“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.

Stories that caught our eye: National Geographic takes a deep dive into iPS cells; Japanese researchers start iPS cell clinical trial for spinal cord injury; and do high fat diets increase your risk of colorectal cancer

Can cell therapy beat the most difficult diseases?

That’s the question posed in a headline in National Geographic. The answer; maybe, but it is going to take time and money.

The article focuses on the use of iPS cells, the man-made equivalent of embryonic stem cells that can be turned into any kind of cell or tissue in the body. The reporter interviews Kemal Malik, the member of the Board of Management for pharmaceutical giant Bayer who is responsible for innovation. When it comes to iPS cells, it’s clear Malik is a true believer in their potential.

“Because every cell in our bodies can be produced from a stem cell, the applicability of cell therapy is vast. iPSC technology has the potential to tackle some of the most challenging diseases on the planet.”

But he also acknowledges that the field faces some daunting challenges, including:

  • How to manufacture the cells on a large scale without sacrificing quality and purity
  • How do you create products that have a stable shelf life and can be stored until needed?
  • How do you handle immune reactions if you are giving these cells to patients?

Nonetheless, Malik remains confident we can overcome those challenges and realize the full potential of these cells.

“I believe human beings are on the cusp of the next big wave of pharmaceutical innovation. The use of living cells to make people better.”

As if to prove Malik right there was also news this week that researchers at Japan’s Keio University have been given permission to start a clinical trial using iPS cells to treat people with spinal cord injuries. This would be the first of its kind anywhere in the world.

Japan launches iPSC clinical trial for spinal cord injury

An article in Biospace says that the researchers plan to treat four patients who have suffered varying degrees of paralysis due to a spinal cord injury.  They will take cells from the patients and, using the iPS method, turn them into the kind of nerve cells found in the spinal cord, and then transplant two million of them back into the patient. The hope is that this will create new connections that restore movement and feeling in the individuals.

This trial is expected to start sometime this summer.

CIRM has already funded a first-of-its-kind clinical trial for spinal cord injury with Asterias Biotherapeutics. That clinical trial used embryonic stem cells turned into oligodendrocyte progenitor cells – which develop into cells that support and protect nerve cells in the central nervous system. We blogged about the encouraging results from that trial here.

High fat diet drives colorectal cancer

Finally today, researchers at Salk have uncovered a possible cause to the rise in colorectal cancer deaths among people under the age of 55; eating too much high fat food.

Our digestive system works hard to break down the foods we eat and one way it does that is by using bile acids. Those acids don’t just break down the food, however, they also break down the lining of our intestines. Fortunately, our gut has a steady supply of stem cells that can repair and replace that lining. Unfortunately, at least according to the team from Salk, mutations in these stem cells can lead to colorectal cancer.

The study, published in the journal Cell, shows that bile acids affect a protein called FXR that is responsible for ensuring that gut stem cells produce a steady supply of new lining for the gut wall. When someone eats a high fat diet it upsets the balance of bile acids, starting a cascade of events that help cancer develop and grow.

In a news release Annette Atkins, a co-author of the study, says there is a strong connection between bile acid and cancer growth:

“We knew that high-fat diets and bile acids were both risk factors for cancer, but we weren’t expecting to find they were both affecting FXR in intestinal stem cells.”

So next time you are thinking about having that double bacon cheese burger for lunch, you might go for the salad instead. Your gut will thank you. And it might just save your life.

Scientists say they’re one step closer to being able to build a new you, using your own stem cells.

Organ transplant

One of the biggest obstacles to transplanting organs from one person to another is that the immune system of the person getting the new life-saving organ often tries to reject it. The immune cells see the new material as “foreign” and attacks it, sometimes destroying it.

Right now, the only way to prevent that is by using powerful immunosuppressive drugs to keep the patient’s immune system at bay and protect the new organ. It’s effective, but it also comes with some long-term health consequences.

But now researchers at Tel Aviv University in Israel say they may have found a way around that, using the patient’s own stem cells.

The team says it was able to take fatty tissue from patients and, using the iPSC procedure, turn them into other kinds of cells to help repair different kinds of tissue.

In a story in the “Times of Israel”, Prof Tal Dvir, the lead researcher, said this new approach could theoretically be used to engineer any tissue type in the body.

“We were able to create a personalized hydrogel from the materials of the biopsy, to differentiate fatty tissue cells into different cell types and to engineer cardiac, spinal cord, cortical and other tissue implants to treat different diseases. Since both the cells and the material used derive from the patient, the implant does not provoke an immune response, ensuring proper regeneration of the defected organ.”

Dvir says the research, published in the journal Advanced Materials, has only been tested in animals so far but has shown great promise, helping regenerate damaged tissues in mice and rats. Their next goal is to see if they can replicate this in people.

“Theoretically we can work in every disease or disorder that cells are involved in, where tissue is dying. We can create the tissue to fix that injury by a simple injection of materials and cells at the injury site,”

While this has long been a goal of many stem cell researchers around the world, problems translating what looks good in animals into what works in people has invariably slowed down the progress of even the most promising approach. At least so far.

Stem Cell Roundup: Lab-grown meat, stem cell vaccines for cancer and a free kidney atlas for all

Here are the stem cell stories that caught our eye this week.

Cool Stem Cell Photo: Kidneys in the spotlight

At an early stage, a nephron forming in the human kidney generates an S-shaped structure. Green cells will generate the kidneys’ filtering device, and blue and red cells are responsible for distinct nephron activities. (Image/Stacy Moroz and Tracy Tran, Andrew McMahon Lab, USC Stem Cell)

I had to take a second look at this picture when I first saw it. I honestly thought it was someone’s scientific interpretation of Vincent van Gogh’s Starry Night. What this picture actually represents is a nephron. Your kidney has over a million nephrons packed inside it. These tiny structures filter our blood and remove waste products by producing urine.

