How many stem cell trials will it take to get a cure?

When I think about how many clinical trials it will take before a stem cell therapy is available to patients, I’m reminded of the decades old Tootsie Pop commercial where a kid asks a series of talking animals, “How many licks does it take to get to the Tootsie Roll center of a Tootsie Pop?”

While Mr. Cow, Mr. Fox, and Mr. Turtle are all stumped, Mr. Owl tackles the question like a true scientist:

“A good question. Let’s find out. [Takes Tootsie pop and starts licking]. A One…A Two-hoo…A Three-hee. [Insert loud crunching sounds] A Three!”

The commercial ends with the narrator concluding that the world may never know how many licks it takes to get to the center (because Mr. Owl failed to complete his experiment…not a true scientist after all).

What do Tootsie Pops have to do with stem cell therapies?

I’m not saying that the Tootsie Pop question holds the same level of importance as the question of when scientists will develop a stem cell therapy that cures a disease, but I find it representative of the confusion and uncertainty that the general public has about when the “promise of stem cell research” will become a reality.

Let me explain…

Mr. Owl claims that it only takes three licks to get to the center of a Tootsie Pop, but three licks obviously aren’t enough to get through the hard candy exterior to the chewy tootsie center. According to the Tootsie “Scientific Endeavors” page, “at least three detailed scientific studies” determined that it takes between 144-411 licks to get to the center. My intuition is to go with the scientists, but depending on how the experiment was conducted or maybe the size of the tongue used, the final answer could vary.

Embryonic stem cells

Embryonic stem cells

For stem cell clinical trials, the situation is similar. The first clinical trial approved in the U.S. using human embryonic stem cells was in 2009. Since then, hundreds of clinical trials have been conducted globally using pluripotent – either embryonic or induced pluripotent stem cells (iPSCs) – or adult stem cells. But so far, none have made their way routinely to patients outside of a clinical trial setting in the U.S., (although a few stem cell-based products have been approved in other countries), and it’s unclear how many more trials it will take to get to this point.

Part of this murkiness is because we’re still in the early days of stem cell research: human embryonic stem cells were first isolated by James Thomson in 1998, and iPSCs weren’t discovered by Shinya Yamanaka until 2006. Scientists need more time to conduct preclinical research to understand how these stem cells can be best used to treat certain diseases and what stem cells will do when transplanted into patients.

Another other issue is that the U.S. Food and Drug Administration (FDA) has only approved one stem cell therapy – cord blood stem cell transplantation – for commercial use in 2011 and none since then. A big debate is currently ongoing about whether the regulatory landscape needs to change so that stem cell treatments that show promise in trials can get to patients who desperately need them.

Hopefully soon, the FDA will adopt a more efficient strategy for approving stem cell therapies that still keeps patient safety at the forefront. Otherwise it could take a lot longer for newer stem cell technologies like iPSCs to make their way to the clinic (although we’ve seen some encouraging preliminary results using iPSC-based therapy in clinical trials for blindness).

Trial, trial, trial again

So how many clinical trials will it take for a stem cell therapy to succeed sufficiently to gain approval and when will that happen?

Unfortunately, we don’t know the answers to these questions, but we do know that scientists need to continue to develop and test new stem cell treatments in human trials if we want to see any progress.

At CIRM, we are currently funding 16 clinical trials involving stem cell therapies for cancer, heart failure, diabetes, spinal cord injury and other diseases. But we need to fund more trials to increase the odds that some will make it through the gauntlet and prove both safe and effective at treating patients. Our goal now is to fund 50 clinical trials in the next five years. It’s an aggressive plan, but one we feel will hopefully take stem cell therapies from promise to reality.

We also know that CIRM is a soldier in a large army of funding agencies, universities, companies, and scientists around the world battling against time to develop stem cell therapies that could help patients in their lifetimes. And with this stem cell army, we believe we’re getting closer to the chewy center of the Tootsie pop, or in this case, an approved stem cell therapy for patients desperate for a cure.

This blog was written as part of the CCRM Signals iPSC anniversary blog carnival. Please click here to read what other bloggers have to say about the future of stem cells and regenerative medicine.

Stem cell stories that caught our eye: Zika virus and adult brains, a step toward precision medicine and source of blood stem cells

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.

Zika virus and the adult brain.  While almost all the press attention for the Zika virus has centered on pregnant women and the devastating impact the virus can have on their developing babies, a few stories have noted that while most adults don’t know they have been infected, a few do. The one significant impact seen is a relatively rare incidence of Guillain-Barre Syndrome, which can cause temporary partial paralysis. That has triggered a few researchers to look for other impacts in adults infected with the mosquito-borne virus.

shutterstock_200494427

Researchers trying to understand why the virus leads to the underdeveloped brains known as microcephaly, in infants have shown the virus does its nasty work at the level of the nerve stem cell. Although adults have far fewer nerve stem cells than a developing fetus, they do have some. So a team at Rockefeller University in New York and the La Jolla Institute for Allergy and Immunology decided to look for any effects of infection on adult nerve stem cells in mice.  They published the work this week in the journal Cell Stem Cell and report a dramatic reduction in adult nerve stem cells in infected mice.

