Stem Cell Stories that Caught our Eye: A Zebrafish’s Stripes, Stem Cell Sound Waves and the Dangers of Stem Cell Tourism

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.

The zebrafish (Danio rerio) owes its name to a repeating pattern of blue stripes alternating with golden stripes. [Credit: MPI f. Developmental Biology/ P. Malhawar]

The zebrafish (Danio rerio) owes its name to a repeating pattern of blue stripes alternating with golden stripes. [Credit: MPI f. Developmental Biology/ P. Malhawar]

How the Zebrafish Got its Stripes. Scientists in Germany have identified the different pigment cells that emerge during embryonic development and that determine the signature-striped pattern on the skins of zebrafish—one of science’s most commonly studied model organisms. These results, published this week in the journal Science, will help researchers understand how patterns, from stripes to spots to everything in between, develop.

In the study, scientists at the Max Planck Institute for Developmental Biology mapped how three distinct pigment cells, called black cells, reflective silvery cells, and yellow cells emerge during development and arrange themselves into the characteristic stripes. While researchers knew these three cell types were involved in stripe formation, what they discovered here was that these cells form when the zebrafish is a mere embryo.

“We were surprised to observe such cell behaviors, as these were totally unexpected from what we knew about color pattern formation”, says Prateek Mahalwar, first author of the study, in a news release.

What most surprised the research team, according to the news release, was that the three cell types each travel across the embryo to form the skin from a different direction. According to Dr. Christiane Nüsslein-Volhard, the study’s senior author:

“These findings inform our way of thinking about color pattern formation in other fish, but also in animals which are not accessible to direct observation during development such as peacocks, tigers and zebras.”

Sound Waves Dispense Individual Stem Cells. It happens all the time in the lab: scientists need to isolate and study a single stem cell. The trick is, how best to do it. Many methods have been developed to achieve this goal, but now scientists at the Regenerative Medicine Institute (REMEDI) at NUI Galway and Irish start-up Poly-Pico Technologies Ltd. have pioneered the idea of using sound waves to isolate living stem cells, in this case from bone marrow, with what they call the Poly-Pico micro-drop dispensing device.

Poly-Pico Technologies Ltd., a start-up that was spun out from the University of Limerick in Ireland, has developed a device that uses sound energy to accurately dispense protein, antibodies and DNA at very low volumes. In this study, REMEDI scientists harnessed this same technology to dispense stem cells.

These results, while preliminary, could help improve our understanding of stem cell biology, as well as a number of additional applications. As Poly-Pico CEO Alan Crean commented in a news release:

“We are delighted to see this new technology opportunity emerge at the interface between biology and engineering. There are other exciting applications of Poly-Pico’s unique technology in, for example, drug screening and DNA amplification. Our objective here is to make our technology available to companies, and researchers, and add value to what they are doing. This is one example of such a success.”

The Dangers of Stem Cell Toursim. Finally, a story from ABC News Australia, in which they recount a woman’s terrifying encounter with an unproven stem cell technique.

In this story, Annie Levington, who has suffered from multiple scleoris (MS) since 2007, tells of her journey from Melbourne to Germany. She describes a frightening experience in which she paid $15,000 to have a stem cell transplant. But when she returned home to Australia, she saw no improvement in her MS—a neuroinflammatory disease that causes nerve cells to whither.

“They said I would feel the effects within the next three weeks to a year. And nothing – I had noticed nothing whatsoever. [My neurologist] sent me to a hematologist who checked my bloods and concluded there was no evidence whatsoever that I received a stem cell transplant.”

Sadly, Levington’s story is not unusual, though it is not as dreadful as other instances, in which patients have traveled thousands of miles to have treatments that not only don’t cure they condition—they actually cause deadly harm.

The reason that these unproven techniques are even being administered is based on a medical loophole that allows doctors to treat patients, both in Australia and overseas, with their own stem cells—even if that treatment is unsafe or unproven.

And while there have been some extreme cases of death or severe injury because of these treatments, experts warn that the most likely outcome of these untested treatments is similar to Levington’s—your health won’t improve, but your bank account will have dwindled.