Scientists at USC Stem Cell are studying kidney development in animals and humans in hopes of gaining new insights that could lead to improved stem cell-based technologies that more accurately model human kidneys (by coincidence, we blogged about another human kidney study on Tuesday). Yesterday, these scientists published a series of articles in the Journal of American Society of Nephrology that outlines a new, open-source kidney atlas they created. The atlas contains a catalog of high resolution images of different structures representing the developing human kidney.

CIRM-funded researcher Andrew McMahon summed it up nicely in a USC news release:

“Our research bridges a critical gap between animal models and human applications. The data we collected and analyzed creates a knowledge-base that will accelerate stem cell-based technologies to produce mini-kidneys that accurately represent human kidneys for biomedical screening and replacement therapies.”

And here’s a cool video of a developing kidney kindly provided by the authors of this study.

Video Caption: Kidney development begins with a population of “progenitor cells” (green), which are similar to stem cells. Some progenitor cells (red) stream out and aggregate into a ball, the renal vesicle (gold). As each renal vesicle grows, it radically morphs into a series of shapes — can you spot the two S-shaped bodies (green-orange-pink structures)? – and finally forms a nephron. Each human kidney contains one million mature nephrons, which form an expansive tubular network (white) that filters the blood, ensuring a constant environment for all of our body’s functions. (Video courtesy of Nils Lindstorm, Andy McMahon, Seth Ruffins and the Microscopy Core Facility at the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at the Keck School of Medicine of USC)


Lab-grown hamburgers coming to a McDonald’s near you…

“Lab-grown meat is coming, whether you like it or not” sure makes a splashy headline! This week, Wired magazine featured two Bay Area startup companies, Just For All and Finless Foods, dedicated to making meat-in-a-dish in hopes of one day reducing our dependence on livestock. The methods behind their products aren’t exactly known. Just For All is engineering “clean meat” from cells. On the menu currently are cultured chorizo, nuggets, and foie gras. I bet you already guessed what Finless Foods specialty is. The company is isolating stem-like muscle progenitor cells from fish meat in hopes of identifying a cell that will robustly create the cell types found in fish meat.

Just’s tacos made with lab-grown chorizo. (Wired)

I find the Wired article particularly interesting because of the questions and issues Wired author Matt Simon raises. Are clean meat companies really more environmentally sustainable than raising livestock? Currently, there isn’t enough data to prove this is the case, he argues. And what about the feasibility of convincing populations that depend on raising livestock for a living to go “clean”? And what about flavor and texture? Will people be willing to eat a hamburger that doesn’t taste and ooze in just the right way?

As clean meat technologies continue to advance and become more affordable, I’ll be interested to see what impact they will have on our eating habits in the future.


Induced pluripotent stem cells could be the next cancer vaccine

Our last story is about a new Cell Stem Cell study that suggests induced pluripotent stem cells (iPSCs) could be developed into a vaccine against cancer. CIRM-funded scientist Joseph Wu and his team at Stanford University School of Medicine found that injecting iPSCs into mice that were transplanted with breast cancer cells reduced the formation of tumors.

The team dug deeper and discovered that iPSCs shared similarities with cancer cells with respect to the panel of genes they express and the types of proteins they carry on their cell surface. This wasn’t surprising to them as both cells represent an immature development stage. Because of these similarities, injecting iPSCs primed the mouse’s immune system to recognize and reject similar cells like cancer cells.

The team will next test their approach on human cancer cells in the lab. Joseph Wu commented on the potential future of iPSC-based vaccines for cancer in a Stanford news release:

“Although much research remains to be done, the concept itself is pretty simple. We would take your blood, make iPS cells and then inject the cells to prevent future cancers. I’m very excited about the future possibilities.”

 

Stem cell stories that caught our eye: lab-grown blood stem cells and puffer fish have the same teeth stem cells as humans

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Scientists finally grow blood stem cells in the lab!

Two exciting stem cell studies broke through the politics-dominated headlines this week. Both studies, published in the journal Nature, demonstrated that human hematopoietic or blood stem cells can be grown in the lab.

This news is a big deal because scientists have yet to make bonafide blood stem cells from pluripotent stem cells or other human cells. These stem cells not only create all the cells in our blood and immune systems, but also can be used to develop therapies for patients with blood cancers and genetic blood disorders.

But to do these experiments, you need a substantial source of blood stem cells – something that has eluded scientists for decades. That’s where these two studies come to the rescue. One study was spearheaded by George Daley at the Boston Children’s Hospital in Massachusetts and the other was led by Shahin Rafii at the Weill Cornell Medical College in New York City.

Researchers have made blood stem cells and progenitor cells from pluripotent stem cells. Credit: Steve Gschmeissner Getty Images

George Daley and his team developed a strategy that matured human induced pluripotent stem cells (iPS cells) into blood-forming stem and progenitor cells. It’s a two-step process that first uses a cocktail of chemicals to make hemogenic endothelium, the embryonic tissue that generates blood stem cells. The second step involved treating these intermediate cells with a combination of seven transcription factors that directed them towards a blood stem cell fate.

These modified human blood stem cells were then transplanted into mice where they developed into blood stem cells that produced blood and immune cells. First author on the study, Ryohichi Sugimura, explained the applications that their technology could be used for in a Boston Children’s Hospital news release,

“This step opens up an opportunity to take cells from patients with genetic blood disorders, use gene editing to correct their genetic defect and make functional blood cells. This also gives us the potential to have a limitless supply of blood stem cells and blood by taking cells from universal donors. This could potentially augment the blood supply for patients who need transfusions.”

The second study by Shahin Rafii and his team at Cornell used a different strategy to generate blood-forming stem cells. Instead of genetically manipulating iPS cells, they selected a more mature cell type to directly reprogram into blood stem cells. Using four transcription factors, they successfully reprogrammed mouse endothelial cells, which line the insides of blood vessels, into blood-forming stem cells that repopulated the blood and immune systems of irradiated mice.

Raffii believe his method is simpler and more efficient than Daley’s. In coverage by Nature News, he commented,

“Using the most efficient method to generate stem cells matters because every time a gene is added to a batch of cells, a large portion of the batch fails to incorporate it and must be thrown out. There is also a risk that some cells will mutate after they are modified in the lab, and could form tumors if they are implanted into people.”