“Adult neurogenesis is implicated in learning and memory,” said the La Jolla Institute’s Sujan Shresta in a press release from the journal. “We don’t know what this would mean in terms of human diseases, or if cognitive behaviors of an individual could be impacted after infection.”

Mice are normally resistant to Zika infection, so the researchers first had to genetically engineer mice to be susceptible to infection. That means several layer of caveats and more research are needed before any assertions about adult impact of Zika infection in humans.

This work captured considerable press attention including in Buzzfeed, NBC and USNews and World Report.

 

Heart felt precision medicine.  With the boost of a special initiative launched by the Obama administration, precision medicine is becoming all the rage, at least as a goal. While a few cancer therapies currently use this concept of matching therapies to a specific patient’s genetic makeup, few doctors outside of oncology can turn to similarly precise therapies.

Cardio cells image

Heart muscle cells

Work from a CIRM-funded team at Stanford has moved other doctors a bit closer to this goal for heart disease. But this research will not lead to treating it, rather it could allow doctors to prevent therapies used for other diseases from causing heart disease. Joseph Wu and his team have made two discoveries that help validate the use of the iPS reprogramming technique to make patient-specific stem cells and then mature them into heart muscle cells and see how those cells react to specific drugs.

“Thirty percent of drugs in clinical trials are eventually withdrawn due to safety concerns, which often involve adverse cardiac effects,” said Wu in a press release picked up by ScienceNewsLine. “This study shows that these cells serve as a functional readout to predict how a patient’s heart might respond to particular drug treatments and identify those who should avoid certain treatments.”

 

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Joseph Wu

There has always been some concern that the genetic manipulation used to create iPS cells changes the genetics of any adult tissue you make from the cells. So, with samples from three patients who were undergoing heart biopsy or transplant, which allowed harvesting mature heart muscle, the team compared the genetic signature of the adult heart muscle and that of heart muscle created from iPS cells.  They found no significant differences.

With skin samples from another seven subjects they created iPS cells and then heart muscle and compared their genetic signatures. The found some slight difference in all seven, but dramatic differences in one. That difference was in a genetic pathway involved in the inner workings of heart muscle. When they treated those cells with a diabetes drug that had been linked to heart problems, the cells reacted quite differently from the cells of the other six subjects treated with the same drug. With this knowledge a doctor could avoid ever choosing to put that particular patient on that diabetes drug.

 

Source of blood stem cells matters.  For years, bone marrow transplant—the one currently routine stem cell therapy—required digging into someone bone to harvest the stem cells. Over the decades that the procedure has been saving thousands of lives doctors have found less invasive methods to get the stem cells using drugs to “mobilize” the marrow stem cells and get them to move into the blood stream where they can be harvested.

While stem cell donors often find the new procedure a vast improvement, no one had done a thorough review of the outcomes for patients who receive stem cells gathered by the different procedures until a paper this week from the Fred Hutchison Cancer Research Center in Seattle. While they did not find any differences in overall life expectancy, they found vastly different outcomes in quality of life including psychological wellbeing and ability to return to work.

The Hutchison team attributed most of this difference to a lower rate of Graft Versus Host Disease (GVHD), possibly the most dangerous side effect of the procedure, which occurs when the stem cell transplant also contains adult immune system cells from the donor and those “graft” cells attack the “host,” the patient. It makes sense that when you harvest cells from the blood stream you would be more likely to also capture mature immune cells than when you harvest cells from marrow. And GVHD can be extremely painful, debilitating, and often deadly.

Stephanie Lee Hutchison

Stephanie Lee

“When both your disease and the recommended treatment are life-threatening, I don’t think people are necessarily asking ‘which treatment is going to give me better quality of life years from now?'” said Stephanie Lee the lead author in a press release from the cancer center. “Yet, if you’re going to make it through, as many patients do, you want to do it with good quality of life. That’s the whole point of having the transplant.”

Better, Faster Quality Control for Stem Cell-Based Therapies

“Based”.

It’s a pretty boring word but I make sure to include it when writing about the development of stem cell therapies, as in: “Asterias Biotherapeutics is testing an embryonic stem cell-based treatment for spinal cord injury”. It’s a key word here because no legitimate clinic would transplant embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) directly into a patient. The ability of these cells to make unlimited copies of themselves is great for growing them in the lab; but in the body, that same property presents a very real risk of tumor formation. Instead, ESCs and iPSCs are merely the base material from which specialized cells are matured from for the many promising therapies being developed for clinical trials.

To ensure safety to patients, minimizing the number of these potentially cancer-causing pluripotent stem cells still lingering in a cell therapy product is one of the main safety concerns of the Food and Drug Administration (FDA), the U.S. federal agency that approves therapies for clinical trials. So during therapy development, researchers run assays, or tests, to detect how many ESCs or iPSCs remain in their cell product and if they can form tumors.

