Stem cell stories that caught our eye: turning on T cells; fixing our brains; progress and trends in stem cells; and one young man’s journey to recover from a devastating injury

Healthy_Human_T_Cell

A healthy T cell

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.

Directing the creation of T cells. To paraphrase the GOP Presidential nominee, any sane person LOVES, LOVES LOVES their T cells, in a HUGE way, so HUGE. They scamper around the body getting rid of viruses and the tiny cancers we all have in us all the time. A CIRM-funded team at CalTech has worked out the steps our genetic machinery must take to make more of them, a first step in letting physicians turn up the action of our immune systems.

We have known for some time the identity of the genetic switch that is the last, critical step in turning blood stem cells into T cells, but nothing in our body is as simple as a single on-off event. The Caltech team isolated four genetic factors in the path leading to that main switch and, somewhat unsuspected, they found out those four steps had to be activated sequentially, not all at the same time. They discovered the path by engineering mouse cells so that the main T cell switch, Bcl11b, glows under a microscope when it is turned on.

“We identify the contributions of four regulators of Bcl11b, which are all needed for its activation but carry out surprisingly different functions in enabling the gene to be turned on,” said Ellen Rothenberg, the senior author in a university press release picked up by Innovations Report. “It’s interesting–the gene still needs the full quorum of transcription factors, but we now find that it also needs them to work in the right order.”

Video primer on stem cells in the brain.  In conjunction with an article in its August issue, Scientific American posted a video from the Brain Forum in Switzerland of Elena Cattaneo of the University of Milan explaining the basics of adult versus pluripotent stem cells, and in particular how we are thinking about using them to repair diseases in the brain.

The 20-minute talk gives a brief review of pioneers who “stood alone in unmarked territory.” She asks how can stem cells be so powerful; and answers by saying they have lots of secrets and those secrets are what stem cell scientist like her are working to unravel.  She notes stem cells have never seen a brain, but if you show them a few factors they can become specialized nerves. After discussing collaborations in Europe to grow replacement dopamine neurons for Parkinson’s disease, she went on to describe her own effort to do the same thing in Huntington’s disease, but in this case create the striatal nerves lost in that disease.

The video closes with a discussion of how basic stem cell research can answer evolutionary questions, in particular how genetic changes allowed higher organisms to develop more complex nervous systems.

kelley and kent

CIRM Science Officers Kelly Shepard and Kent Fitzgerald

A stem cell review that hits close to home.  IEEE Pulse, a publication for scientists who mix engineering and medicine and biology, had one of their reporters interview two of our colleagues on CIRM’s science team. They asked senior science officers Kelly Shepard and Kent Fitzgerald to reflect on how the stem cell field has progressed based on their experience working to attract top researchers to apply for our grants and watching our panel of outside reviewers select the top 20 to 30 percent of each set of applicants.

One of the biggest changes has been a move from animal stem cell models to work with human stem cells, and because of CIRM’s dedicated and sustained funding through the voter initiative Proposition 71, California scientists have led the way in this change. Kelly described examples of how mouse and human systems are different and having data on human cells has been critical to moving toward therapies.

Kelly and Kent address several technology trends. They note how quickly stem cell scientists have wrapped their arms around the new trendy gene editing technology CRISPR and discuss ways it is being used in the field. They also discuss the important role of our recently developed ability to perform single cell analysis and other technologies like using vessels called exosomes that carry some of the same factors as stem cells without having to go through all the issues around transplanting whole cells.

“We’re really looking to move things from discovery to the clinic. CIRM has laid the foundation by establishing a good understanding of mechanistic biology and how stem cells work and is now taking the knowledge and applying it for the benefit of patients,” Kent said toward the end of the interview.

jake and family

Jake Javier and his family

Jake’s story: one young man’s journey to and through a stem cell transplant; As a former TV writer and producer I tend to be quite critical about the way TV news typically covers medical stories. But a recent story on KTVU, the Fox News affiliate here in the San Francisco Bay Area, showed how these stories can be done in a way that balances hope, and accuracy.

Reporter Julie Haener followed the story of Jake Javier – we have blogged about Jake before – a young man who broke his spine and was then given a stem cell transplant as part of the Asterias Biotherapeutics clinical trial that CIRM is funding.

It’s a touching story that highlights the difficulty treating these injuries, but also the hope that stem cell therapies holds out for people like Jake, and of course for his family too.

If you want to see how a TV story can be done well, this is a great example.

