Stem cell stories that caught our eye: Salamander limb regrowth, mass producing cells for kidneys and halting cancer 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.

Fun with axolotls.  Axolotls, the albino aquatic critters that look like they have feathers growing out of the backs of their heads, have long been a favorite model for studying how they and their salamander cousins regrow limbs. But only recently, with refined methods for turning specific genes on and off, have we begun to really understand this amazing feat.

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Carl Zimmer, national correspondent for the online publication STAT, interviewed Jessica Whited of Harvard-affiliated Brigham and Women’s Hospital about her work trying to understand the genetics of limb regrowth and posted both a four-minute video and a short story about the research. Part of the video series Zimmer calls “Science Happens,” the interview lets Whited explain that when a limb is cut off, the animal summons cells called blastemas to the stump. Those cells have properties like stem cells in that they can make different tissues like the bone, skin and muscle needed to grow a limb, but they seem to do this by selectively turning genes on and off.

With a mix of cartoon drawings and real lab images, the video provides an easy to follow explanation of how the researchers turn off individual genes and then look for the effect. And I have to say I agree with Zimmer when talking about the axolotls he declares “I think they’re creepy.”

 

Advance for kidney disease.  Often in stem cell research you don’t want the starting stem cell and you don’t want the end desired tissue, you want the middleman called a progenitor that has already decided it wants to become the end tissue, but can still mass produce itself. Instead of being handed a roll of 10 dollar bills, you have a printing press with Hamilton’s face already set on the printing plate.

kidney progenitors Salk

Progenitor cells (bright red) growing in a kidney

In CIRM-funded research published this week in Cell Stem Cell a team at the Salk Institute has found a way to configure that printing press for nephron progenitor cells, the cells that yield the vital nephrons that allow your kidneys to cleanse your blood. While many have tried to mass produce these vital cells to repair damaged kidneys, they have not had much luck. These cells do not like to stay in the progenitor state. Once they are on the path toward the end tissue they like to keep on moving in that direction.

The Salk team, led by Juan Carlos Izpisua Belmonte, got around this by changing the progenitor cells’ environment. Instead of a flat lab dish, they grew them in 3D cultures and gave them a new mix of signaling molecules.

“We provide a proof-of-principle for how to make and maintain unlimited numbers of precursor kidney cells,” said Izpisua Belmonte in an institute press release posted by HealthMedicineNet. “Having a supply of these cells could be a starting point to grow functional organs in the laboratory as well as a way to begin applying cell therapy to kidneys with malfunctioning genes.”

Their system worked first in mouse cells and then in human cells. They predicted that the methods could be used to grow progenitor cells for many other tissues.

 

Halting cancer stem cells. The bad guys of the stem cell world, cancer stem cells (CSCs), are turning out to have a number of vulnerabilities, and many companies around the world have staked their fortunes on attacking one of those weak spots. While we have known for some time that CSCs require proteins in the Wnt family to grow, we haven’t had a good way of blocking that path. Now researchers at the Riken Center and National Cancer Center in Japan claim they have a candidate drug, at least for colon cancer.

They screened a library of compounds likely to inhibit the Wnt pathway and tested them in mice that had received transplants of human colon cancer. They found one, NCB-0846 that can be administered orally, that was able to suppress the cancer grafts.

 “We’re very encouraged by our promising preclinical data for NCB-0846, especially considering the difficulty in targeting this pathway to date, and shortly we hope to conduct a clinical trial at the NCC hospitals” said Dr. Tesshi Yamada of the National Cancer Center in a Riken release posted by ScienceCodex.

CIRM funds several team trying to halt CSCs, each team targeting a different vulnerability on the CSCs, including teams at Stanford, and at University of California campuses in San Diego and Los Angeles.

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.

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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.”

Stem cell stories that caught our eye: better bone marrow transplants, turbo charging anti-inflammatory stem cells and Zika’s weapons

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.

Three steps to better BMT.  Bone marrow stem cell transplants (BMT) save the lives of many thousands of patients every year, but they also kill a significant number of the blood stem cell transplantcancer and immune disorder patients the procedure is intended to save. In order to make room in the bone marrow for new blood-forming stem cells, you first have to get rid of most of the stem cells already there, and the radiation and chemotherapy to do this proves too toxic for some patients. Also, donor marrow can contain immune cells from the donor that can attack the recipient causing Graft Versus Host Disease (GVHD), which can also be fatal.