To play devil’s advocate, Daley’s technique might appeal more to some because the starting source of iPS cells is much easier to obtain and culture in the lab than endothelial cells that have to be extracted from the blood vessels of animals or people. Furthermore, Daley argued that his team’s method could “be made more efficient, and [is] less likely to spur tumor growth and other abnormalities in modified cells.”

The Nature News article compares the achievements of both studies and concluded,

“Time will determine which approach succeeds. But the latest advances have buoyed the spirits of researchers who have been frustrated by their inability to generate blood stem cells from iPS cells.”

 

Humans and puffer fish have the same tooth-making stem cells.

Here’s a fun fact for your next blind date: humans and puffer fish share the same genes that are responsible for making teeth. Scientists from the University of Sheffield in England discovered that the stem cells that make teeth in puffer fish are the same stem cells that make the pearly whites in humans. Their work was published in the journal PNAS earlier this week.

Puffer fish. Photo by pingpogz on Flickr.

But if you look at this puffer fish, you’ll see a dramatic difference between its smile and ours – their teeth look more like a beak. Research has shown that the tooth-forming stem cells in puffer fish produce tooth plates that form a beak-like structure, which helps them crush and consume their prey.

So why is this shared evolution between humans and puffer fish important when our teeth look and function so differently? The scientists behind this research believe that studying the pufferfish could unearth answers about tooth loss in humans. The lead author on the study, Dr. Gareth Fraser, concluded in coverage by Phys.org,

“Our study questioned how pufferfish make a beak and now we’ve discovered the stem cells responsible and the genes that govern this process of continuous regeneration. These are also involved in general vertebrate tooth regeneration, including in humans. The fact that all vertebrates regenerate their teeth in the same way with a set of conserved stem cells means that we can use these studies in more obscure fishes to provide clues to how we can address questions of tooth loss in humans.”

How Parkinson’s disease became personal for one stem cell researcher

April is Parkinson’s disease Awareness Month. This year the date is particularly significant because 2017 is the 200th anniversary of the publication of British apothecary James Parkinson’s “An Essay on the Shaking Palsy”, which is now recognized as a seminal work in describing the disease.

Schuele_headshotTo mark the occasion we talked with Dr. Birgitt Schuele, Director Gene Discovery and Stem Cell Modeling at the Parkinson’s Institute and Clinical Center in Sunnyvale, California. Dr. Schuele recently received funding from CIRM for a project using new gene-editing technology to try and halt the progression of Parkinson’s.

 

 

What got you interested in Parkinson’s research?

People ask if I have family members with Parkinson’s because a lot of people get into this research because of a family connection, but I don’t.  I was always excited by neuroscience and how the brain works, and I did my medical residency in neurology and had a great mentor who specialized in the neurogenetics of Parkinson’s. That helped fuel my interest in this area.

I have been in this field for 15 years, and over time I have gotten to know a lot of people with Parkinson’s and they have become my friends, so now I’m trying to find answers and also a cure for Parkinson’s. For me this has become personal.

I have patients that I talk to every couple of months and I can see how their disease is progressing, and especially for people with early or young onset Parkinson’s. It’s devastating. It has a huge effect on the person and their family, and on relationships, even how they have to talk to their kids about their risk of getting the disease themselves. It’s hard to see that and the impact it has on people’s lives. And because Parkinson’s is progressive, I get to see, over the years, how it affects people, it’s very hard.

Talk about the project you are doing that CIRM is funding

It’s very exciting. The question for Parkinson’s is how do you stop disease progression, how do you stop the neurons from dying in areas affected by the disease. One protein, identified in 1997 as a genetic form of Parkinson’s, is alpha-synuclein. We know from studying families that have Parkinson’s that if you have too much alpha-synuclein you get early onset, a really aggressive form of Parkinson’s.

I followed a family that carries four copies of this alpha-synuclein gene (two copies is the normal figure) and the age of onset in this family was in their mid 30’s. Last year I went to a funeral for one of these family members who died from Parkinson’s at age 50.

We know that this protein is bad for you, if you have too much it kills brains cells. So we have an idea that if you lower levels of this protein it might be an approach to stop or shield those cells from cell death.

We are using CRISPR gene editing technology to approach this. In the Parkinson’s field this idea of down-regulation of alpha-synuclein protein isn’t new, but previous approaches worked at the protein level, trying to get rid of it by using, for example, immunotherapy. But instead of attacking the protein after it has been produced we are starting at the genomic level. We want to use CRISPR as a way to down-regulate the expression of the protein, in the same way we use a light dimmer to lower the level of light in a room.

But this is a balancing act. Too much of the protein is bad, but so is too little. We know if you get rid of the protein altogether you get negative effects, you cause complications. So we want to find the right level and that’s complex because the right level might vary from person to person.

We are starting with the most extreme levels, with people who have twice as much of this protein as is normal. Once we understand that better, then we can look at people who have levels that are still higher than normal but not at the upper levels we see in early-onset Parkinson’s. They have more subtle changes in their production or expression of this protein. It’s a little bit of a juggling act and it might be different for different patients. We start with the most severe ones and work our way to the most common ones.

One of the frustrations I often hear from patients is that this is all taking so long. Why is that?

Parkinson’s has been overall frustrating for researchers as well. Around 100 years ago, Dr. Lewy first described the protein deposits and the main neuropathology in Parkinson’s. About 20 years ago, mutations in the alpha-synuclein gene were discovered, and now we know approximately 30 genes that are associated with, or can cause Parkinson’s. But it was all very descriptive. It told us what is going on but not why.

Maybe we thought it was straight forward and maybe researchers only focused on what we knew at that point. In 1957, the neurotransmitter dopamine was identified and since the 1960s people have focused on Parkinson’s as a dopamine-deficient problem because we saw the amazing effects L-Dopa had on patients and how it could help ease their symptoms.