CIRM Board targets diabetes and kidney disease with big stem cell research awards

diabetes2

A recent study  estimated there may be more than 500 million people worldwide who have diabetes. That’s an astounding figure and makes diabetes one of the largest chronic disease epidemics in human history.

One of the most serious consequences of untreated or uncontrolled diabetes is kidney damage. That can lead to fatigue, weakness, confusion, kidney failure and even death. So two decisions taken by the CIRM Board today were good news for anyone already suffering from either diabetes or kidney disease. Or both.

The Board awarded almost $10 million to Humacyte to run a Phase 3 clinical trial of an artificial vein needed by people undergoing hemodialysis – that’s the most common form of dialysis for people with kidney damage. Hemodialysis helps clean out impurities and toxins from the blood. Without it waste will build up in the kidneys with devastating consequences.

The artificial vein is a kind of bioengineered blood vessel. It is implanted in the individual’s arm and, during dialysis, is connected to a machine to move the blood out of the body, through a filter, and then back into the body. The current synthetic version of the vein is effective but is prone to clotting and infections, and has to be removed regularly. All this puts the patient at risk.

Humacyte’s version – called a human acellular vessel or HAV – uses human cells from donated aortas that are then seeded onto a biodegradable scaffold and grown in the lab to form the artificial vein. When fully developed the structure is then “washed” to remove all the cellular tissue, leaving just a collagen tube. That is then implanted in the patient, and their own stem cells grow onto it, essentially turning it into their own tissue.

In earlier studies Humacyte’s HAV was shown to be safer and last longer than current versions. As our President and CEO, Randy Mills, said in a news release, that’s clearly good news for patients:

“This approach has the potential to dramatically improve our ability to care for people with kidney disease. Being able to reduce infections and clotting, and increase the quality of care the hemodialysis patients get could have a significant impact on not just the quality of their life but also the length of it.”

There are currently almost half a million Americans with kidney disease who are on dialysis. Having something that makes life easier, and hopefully safer, for them is a big plus.

The Humacyte trial is looking to enroll around 350 patients at three sites in California; Sacramento, Long Beach and Irvine.

While not all people with diabetes are on dialysis, they all need help maintaining healthy blood sugar levels, particularly people with type 1 diabetes. That’s where the $3.9 million awarded to ViaCyte comes in.

We’re already funding a clinical trial with ViaCyte  using an implantable delivery system containing stem cell-derived cells that is designed to measure blood flow, detect when blood sugar is low, then secrete insulin to restore it to a healthy level.

This new program uses a similar device, called a PEC-Direct. Unlike the current clinical trial version, the PEC-Direct allows the patient’s blood vessels to directly connect, or vasularize, with the cells inside it. ViaCyte believes this will allow for a more robust engraftment of the stem cell-derived cells inside it and that those cells will be better able to produce the insulin the body needs.

Because it allows direct vascularization it means that people who get the delivery system  will also need to get chronic immune suppression to stop their body’s immune system attacking it. For that reason it will be used to treat patients with type 1 diabetes that are at high risk for acute complications such as severe hypoglycemic (low blood sugar) events associated with hypoglycemia unawareness syndrome.

In a news release Paul Laikind, Ph.D., President and CEO of ViaCyte, said this approach could help patients most at risk.

“This high-risk patient population is the same population that would be eligible for cadaver islet transplants, a procedure that can be highly effective but suffers from a severe lack of donor material. We believe PEC-Direct could overcome the limitations of islet transplant by providing an unlimited supply of cells, manufactured under cGMP conditions, and a safer, more optimal route of administration.”

The Board also approved more than $13.6 million in awards under our Discovery program. You can see the winners here.

 

Need a new ear, why not grow it from an apple?

apples and ears

That may be one of the strangest headlines you have read in a while, but believe me, the rest of this post is not going to be any less strange. And yet, the work behind that headline could open up the possibility of using everyday produce, such as apples and asparagus, as tools to help treat life-threatening problems.

Let’s back up a little. The idea started in the lab of Andrew Pelling, a scientist who describes himself as a “biohacker and avid dumpster-diver”. He and his team were chatting about the human-eating monster flytrap plant featured in the movie/musical Little Shop of Horrors and wondered if it would be possible to grow that kind of plant in the lab (I told you it wasn’t going to get any less strange).

Anyway, as Pelling explains it, the conversation eventually ended up with them experimenting with apples to create cellulose scaffolds.

