat patients with acute myelogenous leukemia (AML).

In the public release, Dr. Kaufman is also quoted as saying,

“This is a culmination of 15 years of work. My lab was the first to produce natural killer cells from human pluripotent stem cells. Together with Fate Therapeutics, we’ve been able to show in preclinical research that this new strategy to produce pluripotent stem cell-derived natural killer cells can effectively kill cancer cells in cell culture and in mouse models.”

Rats, research and the road to new therapies

Don Reed

Don Reed has been a champion of CIRM even before there was a CIRM. He’s a pioneer in pushing for funding for stem cell research and now he’s working hard to raise awareness about the difference that funding is making.

In a recent article on Daily Kos, Don highlighted one of the less celebrated partners in this research, the humble rat.

A BETTER RAT? Benefit #62 of the California Stem Cell Agency

By Don C. Reed

When I told my wife Gloria I was writing an article about rats, she had several comments, including: “Oo, ugh!” and also “That’s disgusting!”

Obviously, there are problems with rats, such as when they chew through electrical wires, which may cause a short circuit and burn down the house. Also, they are blamed for carrying diseased fleas in their ears and spreading the Black Plague, which in 1340 killed half of China and one-third of Europe—but this is not certain. The plague may in fact have been transmitted by human-carried parasites.

But there are positive aspects to rats as well. For instance: “…a rat paired with  another that has a disability…will be very kind to the other rat. Usually, help is offered with food, cleaning, and general care.”—GUIDE TO THE RAT, by Ginger Cardinal.

Above all, anyone who has ever been sick owes a debt to rats, specifically the Norway rat with that spectacular name, rattus norvegicus domesticus, found in labs around the world.

I first realized its importance on March 1, 2002, when I held in my hand a rat which had been paralyzed, but then recovered the use of its limbs.

The rat’s name was Fighter, and she had been given a derivative of embryonic stem cells, which restored function to her limbs. (This was the famous stem cell therapy begun by Hans Keirstead with a Roman Reed grant, developed by Geron, and later by CIRM and Asterias, which later benefited humans.)

As I felt the tiny muscles struggling to be free, it was like touching tomorrow— while my paralyzed son, Roman Reed, sat in his wheelchair just a few feet away.

Was it different working with rats instead of mice? I had heard that the far smaller lab mice were more “bitey” than rats.  

Wanting to know more about the possibilities of a “better rat”, I went to the CIRM website, (www.cirm.ca.gov) hunted up the “Tools and Technology III” section, and the following complicated sentence::

“Embryonic stem cell- based generation of rat models for assessing human cellular therapies.”

Hmm. With science writing, it always takes me a couple of readings to know what they were talking about. But I recognized some of the words, so that was a start.

“Stemcells… rat models… human therapies….”  

I called up Dr. Qilong Ying, Principle Investigator (PI) of the study.

As he began to talk, I felt a “click” of recognition, as if, like pieces of a puzzle, facts were fitting together.

It reminded me of Jacques Cousteau, the great underwater explorer, when he tried to invent a way to breathe underwater. He had the compressed air tank, and a mouthpiece that would release air—but it came in a rush, not normal breathing.

So he visited his friend, race car mechanic Emil Gagnan, and told him, “I need something that will give me air, but only when I inhale,”– and Gagnan said: “Like that?” and pointed to a metal contraption on a nearby table.

It was something invented for cars. But by adding it to what Cousteau already had, the Cousteau-Gagnan SCUBA (Self Contained Underwater Breathing Apparatus) gear was born—and the ocean could now be explored.

Qi-Long Ying’s contribution to science may also be a piece of the puzzle of cure…

A long-term collaboration with Dr. Austin Smith centered on an attempt to do with rats what had done with mice.

In 2007, the  Nobel Prize in Medicine had been won by Dr. Martin Evans, Mario Capecchi, and Oliver Smithies. Working independently, they developed “knock-out” and “knock-in” mice, meaning to take out a gene, or put one in.  

But could they do the same with rats?

 “We and others worked very, very hard, and got nowhere,” said Dr. Evans.

Why was this important?

Many human diseases cannot be mimicked in the mouse—but might be in the rat. This is for several reasons: the rat is about ten times larger; its internal workings are closer to those of a human; and the rat is considered several million years closer (in evolutionary terms) to humans than the mouse.

In 2008 (“in China, that is the year of the rat,” noted Dr. Ying in our conversation) he received the first of three grants from CIRM.

“We proposed to use the classical embryonic stem cell-based gene-targeting technology to generate rat models mimicking human heart failure, diabetes and neurodegenerative diseases…”

How did he do?

