Back when I was growing up, shortly after the extinction of the dinosaurs, there was a popular video game called Pong. It was, in fact, pretty much the only video game at the time. It was a pretty simple game. You moved a “paddle” to hit a ball and knock it back across the screen to your opponent. If your opponent missed it you won the point. It was a really simplified form of video ping pong (hence the name).
So why am I telling you this? Well, researchers in the UK and Australia have devised a way of teaching blobs of brain cells how to play Pong. I kid you not.
Playing Pong
What they did was turn stem cells into brain cells, as part of a system called Dishbrain. Using software, they helped these neurons or brain cells communicate with each other through electrical stimulation and recordings.
In an article in Newsweek, (yup, Newsweek is still around) the researchers explained that using these electrical signals they could help the cells identify where the “ball” was. For example, if the signals came from the left that meant the “ball” was on the right.
In the study they say: “Using this DishBrain system, we have demonstrated that a single layer of in vitro (in a dish) cortical neurons can self-organize and display intelligent and sentient behavior when embodied in a simulated game-world.” We have shown that even without a substantial filtering of cellular activity, statistically robust differences over time and against controls could be observed in the behavior of neuronal cultures in adapting to goal directed tasks.”
Now you might think this was just something the researchers dreamed up to pass time during COVID, but they say understanding how these brain cells can learn and respond could help them develop other methods of using neurons that might be even cooler than playing video games.
About one third of stroke survivors experience vision loss. It can be a devastating side effect as most patients will not fully recover their vision and there are currently no reliable treatments available. But thanks to a collaborative effort by two teams of researchers from Purdue University and Jinan University in China, there may be a way to use gene therapy to recover lost vision after a stroke.
A stroke happens when part of the brain is starved of oxygen which can result in death of brain cells or neurons. Oftentimes this is caused by a blockage in an artery in the brain. Given the location of these vital arteries, most strokes lead to loss of motor function and in some cases, permanent vision loss.
The brain is an incredible machine and capable of remapping its neural pathways enough to restore some visual function, but this isn’t always the case. The neurons that are destroyed in the process of experiencing a stroke do not regenerate and lose their ability to communicate/transmit information between different areas of the brain, and between the brain and the rest of the nervous system.
Two research teams, one led by Alexander Chubykin at Purdue University’s and the other led by Gong Chen at Jinan University, have taken a different approach to neural regeneration by reprogramming local glial cells into neurons, therefore restoring connections between the old neurons and the newly reprogrammed neurons.
In a news release, Dr. Chubykin says the results in the lab look promising. “We can watch the mice get their vision back. We don’t have to implant new cells, so there’s no immunogenic rejection. This process is easier to do than stem cell therapy, and there’s less damage.”
The collaborative research, published in the journal Frontiers in Cell and Developmental Biology, is promising not only in aiding with vision restoration after a stroke but could also lead to similar treatment for reestablishing motor function. Visual function is easier than motor skills to measure accurately and the scientists are looking into the effectiveness of this procedure in live mice using advanced optical imaging tools. If the study continues to provide positive results, it might not be long before human trials are started.
When someone has a stroke, the blood flow to the brain is blocked. This kills some nerve cells and injures others. The damaged nerve cells are unable to communicate with other cells, which often results in people having impaired speech or movement.
While ischemic and hemorrhagic strokes affect large blood vessels and usually produce recognizable symptoms there’s another kind of stroke that is virtually silent. A ‘white’ stroke occurs in blood vessels so tiny that the impact may not be noticed. But over time that damage can accumulate and lead to a form of dementia and even speed up the progression of Alzheimer’s disease.
Now Dr. Tom Carmichael and his team at the David Geffen School of Medicine at UCLA have developed a potential treatment for this, using stem cells that may help repair the damage caused by a white stroke. This was part of a CIRM-funded study (DISC2-12169 – $250,000).
Instead of trying to directly repair the damaged neurons, the brain nerve cells affected by a stroke, they are creating support cells called astrocytes, to help stimulate the body’s own repair mechanisms.
In a news release, Dr. Irene Llorente, the study’s first author, says these astrocytes play an important role in the brain.
“These cells accomplish many tasks in repairing the brain. We wanted to replace the cells that we knew were lost, but along the way, we learned that these astrocytes also help in other ways.”
The researchers took skin tissue and, using the iPSC method (which enables researchers to turn cells into any other kind of cell in the body) turned it into astrocytes. They then boosted the ability of these astrocytes to produce chemical signals that can stimulate healing among the cells damaged by the stroke.