In a paper published yesterday in Biomaterials, an Emory University research team reported on the development of a new technique that is several thousand-fold (!!!) higher in sensitivity than current assays and could be a game-changer for the quality control of stem cell-based therapies (also see an Emory U. blog about the study).

Surface-enhanced Raman Scattering Assay: it’s one in a million

SERS-schematic

Illustrated overview of the SERS assay workflow (Image: Biomaterials)

In the technique, called a surface-enhanced Raman scattering (SERS) assay, gold nanoparticles are attached to proteins, called antibodies, that specifically bind to the surface of stem cells. These antibody-nanoparticles are mixed with a preparation of the cell product. A laser is then directed at the cells and a device, called a spectrometer, measures the resulting light scatter which ultimately can be converted into the number of stem cells in the cell mix.

Incredibly, this assay can detect one stem cell out of one million specialized cells making it well suited for testing clinical grade cell therapy products. In comparison, the current flow cytometry technique which uses fluorescently tagged antibodies, can spot 1 stem cell in about 1000 cells.

Another current way to detect stem cells in a cell product is through the so-called teratoma assay. In this test, a mouse is injected with the cell therapy and observed for about three months to see if any teratomas, or tumors, form from residual stem cells. While this technique is a more direct safety test, it’s very costly, time-consuming, and impractical for testing very large doses of cell therapies. As the authors mention in the publication, the SERS technique could help overcome the limitations of both the teratoma and flow cytometry assays:

“Because of their remarkable sensitivity, these SERS assays may facilitate safety assessment of cell preparations for transplantations that require a large quantity of cells, which is unachievable using flow cytometry or the teratoma assay in mice. In addition, these assays are cost-effective, easy to use, and can be done within an hour, which is much faster than the traditional teratoma assay.”

“Faster”. Now that’s a pretty exciting word I always like to include when writing about the development of stem cell therapies.

 

Stem Cells May Help Endangered Species Live Long and Prosper

It’s the year 2286. The transmission signal of an alien space probe is wreaking havoc on Earth, knocking out the worldwide power grid and causing massive storms. It turns out the mysterious orbiting probe is trying to communicate with humpback whales through whale song and the devastation won’t stop until contact is made. But there’s a tiny problem: in that future, the humpback has long since become extinct. So the captain and crew travel back in time to snag two whales and save 23rd century civilization. Phew!

My fellow science fiction nerds will recognize that plot line from 1986’s Star Trek IV: A Voyage Home. It’s pure fantasy and yet there is a real lesson for our present day world: you shouldn’t underestimate how the extinction of a species will impact our world. For instance, the collapse and potential extinction of the bee population and other pollinators threatens to destabilize our global food supply.

Northern White Rhinos: At the Brink of Extinction
Beyond how it may affect us humans, I think there’s also a moral obligation to save endangered species that have dwindled in number directly due to human actions. It may be too late for the northern white rhino though. Because their horns are highly sought after as a status symbol and for use in traditional medicine, poachers have wiped out the population and now only three – Sudan, Najin and Fatu (grandfather, mother and daughter) – exist in the world. Sadly, none of them can breed naturally so they quietly graze in a Kenyan conservation park as their species heads towards extinction.

whiterhino

One of the three remaining northern white rhinos in the world (Image source: The Guardian)

Jeanne Loring, a CIRM grantee and professor at The Scripps Research Institute, still sees a glimmer of hope in the form of stem cells. In an essay published yesterday in Genetic Engineering and Biotechnology News, Loring describes her research team’s efforts to apply stem cell technology toward saving the Northern White Rhino and other endangered species.

Their efforts began about ten years ago in 2007, the same year that Shinya Yamanaka’s lab first reported that human fibroblasts, collected from a skin sample, can be reprogrammed into an embryonic stem cell-like state with the capacity to indefinitely make copies of themselves and to specialize into almost every cell type of the body. The properties of these induced pluripotent stem (iPS) cells have provided an important means for studying all sorts of human diseases in a lab dish and for deriving potential cell therapies.

FrozenZoo® and iPS Cells: A Modern Day Noah’s Ark?

But it was a free tour at the San Diego Safari Park just two months after Yamanka’s discovery which inspired the Loring lab to chart this additional research path using iPS cells. In exchange for the free safari ride, the team reciprocated by chatting with Oliver Ryder, director of the San Diego Zoo Institute for Conservation Research, about using stem cells to help save endangered species. Ryder’s institute runs the FrozenZoo® a cell and tissue bank containing thousands of frozen samples from a diverse set of species. In her essay, Loring recounts what happened after the visit:

“It was obvious to us: why not try to reprogram fibroblasts from the FrozenZoo®? When my group returned to the lab from the safari, I asked them: who would like to try to reprogram fibroblasts from an endangered species? It was far from a safe bet, but a young postdoctoral researcher who had recently joined my lab from Israel said that she’d love to give it a try. Inbar Friedrich Ben-Nun spent the next couple of years trying out methods in parallel on human cells and fibroblasts from the zoo. We chose fibroblasts from the drill because it is [an endangered] primate, making it more likely that the technology used for humans would work.

