“Brains” in a dish that can create electrical impulses

Brain organoids in a petri dish: photo courtesy UCSD

For several years, researchers have been able to take stem cells and use them to make three dimensional structures called organoids. These are a kind of mini organ that scientists can then use to study what happens in the real thing. For example, creating kidney organoids to see how kidney disease develops in patients.

Scientists can do the same with brain cells, creating clumps of cells that become a kind of miniature version of parts of the brain. These organoids can’t do any of the complex things our brains do – such as thinking – but they do serve as useful physical models for us to use in trying to develop a deeper understanding of the brain.

Now Alysson Muotri and his team at UC San Diego – in a study supported by two grants from CIRM – have taken the science one step further, developing brain organoids that allow us to measure the level of electrical activity they generate, and then compare it to the electrical activity seen in the developing brain of a fetus. That last sentence might cause some people to say “What?”, but this is actually really cool science that could help us gain a deeper understanding of how brains develop and come up with new ways to treat problems in the brain caused by faulty circuitry, such as autism or schizophrenia.

The team developed new, more effective methods of growing clusters of the different kinds of cells found in the brain. They then placed them on a multi-electrode array, a kind of muffin tray that could measure electrical impulses. As they fed the cells and increased the number of cells in the trays they were able to measure changes in the electrical impulses they gave off. The cells went from producing 3,000 spikes a minute to 300,000 spikes a minute. This is the first time this level of activity has been achieved in a cell-based laboratory model. But that’s not all.

When they further analyzed the activity of the organoids, they found there were some similarities to the activity seen in the brains of premature babies. For instance, both produced short bursts of activity, followed by a period of inactivity.

Alysson Muotri

In a news release Muotri says they were surprised by the finding:

“We couldn’t believe it at first — we thought our electrodes were malfunctioning. Because the data were so striking, I think many people were kind of skeptical about it, and understandably so.”

Muotri knows that this research – published in the journal Cell Stem Cell – raises ethical issues and he is quick to say that these organoids are nothing like a baby’s brain, that they differ in several critical ways. The organoids are tiny, not just in size but also in the numbers of cells involved. They also don’t have blood vessels to keep them alive or help them grow and they don’t have any ability to think.

“They are far from being functionally equivalent to a full cortex, even in a baby. In fact, we don’t yet have a way to even measure consciousness or sentience.”

What these organoids do have is the ability to help us look at the structure and activity of the brain in ways we never could before. In the past researchers depended on mice or other animals to test new ideas or therapies for human diseases or disorders. Because our brains are so different than animal brains those approaches have had limited results. Just think about how many treatments for Alzheimer’s looked promising in animal models but failed completely in people.

These new organoids allow us to explore how new therapies might work in the human brain, and hopefully increase our ability to develop more effective treatments for conditions as varied as epilepsy and autism.

Boosting the blood system after life-saving therapy

Following radiation, the bone marrow shows nearly complete loss of blood cells in mice (left). Mice treated with the PTP-sigma inhibitor displayed rapid recovery of blood cells (purple, right): Photo Courtesy UCLA

Chemotherapy and radiation are two of the front-line weapons in treating cancer. They can be effective, even life-saving, but they can also be brutal, taking a toll on the body that lasts for months. Now a team at UCLA has developed a therapy that might enable the body to bounce back faster after chemo and radiation, and even make treatments like bone marrow transplants easier on patients.

First a little background. Some cancer treatments use chemotherapy and radiation to kill the cancer, but they can also damage other cells, including those in the bone marrow responsible for making blood stem cells. Those cells eventually recover but it can take weeks or months, and during that time the patient may feel fatigue and be more susceptible to infections and other problems.

In a CIRM-supported study, UCLA’s Dr. John Chute and his team developed a drug that speeds up the process of regenerating a new blood supply. The research is published in the journal Nature Communications.

They focused their attention on a protein called PTP-sigma that is found in blood stem cells and acts as a kind of brake on the regeneration of those cells. Previous studies by Dr. Chute showed that, after undergoing radiation, mice that have less PTP-sigma were able to regenerate their blood stem cells faster than mice that had normal levels of the protein.