Want to learn more about the dangers of stem cell tourism? Check out our Stem Cell Tourism Fact Sheet.

A Tumor’s Trojan Horse: CIRM Researchers Build Nanoparticles to Infiltrate Hard-to-Reach Tumors

Some tumors are hard to find, while others are hard to destroy. Fortunately, a new research study from the University of California, Davis, has developed a new type of nanoparticle that could one day do both.

UC Davis scientists have developed a new type of nanoparticle to target tumor cells.

UC Davis scientists have developed a new type of nanoparticle to target tumor cells.

Reporting in the latest issue of Nature Communications, researchers in the laboratory of UC Davis’ Dr. Kit Lam describe a type of ‘dynamic nanoparticle’ that they created, which not only lights up tumors during an MRI or PET scan, but which may also serve as a microscopic transport vehicle, carrying chemotherapy drugs through the blood stream—and releasing them upon reaching the tumor.

This is not the first time scientists have attempted to develop nanoparticles for medicinal purposes, but is perhaps one of the more successful. As Yuanpei Li, one of the study’s co-first authors stated in a news release:

“These are amazingly useful particles. As a contrast agent, they make tumors easier to see on MRI and other scans. We can also use them as vehicles to deliver chemotherapy directly to tumors.”

Nanoparticles can be constructed out of virtually any material—but the material used often determines for what purpose they can be used. Nanoparticles made of gold-based materials, for example, may be strong for diagnostic purposes, but have been shown to have issues with safety and toxicity. On the flip side, nanoparticles made from biological materials are safer, but inherently lack imaging ability. What would be great, the team reasoned, was a new type of nanoparticle that had the best qualities of both.

In this study, which was funded in part by CIRM, Lam and the UC Davis team devised a new type of nanoparticle that was ‘just right,’—simple to make, safe and able to perform the desired task, in this case: attack tumors.

Built of organic porphyrin and cholic acid polymers and coated with the amino acid cysteine, the 32 nanometer-wide particles developed in this study offer a number of advantages over other models. They are small enough to pass into tumors, can be filled with a chemo agent and with a specially designed cysteine coating, and don’t accidentally release their payload before reaching their destination.

And this is where the truly ingenious part kicks in. With a simple flash of light, the researchers could direct the particles to drop their payload—at just the right time, offering some intriguing possibilities for new ways to deliver chemotherapy drugs.

But wait, there’s more. The fact that these new particles, which the team are calling cysteine nanoparticles, or CNP’s, appear to congregate inside tumors means that they also end up being easy to spot on an MRI.

Continued Li in the same release:

“These particles can combine imaging and therapeutics. We could potentially use them to simultaneously deliver treatment and monitor treatment efficacy. This is the first nanoparticle to perform so many different jobs. From delivering chemo, photodynamic and photothermal therapies to enhancing diagnostic imaging. It’s the complete package.”

And while the team cautions that these results are preliminary, they open the door to an entirely new and far more exact method of drug delivery to tumors—no matter how well-hidden in the body they may be.

FDA gives Asterias green light to start CIRM-funded clinical trial in spinal cord injury

This morning Asterias Biotherapeutics announced that they have been cleared by the Food and Drug Administration (FDA) to start a clinical trial using stem cells to treat spinal cord injury. It’s great news, doubly so as we are funding that trial.

1773071

You can read more about the trial in a news release we just sent out.

This trial is a follow-on to the Geron trial that we funded back in 2010 that was halted after 5 patients, not because of any safety concerns but because of a change in Geron’s business strategy.

Katie Sharify was the fifth and final patient enrolled in that trial and treated with the stem cells. Like all of us she was disappointed when the trial was halted. And like all of us she is delighted that Asterias is now taking that work and building on it.