But I would say in the last 15 years we have looked at it more closely and realized it’s more complicated than that. There’s also a loss of sense of smell, there’s insomnia, episodes of depression, and other things that are not physical symptoms. In the last 10 years or so we have really put the pieces together and now see Parkinson’s as a multi-system disease with neuronal cell death and specific protein deposits called Lewy Bodies. These Lewy Bodies contain alpha-synuclein and you find them in the brain, the gut and the heart and these are organs people hadn’t looked at because no one made the connection that constipation or depression could be linked to the disease. It turns out that Parkinson’s is much more complicated than just a problem in one particular region of the brain.

The other reason for slow progress is that we don’t have really good models for the disease that are predictive for clinical outcomes. This is why probably many clinical trials in the neurodegenerative field have failed to date. Now we have human induced pluripotent stem cells (iPSCs) from people with Parkinson’s, and iPSC-derived neurons allow us to better model the disease in the lab, and understand its underlying mechanisms  more deeply. The technology has now advanced so that the ability to differentiate these cells into nerve cells is better, so that you now have iPSC-derived neurons in a dish that are functionally active, and that act and behave like dopamine-producing neurons in the brain. This is an important advance.

Will this lead to a clinical trial?

That’s the idea, that’s our hope.

We are working with professor Dr. Deniz Kirik at the University of Lund in Sweden. He’s an expert in the field of viral vectors that can be used in humans – it’s a joint grant between us – and so what we learn from the human iPS cultures, he’ll transfer to an animal model and use his gene vector technology to see if we can see the same effects in vivo, in mice.

We are using a very special Parkinson’s mouse model – developed at UC San Francisco – that has the complete human genomic structure of the alpha-synuclein gene. If all goes well, we hope that ultimately we could be ready in a couple of years to think about preclinical testing and then clinical trials.

What are your hopes for the future?

My hope is that I can contribute to stopping disease progression in Parkinson’s. If we can develop a drug that can get rid of accumulated protein in someone’s brain that should stop the cells from dying. If someone has early onset PD and a slight tremor and minor walking problems, stopping the disease and having a low dose of dopamine therapy to control symptoms is almost a cure.

The next step is to develop better biomarkers to identify people at risk of developing Parkinson’s, so if you know someone is a few years away from developing symptoms, and you have the tools in place, you can start treatment early and stop the disease from kicking in, even before you clinically have symptoms.

Thinking about people who have been diagnosed with a disease, who are ten years into the disease, who already have side effects from the disease, it’s a little harder to think of regenerative medicine, using embryonic or iPSCs for this. I think that it will take longer to see results with this approach, but that’s the long-term hope for the future. There are many  groups working in this space, which is critical to advance the field.

Why is Parkinson’s Awareness Month important?

It’s important because, while a lot of people know about the disease, there are also a lot of misconceptions about Parkinson’s.

Parkinson’s is confused with Alzheimer’s or dementia and cognitive problems, especially the fact that it’s more than just a gait and movement problem, that it affects many other parts of the body too.

Stem Cell Stories That Caught Our Eye: Plasticity in the pancreas and two cool stem cell tools added to the research toolbox

There’s more plasticity in the pancreas than we thought. You’re taught a lot of things about the world when you’re young. As you get older, you realize that not everything you’re told holds true and it’s your own responsibility to determine fact from fiction. This evolution in understanding happens in science too. Scientists do research that leads them to believe that biological processes happen a certain way, only to sometimes find, a few years later, that things are different or not exactly what they had originally thought.

There’s a great example of this in a study published this week in Cell Metabolism about the pancreas. Scientists from UC Davis found that the pancreas, which secretes a hormone called insulin that helps regulate the levels of sugar in your blood, has more “plasticity” than was originally believed. In this case, plasticity refers to the ability of a tissue or organ to regenerate itself by replacing lost or damaged cells.

The long-standing belief in this field was that the insulin producing cells, called beta cells, are replenished when beta cells actively divide to create more copies of themselves. In patients with type 1 diabetes, these cells are specifically targeted and killed off by the immune system. As a result, the beta cell population is dramatically reduced, and patients have to go on life-long insulin treatment.

UC Davis researchers have identified another type of insulin-producing cell in the islets, which appears to be an immature beta cell shown in red. (UC Davis)

But it turns out there is another cell type in the pancreas that is capable of making beta cells and they look like a teenage, less mature version of beta cells. The UC Davis team identified these cells in mice and in samples of human pancreas tissue. These cells hangout at the edges of structures called islets, which are clusters of beta cells within the pancreas. Upon further inspection, the scientists found that these immature beta cells can secrete insulin but cannot detect blood glucose like mature beta cells. They also found their point of origin: the immature beta cells developed from another type of pancreatic cell called the alpha cell.

Diagram of immature beta cells from Cell Metabolism.

In coverage by EurekAlert, Dr Andrew Rakeman, the director of discovery research at the Juvenile Diabetes Research Foundation, commented on the importance of this study’s findings and how it could be translated into a new approach for treating type 1 diabetes patients:

“The concept of harnessing the plasticity in the islet to regenerate beta cells has emerged as an intriguing possibility in recent years. The work from Dr. Huising and his team is showing us not only the degree of plasticity in islet cells, but the paths these cells take when changing identity. Adding to that the observations that the same processes appear to be occurring in human islets raises the possibility that these mechanistic insights may be able to be turned into therapeutic approaches for treating diabetes.”

 

Say hello to iPSCORE, new and improved tools for stem cell research. Stem cells are powerful tools to model human disease and their power got a significant boost this week from a new study published in Stem Cell Reports, led by scientists at UC San Diego School of Medicine.

The team developed a collection of over 200 induced pluripotent stem cell (iPS cell) lines derived from people of diverse ethnic backgrounds. They call this stem cell tool kit “iPSCORE”, which stands for iPSC Collection for Omic Research (omics refers to a field of study in biology ending in -omics, such as genomics or proteomics). The goal of iPSCORE is to identify particular genetic variants (unique differences in DNA sequence between people’s genomes) that are associated with specific diseases and to understand why they cause disease at the molecular level.