In 2010, Science Magazine honored him with inclusion in their “Top 10 Breakthroughs for using embryonic stem cell-based gene targeting to produce the world’s first knockout rats, modified to lack one or more genes…”

And in 2016, he and Dr. Smith received the McEwen Award for Innovation,  the highest honor bestowed by the International Society for Stem Cell Research (ISSCR).

Using knowledge learned from the new (and more relevant to humans) lab rat, it may be possible to develop methods for the expansion of stem cells directly inside the patient’s own bone marrow. Stem cells derived in this fashion would be far less likely to be rejected by the patient.  To paraphrase Abraham Lincoln, they would be “of the patient, by the patient and for the patient—and shall not perish from the patient”—sorry!

Several of the rats generated in Ying’s lab (to mimic human diseases) were so successful that they have been donated to the Rat Research Resource center so that other scientists can use them for their study.

“Maybe in the future we will develop a cure for some diseases because of knowledge from using rat models,” said Ying. “I think it’s very possible. So we want more researchers from USC and beyond to come and use this technology.”

And it all began with the humble rat…

Of Mice and Men, and Women Too; Stem cell stories you might have missed

Mice brains can teach us a lot

Last week’s news headlines were dominated by one big story, the use of a stem cell transplant to effectively cure a person of HIV. But there were other stories that, while not quite as striking, did also highlight how the field is advancing.

A new way to boost brain cells (in mice!)

It’s hard to fix something if you don’t really know what’s wrong in the first place. It would be like trying to determine why a car is not working just by looking at the hood and not looking inside at the engine. The human brain is far more complex than a car so trying to determine what’s going wrong is infinitely more challenging. But a new study could help give us a new option.

Researchers in Luxembourg and Germany have developed a new computer model for what’s happening inside the brain, identifying what cells are not operating properly, and fixing them.

Antonio del Sol, one of the lead authors of the study – published in the journal Cell – says their new model allows them to identify which stem cells are active and ready to divide, or dormant. 

“Our results constitute an important step towards the implementation of stem cell-based therapies, for instance for neurodegenerative diseases. We were able to show that, with computational models, it is possible to identify the essential features that are characteristic of a specific state of stem cells.”

The work, done in mice, identified a protein that helped keep brain stem cells inactive in older animals. By blocking this protein they were able to help “wake up” those stem cells so they could divide and proliferate and help regenerate the aging brain.

And if it works in mice it must work in people right? Well, that’s what they hope to see next.

Deeper understanding of fetal development

According to the Mayo Clinic between 10 and 20 percent of known pregnancies end in miscarriage (though they admit the real number may be even higher) and our lack of understanding of fetal development makes it hard to understand why. A new study reveals a previously unknown step in this development that could help provide some answers and, hopefully, lead to ways to prevent miscarriages.

Researchers at the Karolinska Institute in Sweden used genetic sequencing to follow the development stages of mice embryos. By sorting those different sequences into a kind of blueprint for what’s happening at every stage of development they were able to identify a previously unknown phase. It’s the time between when the embryo attaches to the uterus and when it begins to turn these embryonic stem cells into identifiable parts of the body.

Qiaolin Deng, Karolinska Institute

Lead researcher Qiaolin Deng says this finding provides vital new evidence.

“Being able to follow the differentiation process of every cell is the Holy Grail of developmental biology. Knowledge of the events and factors that govern the development of the early embryo is indispensable for understanding miscarriages and congenital disease. Around three in every 100 babies are born with fetal malformation caused by faulty cellular differentiation.”

The study is published in the journal Cell Reports.

Could a new drug discovery reduce damage from a heart attack?

Every 40 seconds someone in the US has a heart attack. For many it is fatal but even for those who survive it can lead to long-term damage to the heart that ultimately leads to heart failure. Now British researchers think they may have found a way to reduce that likelihood.

Using stem cells to create human heart muscle tissue in the lab, they identified a protein that is activated after a heart attack or when exposed to stress chemicals. They then identified a drug that can block that protein and, when tested in mice that had experienced a heart attack, they found it could reduce damage to the heart muscle by around 60 percent.

Prof Michael Schneider, the lead researcher on the study, published in Cell Stem Cell, said this could be a game changer.

“There are no existing therapies that directly address the problem of muscle cell death and this would be a revolution in the treatment of heart attacks. One reason why many heart drugs have failed in clinical trials may be that they have not been tested in human cells before the clinic. Using both human cells and animals allows us to be more confident about the molecules we take forward.”