“We took a totally innocent McIntosh apple, removed all the apple cells and DNA and then implanted human cells. And what we are left with once you remove all those apple cells is this cellular scaffold. This is the stuff that gives plants their shape, and texture.”

Next he wondered if you could use that kind of scaffold for a truly valuable purpose and not just for creating copies of fictional movie monsters. So he thought about ears. He wondered if you could use that cellulose scaffold as the basis to create replacement ears.

“So we come along, plant some mammalian cells on it and they start multiplying and fill up the scaffold. As weird as this is, it’s actually really reminiscent of how our own tissues are organized.  And we found in our preclinical work that you can implant these scaffolds in the body and the body will send in cells and a blood supply and actually keep these things alive.”

But what does this have to do with stem cells you are probably asking? Well, researchers have been trying to create replacement ears – and other body parts too of course – using stem cells and artificial scaffolds for some time (we have blogged about this here.) Pelling says his approach gets around some major problems.

“Commercial scaffolds can be really expensive or problematic because they can be made from proprietary products, animals or cadavers. We made these from apples, and they cost pennies.”

But he doesn’t stop there. If you can make ears from apples why not a spinal cord or blood vessel from asparagus? Pelling says when you look down the stalk of an asparagus spear it looks a bit like a blood vessel, or even the spinal cord. Which got him thinking,could he use the channels in asparagus to link severed nerve cells, such as neurons, back together.

It may seem like a bizarre notion but he’s launched some pilot experiments trying to do just that in rats.

The question, of course, is can you do this in people? The answer, of course, is we don’t know. But great ideas often begin with someone posing a thought provoking, occasionally oddball, question, like this one from Pelling:

“What I’m actually really curious about is that if one day it might actually be possible to repair, rebuild and augment our own bodies with stuff we make in the kitchen.”

You can read about Pelling’s work, and see his TED talk at OZY, which bills itself as “the world’s most unique magazine”.

 

 

 

 

 

 

 

Accelerating the drive for new stem cell treatments

Acceleration

Acceleration is defined as the “increase in the rate or speed of something.” For us that “something” is new stem cell treatments for patients with unmet medical needs. Today our governing Board just approved a $15 million partnership with Quintiles to help us achieve that acceleration.

Quintiles was awarded the funding to create a new Accelerating Center. The goal of the center is to give stem cell researchers the support they need to help make their clinical trials successful.

As our President and CEO Randy Mills said in a news release:

randy-at-podium1CIRM President Randy Mills addresses the CIRM Board

“Many scientists are brilliant researchers but have little experience or expertise in running a clinical trial; this Accelerating Center means they don’t have to develop those skills; we provide them for them. This partnership with Quintiles means that scientists don’t have to learn how to manage patient enrollment or how to create a data base to manage the results. Instead they are free to focus on what they do best, namely science.”

How does it work? Well, if a researcher has a promising therapy and approval from the US Food and Drug Administration (FDA) to start a clinical trial, the Accelerating Center helps them get that trial off the ground. It helps them find the patients they need, get those patients consented and ready for the trial, and then helps manage the trial and the data from the trial.

The devil is in the details

Managing those details can be a key factor in determining whether a clinical trial is going to be successful. Last year, a study in the New England Journal of Medicine listed the main reasons why clinical trials fail.

Among the reasons are:

  • Poor study design: Selecting the wrong patients, the wrong dosing and the wrong endpoint, as well as bad data and bad site management cause severe problems.
  • Poor management: A project manager who does not have enough experience in costing and conducting clinical trials will lead to weak planning, with no clear and real timelines, and to ultimate failure.

We hope our partnership with Quintiles in this Accelerating Center will help researchers avoid those and the other pitfalls. As the world’s largest provider of biopharmaceutical development and commercial outsourcing services, Quintiles has a lot of experience and expertise in this area. On its Twitter page it’s slogan is “Better, smarter, faster trials” so I think we made a smart choice.

When Randy Mills first pitched this idea to the Board, he said that he is a great believer in “not asking fish to learn how to fly, they should just do what they do best”.

The Accelerating Center means scientists can do what they do best, and we hope that leads to what patients need most; treatments and cures.


Related Links:

Knowledge is on the menu at Dinner with a Scientist:

Helen Budworth, Ph.D., is one of the Science Officers at CIRM. She wrote this blog about her experiences talking to some budding local scientists who just happen to be ten years old.kids dinner

Recently I had the pleasure of attending the Oakland Unified School District (OUSD) “Dinner with a Scientist” event held at the Oakland Zoo. OUSD has been hosting this annual event since 2009 to bring together local scientists, teachers, and students to celebrate science in an evening of activities and science conversation.