These astrocytes were then not only able to help repair some of the damaged neurons, enabling them to once again communicate with other neurons, but they also helped another kind of brain cell called oligodendrocyte progenitor cells or OPCs. These cells help make a protective sheath around axons, which transmit electrical signals between brain cells. The new astrocytes stimulated the OPCs into repairing the protective sheath around the axons.
Mice who had these astrocytes implanted in them showed improved memory and motor skills within four months of the treatment.
And now the team have taken this approach one step further. They have developed a method of growing these astrocytes in large amounts, at very high quality, in a relatively short time. The importance of that is it means they can produce the number of cells needed to treat a person.
“We can produce the astrocytes in 35 days,” Llorente says. “This process allows rapid, efficient, reliable and clinically viable production of our therapeutic product.”
The next step is to chat with the Food and Drug Administration (FDA) to see what else they’ll need to do to show they are ready for a clinical trial.
Astrocytes, which provide structural support and protection for neurons and also supply them with nutrients and oxygen.
Bipolar disorder (BPD) is a mental disorder that causes unusual shifts in mood, energy, activity levels, concentration, and the ability to carry out day-to-day tasks. In the United States, recent research has shown that 1.6% of the population has BPD, which is roughly over 4 million people. Those with BPD are more likely to have conditions associated with chronic inflammation such as hypertension and diabetes. It is because of this that scientists have been studying the connection between inflammation and BPD for quite some time.
In a new study, researchers at the Salk Institute for Biological Studies, UC San Diego, and the Institute of Psychiatry and Neuroscience of Paris have found evidence that astrocytes, a certain type of brain cell, can trigger inflammation more easily in those that have BPD. What’s more, these astrocytes can be linked to decreased brain activity that could be harmful to mental health.
Astrocytes are star shaped (as the word “astro” might suggest) and help support neurons, the cells that relay information around the brain. One of these supporting roles includes helping trigger inflammation in the brain and the surrounding nervous system to help with injury or infection. The researchers believe that this process can go wrong in people with BPD and that astrocytes can play a role in this dysfunctional inflammation.
For this study, the team used induced pluripotent stem cells (iPSCs), a kind of stem cell that can turn into virtually any type of cell, that they created from patients with BPD and patients without BPD. They converted these iPSCs into astrocytes and compared those that came from BPD patients to those that did not. What they found is that the astrocytes from patients with BPD were noticeably different. The BPD astrocytes had a higher expression of a protein that triggers an inflammatory response when compared to the non-BPD astrocytes. When they exposed neurons to the BPD astrocytes, the team saw decreased levels of neural activity compared to the non-BPD astrocytes. Lastly, when the researchers blocked the inflammatory protein, the neurons were less affected by the BPD astrocytes.
“Our study suggests that normal function of astrocytes is affected in bipolar disorder patients’ brains, contributing to neuroinflammation,” said Dr. Renata Santos, a researcher at the Salk Institute as well as the Institute of Psychiatry and Neuroscience of Paris, in a news release.
The team hopes that their findings can not only provide insight into BPD, but to other mental illnesses linked to inflammation such as schizophrenia. The ultimate goal is to help advance research into astrocytes and inflammation in order to develop treatments that might reverse the harmful bodily changes seen in those with BPD and other mental disorders.
The full study was published in Stem Cell Reports.
Dr. Yanhong Shi (left) and Dr. Vaithilingaraja Arumugaswami (right)
All this month we are using our blog and social media to highlight a new chapter in CIRM’s life, thanks to the voters approving Proposition 14. We are looking back at what we have done since we were created in 2004, and also looking forward to the future. Today we focus on groundbreaking CIRM funded research related to COVID-19 that was recently published.
It’s been almost a year since the world started hearing about SARS-CoV-2, the virus that causes COVID-19. In our minds, the pandemic has felt like an eternity, but scientists are still discovering new things about how the virus works and if genetics might play a role in the severity of the virus. One population study found that people who have ApoE4, a gene type that has been found to increase the risk of developing Alzheimer’s, had higher rates of severe COVID-19 and hospitalizations.
It is this interesting observation that led to important findings of a study funded by two CIRM awards ($7.4M grantand $250K grant) and conducted by Dr. Yanhong Shi at City of Hope and co-led by Dr. Vaithilingaraja Arumugaswami, a member of the UCLA Broad Stem Cell Research Center. The team found that the same gene that increases the risk for Alzheimer’s disease can increase the susceptibility and severity of COVID-19.