Here’s what Katie had to say when she heard the news:

“Of course, I’m very happy that the trial has been revived. Knowing that the FDA approved the continuation based on the safety data I was a part of is great news. As you know, the trial was halted 2 days before I received the stem cells. A big part of why I ended up participating was because I figured that once the study is revived a bigger sample size (even if just by 1 person) was more valuable than a smaller one. I never regretted my choice to participate but I have doubted whether my contribution actually meant anything. I think now I finally feel a sense of accomplishment because the trial is not only being continued but also progressing in the right direction as a higher dose is going to be used. A lot remains unknown about human embryonic stem cells and that’s exactly why this research is so important. The scientific community is going to have a much greater understanding of these stem cells from the data that will be collected throughout the study and I’m glad to have been a part of this advancement.”

Building a Blueprint for the Human Brain

How does a brain blossom from a small cluster of cells into nature’s most powerful supercomputer? The answer has long puzzled scientists, but with new advances in stem cell biology, researchers are quickly mapping the complex suite of connections that together make up the brain.

UCLA scientists have developed a new system that can map the development of brain cells.

UCLA scientists have developed a new system that can map the development of brain cells.

One of the latest breakthroughs comes from Dr. Daniel Geschwind and his team at the University of California, Los Angeles (UCLA), who have found a way to track precisely how early-stage brain cells are formed. These findings, published recently in the journal Neuron, shed important light on what had long been considered one of biology’s black boxes—how a brain becomes a brain.

Along with co-lead authors and UCLA postdoctoral fellows Drs. Luis de la Torre-Ubieta and Jason Stein, Geschwind developed a new system that measures key data points along the lifetime of a cell, as it matures from an embryonic stem cell into a functioning brain cell, or neuron. These new data points, such as when certain genes are switched on and off, then allow the team to map how the developing human fetus constructs a functioning brain.

Geschwind is particularly excited about how this new information can help inform how complex neurological conditions—such as autism—can develop. As he stated in a news release:

“These new techniques offer extraordinary promise in the study of autism, because we now have an unbiased and genome-wide view of how genes are used in the development of the disease, like a fingerprint. Our goal is to develop new treatments for autism, and this discovery can provide the basis for improved high-efficiency screening methods and open up an enormous new realm of therapeutic possibilities that didn’t exist before.”

This research, which was funded in part by a training grant from CIRM, stands to improve the way that scientists model disease in a dish—one of the most useful applications of stem cell biology. To that end, the research team has developed a program called CoNTEXT that can identify the maturity levels of cells in a dish. They’ve made this program freely available to researchers, in the hopes that others can benefit. Said de la Torre-Ubieta:

“Our hope is that the scientific community will be able to use this particular program to create the best protocols and refine their methods.”

Want to learn more about how stem cell scientists study disease in a dish? Check out our pilot episode of “Stem Cells in your Face.”

Stem cell stories that caught our eye: heart stem cells, lizard tails and mapping progress in the field

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.

Could cells in arteries be elusive heart stem cells?
Our hearts have a modest limited ability to regenerate and repair themselves, suggesting we must have a few heart stem cells. But no one has figured out where those cells hang out. Now, a team at Vanderbilt in Nashville has shown that cells in the lining of the heart’s arteries can contribute to new heart muscle.

They made the discovery using a labeling technique that let them tag those cells, called endothelial cells, and show that the same tag showed up in new muscle in the heart. This suggests those cells have the properties of heart stem cells.

The finding also suggests that coronary heart disease, where plaque builds up inside the arteries, could damage the heart with a one-two-punch. Besides narrowing the artery it may also make it more difficult to mobilize these heart stem cells that reside inside the artery lining. The research published in Cell Reports was written up by Genetic Engineering & Biotechnology News.

Secrets of the lizard’s tail. Most folks who have spent any time watching nature programing on TV have seen the handy trick of the green anole lizard. If a predator catches it by the tail it can shed its tail and grow a new one. A team at Arizona State University has uncovered the genetic recipe for how the lizard pulls off this trick.

anole_5They analyzed various segments of tails as they were regrowing to see which genes were turned on that would not normally be turned on in adult tissue. They identified 325 genes. The beauty of the finding is 302 of those genes have matching genes in humans. Those genes become immediate candidates for research into finding ways to allow humans to regrow lost or damaged tissue.

Discover did a nice job of explaining how this lizard is a better model for human comparisons than other animals such as salamanders and fish that can also regrow body parts but use a very different process. And the university press release offers a bit more detail of what the team did.