I was dining with 4th and 5th grade elementary students and their teachers from Think College Now and from Brookfield Elementary in Oakland. They included many budding scientists, with interests ranging from biology and chemistry, to geology and astronomy. The students were eager to learn about how I became a scientist, what interests me about my job and how they can prepare themselves for a future scientific career. I explained that my interest in science began in childhood because I loved puzzles and really enjoyed trying to work things out, and that my interest in science naturally flowed from that. Both students and teachers alike were interested to learn more about CIRM and what our scientists are working on.

The evening began with the students being asked a simple question: “What is science?” One of the kids said it was finding out new things; another said it meant conducting experiments to answer questions. One said it was a way of making money. He’s in for a rude surprise when he grows up!

kids dinner2

In order to demonstrate the potential of stem cells, I led an activity that allowed the groups to use Play Doh to model the early stages of human development from a zygote, the earliest stage of a fertilized egg, through the first few weeks of embryonic development. What I learned from this event is that when you ask a 4th/5th grader if they know how babies are made, you will get many giggles and some interesting descriptions of ways that sperm and egg can meet – but few details of what happens after that.

This hands-on activity showed the students the processes of cell division, differentiation and development of a multi-cellular organism from a single-celled zygote. Scientific studies of stem cells, such as those found at early stages of development, have allowed us to reach the point where we are now harnessing the power of these cells to create treatments for diseases. They were very intrigued by the idea that you begin life as a single cell, that grows and multiplies and changes until all those cells become the different parts of you and creates a whole human being.

The exercise, indeed the whole evening, gave the students an opportunity to see how scientific careers are translated to real world applications and will hopefully inspire some future scientists and doctors.

I asked one of the students what kind of scientist she wanted to be, and she replied that she wanted to be a chemist. When I asked why she said because she likes mixing things. That seems as good a reason to think about a career in science as any.

 

 

 

Helping stem cells sleep can boost their power to heal

Mouse muscle

Mighty mouse muscle cells

We are often told that sleep is one of the most important elements of a healthy lifestyle, that it helps in the healing and repair of our heart and blood vessels – among other things.

It turns out that sleep, or something very similar, is equally important for stem cells, helping them retain their power or potency, which is a measure of their effectiveness and efficiency in generating the mature adult cells that are needed to repair damage. Now researchers from Stanford, with a little help from CIRM, have found a way to help stem cells get the necessary rest before kicking in to action. This could pave the way for a whole new approach to treating a variety of genetic disorders such as muscular dystrophy.

Inside out

One problem that has slowed down the development of stem cell therapies has been the inability to manipulate stem cells outside of the body, without reducing their potency. In the body these cells can remain quiescent or dormant for years until called in to action to repair an injury. That’s because they are found in a specialized environment or niche, one that has very particular physical, chemical and biological properties. However, once the stem cells are removed from that niche and placed in a dish in the lab they become active and start proliferating and changing into other kinds of cells.

You might think that’s good, because we want those stem cells to change and mature, but in this case we don’t, at least not yet. We want them to wait till we return them to the body to do their magic. Changing too soon means they have less power to do that.

Researchers at Stanford may have found a way to stop that happening, by creating an environment in the lab that more closely resembles that in the body, so the stem cells remain dormant longer.

As senior author, Thomas Rando, said in a Stanford news release, they have found a way to keep the stem cells dormant longer:

Dr. Thomas Rando, Stanford

Dr. Thomas Rando, Stanford

“Normally these stem cells like to cuddle right up against their native muscle fibers. When we disrupt that interaction, the cells are activated and begin to divide and become less stemlike. But now we’ve designed an artificial substrate that, to the cells, looks, smells and feels like a real muscle fiber. When we also bathe these fibers in the appropriate factors, we find that the stem cells maintain high-potency and regenerative capacity.”

Creating an artificial home

When mouse muscle stem cells (MuSCs) are removed from the mouse they lose their potency after just two days. So the Stanford team set out to identify what elements in the mouse niche helped the cells remain dormant. They identified the molecular signature of the quiescent MuSCs and used that to help screen different compounds to see which ones could help keep those cells dormant, even after they were removed from the mouse and collected in a lab dish.