At the beginning of the study, the team was interested in the connection between SARS-CoV-2 and its effect on the brain. Due to the fact that patients typically lose their sense of taste and smell, the team theorized that there was an underlying neurological effect of the virus.
The team first created neurons and astrocytes. Neurons are cells that function as the basic working unit of the brain and astrocytes provide support to them. The neurons and astrocytes were generated from induced pluripotent stem cells (iPSCs), which are a kind of stem cell that can become virtually any type of cell and can be created by “reprogramming” the skin cells of patients. The newly created neurons and astrocytes were then infected with SARS-CoV-2 and it was found that they were susceptible to infection.
Next, the team used iPSCs to create brain organoids, which are 3D models that mimic certain features of the human brain. They were able to create two different organoid models: one that contained astrocytes and one without them. They infected both brain organoid types with the virus and discovered that those with astrocytes boosted SARS-CoV-2 infection in the brain model.
The team then decided to further study the effects of ApoE4 on susceptibility to SARS-CoV-2. They did this by generating neurons from iPSCs “reprogrammed” from the cells of an Alzheimer’s patient. Because the iPSCs were derived from an Alzheimer’s patient, they contained ApoE4. Using gene editing, the team modified some of the ApoE4 iPSCs created so that they contained ApoE3, which is a gene type considered neutral. The ApoE3 and ApoE4 iPSCs were then used to generate neurons and astrocytes.
The results were astounding. The ApoE4 neurons and astrocytes both showed a higher susceptibility to SARS-CoV-2 infection in comparison to the ApoE3 neurons and astrocytes. Moreover, while the virus caused damage to both ApoE3 and ApoE4 neurons, it appeared to have a slightly more severe effect on ApoE4 neurons and a much more severe effect on ApoE4 astrocytes compared to ApoE3 neurons and astrocytes.
“Our study provides a causal link between the Alzheimer’s disease risk factor ApoE4 and COVID-19 and explains why some (e.g. ApoE4 carriers) but not all COVID-19 patients exhibit neurological manifestations” says Dr. Shi. “Understanding how risk factors for neurodegenerative diseases impact COVID-19 susceptibility and severity will help us to better cope with COVID-19 and its potential long-term effects in different patient populations.”
In the last part of the study, the researchers tested to see if the antiviral drug remdesivir inhibits virus infection in neurons and astrocytes. They discovered that the drug was able to successfully reduce the viral level in astrocytes and prevent cell death. For neurons, it was able to rescue them from steadily losing their function and even dying.
The team says that the next steps to build on their findings is to continue studying the effects of the virus and better understand the role of ApoE4 in the brains of people who have COVID-19. Many people that developed COVID-19 have recovered, but long-term neurological effects such as severe headaches are still being seen months after.
“COVID-19 is a complex disease, and we are beginning to understand the risk factors involved in the manifestation of the severe form of the disease” says Dr. Arumugaswami. “Our cell-based study provides possible explanation to why individuals with Alzheimer’s’ disease are at increased risk of developing COVID-19.”
The full results to this study were published in Cell Stem Cell.
Fragile X syndrome (FXS) is a genetic disorder that is the most common form of inherited intellectual disability in children, and has also been linked to a form of autism. Uncovering the cause of FXS could help lead to a deeper understanding of autism, what causes it and ultimately, it’s hoped, to treating or even preventing it.
Researchers at Children’s Hospital in Chicago looked at FXS at the stem cell level and found how a genetic defect has an impact on the development of neurons (nerve cells in the brain) and how that in turn has an impact on the developing brain in the fetus.
In a news release on Eurekalert, Dr. Yongchao Ma, the senior author of the study, says this identified a problem at a critical point in the development of the brain:
“During embryonic brain development,
the right neurons have to be produced at the right time and in the right
numbers. We focused on what happens in the stem cells that leads to slower
production of neurons that are responsible for brain functions including learning
and memory. Our discoveries shed light on the earliest stages of disease
development and offer novel targets for potential treatments.”
The team looked at neural stem cells and found that a lack
of one protein, called FMRP, created a kind of cascade that impacted the
ability of the cells to turn into neurons. Fewer neurons meant impaired brain
development.
The findings, published in the journal Cell Reports, help explain how
genetic information flows in cells in developing babies and, according to Dr.