In an interview with Phys.org, lead scientist on the study, Dr. Kelly Frazer, further explained the power of iPSCORE:

“The iPSCORE collection contains 75 lines from people of non-European ancestry, including East Asian, South Asian, African American, Mexican American, and Multiracial. It includes multigenerational families and monozygotic twins. This collection will enable us to study how genetic variation influences traits, both at a molecular and physiological level, in appropriate human cell types, such as heart muscle cells. It will help researchers investigate not only common but also rare, and even family-specific variations.”

This research is a great example of scientists identifying a limitation in stem cell research and expanding the stem cell tool kit to model diseases in a diverse human population.

A false color scanning electron micrograph of cultured human neuron from induced pluripotent stem cell. Credit: Mark Ellisman and Thomas Deerinck, UC San Diego.

Stem cells that can grow into ANY type of tissue. Embryonic stem cells can develop into any cell type in the body, earning them the classification of pluripotent. But there is one type of tissue that embryonic stem cells can’t make and it’s called extra-embryonic tissue. This tissue forms the supportive tissue like the placenta that allows an embryo to develop into a healthy baby in the womb.

Stem cells that can develop into both extra-embryonic and embryonic tissue are called totipotent, and they are extremely hard to isolate and study in the lab because scientists lack the methods to maintain them in their totipotent state. Having the ability to study these special stem cells will allow scientists to answer questions about early embryonic development and fertility issues in women.

Reporting this week in the journal Cell, scientists from the Salk Institute in San Diego and Peking University in China identified a cocktail of chemicals that can stabilize human stem cells in a totipotent state where they can give rise to either tissue type. They called these more primitive stem cells extended pluripotent stem cells or EPS cells.

Salk Professor Juan Carlos Izpisua Bemonte, co–senior author of the paper, explained the problem their study addressed and the solution it revealed in a Salk news release:

“During embryonic development, both the fertilized egg and its initial cells are considered totipotent, as they can give rise to all embryonic and extra-embryonic lineages. However, the capture of stem cells with such developmental potential in vitro has been a major challenge in stem cell biology. This is the first study reporting the derivation of a stable stem cell type that shows totipotent-like bi-developmental potential towards both embryonic and extra-embryonic lineages.”

Human EPS cells (green) can be detected in both the embryonic part (left) and extra-embryonic parts (placenta and yolk sac, right) of a mouse embryo. (Salk Institute)

Using this new method, the scientists discovered that human EPS stem cells were able to develop chimeric embryos with mouse stem cells more easily than regular embryonic stem cells. First author on the study, Jun Wu, explained why this ability is important:

“The superior chimeric competency of both human and mouse EPS cells is advantageous in applications such as the generation of transgenic animal models and the production of replacement organs. We are now testing to see whether human EPS cells are more efficient in chimeric contribution to pigs, whose organ size and physiology are closer to humans.”

The Salk team reported on advancements in generating interspecies chimeras earlier this year. In one study, they were able to grow rat organs – including the pancreas, heart and eyes – in a mouse. In another study, they grew human tissue in early-stage pig and cattle embryos with the goal of eventually developing ways to generate transplantable organs for humans. You can read more about their research in this Salk news release.

One scientist’s quest to understand autism using stem cells

April is National Autism Awareness Month and people and organizations around the world are raising awareness about a disorder that affects more than 20 million people globally. Autism affects early brain development and causes a wide spectrum of social, mental, physical and emotional symptoms that appear during childhood. Because the symptoms and their severity can vary extremely between people, scientists now use the classification of autism spectrum disorder (ASM).

Alysson Muotri UC San Diego

In celebration of Autism Awareness Month, we’re featuring an interview with a CIRM-funded scientist who is on the forefront of autism and ASD research. Dr. Alysson Muotri is a professor at UC San Diego and his lab is interested in unlocking the secrets to brain development by using molecular tools and stem cell models.

One of his main research projects is on autism. Scientists in his lab are using induced pluripotent stem cells (iPSCs) derived from individuals with ASD to model the disease in a dish. From these stem cell models, his team is identifying genes that are associated with ASD and potential drugs that could be used to treat this disorder. Ultimately, Dr. Muotri’s goal is to pave a path for the development of personalized therapies for people with ASD.

I reached out to Dr. Muotri to ask for an update on his Autism research. His responses are below.

Q: Can you briefly summarize your lab’s work on Autism Spectrum Disorders?

AM: As a neuroscientist studying autism, I was frustrated with the lack of a good experimental model to understand autism. All the previous models (animal, postmortem brain tissues, etc.) have serious experimental limitations. The inaccessibility of the human brain has blocked the progress of research on ASD for a long time. Cellular reprogramming allows us to transform easy-access cell types (such as skin, blood, dental pulp, etc.) into brain cells or even “mini-brains” in the lab. Because we can capture the entire genome of the person, we can recapitulate early stages of neurodevelopment of that same individual. This is crucial to study neurodevelopment disorders, such as ASD, because of the strong genetic factor underlying the pathology [the cause of a disease]. By comparing “mini-brains” between an ASD and neurotypical [non-ASD] groups, we can find anatomical and functional differences that might explain the clinical symptoms.

Q: What types of tools and models are you using to study ASD?

AM: Most of my lab takes advantage of reprogramming stem cells and genome editing techniques to generate 3D organoid models of ASD. We use the stem cells to create brain organoids, also called “mini-brains” in the lab. These mini-brains will develop from single cells and grow and mature in the same way as the fetal brain. Thus, we can learn about their structure and connectivity over time.

A cross section of a cerebral organoid or mini-brain courtesy of Alysson Muotri.

This new model brings something novel to the table: the ability to experimentally test specific hypotheses in a human background.  For example, we can ask if a specific genetic variant is causal for an autistic individual. Thus, we can edit the genome of that autistic individual, fixing target mutations in these mini-brains and check if now the fixed mini-brains will develop any abnormalities seen in ASD.