They whittled down the number of potential compounds involved in this process from 50 to 10, and then tested these in different combinations until they found a formulation that kept the stem cells quiescent for at least 2 days outside of the mouse.

But that was just the start. Next they experimented with different kinds of engineered muscle fibers, to simulate the physical environment inside the mouse niche. After testing various materials, they found that the one with the greatest elasticity was the most effective and used that to create a kind of scaffold for the stem cells.

The big test

The artificial niche they created clearly worked in helping keep the MuSCs in a dormant state outside of the mouse. But would they work when transplanted back into the mouse? To answer this question they tested these stem cells to see if they retained their ability to self-renew and to change into other kinds of cells in the mouse. The good news is they did, and were far more effective at both than MuSCs that had not been stored in the artificial niche.

So, great news for mice but what about people, would this same approach work with human muscle stem cells (hMuSCs)? They next tested this approach using hMuSCs and found that the hMuSCs cultured on the artificial niche were more effective at both self-renewal and retaining their potency than hMuSCs kept in more conventional conditions, at least in the lab.

In the study, published in the journal Nature Biotechnology, the researchers say this finding could help overcome some of the challenges that have slowed down the development of effective therapies:

“Research on MuSCs, hematopoietic stem cells and neural stem cells has shown that very small numbers of quiescent stem cells, even single cells, can replace vast amounts of tissue; culture systems that that maintain stem cell quiescence may allow these findings to be translated to clinical practice. In addition, the possibility of culturing hMuSCs for longer time periods without loss of potency in order to correct mutations associated with genetic disorders, such as muscular dystrophy, followed by transplantation of the corrected cells to replace the pathogenic tissue may enable improved stem cell therapeutics for muscle disorders.”

Why is a cell therapy that restores sight to the blind against the law?

FDA

A lot of people are frustrated with the US Food and Drug Administration (FDA) and its woefully slow process for approving stem cell therapies. That’s one of the reasons why we started the CIRM Stem Cell Champions campaign, to gather as many like-minded supporters of stem cell research as possible and help to change the way the FDA works, to create a more efficient approval process.

You can read more about that campaign and watch a short video on what being a Stem Cell Champion involves (hint: not very much).

Now Randy Mills, our President and CEO, has teamed up with former US Senator Bill Frist to explain precisely why the FDA needs to change the way it regulates stem cells, and to offer a simple way to create the system that will best serve the needs of patients.

This Op Ed appeared on Fox News’ online Opinion section on Friday, May 20th.


Cell therapy reversed blindness for 47,000 patients in 2015. So why is it against the law?

By C. Randal Mills Ph.D., Sen. Bill Frist M.D.

As medical miracles go, restoring sight to the blind is right up there. A mother seeing her baby for the first time, or a child being able to count the stars is a beautiful gift, and its value cannot be overstated. Last year 47,000 Americans received that gift and had their blindness reversed through the transplantation of cells from a corneal donor’s final selfless act.

It is safe, it is effective, and because it is curative, it is a relatively cost effective procedure. It is medicine at its most beautiful. And according to FDA regulations, the distribution of this cell therapy is in violation of federal law.

That’s right. The regulation says that no matter how competent the surgeon, the FDA must first approve cells from donated corneas as if they were a drug—a process that takes over a decade and can costs billions of dollars — all for a practice that has been successfully restoring sight for more than 50 years. And this is only one example.

The good news: the FDA doesn’t always adhere to its regulations and has not in this case.

The bad news: inconsistent enforcement creates uncertainty, deterring innovation for other unmet medical needs such as arthritis, back pain, and diabetic ulcers.

How did a country known for pioneering medical breakthroughs get here?

Appropriate regulation of living cells that treat disease is inherently complex. Some therapies, like corneal cell transplants, are well-understood. Others are far more sophisticated and can involve forcing cells to change from one type to another, cutting out defective genes, and growing cells in culture to expand their numbers into the billions. Although this may sound like science fiction, it’s the type of very real science that will revolutionize the practice of medicine. And it is a challenging spectrum to regulate.

Unfortunately, what we have today amounts to a regulatory light switch for cell therapy; one that is either OFF or ON. For some cell therapies there is essentially no pre-market regulation. But at some point of added complexity, often arbitrarily decided by the FDA, the switch flips to ON and the cell becomes a drug in the minds of the Agency. And the consequences could not be more profound.