Ma, could lead to new ideas on how to treat problems.
“Currently we are exploring how to
stimulate FMRP protein activity in the stem cell, in order to correct the
timing of neuron production and ensure that the correct amount and types of
neurons are available to the developing brain. There may be potential for gene
therapy for fragile X syndrome.”
Sergiu Pasca’s three-dimensional culture makes it possible to watch how three different brain-cell types – oligodendrocytes (green), neurons (magenta) and astrocytes (blue) – interact in a dish as they do in a developing human brain. Courtesy of the Pasca lab
Neurological diseases are among the most daunting diagnoses for a patient to receive, because they impact how the individual interacts with their surroundings. Central to our ability to provide better treatment options for these patients, is scientists’ capability to understand the biological factors that influence disease development and progression. Researchers at the Stanford University School of Medicine have made an important step in providing neuroscientists a better tool to understand the brain.
While animal models are excellent systems to study the intricacies of different diseases, the ability to translate any findings to humans is relatively limited. The next best option is to study human stem cell derived tissues in the laboratory. The problem with the currently available laboratory-derived systems for studying the brain, however, is the limited longevity and diversity of neuronal cell types. Dr. Sergiu Pasca’s team was able to overcome these hurdles, as detailed in their study, published in the journal Nature Neuroscience.
A new approach
Specifically, Dr. Pasca’s group developed a method to differentiate or transform skin derived human induced pluripotent stem cells (iPSCs – which are capable of becoming any cell type) into brain-like structures that mimic how oligodendrocytes mature during brain development. Oligodendrocytes are most well known for their role in myelinating neurons, in effect creating a protective sheath around the cell to protect its ability to communicate with other brain cells. Studying oligodendrocytes in culture systems is challenging because they arise later in brain development, and it is difficult to generate and maintain them with other cell types found in the brain.
These scientists circumvented this problem by using a unique combination of growth factors and nutrients to culture the oligodendrocytes, and found that they behaved very similarly to oligodendrocytes isolated from humans. Most excitingly, they observed that the stem cell-derived oligodendrocytes were able to myelinate other neurons in the culture system. Therefore they were both physically and functionally similar to human oligodendrocytes.
Importantly, the scientists were also able to generate astrocytes alongside the oligodendrocytes. Astrocytes perform many important functions such as providing essential nutrients and directing the electrical signals that help cells in the brain communicate with each other. In a press release, Dr. Pasca explains the importance of generating multiple cell types in this in vitro system:
“We now have multiple cell types interacting in one single
culture. This permits us to look close-up at how the main cellular players in
the human brain are talking to each other.”
This in vitro or laboratory-developed system has the potential to help scientists better understand oligodendrocytes in the context of diseases such as multiple sclerosis and cerebral palsy, both of which stem from improper myelination of brain nerve cells.
This work was partially supported by a CIRM grant.
Currently, there is nothing that completely reverses SCI damage and most treatment is aimed at rehabilitation and empowering patients to lead as normal a life as possible under the circumstances. Improved treatment options are necessary both to improve patients’ overall quality of life, and to reduce associated healthcare costs.
Scientists at UC San Diego’s School of Medicine and Institute of Engineering in Medicine have made critical progress in providing SCI patients with hope towards a more comprehensive and longer lasting treatment option.
Prof. Shaochen Chen and his 3D printer
In a study partially funded by CIRM and published in Nature Medicine, Dr. Mark Tuszynski’s and Dr. Shaochen Chen’s groups used a novel 3D printing method to grow a spinal cord in the lab.
Previous studies have seen some success in lab grown neurons or nerve cells, improving SCI in animal models. This new study, however, is innovative both for the speed at which the neurons are printed, and the extent of the neuronal network that is produced.
To achieve this goal, the scientists used a biological scaffold that directs the growth of the neurons so they grow to the correct length and generate a complete neuronal network. Excitingly, their 3D printing technology was so efficient that they were able to grow implants for an animal model in 1.6 seconds, and a human-sized implant in just ten minutes, showing that their technology is scalable for injuries of different sizes.
When they tested the spinal cord implants in rats, they found that not only did the implant repair the damaged spinal cord tissue, but it also provided sustained improvement in motor function up to six months after implantation.
Just as importantly, they also observed that blood vessels had infiltrated the implanted tissue. The absence of vascularized tissue is one of the main reasons engineered implants do not last long in the host, because blood vessels are necessary to provide nutrients and support tissue growth. In this case, the animal’s body solved the problem on its own.
