iPS cells

Turning back the clock to make old skin cells young again

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Dr. Diljeet Gill, photo courtesy Babraham Institute, Cambridge UK

Sometimes when I am giving public presentations people ask if stem cells are good for the face. I always say that if stem cells could help improve people’s faces would I look like this. It’s a line that gets a laugh but it’s also true. The ads you see touting stem cells as being beneficial for skin are all using plant stem cells. But now some new research has managed to turn back the clock for skin cells, and it might do a lot more than just help skin look younger.

Back in 2007 Japanese scientist Shinya Yamanaka discovered a way to turn ordinary skin cells back into an embryonic-like state, meaning those cells could then be turned into any other cell in the body. He called these cells induced pluripotent stem cells or iPSCs. Dr. Yamanaka was later awarded the Nobel Prize for Medicine for this work.

Using this work as their starting point, a team at Cambridge University in the UK, have developed a technique that can rewind the clock on skin cells but stop it less than a third of the way through, so they have made the cells younger but didn’t erase their identity as skin cells.

The study, published in the journal ELifeSciences, showed the researchers were able to make older skin cells 30 years younger. This wasn’t about restoring a sense of youthful beauty to the skin, instead it was about something far more important, restoring youthful function to the skin.

In a news release, Dr Diljeet Gill, a lead author on the study, said: “Our understanding of ageing on a molecular level has progressed over the last decade, giving rise to techniques that allow researchers to measure age-related biological changes in human cells. We were able to apply this to our experiment to determine the extent of reprogramming our new method achieved.”

The team proved the potential for their work using fibroblasts, the most common kind of cell found in connective tissues such as skin. Fibroblasts are important because they produce collagen which helps provide support and structure to tissues and also helps in healing wounds. When the researchers examined the rejuvenated skin cells they found they were producing more collagen than cells that had not been rejuvenated. They also saw signs that these rejuvenated cells could help heal wounds better than the old cells.

The researchers also noted that this approach had an effect on other genes linked to age-related conditions, such Alzheimer’s disease and the development of cataracts.

The researchers acknowledge that this is all very early on, but the fact that they were able to make the cells behave and act like younger cells, without losing their identity as skin cells, holds tremendous promise not just for conditions affecting the skin, but for regenerative medicine as a whole.

Dr. Diljeet concluded: “Our results represent a big step forward in our understanding of cell reprogramming. We have proved that cells can be rejuvenated without losing their function and that rejuvenation looks to restore some function to old cells. The fact that we also saw a reverse of ageing indicators in genes associated with diseases is particularly promising for the future of this work.”

A Month of CIRM: Where we’ve been, where we’re going

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All this month we are using our blog and social media to highlight a new chapter in CIRM’s life, thanks to the voters approving Proposition 14. We are looking back at what we have done since we were created in 2004, and also looking forward to the future. We kick off this event with a letter from our the Chair of our Board, Jonathan Thomas.

When voters approved Proposition 14 last November, they gave the Stem Cell Agency a new lease on life and a chance to finish the work we began with the approval of Proposition 71 in 2004. It’s a great honor and privilege. It’s also a great responsibility. But I think looking back at what we have achieved over the last 16 years shows we are well positioned to seize the moment and take CIRM and regenerative medicine to the next level and beyond.

When we started, we were told that if we managed to get one project into a clinical trial by the time our money ran out we would have done a good job. As of this moment we have 68 clinical trials that we have funded plus another 31 projects in clinical trials where we helped fund crucial early stage research. That inexorable march to therapies and cures will resume when we take up our first round of Clinical applications under Prop 14 in March.

But while clinical stage projects are the end game, where we see if therapies really work and are safe in people, there’s so much more that we have achieved since we were created. We have invested $900 million in  basic research, creating a pipeline of the most promising stem cell research programs, as well as investing heavily on so-called “translational” projects, which move projects from basic science to where they’re ready to apply to the Food and Drug Administration (FDA) to begin clinical trials.