A product can be introduced through the OFF pathway in days with no FDA review and at very little cost. The ON pathway on the other hand, takes 10-20 years and can cost over a billion dollars. For cell therapy, there is no in between.

It is not possible to regulate the continuum of cell therapies fairly and effectively by using this binary approach. The system is broken and is impeding the hunt for safe and effective treatments for suffering patients.

Why? Because sensible people don’t invest significant capital gambling that the FDA will give them a pass out of its rules. They evaluate the time and cost of development assuming they will be forced down the ON pathway. They also assume that this arbitrary approach to regulation will (and often does) work against them by allowing a competitor to enter the market through the OFF pathway, placing them at a prohibitive disadvantage. The results speak for themselves. After 15 years under this paradigm we have had only a few cell therapies approved, all commercial disasters.

This is because the ON-OFF approach fails to adequately account for the difference in cell therapy complexity. To better understand, imagine this methodology applied to the regulation of automobiles. The government might permit low tech cars, say the Model T, to be sold without pre-market regulation. But if a manufacturer wanted to improve the vehicle by adding air conditioning, a radio or other such feature, the car would be subject to massive pre-market regulation. And not just on the new feature. Instead, the addition of the new feature would trigger a bumper-to-bumper evaluation of the entire car, increasing its development cost from basically nothing to that of a Lamborghini. The result would be streets full of hot, radio-less go-karts, except for a few ultra-high-end sports cars whose manufacturers are now defunct because they were never able to recoup the disproportionate costs of satisfying the regulatory system. This is what we see with cell therapies today: progress that is sluggish at best.

How can we move forward?

Ironically, the FDA identified a solution to the problem. In order to account for the broad spectrum inherent to cell therapy, in the late 90’s the FDA proposed a progressive, risk-based approach. The higher the risk, the greater the regulation. This guards against under regulation that might put patients at risk and prevents overregulation that can disincentivize the development of new or improved products.

In the FDA’s own words, the regulation they proposed would abide by a few basic principles:

  • “Under this tiered, risk-based approach, we propose to exert only the type of government regulation necessary to protect the public health.”
  • “The regulation of different types of human cells… will be commensurate with the public health risks…”
  • “These planned improvements will increase the safety of human cells… while encouraging the development of new products.”

It was a remarkably common sense approach that would have balanced safety with the need for innovation over an exceptionally broad range of technological complexity and risk.

It would have.

Unfortunately, the regulatory framework that was promised was never delivered, and it is time to resuscitate it. The burden placed on the development of cell therapies must accurately reflect the risks; must be balanced against the very real consequences of doing nothing (patients continuing to suffer); and must be consistently and fairly applied. In short, the FDA had it right and we need to give them the tools to deliver the regulatory paradigm they originally envisioned.

If we fix this highly fixable problem, we can create a system that will drive new innovations and better outcomes. Europe and Japan have already acted and are seeing the benefits. People with great ideas are coming off the bench, and game changing therapies are entering practice. While challenging the status quo does not sit well with some, particularly those who stand to prosper from the built-in barriers to entry the current structure provides, in the United States we have a responsibility to do better for patients and fix this broken system.

Randal Mills, Ph.D., is the President and CEO of the California Institute for Regenerative Medicine

William “Bill” H. Frist, M.D. is a nationally-acclaimed heart and lung transplant surgeon, former U.S. Senate Majority Leader, and chairman of the Executive Board of the health service private equity firm Cressey & Company.

A Dream made me change my mind. Almost.

Dream Alliance

Dream Alliance: photo courtesy Daily Telegraph, UK

On Friday I was faced with the real possibility that a horse had made an ass out of me.

Over the years we have written many articles about the risks of unproven stem cell therapies, treatments that have not yet been shown in clinical trials to be safe and effective. Often we have highlighted the cases of high profile athletes who have undergone stem cell treatments for injuries when there is little evidence that the treatments they are getting work.

Well, on Friday I saw an athlete who bounced back from a potentially career-ending injury to enjoy an amazing career thanks to a stem cell treatment. I wondered if I was going to have to revise my thoughts on this topic. Then my wife pointed out to me that the athlete was a horse.

We had been watching the movie Dark Horse, a truly delightful true story about a group of working class people in a Welsh mining village who bred and raised a horse that went on to great success as a race horse – often beating out thoroughbreds that were worth millions of dollars.

 

At one point the horse, Dream Alliance, suffered an almost fatal injury. Everyone assumed his career was over. But thanks to a stem cell treatment he was able to return to the track and became the first horse to win a major race after undergoing stem cell surgery.