Review maps where the field is going. Six leaders in the stem cell field wrote a review in the journal Science this week of what to expect in the next few years from research with pluripotent stem cells—those stem cells that can become any tissue in the body, both embryonic stem cells and reprogrammed iPS type stem cells. The authors included researchers from the University of Rochester, the University of Pittsburgh, Harvard, and the University of Wisconsin.

The main hurdles researchers are working to overcome involve maturing the stem cells to the right adult tissue, making sure they are purely those cells, and getting them to integrate with the patient’s own tissue after transplant. They note progress is each of these areas, but in most cases much more work needs to be done.

The University of Rochester put out a press release detailing their faculty member’s contribution to the paper focusing on neural diseases. He suggests that complex diseases that impact multiple types of cells, such as Alzheimer’s, would be the most difficult to treat with stem cells. But diseases impacting a single type of nerve cell, such as Huntington’s, Parkinson’s and multiple sclerosis would be the first to benefit from cells generated from pluripotent stem cells. HealthCanal picked up the university’s release.

Don Gibbons

World’s largest pharmaceutical company signs deal with ViaCyte supporting stem cell therapy for type 1 diabetes

It’s been a good week for ViaCyte, a good week for us here at the stem cell agency and potentially a great week for people with type 1 diabetes.

Earlier this week ViaCyte announced they have been given approval to start a clinical trial for their new approach to treating type 1 diabetes. Then today they announced that they have signed an agreement with Janssen Research & Development LLC and its affiliated investment fund, Johnson & Johnson Development Corporation (JJDC).

ViaCyte's President & CEO, Paul Laikind

ViaCyte’s President & CEO, Paul Laikind

Under this new agreement Janssen and JJDC will provide ViaCyte with $20 million with a future right to consider a longer-term transaction related to the product candidate that ViaCyte is developing for type 1 diabetes.

The agreement is a big deal because Janssen is a division of Johnson & Johnson, which just happens to be the largest pharmaceutical company in the world (they were also ranked the world’s most respected company by Barron’s Magazine in 2008, not a bad reputation to have). Companies like this have traditionally been shy about jumping into the stem cell arena, as they wanted to be sure that they had a good chance to see a return on any investment they made. Not surprising really. You don’t get to be as successful as they are by throwing your money away.

The fact that they have decided that ViaCyte is a good investment reflects on the quality of the company, the years of hard work the people at ViaCyte have put in developing their therapy, and the impressive pre-clinical evidence that it works. It also reflects the fact that we helped fund the project, investing almost $40 million in the program, and get it to this point

In a news release we issued about the announcement our President and CEO, C. Randal Mills, said:

“This is excellent news as it demonstrates that pharmaceutical companies are recognizing stem cell therapies hold tremendous promise and need to be part of their development portfolio,” says C. Randal Mills, Ph.D., President and CEO of the stem cell agency. “This kind of serious financial commitment from industry is vital in helping get promising therapies like this through all the phases of clinical trials and, most importantly, to the patients in need.”

What’s nice is that this is not just a one-off deal. This is the third time this year that a large company has stepped in to make a deal with a company that we are funding.

In January Capricor Therapeutics signed a deal with Janssen Biotech that could ultimately be worth almost $340 million for its work using stem cells to treat people who have had a heart attack. The same month Sangamo, who we are funding to develop a treatment for beta-thalassemia, signed a potential $320 million agreement with Biogen Idec.

As Randy Mills said:

“Our goal at CIRM is to do everything we can to accelerate the development of successful therapies for people in need,” says Mills. “These kinds of agreements and investments help us do that, not only by adding an extra layer of funding for development, but also by validating the scientific and commercial potential of regenerative medicine.”

It’s great news for ViaCyte. It’s confirmation for us that we have been investing our money well in a promising therapy. But most of all it’s encouraging for anyone with type 1 diabetes, giving them a sense of hope that a new treatment could be on the horizon.

Disease in a Dish – That’s a Mouthful: Using Human Stem Cells to Find ALS Treatments

Saying “let’s put some shrimp on the barbie” will whet an Australian’s appetite for barbequed prawns but for an American it conjures up an odd image of placing shrimp on a Barbie doll. This sort of word play confusion doesn’t just happen across continents but also between scientists and the public.