The ability to combine all these recent technologies to create a human experimental model of ASD in the lab is quite new and very exciting. As with any other model, there are limitations. For example, the mini-brains don’t have all the complexity and cell types seen in the developing human embryo/fetus. We also don’t know exactly if we are giving them the right and necessary environment (nutrients, growth factors, etc.) to mature. Nonetheless, the progress in this field is taking off quickly and it is all very promising.

Two mini-brains grown in a culture dish send out cellular extensions to connect with each other. Neurons are in green and astrocytes are in pink. Image courtesy of Dr. Muotri.

Q: We’ve previously written about your lab’s work on the Tooth Fairy Project and how you identified the TRPC6 gene. Can you share updates on this project and any new insights?

AM: The Tooth Fairy Project was designed to collect dental pulp cells from ASD and control individuals in a non-invasive fashion (no need for skin biopsy or to draw blood). We used social media to connect with families and engage them in our research. It was so successful we have now hundreds of cells in the lab. We use this material to reprogram into stem cells and to sequence their DNA.

One of the first ASD participants had a mutation in one copy of the TRPC6 gene, a novel ASD gene candidate. Everybody has two copies of this gene in the genome, but because of the mutation, this autistic kid has only one functional copy. Using stem cells, we re-created cortical neurons from that individual and confirmed that this mutation inhibits the formation of excitatory synapses (connections required to propagate information).

Interestingly, while studying TRPC6, we realized that a molecule found in Saint John’s Wort, hyperforin, could stimulate the functional TRPC6. Since the individual still has one functional TRPC6 gene copy, it seemed reasonable to test if hyperforin treatment could compensate the mutation on the other copy. It did. A treatment with hyperforin for only two weeks could revert the deficits on the neurons derived from that autistic boy. More exciting is the fact that the family agreed to incorporate St. John’s Wort on his diet. We have anecdotal evidence that this actually improved his social and emotional skills.

To me, this is the first example of personalized treatment for ASD, starting with genome sequencing, detecting potential causative genetic mutations, performing cellular modeling in the lab, and moving into clinic. I believe that there are many other autistic cases where this approach could be used to find better treatments, even with off the counter medications. To me, that is the greatest insight.

Watch Dr. Muotri’s Spotlight presentation about the Tooth Fairy Project and his work on autism.

Q: Is any of the research you are currently doing in autism moving towards clinical trials?

AM: IGF-1, or insulin growth factor-1, a drug we found promising for Rett syndrome and a subgroup of idiopathic [meaning its causes are spontaneous or unknown] ASD is now in clinical trials. Moreover, we just concluded a CIRM award on a large drug screening for ASD. The data is very promising, with several candidates. We have 14 drugs in the pipeline, some are repurposed drugs (initially designed for cancer, but might work for ASD). It will require additional pre-clinical studies before we start clinical trials.

Q: What do you think the future of diagnosis and treatment will be for patients with ASD?

AM: I am a big enthusiastic fan of personalized treatments for ASD. While we continue to search for a treatment that could help a large fraction of ASD people, we also recognized that some cases might be easier than others depending on their genetic profile. The idea of using stem cells to create “brain avatars” of ASD individuals in the lab is very exciting. We are also studying the possibility of using this approach as a future diagnostic tool for ASD. I can imagine every baby having their “brain avatar” analyses done in the lab, eventually pointing out “red flags” on the ones that failed to achieve neurodevelopment milestones. If we could capture these cases, way before the autism symptoms onset, we could initiate early treatments and therapies, increasing the chances for a better prognostic and clinical trajectory. None of these would be possible without stem cell research.

Q: What other types of research is your lab doing?

Mini-brains grown in a dish in Dr. Muotri’s lab.

AM: My lab is also using these human mini-brains to test the impact of environmental factors in neurodevelopment. By exposing the mini-brains to certain agents, such as pollution particles, household chemicals, cosmetics or agrotoxic products [pesticides], we can measure the concentration that is likely to induce brain abnormalities (defects in neuronal migration, synaptogenesis, etc.). This toxicological test can complement or substitute for other commonly used analyses, such as animal models, that are not very humane or predictive of human biology. A nice example from my lab was when we used this approach to confirm the detrimental effect of the Zika virus on brain development. Not only did we show causation between the circulating Brazilian Zika virus and microcephaly [a birth defect that causes an abnormally small head], but our data also pointed towards a potential mechanism (we showed that the virus kills neural progenitor cells, reducing the thickness of the cortical layers in the brain).

You can learn more about Dr. Muotri’s research on his lab’s website.


Related Links:

Stem Cell Stories that Caught our Eye: stem cell insights into anorexia, Zika infection and bubble baby disease

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Stem cell model identifies new culprit for anorexia.

Eating disorders like anorexia nervosa are often thought to be caused by psychological disturbances or societal pressure. However, research into the genes of anorexia patients suggests that what’s written in your DNA can be associated with an increased vulnerability to having this disorder. But identifying individual genes at fault for a disease this complex has remained mostly out of scientists’ reach, until now.

A CIRM-funded team from the UC San Diego (UCSD) School of Medicine reported this week that they’ve developed a stem cell-based model of anorexia and used it to identify a gene called TACR1, which they believe is associated with an increased likelihood of getting anorexia.

They took skin samples from female patients with anorexia and reprogrammed them into induced pluripotent stem cells (iPSCs). These stem cells contained the genetic information potentially responsible for causing their anorexia. The team matured these iPSCs into brain cells, called neurons, in a dish, and then studied what genes got activated. When they looked at the genes activated by anorexia neurons, they found that TACR1, a gene associated with psychiatric disorders, was switched on higher in anorexia neurons than in healthy neurons. These findings suggest that the TACR1 gene could be an identifier for this disease and a potential target for developing new treatments.

In a UCSD press release, Professor and author on the study, Alysson Muotri, said that they will follow up on their findings by studying stem cell lines derived from a larger group of patients.