It shouldn’t be too surprising that stem cells can help heal serious injuries in horses, the researchers at UC Davis have been using them to help treat horses for years – with great success. The danger comes in then assuming that just because stem cells work for horses, they’ll work for people. And that if they can cure one kind of injury, why not another.

That thought was driven home to me on Saturday when I was giving a talk to a support group for ALS or Lou Gehrig’s disease. ALS is a nasty, rapidly progressive disease that attacks the motor nerve cells in the brain and spinal cord, destroying a person’s ability to move, eat, speak or breath.

One person asked about a clinic they had been talking to which claimed it might be able to help them. The clinic takes fat from the person with ALS, isolates the stem cells in the fat and injects it back into the person. The clinic claims it’s been very effective in treating injuries such as torn muscles, and that it also works for other problems like Parkinson’s so it might help someone with ALS.

And that’s the problem. We hear about one success story that seems to prove stem cells can do amazing things, and then we are tempted to hope that if it works for one kind of injury, it might work for another, or even for a neurodegenerative disease.

And hope doesn’t come cheap. The cost of the procedure was almost $10,000.

If you have a disease like ALS for which there is no cure, and where the life expectancy is between two to five years, you can understand why someone would be tempted to try anything, no matter how implausible. What is hard is when you have to tell them that without any proof that it works, and little scientific rational as to why it would work, that it’s hard to recommend they try using their own fat cells to treat their ALS.

At CIRM we are investing more than $56.5 million in 21 different projects targeting ALS.   We are hopeful one of them, Clive Svendsen’s research at Cedars-Sinai Medical Center,  will soon get approval from the FDA to start a clinical trial.

Much as we would like to believe in miracles, medical breakthroughs usually only come after years of hard, methodical work. It would be great if injecting your own fat-derived stem cells into your body could cure you of all manner of ailments. But there’s no evidence to suggest it will.

The movie Dark Horse shows that for one horse, for one group of people in a small Welsh mining village, stem cells helped create a happy ending. We are hoping stem cells will one day offer the same sense of hope and possibility for people battling deadly diseases like ALS. But that day is not yet here.

 

 

Approach that inspires DREADD could create new way to treat Parkinson’s disease

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Dopamine producing brain nerve cells, made from embryonic stem cells

Imagine having a treatment for Parkinson’s that acts like a light switch, enabling you to turn it on or off depending on your needs. Well, that’s what researchers at the University of Wisconsin-Madison have come up with. And if it works, it might help change the way we treat many other diseases.

For years researchers have been trying to come up with a way of replacing the dopamine-producing brain nerve cells, or neurons, that are attacked and destroyed by Parkinson’s. Those cells regulate movement and as they are destroyed they diminish a person’s ability to control their body, their movement and even their emotions.

Attempts to transplant dopamine-producing cells into the brains of people with Parkinson’s disease have met with mixed results. In some cases the transplanted cells have worked. In many cases the cells don’t make enough dopamine to control movement. In about 10 percent of cases the cells make too much dopamine, causing uncontrolled movements called graft-induced dyskinesia.

But now the researchers at UW Madison have found a new approach that might change that. Using the gene-editing tool CRISPR (you can read about that here) they reprogrammed embryonic stem cells to become two different types of neurons containing a kind of genetic switch called a DREADD, which stands for designer receptor exclusively activated by designer drug. When they gave mice the designer drug they created to activate DREADD, one group of cells boosted production of dopamine, the other group shut down its dopamine production.

In a news release about the study, which is published in the journal Cell Stem Cell, lead author Su-Chun Zhang says this kind of control is essential in developing safe, effective therapies:

“If we are going to use cell therapy, we need to know what the transplanted cell will do. If its activity is not right, we may want to activate it, or we may need to slow or stop it.”

Zhang says the cells developed using this approach have another big advantage:

“We can turn them on or off, up or down, using a designer drug that can only act on cells that express the designer receptor. The drug does not affect any host cell because they don’t have that specialized receptor. It’s a very clean system.”

Tests in mice showed that the cells, and the designer drug, worked as the researchers hoped they would with some cells producing more dopamine, and others halting production.

It’s an encouraging start but a lot more work needs to be done to make sure the the genetically engineered stem cells, and the designer drug, are safe and that they can get the cells to go to the part of the brain that needs increased dopamine production.