Take “disease in a dish” for example. To a stem cell scientist, this phrase right away describes a powerful way to study human disease in the lab using a Nobel Prize winning technique called induced pluripotent stem cells (iPSC). But to a non-scientist it sounds like a scene from some disgusting sci-fi horror cooking show.

Our latest video Disease in a Dish: That’s a Mouthful takes a lighthearted approach to help clear up any head scratching over this phrase. Although it’s injected with humor, the video focuses on a dreadful disease: amyotrophic lateral sclerosis (ALS). Also known as Lou Gehrig’s disease, it’s a disorder in which nerve cells that control muscle movement die. There are no effective treatments and it’s always fatal, usually within 3 to 5 years after diagnosis.

To explain disease in a dish, the video summarizes a Science Translation Medicine publication of CIRM-funded research reported by the laboratory of Robert Baloh, M.D., Ph.D., director of Cedars-Sinai’s multidisciplinary ALS Program. In the study, skin cells from patients with an inherited form of ALS were used to create nerve cells in a petri dish that exhibit the same genetic defects found in the neurons of ALS patients. With this disease in a dish, the team identified a possible cause of the disease: the cells overproduce molecules causing a toxic buildup that affects neuron function. The researchers devised a way to block the toxic buildup, which may point to a new therapeutic strategy.

In a press release, Clive Svendsen, Ph.D., a co-author on the publication and director of the Cedars-Sinai Regenerative Medicine Institute had this perspective on the results:

“ALS may be the cruelest, most severe neurological disease, but I believe the stem cell approach used in this collaborative effort holds the key to unlocking the mysteries of this and other devastating disorders.”

The video is the pilot episode of Stem Cells in Your Face, which we hope will be an ongoing informational series that helps explain the latest advances toward stem cell-based therapies.

For more information about CIRM-funded ALS research, visit our ALS fact sheet.

Tiny transparent zebra fish yields big clue to black box of Alzheimer’s disease

The PR folks at the Flanders Institute for Biotechnology in Belgium produced an unusual press release to describe recent work there published in Developmental Cell. They devoted the first half to the marvels of their animal model the zebra fish.

zebrafish1For those who have only seen these nearly transparent little guys in a home aquarium the story provides a nice explanation for why they are such popular lab models. It is not unusual to walk into a lab with dozens of small fish tanks holding thousands of zebra fish. A couple key reasons: their DNA matches 90 percent of ours and the guys reproduce quickly, just three months after birth.

Nerve stem cells, key players to brain development in the embryo, become few in number in adults. More important, those few we have left seem to be less active when we need them most, when Alzheimer’s disease or other neurodegenerative disease destroys some of our existing nerves. Evgenia Salta at the Institute used the fish to try to discern why.

We have known for some time that the genes in a pathway known as Notch regulate the ability of nerve stem cells to mature into adult nerves. But we don’t know why that goes awry in disease. She focused on a genetic regulatory molecule called a microRNA that is known to be in abnormally low supply in cells from patients with Alzheimer’s.

When they manipulated the fish to lower the levels of this microRNA, the nerve stem cells in the fish failed to mature properly into nerve cells. In the press release published on ScienceDaily Salta is quoted saying:

“To our surprise, the reduced activity of miRNS-132 in the zebra fish blocks the further ripening of the stem cell into nerves cells. This new knowledge about the molecular signaling pathway that underlies this process gives us an insight into the exact blocking mechanism. Thanks to this work in zebra fish, we can now examine in detail what exactly goes wrong in the brains of patients with Alzheimer’s disease.”

You can read about CIRMM-funded projects seeking solutions to Alzheimer’s Disease on our fact sheet.

Don Gibbons

First of its kind stem cell production facility sets its sights on deadly childhood disease

We are used to hearing about immune suppression when transplanting organs or cells from one person to another. It’s a necessary step in preventing the body from attacking the transplanted material. Now Children’s Hospital of Orange County (CHOC) has just unveiled its newest tool to treat rare childhood diseases. Instead of focusing on immune suppression this focuses on immune-matching.