Oliver [Ryder] chose the northern white rhino, a particular favorite of his, and one of the world’s most endangered mammals.  Through hard work and insight, Inbar reprogrammed both species, and in 2011, we published the first report of making iPSCs from endangered species (Ben-Nun, et al., 2011). Nature Methods featured our work, with a cover illustration of an ark stuffed with endangered animals.”

 

 

 

So how exactly would these iPS cells be used to save the northern white rhino and other animals from the brink of extinction? Last December, Ben-Nun along with 20 other scientists and zoologists from four continents met in Vienna to map out a strategy. They published their plan on May 3rd in Zoo Biology.

The Stem Cell-Based Plan to Save the Northern White
In the first phase, an in vitro fertilization (IVF) procedure for the rhino – never before attempted – will be worked out. Frozen sperm samples from four now-deceased rhinos plus one sample from Sudan are ready for IVF. Researchers then hope to collect eggs from Najin and Fatu and implant embryos in surrogates of a related species, the southern white rhino. However, even if IVF is successful, the offspring would not represent enough genetic diversity to ultimately thrive as a species in the wild. So in the second phase, iPS cells will be generated using tissue fibroblast samples from several more northern whites that were banked in The FrozenZoo®. Those iPS cells will be specialized into sperm and eggs to provide a larger, more diverse set of embryos which again will be implanted in surrogate rhinos. Breeding animals using iPS-derived sperm and eggs has only been successful in mice so much work remains.

“Does this plan have any chance of succeeding?” Loring asks. Her response is cautiously optimistic:

“I know it will be difficult, but I think it’s not impossible. Perhaps the most important advance is that such a diverse group agreed on a plan—it wasn’t just a stem cell biologist like me imagining how the cells might be used, but rather a whole chain of experts who can imagine how to accomplish each step.”

 

Not all experts agree with this strategy. In a Nature News interview back in May, Michael Knight, chair of the International Union for Conservation Nature’s African Rhino Specialist Group, expressed concerns that the effort is misdirected:

“It’s Star Trek-type science. They should not be pushing this idea that they’re saving a species. If you want to save a [rhino] species, put your money into southern white conservation.”

IMHO
Knight’s point is well-taken that conventional conservation approaches are critical to ensure that the southern white rhino doesn’t meet the same disastrous fate as the northern white. But if the funding is available, it seems worth the effort to also attempt this innovative iPS strategy, a technology that’s deep in development now and not awaiting Captain Kirk’s distant Star Trek future.

Stem cell stories that caught our eye: potential glaucoma therapy, Parkinson’s model, clinical trial list, cancer immune therapy

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

Stem cells may be option in glaucoma.  A few (potentially) blind mice did not run fast enough in an Iowa lab. But lucky for them they did not run into a farmer’s wife wielding a knife. Instead they had their eye sight saved by a team at the University of Iowa that corrected the plumbing in the back of their eyes with stem cells. They had a rodent version of glaucoma, which allows fluid to build up in the eye causing pressure that eventually damages the optic nerve and leads to blindness.

human eye

The fluid buildup results from a breakdown of the trabecular meshwork, a patch of cells that drains fluid from the eye. The Iowa researchers repaired that highly valuable patch with cells grown from iPS type stem cells created by reprogramming adult cells into an embryonic-like state. The trick with any early stage stem cell is getting it to mature into the desired tissue. This team pulled that off by growing the cells in a culture dish that had previously housed trabecular meshwork cells, which must have left behind some chemical signals that directed the growth of the stem cells.

The cells restored proper drainage in the mice. Also notable, the cells not only acted to replace damaged tissue directly, but they also seem to have summoned the eye’s own healing powers to do more repair. The research team also worked at the university affiliated Veterans Affairs Hospital, and the VA system issued a press release on the work published in the Proceedings of the National Academy of sciences, which was posted by Science Codex.

 

A “mini-brain” from a key area.   The brain is far from a uniform organ. Its many distinct divisions have very different functions. A few research teams have succeeded in coaxing stem cells into forming multi-layered clumps of cells referred to as “brain organoids” that mimic some brain activity, but those have generally been parts of the brain near the surface responsible for speech, learning and memory. Now a team in Singapore has created an organoid that shows activity of the mid-brain, that deep central highway for signals key to vision, hearing and movement.

The midbrain houses the dopamine nerves damaged or lost in Parkinson’s disease, so the mini-brains in lab dishes become immediate candidates for studying potential therapies and they are likely to provide more accurate results than current animal models.

 “Considering one of the biggest challenges we face in PD research is the lack of accessibility to the human brains, we have achieved a significant step forward. The midbrain organoids display great potential in replacing animals’ brains which are currently used in research,” said Ng Huck Hui of A*Star’s Genome Institute of Singapore where the research was conducted in a press release posted by Nanowerk.