In a press release, one of the co-first authors of the paper, Dr. Kobi Koffler, states the importance and novelty of this work:
“This marks another key step toward conducting clinical trials to repair spinal cord injuries in people. The scaffolding provides a stable, physical structure that supports consistent engraftment and survival of neural stem cells. It seems to shield grafted stem cells from the often toxic, inflammatory environment of a spinal cord injury and helps guide axons through the lesion site completely.”
In order to make this technology viable for human clinical trials, the scientists are testing their technology in larger animal models before moving into humans, as well as investigating how to improve the longevity of the neuronal network by introducing proteins into the scaffolds.
Every year millions of Americans undergo chemotherapy. The goal of the treatment is to destroy cancer, but along the way more than half of the people treated lose something else. They suffer from something called “chemo brain” which causes problems with thinking and memory. In some cases it can be temporary, lasting a few months. In others it can last years.
Now a CIRM-funded study by researchers at Stanford has found what may be behind chemo brain and identifying potential treatments.
“Cognitive dysfunction after cancer therapy is a real and recognized syndrome. In addition to existing symptomatic therapies — which many patients don’t know about — we are now homing in on potential interventions to promote normalization of the disorders induced by cancer drugs. There’s real hope that we can intervene, induce regeneration and prevent damage in the brain.”
The team first looked at the postmortem brains of children, some of whom had undergone chemotherapy and some who had not. The chemotherapy-treated brains had far fewer oligodendrocyte cells, a kind of cell important in protecting nerve cells in the brain.
Next the team injected methotrexate, a commonly used chemotherapy drug, into mice and then several weeks later compared the brains of those mice to untreated mice. They found that the brains of the treated mice had fewer oligodendrocytes and that the ones they had were in an immature state, suggested the chemo was blocking their development.
The inner changes were also reflected in behavior. The treated mice had slower movement, showed more anxiety, and impaired memory compared to untreated mice; symptoms that persisted for up to six months after the injections.
As if that wasn’t enough, they also found that the chemo affected other cells in the brain, creating a kind of cascade effect that seemed to amplify the impaired memory and other cognitive functions.
However, there is some encouraging news in the study, which is published in the journal Cell. The researchers gave the treated mice a drug to reverse some of the side effects of methotrexate, and that seemed to reduce some of the cognitive problems the mice were having.
Monje says that’s where her research is heading next.
“If we understand the cellular and molecular mechanisms that contribute to cognitive dysfunction after cancer therapy, that will help us develop strategies for effective treatment. It’s an exciting moment.”
Neurons derived from stem cells.Credit: Silvia Riccardi/SPL
Currently, more than 10 million people worldwide live with Parkinson’s disease (PD). By 2020, in the US alone, people living with Parkinson’s are expected to outnumber the cases of multiple sclerosis, muscular dystrophy and Lou Gehrig’s disease combined.
There is no cure for Parkinson’s and treatment options consist of medications that patients ultimately develop tolerance to, or surgical therapies that are expensive. Therefore, therapeutic options that offer long-lasting treatment, or even a cure, are essential for treating PD.
To understand their treatment strategy, however, we first have to understand what causes this disease. Parkinson’s results from decreased numbers of neurons that produce dopamine, a molecule that helps control muscle movements. Without proper dopamine production, patients experience a wide range of movement abnormalities, including the classic tremors that are associated with PD.
The current treatment options only target the symptoms, as opposed to the root cause of the disease. Takashi’s group decided to go directly to the source and improve dopamine production in these patients by correcting the dopaminergic neuron shortage.
The scientists harvested skin cells from a healthy donor and reprogrammed them to become induced pluripotent stem cells (iPSCs), or stem cells that become any type of cell. These iPSCs were then turned into the precursors of dopamine-producing neurons and implanted into 12 brain regions known to be hotspots for dopamine production.
The procedure was carried out in October and the patient, a male in his 50s, is still healthy. If his symptoms continue to improve and he doesn’t experience any bad side effects, he will receive a second dose of dopamine-producing stem cells. Six other patients are scheduled to receive this same treatment and Takashi hopes that, if all goes well, this type of treatment can be ready for the general public by 2023.
This treatment was first tested in monkeys, where the researchers saw that not only did the implanted stem cells improve Parkinson’s symptoms and survive in the brain for at least two years, but they also did not cause any negative side effects.
The Stem Cellar 