John Chute: Photo courtesy UCLA

So they set out to identify something that could help reduce levels of PTP-sigma without affecting other cells. They first identified an organic compound with the charming name of 6545075 (Chembridge) that was reported to be effective against PTP-sigma. Then they searched a library of 80,000 different small molecules to find something similar to 6545075 (and this is why science takes so long).

From that group they developed more than 100 different drug candidates to see which, if any, were effective against PTP-sigma. Finally, they found a promising candidate, called DJ009. In laboratory tests DJ009 proved itself effective in blocking PTP-sigma in human blood stem cells.

They then tested DJ009 in mice that were given high doses of radiation. In a news release Dr. Chute said the results were very encouraging:

“The potency of this compound in animal models was very high. It accelerated the recovery of blood stem cells, white blood cells and other components of the blood system necessary for survival. If found to be safe in humans, it could lessen infections and allow people to be discharged from the hospital earlier.”

Of the radiated mice, most that were given DJ009 survived. In comparison, those that didn’t get DJ009 died within three weeks.

They saw similar benefits in mice given chemotherapy. Mice with DJ009 saw their white blood cells – key components of the immune system – return to normal within two weeks. The untreated mice had dangerously low levels of those cells at the same point.

It’s encouraging work and the team are already getting ready for more research so they can validate their findings and hopefully take the next step towards testing this in people in clinical trials.

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.

Breaking bad news to stem cell researchers

It’s never easy to tell someone that they are too late, that they missed the deadline. It’s particularly hard when you know that the person you are telling that to has spent years working on a project and now needs money to take it to the next level. But in science, as in life, it’s always better to tell people what they need to know rather than what they would like to hear.

And so, we have posted a notice on our website for researchers thinking about applying for funding that, except in a very few cases, they are too late, that there is no money available for new projects, whether it’s Discovery, Translational or Clinical.

Here’s that notice:

CIRM anticipates that the budget allocation of funds for new awards under the CIRM clinical program (CLIN1, CLIN2 and CLIN3) may be depleted within the next two to three months. CIRM will accept applications for the monthly deadline on June 28, 2019 but will suspend application submissions after that date until further notice. All applicants should note that the review of submitted applications may be halted at any point in the process if funds are depleted prior to completion of the 3-month review cycle. CIRM will notify applicants of such an occurrence. Therefore, submission and acceptance of an application to CIRM does not guarantee the availability of funds or completion of a review cycle.

The submission of applications for the CIRM/NHLBI Cure Sickle Cell Initiative (CLIN1 SCD, CLIN2 SCD) are unaffected and application submissions for this program will remain open.

We do, of course, have enough money set aside to continue funding all the projects our Board has already approved, but we don’t have money for new projects (except for some sickle cell disease projects).

In truth our funding has lasted a lot longer than anyone anticipated. When Proposition 71 was approved the plan was to give CIRM $300 million a year for ten years. That was back in 2004. So what happened?

Well, in the early years stem cell science was still very much in its infancy with most of the work being done at a basic or Discovery level. Those typically don’t require very large sums so we were able to fund many projects without hitting our $300m target. As the field progressed, however, more and more projects were at the clinical trial stage and those need multiple millions of dollars to be completed. So, the money went out faster.

To date we have funded 55 clinical trials and our early support has helped more than a dozen other projects get into clinical trials. This includes everything from cancer and stroke, to vision loss and diabetes. It’s a good start, but we feel there is so much more to do.

Followers of news about CIRM know there is talk about a possible ballot initiative next year that would provide another $5.5 billion in funding for us to help complete the mission we have started.

Over the years we have built a pipeline of promising projects and without continued support many of those projects face a difficult future. Funding at the federal level is under threat and without CIRM there will be a limited number of funding alternatives for them to turn to.

Telling researchers we don’t have any money to support their work is hard. Telling patients we don’t have any money to support work that could lead to new treatments for them, that’s hardest of all.

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

CIRM-funded study helps unlock some of the genetic secrets behind macular degeneration

Retina affected by age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of vision loss in people over 60. It affects 10 million Americans. That’s more than cataracts and glaucoma combined. The causes of AMD are not known but are believed to involve a mixture of hereditary and environmental factors. There is no treatment for it.