We have funded more than 1,000 projects, with each one giving us valuable information to help advance the science. Our funding has helped attract some of the best stem cell scientists in the world to California and, because we only fund research in California, it has persuaded many companies to either move here or open offices here to be eligible for our support. We have helped create the Alpha Stem Cell Clinics, a network of leading medical centers around the state that have the experience and expertise to deliver stem cell therapies to patients. All of those have made California a global center in the field.

That result is producing big benefits for the state. An independent Economic Impact Analysis reported that by the end of 2018 we had already helped generate an extra $10.7 billion in new sales revenue and taxes for California, hundreds of millions more in federal taxes and created more than 56,000 new jobs.

As if that wasn’t enough, we have also:

  • Helped develop the largest iPSC research bank in the world.
  • Created the CIRM Center of Excellence in Stem Cell Genomics to accelerate fundamental understanding of human biology and disease mechanisms.
  • Helped fund the construction of 12 world class stem cell institutes throughout the state.
  • Reached a unique partnership with the National Heart, Lung and Blood Institutes to find a cure for sickle cell disease.
  • Used our support for stem cell research to leverage an additional $12 billion in private funding for the field.
  • Enrolled more than 2700 patients in CIRM funded clinical trials

In many ways our work is just beginning. We have laid the groundwork, helped enable an extraordinary community of researchers and dramatically accelerated the field. Now we want to get those therapies (and many more) over the finish line and get them approved by the FDA so they can become available to many more people around the state, the country and the world.

We also know that we have to make these therapies available to all people, regardless of their background and ability to pay. We have to ensure that underserved communities, who were often left out of research in the past, are an integral part of this work and are included in every aspect of that research, particularly clinical trials. That’s why we now require anyone applying to us for funding to commit to engaging with underserved communities and to have a written plan to show how they are going to do that.

Over the coming month, you will hear more about some of the remarkable things we have managed to achieve so far and get a better sense of what we hope to do in the future. We know there will be challenges ahead and that not everything we do or support will work. But we also know that with the team we have built at CIRM, the brilliant research community in California and the passion and drive of the patient advocate community we will live up to the responsibility the people of California placed in us when they approved Proposition 14.

An off-the-shelf cancer killer

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iPS Cell: Photo from the lab of Kathrin Plath at UCLA

One of the hottest areas in cancer research right now is the use of CAR-T treatments. These use the patient’s own re-engineered immune system cells to target and kill the tumor. But the thing that makes it so appealing – using the patient’s own cells – also makes it really complicated and expensive. Creating a custom-made therapy from each patient’s own cells takes time and costs a lot of money. But now a new approach could change that.

Fate Therapeutics has developed an off-the-shelf therapy (thanks to CIRM funding) that could, theoretically, be stored at hospitals and clinics around the country and used whenever it’s needed for anyone who needs it.

At this year’s meeting of the American Society of Hematology (ASH) Fate announced that the first patient treated with this new approach seems to be doing very well. The patient had acute myeloid leukemia and wasn’t responding to conventional treatments. However, following treatment with Fate’s FT516 the patient responded quickly and – according to STAT News’ Adam Feuerstein – was able to leave the hospital and spend Thanksgiving with his family.

Equally impressive is that 42 days after being treated with FT516, the man showed no signs of leukemia in either his bone marrow or blood.

FT516 is designed to provide a one-two combination attack on cancer. It’s made up of the wonderfully named natural killer (NK) cells, which are a critical part of our immune system defenses against cancer. These NK cells are created by using the iPSC process and have been genetically modified to express a protein that boosts their cancer-killing abilities.

Because these cells are manufactured they can, if effective, be produced in large numbers and stored for whenever needed. That would not only dramatically reduce costs but also make them more widely available when they are needed.

This is only one patient and the follow-up is still relatively short. Even so, the results are encouraging and certainly give hope that Fate is on to something big. We’ll be keeping track and let you know how things progress.

“Brains” in a dish that can create electrical impulses

/ Kevin McCormack / 2 Comments
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

/ Kevin McCormack / 1 Comment

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.

/ Kevin McCormack / 3 Comments

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

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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

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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

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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

/ Karen Ring / Leave a comment

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.