Alysson Muotri UC San Diego

“But more to the point, this work helps make that possible. It’s a novel technological advance in the field of eating disorders, which impacts millions of people. These findings transform our ability to study how genetic variations alter brain molecular pathways and cellular networks to change risk of anorexia nervosa — and perhaps our ability to create new therapies.”

Anorexia is a disease that affects 1% of the global population and although therapy can be an effective treatment for some, many do not make a full recovery. Stem cell-based models could prove to be a new method for unlocking new clues into what causes anorexia and what can cure it.

Nature versus Zika, who will win?

Zika virus is no longer dominating the news headlines these days compared to 2015 when large outbreaks of the virus in the Southern hemisphere came to a head. However, the threat of Zika-induced birth defects, like microcephaly to pregnant women and their unborn children is no less real or serious two years later. There are still no effective vaccines or antiviral drugs that prevent Zika infection but scientists are working fast to meet this unmet need.

Speaking of which, scientists at UCLA think they might have a new weapon in the war against Zika. Back in 2013, they reported that a natural compound in the body called 25HC was effective at attacking viruses and prevented human cells from being infected by viruses like HIV, Ebola and Hepatitis C.

When the Zika outbreak hit, they thought that this compound could potentially be effective at preventing Zika infection as well. In their new study published in the journal Immunity, they tested a synthetic version of 25HC in animal and primate models, they found that it protected against infection. They also tested the compound on human brain organoids, or mini brains in a dish made from pluripotent stem cells. Brain organoids are typically susceptible to Zika infection, which causes substantial cell damage, but this was prevented by treatment with 25HC.

Left to right: (1) Zika virus (green) infects and destroys the formation of neurons (pink) in human stem cell-derived brain organoids.  (2) 25HC blocks Zika infection and preserves neuron formation in the organoids. (3) Reduced brain size and structure in a Zika-infected mouse brain. (4) 25HC preserves mouse brain size and structure. Image courtesy of UCLA Stem Cell.

A UCLA news release summarized the impact that this research could have on the prevention of Zika infection,

“The new research highlights the potential use of 25HC to combat Zika virus infection and prevent its devastating outcomes, such as microcephaly. The research team will further study whether 25HC can be modified to be even more effective against Zika and other mosquito-borne viruses.”

Harnessing a naturally made weapon already found in the human body to fight Zika could be an alternative strategy to preventing Zika infection.

Gene therapy in stem cells gives hope to bubble-babies.

Last week, an inspiring and touching story was reported by Erin Allday in the San Francisco Chronicle. She featured Ja’Ceon Golden, a young baby not even 6 months old, who was born into a life of isolation because he lacked a properly functioning immune system. Ja’Ceon had a rare disease called severe combined immunodeficiency (SCID), also known as bubble-baby disease.

 

Ja’Ceon Golden is treated by patient care assistant Grace Deng (center) and pediatric oncology nurse Kat Wienskowski. Photo: Santiago Mejia, The Chronicle.

Babies with SCID lack the body’s immune defenses against infectious diseases and are forced to live in a sterile environment. Without early treatment, SCID babies often die within one year due to recurring infections. Bone marrow transplantation is the most common treatment for SCID, but it’s only effective if the patient has a donor that is a perfect genetic match, which is only possible for about one out of five babies with this disease.

Advances in gene therapy are giving SCID babies like Ja’Ceon hope for safer, more effective cures. The SF Chronicle piece highlights two CIRM-funded clinical trials for SCID run by UCLA in collaboration with UCSF and St. Jude Children’s Research Hospital. In these trials, scientists isolate the bone marrow stem cells from SCID babies, correct the genetic mutation causing SCID in their stem cells, and then transplant them back into the patient to give them a healthy new immune system.

The initial results from these clinical trials are promising and support other findings that gene therapy could be an effective treatment for certain genetic diseases. CIRM’s Senior Science Officer, Sohel Talib, was quoted in the Chronicle piece saying,

“Gene therapy has been shown to work, the efficacy has been shown. And it’s safe. The confidence has come. Now we have to follow it up.”

Ja’Ceon was the first baby treated at the UCSF Benioff Children’s Hospital and so far, he is responding well to the treatment. His great aunt Dannie Hawkins said that it was initially hard for her to enroll Ja’Ceon in this trial because she was a partial genetic match and had the option of donating her own bone-marrow to help save his life. In the end, she decided that his involvement in the trial would “open the door for other kids” to receive this treatment if it worked.

Ja’Ceon Golden plays with patient care assistant Grace Deng in a sterile play area at UCSF Benioff Children’s Hospital.Photo: Santiago Mejia, The Chronicle

It’s brave patients and family members like Ja’Ceon and Dannie that make it possible for research to advance from clinical trials into effective treatments for future patients. We at CIRM are eternally grateful for their strength and the sacrifices they make to participate in these trials.

Stem Cell Stories That Caught our Eye: Making blood and muscle from stem cells and helping students realize their “pluripotential”

Stem cells offer new drug for blood diseases. A new treatment for blood disorders might be in the works thanks to a stem cell-based study out of Harvard Medical School and Boston Children’s hospital. Their study was published in the journal Science Translational Medicine.

The teams made induced pluripotent stem cells (iPSCs) from the skin of patients with a rare blood disorder called Diamond-Blackfan anemia (DBA) – a bone marrow disease that prevents new blood cells from forming. iPSCs from DBA patients were then specialized into blood progenitor cells, the precursors to blood cells. However, these precursor cells were incapable of forming red blood cells in a dish like normal precursors do.

Red blood cells were successfully made via induced pluripotent stem cells from a Diamond-Blackfan anemia patient. Image: Daley lab, Boston Children’s

Red blood cells were successfully made via induced pluripotent stem cells from a Diamond-Blackfan anemia patient. Image: Daley lab, Boston Children’s

The blood progenitor cells from DBA patients were then used to screen a library of compounds to identify drugs that could get the DBA progenitor cells to develop into red blood cells. They found a compound called SMER28 that had this very effect on progenitor cells in a dish. When the compound was tested in zebrafish and mouse models of DBA, the researchers observed an increase in red blood cell production and a reduction of anemia symptoms.