The website Mashable had a reporter at the press conference in Singapore when the institute announce the publication of the research in Cell Stem Cell. They have some nice photos of the organoids as well as a microscopic image showing the cells containing a black pigment typical of midbrain cells, one of the bits of proof the team needed to show they created what they wanted.

 

Stem cell clinical trials listings.  Not a day goes by that I, or one of my colleagues, do not refer a desperate patient or family member—often several per day—to the web site clinicaltrials.gov. We do it with a bit of unease and usually some caveats but it is the only resource out there providing any kind of searchable listing of clinical trials. Not everything listed at this site maintained by the National Institutes of Health (NIH) is a great clinical trial. NIH maintains the site, and sets certain baseline criteria to be listed, but the agency does not vet postings.

Over the past year a new controversy has cropped up at the site. A number of for profit clinics have registered trials that require patients to pay many thousands of dollars for the experimental stem cell procedure.  Generally, in clinical trials, participation is free for patients. Kaiser Health News, an independent news wire supported by the Kaiser Family Foundation distributed a story this week on the phenomenon that was picked up by a few outlets including the Washington Post. But the version with the best links to added information ran in Stat, an online health industry portal developed by The Boston Globe, which has become one of my favorite morning reads.

The story leads with an anecdote about Linda Smith who went to the trials site to look for stem cell therapies for her arthritic knees. She found a listing from StemGenex and called the listed contact only to find out she would first have to pay $14,000 for the experimental treatment. The company told the author that they are not charging for participation in the posted clinical trial because it only covers the observation phase after the therapy, not the procedure itself. The reporter found multiple critics who suggested the company was splitting hairs a bit too finely with that explanation.

But the NIH came in for just as much criticism for allowing those trials to be listed at all. The web site already requires organizations listing trials to disclose information about the committees that oversee the safety of the patients in the trial, and critics said they should also demand disclosure of payment requirements, or outright ban such trials from the site.

Paul-Knoepfler-2013 “The average patient and even people in health care … kind of let their guard down when they’re in that database. It’s like, ‘If a trial is listed here, it must be OK,’” said Paul Knoepfler, a CIRM grantee and fellow blogger at the University of California, Davis. “Most people don’t realize that creeping into that database are some trials whose main goal is to generate profit.”

The NIH representative quoted in the article made it sound like the agency was open to making some changes. But no promises were made.

Added note 7/30. While this post factually describes an article that appeared in the mainstream media, the role of this column, I should add that while I did not take a position on paid trials, I am thrilled Stemgenex is collecting data and look forward to them sharing that data in a timely, peer-reviewed fashion.

 

Off the shelf T cells.  We at CIRM got some good news this week. We always like it when we see an announcement that technology from a researcher we have supported gets licensed to a company. That commercialization moves it a giant step closer to helping patients.

This week, Kite Pharma licensed a system developed in the lab of Gay Crooks at the University of California, Los Angeles, that creates an artificial thymus “organoid” in a dish capable of mass producing the immune system’s T cells from pluripotent stem cells. Just growing stem cells in the lab yields tiny amounts of T cells. They naturally mature in our bodies in the thymus gland, and seem to need that nurturing to thrive.

T-cell based immune therapy is all the rage now in cancer therapy because early trials are producing some pretty amazing results, and Kite is a leader in the field. But up until now those therapies have all been autologous—they used the patient’s own cells and manipulate them individually in the lab. That makes for a very expensive therapy. Kite sees the Crooks technology as a way to turn the procedure into an allogeneic one—using donor cells that could be pre-made for an “off-the-shelf” therapy. Their press release also envisioned adding some genetic manipulation to make the cells less likely to cause immune complications.

FierceBiotech published a bit more analysis of the deal, but we are not going to go into more detail on the actual science now. Crooks is finalizing publication of the work in a scientific journal, and when she does you can get the details here. Stay tuned.

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.

Stem cell stories that caught our eye: herding stem cells, mini autistic brains, tendon repair and hair replacement

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.

Major advance in getting stem cells to behave.  The promise of embryonic stem cells comes from their ability to become any cell type in the body, but medical uses of the cells have been hampered by our poor ability to quickly get them to mature into pure populations of a desired adult tissue. Scientists at Stanford, partially funded by CIRM, and the Genome Institute of Singapore have teamed up to better understand the normal road map of how the various tissues develop in the embryo and in turn fine tune the recipes used to make specific tissues in the lab. They claim to have created pure colonies of 12 different specialized tissues in half the time or less of normal procedures, which usually result in an undesired mix of cells.

 “The problems of making or isolating pure samples of one specific cell type has been a substantial barrier to medical uses of embryonic stem cells. This research looks like a way around that problem,” said Hank Greely, a medical ethicist at Stanford not involved in the work in an article in the East Bay Times.