As Zhang says, having a method of remotely controlling the action of transplanted cells, one that is reversible, could create a whole new way of treating diseases.

“This is the first proof of principle, using Parkinson’s disease as the model, but it may apply to many other diseases, and not just neurological diseases.”

Stem cell stories that caught our eye: Trifecta of nerve news on aging, Parkinson’s and myelin diseases, also expanding cord blood

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.

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Untreated (top) and treated nerves

To save nerves, make them slow down. Nerves, like all cells, constantly make protein, but that task uses up a lot of energy and older nerves have a limited energy supply. A CIRM-funded team at the Salk Institute has shown that an approved drug can slow down protein production in nerves, conserve energy and help them survive.

The Salk team led by Tony Hunter saw the tamping down effect in a disease-in-a-dish model of Leigh syndrome, an inherited neurodegenerative condition caused by a mutation in mitochondria, the cell’s power plant. They created iPS type stem cells by reprogramming skin cells from a Leigh syndrome patient, grew them into nerves and saw evidence of energy depletion that was reversed when they treated the cells with the drug rapamycin.

 “Reducing protein production in ageing neurons allows more energy for the cell to put toward folding proteins correctly and handling stress,” said team member Xinde Zheng, in a Salk release posted by Scicasts. “The impact of our finding is that modulation of protein synthesis could be a general approach to treating neurodegeneration.”

Next step for the team will be seeing if their finding holds true in an animal model of the syndrome. They published their findings in eLife.

 

For dopamine nerves turn them on and off.  Many researchers strive to turn stem cells into dopamine producing nerves to replace the chemical signal that is in short supply in Parkinson’s disease patients. But what if they succeed, put the new nerves in patients and they produce too much dopamine? A team, at the University of Wisconsin has a solution, make the new nerves responsive to a drug that can act as an on-and-off switch.

The team grew nerves from stem cells made from iPS type stem cells and genetically engineered them so that they would only produce dopamine in the presence of a certain drug. Brad Fikes at the San Diego Union Tribune wrote a brief story about the research that the team published in Cell Stem Cell.

 He put the news into perspective by noting that early trials implanting dopamine nerves from fetal tissue resulted in some patients having side effects from over production of the nerve signal transmitter.

 

And restoring nerves protective myelin.  Neurons form the basis of all brain function, but they take a family of support cells and tissues to do a good job of directing our muscles, recording memory, etc.  First nerves need the protective insulation called myelin to properly transmit signals. Cells called oligodendrocytes produce the myelin, but they need signals from cells called astrocytes to do their job well. Researchers have known for some time that immature astrocytes do a great job of fostering oligodendrocytes, but mature astrocytes do not, but they have not known why.

Now, CIRM-funded researchers at the University of California, Davis, have isolated a protein secreted by immature astrocytes called TIMP-1 that promotes proliferation of the needed oligodendrocytes, and down the line, the myelin needed to protect neurons.

In the study published in Cell Reports, the researchers created iPS type stem cells and directed them to become astrocytes, stopping the growth at an immature state and implanted them in mice. But before the transplants, they shut down the production of TIMP-1 in some of the astrocytes, and in those mice they saw no increase in the production of myelin.

 

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Wenbin Deng of UC Davis

The research project leader, Wenbin Deng, speculated in a Davis press release on how the research could eventually help patients with any number of diseases involving myelin loss:

 “We are hopeful that his could lead to a promising therapy for premature brain injury, cerebral palsy, multiple sclerosis, spinal cord injury, white matter stroke and many neurodegenerative diseases.”

 

Key protein for developing blood stem cells.  The stem cells found in umbilical cord have saved thousands of cancer patients by rebuilding their immune system after chemotherapy. But cord blood samples often have too few stem cells to be effective and while a couple teams have reported some progress in expanding the number of stem cells in any one cord sample, more progress is needed.

Researchers at McMaster University reported in the journal Nature this week that they had isolated a protein that controls the development of blood stem cells. That protein, Musashi-2, does not regulate genetic activity at the DNA level, but rather at the next step in the gene-to-protein pathway, regulating the activity of RNA.

In an article posted on the Bioscience Technology website, the team leader Kristin Hope speculated on the value to patients when they learn how to turn this knowledge into making cells for therapy:

“Providing enhanced numbers of stem cells for transplantation could alleviate some of the current post-transplantation complications and allow for faster recoveries, in turn reducing overall health care costs and wait times for newly diagnosed patients seeking treatment.”