Getting pluripotent stem cells like iPSCs to turn into blood progenitor cells and expand these cells into a population large enough for drug screening has not been an easy task for stem cell researchers.

Co-first author on the study, Sergei Doulatov, explained in a press release, “iPS cells have been hard to instruct when it comes to making blood. This is the first time iPS cells have been used to identify a drug to treat a blood disorder.”

In the future, the researchers will pursue the questions of why and how SMER28 boosts red blood cell generation. Further work will be done to determine whether this drug will be a useful treatment for DBA patients and other blood disorders.

 

Students realize their “pluripotential”. In last week’s stem cell stories, I gave a preview about an exciting stem cell “Day of Discovery” hosted by USC Stem Cell in southern California. The event happened this past Saturday. Over 500 local middle and high school students attended the event and participated in lab tours, poster sessions, and a career resource fair. Throughout the day, they were engaged by scientists and educators about stem cell science through interactive games, including the stem cell edition of Family Feud and a stem cell smartphone videogame developed by USC graduate students.

In a USC press release, Rohit Varma, dean of the Keck School of Medicine of USC, emphasized the importance of exposing young students to research and scientific careers.

“It was a true joy to welcome the middle and high school students from our neighboring communities in Boyle Heights, El Sereno, Lincoln Heights, the San Gabriel Valley and throughout Los Angeles. This bright young generation brings tremendous potential to their future pursuits in biotechnology and beyond.”

Maria Elena Kennedy, a consultant to the Bassett Unified School District, added, “The exposure to the Keck School of Medicine of USC is invaluable for the students. Our students come from a Title I School District, and they don’t often have the opportunity to come to a campus like the Keck School of Medicine.”

The day was a huge success with students posting photos of their experiences on social media and enthusiastically writing messages like “stem cells are our future” and “USC is my goal”. One high school student acknowledged the opportunity that this day offers to students, “California currently has biotechnology as the biggest growing sector. Right now, it’s really important that students are visiting labs and learning more about the industry, so they can potentially see where they’re going with their lives and careers.”

You can read more about USC’s Stem Cell Day of Discovery here. Below are a few pictures from the event courtesy of David Sprague and USC.

Students have fun with robots representing osteoblast and osteoclast cells at the Stem Cell Day of Discovery event held at the USC Health Sciences Campus in Los Angeles, CA. February 4th, 2017. The event encourages students to learn more about STEM opportunities, including stem cell study and biotech, and helps demystify the fields and encourage student engagement. Photo by David Sprague

Students have fun with robots representing osteoblast and osteoclast cells at the USC Stem Cell Day of Discovery. Photo by David Sprague

Dr. Francesca Mariana shows off a mouse skeleton that has been dyed to show bones and cartilage at the Stem Cell Day of Discovery event held at the USC Health Sciences Campus in Los Angeles, CA. February 4th, 2017. The event encourages students to learn more about STEM opportunities, including stem cell study and biotech, and helps demystify the fields and encourage student engagement. Photo by David Sprague

Dr. Francesca Mariana shows off a mouse skeleton that has been dyed to show bones and cartilage. Photo by David Sprague

USC masters student Shantae Thornton shows students how cells are held in long term cold storage tanks at -195 celsius at the Stem Cell Day of Discovery event held at the USC Health Sciences Campus in Los Angeles, CA. February 4th, 2017. The event encourages students to learn more about STEM opportunities, including stem cell study and biotech, and helps demystify the fields and encourage student engagement. Photo by David Sprague

USC masters student Shantae Thornton shows students how cells are held in long term cold storage tanks at -195 celsius. Photo by David Sprague

Genesis Archila, left, and Jasmine Archila get their picture taken at the Stem Cell Day of Discovery event held at the USC Health Sciences Campus in Los Angeles, CA. February 4th, 2017. The event encourages students to learn more about STEM opportunities, including stem cell study and biotech, and helps demystify the fields and encourage student engagement. Photo by David Sprague

Genesis Archila, left, and Jasmine Archila get their picture taken at the USC Stem Cell Day of Discovery. Photo by David Sprague

New stem cell recipes for making muscle: new inroads to study muscular dystrophy (Todd Dubnicoff)

Embryonic stem cells are amazing because scientists can change or specialize them into virtually any cell type. But it’s a lot easier said than done. Researchers essentially need to mimic the process of embryo development in a petri dish by adding the right combination of factors to the stem cells in just the right order at just the right time to obtain a desired type of cell.

Making human muscle tissue from embryonic stem cells has proven to be a challenge. The development of muscle, as well as cartilage and bone, are well characterized and known to form from an embryonic structure called a somite. Researches have even been successful working out the conditions for making somites from animal stem cells. But those recipes didn’t work well with human stem cells.

Now, a team of researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA has overcome this roadblock by carrying out a systematic approach using human tissue. As described in Cell Reports, the scientists isolated somites from early human embryos and studied their gene activity. By comparing somites that were just beginning to emerge with fully formed somites, the researchers pinpointed differences in gene activity patterns. With this data in hand, the team added factors to the cells that were known to affect the activity of those genes. Through some trial and error, they produced a recipe – different than those used in animal cells – that could convert 90 percent of the human stem cells into somites in only four days. Those somites could then readily transform into muscle or bone or cartilage.

This new method for making human muscle will be critical for the lab’s goal to develop therapies for Duchenne muscular dystrophy, an incurable muscle wasting disease that strikes young boys and is usually fatal by their 20’s.

The new protocol turned 90 percent of human pluripotent stem cells into somite cells in just four days; those somite cells then generated (left to right) cartilage, bone and muscle cells.  Image: April Pyle Lab/UCLA

The new protocol turned 90 percent of human pluripotent stem cells into somite cells in just four days; those somite cells then generated (left to right) cartilage, bone and muscle cells. Image: April Pyle Lab/UCLA