Now, in a CIRM-funded study, researchers at UC San Diego (UCSD) have used stem cells to help identify genetic elements that could provide some clues as to the cause, and maybe give some ideas on how to treat it.

Before we get into what the researchers did let’s take a look at what AMD does. At a basic level it attacks the retina, the thin layer of tissue that lines the back of the eye. The retina receives light, turns it into electrical signals and sends it to the brain which turns it into a visual image.

The disease destroys the macula, the part of the retina that controls our central vision. At first, sight becomes blurred or fuzzy but over time it progresses to the point where central vision is almost completely destroyed.

To try and understand why this happens the team at UCSD took skin samples from six people with AMD and, using the iPSC method, turned those cells into the kinds of cell found in the retina. Because these cells came from people who had AMD they now displayed the same characteristics as AMD-affected retinal cells. This allowed the researchers to create what is called a “disease-in-a-dish” model that allowed them to see, in real time, what is happening in AMD.

They were able to identify a genetic variant that reduces production of a protein called VEGFA, which is known to promote the growth of new blood vessels.

In a news release Kelly Frazer, director of the Institute for Genomic Medicine at UCSD and the lead author of the study, said the results were unexpected.

Kelly Frazer, PhD, UC San Diego

“We didn’t start with the VEGFA gene when we went looking for genetic causes of AMD. But we were surprised to find that with samples from just six people, this genetic variation clearly emerged as a causal factor.”

Frazer says this discovery, published in the journal Stem Cell Reports, could ultimately lead to new approaches to developing new treatments for AMD.

CIRM already funds one clinical trial-stage project targeting AMD.

The Past, the Present, and the Uncertain Future of Stem Cell Research

Ronnie, a boy who was born without a functioning immune system but who is thriving today because of CIRM funded research

When CIRM was created in 2004 the field of stem cell research was still very much in its infancy. Fast forward 15 years and it’s moving ahead at a rapid pace, probably faster than most scientists would have predicted. How fast? Find out for yourself at a free public event at UC San Diego on May 28th from 12.30 to 1.30p.

In the last 15 years CIRM has funded 53 clinical trials in everything from heart disease and stroke, to spinal cord injury, vision loss, sickle cell disease and HIV/AIDS.

UCSD was one of the first medical centers chosen to host a CIRM Alpha Stem Cell Clinic – a specialist center with the experience and expertise to deliver stem cell therapies to patients – and to date is running more than a dozen clinical trials for breast cancer, heart failure, leukemia and chronic lower back pain.

Clearly progress is being made. But the field is also facing some challenges. Funding at the federal level for stem cell research is under threat, and CIRM is entering what could be its final phase. We have enough money left to fund new projects through this year (and these are multi-year projects so they will run into 2021 or 2022) but unless there is a new round of funding we will slowly disappear. And with us, may also disappear the hopes of some of the most promising projects underway.

If CIRM goes, then projects that we have supported and nurtured through different phases of research may struggle to make it into a clinical trial because they can’t get the necessary funding.

Clearly this is a pivotal time in the field.

We will discuss all this, the past, the present and the uncertain future of stem cell research at the meeting at UC San Diego on May 28th. The doors will open at noon for registration (snacks and light refreshments will also be available) and the program runs from 12.30p to 1.30p.

The speakers are:

  • Dr. Catriona Jamieson, Director of the UC San Diego Health CIRM Alpha Stem Cell Clinic and Sanford Stem Cell Clinical Center.
  • Dr. Maria Millan, President and CEO of CIRM
  • Dr. David Higgins, CIRM Board member and Patient Advocate for Parkinson’s Disease.

And of course, we want to hear from you, so we’ll leave plenty of time for questions.

Free parking is available.

Go here for more information about the event and how you can register

Free free to share this with anyone you think might be interested in joining us and we look forward to seeing you there.

New model unlocks clues to treating deadly childhood cancer

CIRM-funded research at Sanford Burnham Prebys Medical Discovery Institute in San Diego is identifying compounds that could be used to help children battling a deadly brain cancer.

The cancer is choroid plexus carcinoma (CPC), a rare brain tumor that occurs mainly in children. As it grows the tumor can affect nearby parts of the brain resulting in nausea, vomiting and headaches.