 

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Weissman

This is a problem researchers around the world have been trying to crack since human embryonic stem cells were first isolated in 2008. The brief paragraph above on how they did it does not do justice to a very elegant and complex research project led by one of the leaders of the field, Irving Weissmann. Stanford’s press release provides more detail about how they achieved the milestone, which should significantly accelerate the field of regenerative medicine.

 

 

Mini brains to figure out oversize brains.  The many forms of autism have many different causes—though most are unknown—and a wide array of symptoms and physical manifestations. An international team has used a lab dish “mini-brain” model to discover the cause of one form of autism, one linked to over-sized brains, which occurs in about 20 percent of children with autism spectrum disorder (ASD).

Autistic neurons Muotri

Nerve precursor cells grown from iPS cells created from children with autism. Inhibitory nerves (in red) are not in sufficient numbers.

A team led by Alysson Muotri at the University of California, San Diego (UCSD), started with tissue samples from children with the disorder and reprogrammed them into iPS type stem cells. They matured those stem cells, first into nerve progenitors and then into the various nerves that in normal cells would result in mini-brains in the lab dish.  But instead of a healthy mix of cells that promote and inhibit nerve growth, they found a lack of inhibitory nerves allowing the overgrowth seen in the condition. They also showed the nerve cells did not send signals to each other properly; they lacked synchronization.

 “The bottom line is that we can now effectively model idiopathic ASD using a cohort of individuals selected by a clear endophenotype. In this case, brain volume,” said Muotri, in a university press release posted by Health Canal. “And early developmental brain enlargement can be explained by underlying molecular and cellular pathway dysregulation, leading to altered neuronal cortical networks.”

More important, they treated the nerves in the dish with a drug, IGF-1, that is currently being tested in the clinic for autism,  and found a reversal of the nerve miss-firing in some of the samples. Their model should make it easier to test more potential drugs, as well.

It has been a big week for improved understanding of ASD. Earlier in the week Fred Gage’s team across the street from UCSD at the Salk institute—where Muotri worked as a post-doctoral fellow—published a causal link for another form of autism, which my colleague Karen Ring wrote about earlier this week in The Stem Cellar.

 

shutterstock_425039020Help for weekend warriors. How many of your friends have ended up on crutches after a weekend of too much basketball or tennis, with a diagnosis of a torn ligament or tendon? And have they said they wished they had broken a bone instead because it would heal faster? Medicine has not been able to speed the healing of those delicate connecting straps in large part because we haven’t known much about how they are created during development. So a team at the Scripps Research Institute set out to find out how they develop and heal naturally.

 “If we understand the molecular mechanisms of tendon development, we can apply the findings to develop a new regenerative therapy for tendon diseases and injuries,” said team leader Hiroshi Asahara in an institution release posted by Sciencecodex.

 They found one gene in particular linked to tendon development and repair in an animal model. They used the new trendy gene editing tool CRISP to regulate the gene in rats. They found the gene results in the production of more tenocytes, which are needed to maintain healthy tendon. That pathway now becomes a target for developing new therapies to help those hobbling friends.

 

For the follicular challenged. On a lighter note, one of the least impactful but most common medical conditions, hair loss, has become a target of therapy development by many university and industry teams. Forbes posted a run down about the activities of some of the leaders of the hair pack.

Not all the author’s science is spot on, for example, when talking about the only organs that constantly regenerate the author ignored the fact that our gut lining turns over about every four days. But he provides a good review of how our hair follicles generally do a good job of replenishing hair and what goes wrong when they fail.

The author focuses most on the work of Japan’s RIKEN Institute, providing an easy to follow info-graphic on how the team there envisions harvesting a small skin sample, sorting the stem cells out of the hair follicles in the sample, growing those stem cells in the lab many fold and then injecting cells back to where they are needed. That team hopes to have a commercial product by 2020. In the meantime, the top of my head will remain intimately acquainted with sun screen.

Salk Scientists Unlock New Secrets of Autism Using Human Stem Cells

Autism is a complex neurodevelopmental disorder whose mental, physical, social and emotional symptoms are highly variable from person to person. Because individuals exhibit different combinations and severities of symptoms, the concept of autism spectrum disorder (ASD) is now used to define the range of conditions.

There are many hypotheses for why autism occurs in humans (which some estimates suggest now affects around 3.5 million people in the US). Some of the disorders are thought to be at the cellular level, where nerve cells do not develop normally and organize properly in the brain, and some are thought to be at the molecular level where the building blocks in cells don’t function properly. Scientists have found these clues by using tools such as studying human genetics and animal models, imaging the brains of ASD patients, and looking at the pathology of ASD brains to see what has gone wrong to cause the disease.

Unfortunately, these tools alone are not sufficient to recreate all aspects of ASD. This is where cellular models have stepped in to help. Scientists are now developing human stem cell derived models of ASD to create “autism in a dish” and are finding that the nerve cells in these models show characteristics of these disorders.