CHOC's new stem cell production facility

CHOC’s new stem cell production facility

CHOC has opened up a new stem cell production facility. It’s funded by CIRM and it’s a state-of-the-art mini clean room/manufacturing facility that will allow researchers to produce patient-specific cells for future immune-matching therapies.

“We are excited. We’ve been planning this for at least five years,” says Philip Schwartz, Ph.D., senior scientist at the CHOC Children’s Research Institute and managing director of the National Human Neural Stem Cell Resource.

“The major thing is that the footprint is much smaller than a traditional stem cell manufacturing facility, it’s all housed in one room so that keeps the cost down. The device we use to reproduce the cells is also much smaller so this set up doesn’t require multiple rooms and complex pass-throughs as you move from one room to another. All that meant the cost was only around $500,000 which is many times smaller than the more conventional facility.”

Dr. Schwartz is wasting little time putting the new facility to work. It’s already up and running and culturing cells for his work in developing a treatment for mucopolysaccharidosis (MPS-1), a rare neurodegenerative disease that usually kills children before the age of 10.

He is working on a kind of 1-2 punch approach to the disease. Using donated umbilical cord blood to help replace the child’s damaged immune system and then turning some of those blood stem cells into neural cells, the kind damaged by MPS-1, and transplanting those into the brain to repair and prevent further damage.

“This is a really interesting approach. Bone marrow transplants treat a neck down disease. Brain transplants treat a neck up disease. But conditions like MPS-1 are system wide and need both a neck down and neck up approach. Our approach could help combine those and because the cells are carefully matched also mean they won’t need to be on immune-suppressant therapy for life.”

Dr. Schwartz says animal studies using this two pronged approach have been very encouraging but he cautions there is still a lot of work to do before it would be ready for a clinical trial in people. However, if this approach is effective then it could be useful for more than just MPS-1:

“I have a high level of confidence that this will work and if it does work then we can use it in other conditions as well, such as Multiple Sclerosis. Some clinical studies show that MS patients with leukemia who got a bone marrow transplant also saw a decrease in their MS symptoms.”

Kevin McCormack

CIRM funded therapy for type 1 diabetes gets FDA approval for clinical trial

diabetes

It’s always nice to start the week off with some good news and we got this week off to a great start with some great news. ViaCyte has been given the green light to start a clinical trial with its therapy for type 1 diabetes, a program we are funding.

ViaCyte applied to the Food and Drug Administration for approval in mid-July, a process that can sometimes take months. They got their approval in a matter of weeks, which, considering the device they are using is so novel and complicated, is a really significant achievement.

As the Chairman of our governing Board, Jonathan Thomas, J.D., Ph.D., noted in a press release we sent out about the news:

“This is a therapy that we have funded from its earliest days so it’s exciting to see that it is now ready to start a First-in-Human trial. Reaching this milestone is a tribute to years of hard work by the team at ViaCyte, but also to the vision of the people of California who created the stem cell agency to support work like this. That vision is one step closer to being realized.”

So what is this new approach that ViaCyte is trying? Well, in type 1 diabetes the pancreas no longer produces the insulin our bodies need to regulate blood sugar levels. That can increase your risk of heart disease, stroke, kidney failure, blindness, even death. ViaCyte has developed a thin plastic pouch, containing an immature form of pancreatic cells, to mimic the blood glucose regulating function of the pancreas. When the device is implanted under the skin these cells are designed to become the insulin-producing and other cells needed to regulate blood glucose levels. It is believed that these cells will be able to sense when blood glucose is high, and then secrete insulin to restore it to a healthy level.

It’s fascinating science but more than that, it’s a really promising program that has the potential to end reliance on daily testing and injections of insulin for people with type 1 diabetes. It could dramatically change their lives.

Of course this is just one step along the way and, encouraging as it is, it is also important to place it in context. This is the first time it’s being tried in people. In all the pre-clinical testing it’s looked promising, but this is the only test that really counts, seeing if it works in patients with type 1 diabetes. Now we get to find out.