Treatment involves surgery to remove the tumor followed by chemotherapy and radiation. However, many of the children are too young to undergo radiation and only around 40 percent are still alive five years after being diagnosed. Even those who do survive often experience life-long consequences such as developmental disabilities.

One obstacle to developing better therapies has been the lack of a good animal model to enhance our understanding of the disease. That’s where this later research, published in the journal Cancer Research, comes in.

The team at Sanford Burnham developed a new mouse model, by knocking out p53, a gene known to suppress tumor formation, and activating a gene called Myc, which is known to cause cancer.  

Robert Wechsler-Reya

In a news release, Robert Wechsler-Reya, the senior author of the paper, says this new model mirrors the way CPC grows and develops in humans.

“This model is a valuable tool that will increase our understanding of the biology of the cancer and allow us to identify and test novel approaches to therapy. This advance brings us one step closer to a future where every child survives—and thrives—after diagnosis with CPC.”

As proof of that the team tested nearly 8,000 compounds against the mouse tumor cells, to see if they could help stop or slow the progression of the disease. They identified three that showed potential of not just stopping the cancer, but of also not harming healthy surrounding cells.

“These compounds are promising, much-needed leads in the quest for an effective CPC treatment,” says Wechsler-Reya. “Our laboratory plans to evaluate these and additional compounds that can effectively treat this cancer.”

Organoids revolutionize approach to studying a variety of diseases

Organoids

There are limitations to studying cells under a microscope. To understand some of the more complex processes, it is critical to see how these cells behave in an environment that is similar to conditions in the body. The production of organoids has revolutionized this approach.

Organoids are three-dimensional structures derived from stem cells that have similar characteristics of an actual organ. There have been several studies recently published that have used this approach to understand a wide scope of different areas.

In one such instance, researchers at The University of Cambridge were able to grow a “mini-brain” from human stem cells. To demonstrate that this organoid had functional capabilities similar to that of an actual brain, the researchers hooked it up to a mouse spinal cord and surrounding muscle. What they found was remarkable– the “mini-brain” sent electrial signals to the spinal cord that made the surrounding muscles twitch. This model could pave the way for studying neurodegenerative diseases such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS).

Spinal muscular atrophy

Speaking of SMA, researchers in Singapore have used organoids to come up with some findings that might be able to help people battling the condition.

SMA is a neurodegenerative disease caused by a protein deficiency that results in nerve degeneration, paralysis and even premature death. The fact that it mainly affects children makes it even worse. Not much is known how SMA develops and even less how to treat or prevent it.

That’s where the research from the A*STAR’s Institute of Molecular and Cell Biology (IMCB) comes in. Using the iPSC method they turned tissue samples from healthy people and people with SMA into spinal organoids.

They then compared the way the cells developed in the organoids and found that the motor nerve cells from healthy people were fully formed by day 35. However, the cells from people with SMA started to degenerate before they got to that point.

They also found that the protein problem that causes SMA to develop did so by causing the motor nerve cells to divide, something they don’t normally do. So, by blocking the mechanism that caused the cells to divide they were able to prevent the cells from dying.

In an article in Science and Technology Research News lead researcher Shi-Yan Ng said this approach could help unlock clues to other diseases such as ALS.

“We are one of the first labs to report the formation of spinal organoids. Our study presents a new method for culturing human spinal-cord-like tissues that could be crucial for future research.”

Just yesterday the CIRM Board awarded almost $4 million to Ankasa Regenerative Therapeutics to try and develop a treatment for another debilitating back problem called degenerative spondylolisthesis.

And finally, organoid modeling was used to better understand and study an infectious disease. Scientists from the Max Planck Institute for Infection Biology in Berlin created fallopian tube organoids from normal human cells. Fallopian tubes are the pair of tubes found inside women along which the eggs travel from the ovaries to the uterus. The scientists observed the effects of chronic infections of Chlamydia, a sexually transmittable infection. It was discovered that chronic infections lead to permanent changes at the DNA level as the cells age. These changes to DNA are permanent even after the infection is cleared, and could be indicative of the increased risk of cervical cancer observed in women with Chlamydia or those that have contracted it in the past.

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.”