Stem cell models of autism and ASD

We’ve reported on some of these studies in previous blogs. A group from UCSD lead by CIRM grantee Alysson Muotri used induced pluripotent stem cells or iPS cells to model non-syndromic autism (where autism is the primary diagnosis). The work has been dubbed the “Tooth Fairy Project” – parents can send in their children’s recently lost baby teeth which contain cells that can be reprogrammed into iPS cells that can then be turned into brain cells that exhibit symptoms of autism. By studying iPS cells from individuals with non-syndromic autism, the team found a mutation in the TRPC6 gene that was linked to abnormal brain cell development and function and is also linked to Rett syndrome – a rare form of autism predominantly seen in females.

Another group from Yale generated “mini-brains” or organoids derived from the iPS cells of ASD patients. They specifically found that ASD mini-brains had an increased number of a type of nerve cell called inhibitory neurons and that blocking the production of a protein called FOXG1 returned these nerve cells back to their normal population count.

Last week, a group from the Salk Institute in collaboration with scientists at UC San Diego published findings about another stem cell model for ASD that offers new clues into the early neurodevelopmental defects seen in ASD patients.  This CIRM-funded study was led by senior author Rusty Gage and was published last week in the Nature journal Molecular Psychiatry.

Unlocking clues to autism using patient stem cells

Gage and his team were fascinated by the fact that as many as 30 percent of people with ASD experience excessive brain growth during early in development. The brains of these patients have more nerve cells than healthy individuals of the same age, and these extra nerve cells fail to organize properly and in some cases form too many nerve connections that impairs their overall function.

To understand what is going wrong in early stages of ASD, Gage generated iPS cells from ASD individuals who experienced abnormal brain growth at an early age (their brains had grown up to 23 percent faster when they were toddlers compared to normal toddlers). They closely studied how these ASD iPS cells developed into brain stem cells and then into nerve cells in a dish and compared their developmental progression to that of healthy iPS cells from normal individuals.

Neurons derived from people with ASD (bottom) form fewer inhibitory connections (red) compared to those derived from healthy individuals (top panel). (Salk Institute)

Neurons derived from people with ASD (bottom) form fewer inhibitory connections (red) compared to those derived from healthy individuals (top panel). (Salk Institute)

They quickly observed a problem with neurogenesis – a term used to describe how brain stem cells multiply and create new nerve cells in the brain. Brain stem cells derived from ASD iPS cells displayed more neurogenesis than normal brain stem cells, and thus were creating an excess amount of nerve cells. The scientists also found that the extra nerve cells failed to form as many synaptic connections with each other, an essential process that allows nerve cells to send signals and form a functional network of communication, and also behaved abnormally and overall had less activity compared to healthy neurons. Interestingly, they saw fewer inhibitory neuron connections in ASD neurons which is contrary to what the Yale study found.

The abnormal activity observed in ASD neurons was partially corrected when they treated the nerve cells with a drug called IGF-1, which is currently being tested in clinical trials as a possible treatment for autism. According to a Salk news release, “the group plans to use the patient cells to investigate the molecular mechanisms behind IGF-1’s effects, in particular probing for changes in gene expression with treatment.”

Will stem cells be the key to understanding autism?

It’s clear that human iPS cell models of ASD are valuable in helping tease apart some of the mechanisms behind this very complicated group of disorders. Gage’s opinion is that:

“This technology allows us to generate views of neuron development that have historically been intractable. We’re excited by the possibility of using stem cell methods to unravel the biology of autism and to possibly screen for new drug treatments for this debilitating disorder.”

However, to me it’s also clear that different autism stem cell models yield different results, but these differences are likely due to which populations the iPS cells are derived from. Creating more cell lines from different ASD subpopulations will surely answer more questions about the developmental differences and differences in brain function seen in adults.

Lastly, one of the co-authors on the study, Carolina Marchetto, made a great point in the Salk news release by acknowledging that their findings are based on studying cells in a dish, not actual patient’s brains. However, Marchetto believes that these cells are useful tools for studying autism:

“It never fails to amaze me when we can see similarities between the characteristics of the cells in the dish and the human disease.”

Rusty Gage and Carolina Marchetto. (Salk Institute)

Rusty Gage and Carolina Marchetto. (Salk Institute)


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The Spanish Inquisition and a tale of two stem cell agencies

Monty

Monty Python’s Spanish Inquisition sketch: Photo courtesy Daily Mail UK

It’s not often an article on stem cell research brings the old, but still much loved, British comedy series Monty Python into the discussion but a new study in the journal Cell Stem Cell does just that, comparing the impact of CIRM and the UK’s Regenerative Medicine Platform (UKRMP).

The article, written by Fiona Watt of King’s College London and Stanford’s Irv Weissman (a CIRM grantee – you can see his impressive research record here) looks at CIRM and UKRMP’s success in translating stem cell research into clinical applications in people.

It begins by saying that in research, as in real estate, location is key:

“One thing that is heavily influenced by location, however, is our source of funding. This in turn depends on the political climate of the country in which we work, as exemplified by research on stem cells.”

And, as Weissman and Watt note, political climate can have a big impact on that funding. CIRM was created by the voters of California in 2004, largely in response to President George W. Bush’s restrictions on the use of federal funds for embryonic stem cell research. UKRMP, in contrast was created by the UK government in 2013 and designed to help strengthen the UK’s translational research sector. CIRM was given $3 billion to do its work. UKRMP has approximately $38 million.

Inevitably the two agencies took very different approaches to funding, shaped in part by the circumstances of their birth – one as a largely independent state agency, the other created as a tool of national government.

CIRM, by virtue of its much larger funding was able to create world-class research facilities, attract top scientists to California and train a whole new generation of scientists. It has also been able to help some of the most promising projects get into clinical trials. UKRMP has used its more limited funding to create research hubs, focusing on areas such as cell behavior, differentiation and manufacturing, and safety and effectiveness. Those hubs are encouraged to work collaboratively, sharing their expertise and best practices.

Weissman and Watt touch on the problems both agencies ran into, including the difficulty of moving even the best research out of the lab and into clinical trials:

“Although CIRM has moved over 20 projects into clinical trials most are a long way from becoming standard therapies. This is not unexpected, as the interval between discovery and FDA approved therapeutic via clinical trials is in excess of 10 years minimum.”

 

And here is where Monty Python enters the picture. The authors quote one of the most famous lines from the series: “Nobody expects the Spanish Inquisition – because our chief weapon is surprise.”

They use that to highlight the surprises and uncertainty that stem cell research has gone through in the more than ten years since CIRM was created. They point out that a whole category of cells, induced pluripotent stem (iPS) cells, didn’t exist until 2006; and that few would have predicted the use of gene/stem cell therapy combinations. The recent development of the CRISPR/Cas9 gene-editing technology shows the field is progressing at a rate and in directions that are hard to predict; a reminder that that researchers and funding agencies should continue to expect the unexpected.

With two such different agencies the authors wisely resist the temptation to make any direct comparisons as to their success but instead conclude:

“…both CIRM and UKRMP have similar goals but different routes (and funding) to achieving them. Connecting people to work together to move regenerative medicine into the clinic is an over-arching objective and one that, we hope, will benefit patients regardless of where they live.”

Spotlight on CIRM Grantee Joe Wu: Clinical Trials for Heart Disease in a Dish?

It’s always exciting to read a science article featuring a talented scientist who is breaking boundaries in the field of regenerative medicine. It’s especially exciting to us at CIRM when the scientist is a CIRM grantee.

Last week, OZY published a fun and inspiring piece on Stanford scientist Joe Wu. Dr. Wu is the Director of the Stanford Cardiovascular Institute and his lab studies how stem cells (both adult and pluripotent) function and how they can be used to model heart diseases and screen for new drug therapies. He also is a CIRM grantee and has a Disease Team Therapy Development grant that aims to clinically test human embryonic stem cell-derived cardiomyocytes (heart cells) in end stage heart failure patients.

Dr. Joe Wu. (Image Source: Sean Culligan/OZY)

Dr. Joe Wu. (Image Source: Sean Culligan/OZY)

The OZY piece does a great job of highlighting Dr. Wu’s recent efforts to use human induced pluripotent stem cells (iPS cells) to make heart tissue in a dish and model cardiovascular disease. And without getting too technical, the article explains Dr. Wu’s larger mission to combine precision medicine and stem cell research to identify drugs that would be best suited for specific patient populations.

The article commented,

“He envisions treatments based on an individual’s own iPS cells. For example, a popular breast cancer drug has an 8 percent chance of giving patients heart failure. In Wu’s world, we’d test the drug on stem cells first, and if a patient lands in that 8 percent, begin treatment for the side effects preemptively or avoiding the drug totally and avoiding heart failure, too.”

Basically, Dr. Wu sees the future of clinical trials in a dish using human stem cells. “His goal is to take these stem cells from thousands of patients to create a genetically diverse enough bank that will allow for “clinical trials in a dish” — Wu’s go-to phrase.”

Instead of following the traditional drug development paradigm that takes more than 10 years, billions of dollars, and unfortunately usually ends in failure, Dr. Wu wants to follow an accelerated path where stem cells are used for drug toxicity and efficacy testing.

This alternative path could improve overall drug development and approval by the FDA. The article explained,

“Testing drugs on stem cells will give big pharma and the FDA vastly improved heads up for toxic complications. Stem cells are “absolutely” the best avenue going forward, says Norman Stockbridge, director of the division of cardiovascular and renal products at the FDA’s Center for Drug Evaluation and Research.”

Not everyone is on the same page with Dr. Wu’s bold vision of the future of precision medicine, stem cells, and treatments for heart disease. Some believe he is overly ambitious, however top scientists in the stem cell field have praised Dr. Wu’s “systematic approach” to research and how he doesn’t stop at data discovery, he focuses on the big picture and how his work can ultimately help patients.

You can read more about Dr. Wu’s research on his lab website and I highly encourage you to check out the OZY article which is a great example of science communication for the general public.


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