Add this all together and physicians tend to save BMT for the patients with the most life threatening forms of the diseases.  A CIRM-funded team at Stanford has developed a three-step process that seems to dramatically reduce all those risks potentially opening up the procedure to less-sick patients including patients with life-altering, but not life-threatening, autoimmune diseases such as lupus and less severe forms of multiple sclerosis.

Experimenting in mice, they first used an antibody that attaches to a marker on blood stem cells called c-kit. But by itself that antibody could not get rid of enough of the stem cells. So, they added a second agent that blocked another protein, CD47, on the surface of blood stem cells. With that protein blocked, the animals own immune cells called macrophages, could destroy the blood stem cells. Then to make the donor cells safer, they used a technology they had developed many years ago to remove any straggler immune cells from the donor stem cells, thus drastically eliminating the chances for GVHD.

judith shizuru

Shizuru

“If it works in humans like it did in mice, we would expect that the risk of death from blood stem cell transplant would drop from 20 percent to effectively zero,” said senior author Judith Shizuru in a university press release posted by HealthCanal.

She went on to compare blood stem cell transplants to planting a new field of crops saying they were looking for a better way to first clear the field for planting and then a better way to do the planting. CIRM funded the team to develop the method for use with Severe Combined Immune Deficiency (SCID). The team published the current mouse study in the journal Science Translational Medicine.

 

Building a better anti-inflammatory stem cell.  Of the more than 700 stem cell therapy clinical trials underway around the world, more than half use the type of stem cell called a mesenchymal stem cell (MSC) found in bone marrow and fat—in marrow it resides alongside the blood-forming stem cells. Some of those trials are tapping into MSC’s ability to build bone, cartilage and blood vessels, but many are counting on their strong anti-inflammatory properties to fight autoimmune diseases.

When MSCs find themselves in an environment with pro-inflammatory proteins they respond by producing anti-inflammatory proteins. To enhance that effect some teams have bathed their MSC’s in pro-inflammatory proteins before injecting them into patients, but the effect of those proteins wears off quickly. So, a team led by CIRM-funded researcher Todd McDevitt at the Gladstone Institutes in San Francisco has bioengineered a way to make the effect long term.

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Gladstone used a CIRM Research Leadership award to recruit McDevitt from Georgia Tech

They loaded the pro-inflammatory proteins onto sugar-based particles that they imbedded in the middle of clusters of MSCs. The bioengineered complex slowly releases the cues to the MSCs and they in turn produced the desired anti-inflammatory proteins in greater quantities and much longer than in any other experiment.

 “A patient taking anti-inflammatory medication may not have high enough levels of inflammation to trigger the cells. We engineered the MSCs to ensure that they are consistently activated, so they can reliably dampen the immune response for longer,” said McDevitt in an institute press release.

The team published their research in Stem Cells Translational Medicine.

 

Stem cells used to identify Zika’s weapon.  It has been difficult for researchers to think about how to stop the Zika virus’ havoc on fetal brains without knowing how the virus does

Zika Virus

its evil deed. Now, a team at the University of Southern California (USC) has used fetal stem cells to discover two proteins that seem to be Zika’s key weapons.

Viruses often hijack our normal cell processes to enhance their ability to multiply and at the same time do harm to the host. In this case, the two proteins named NS4A and NS4B play key roles in the cell path for normal cell growth and disposal of damaged cells. When exploited by the virus, the two proteins result in cells being destroyed and not replaced.

“Those two viral proteins are ultimately the target for therapy development,” said USC’s Jae Jung in an article posted by Kaiser Health News.

As is typical with this news source, the author goes on to provide considerable high quality background about the Zika outbreak and efforts to find a vaccine or therapy, in this case quoting experts from Texas Children’s Hospital and Baylor.

 

Cloning fact timeline.  With the 20th anniversary last month of the birth of Dolly the sheep, the first cloned mammal, cloning seems to be much in discussion these days. So for

dolly-the-sheep

science nerds who like to keep back up facts handy CNN published a timeline of key events starting with the 1952 Nobel-winning discovery that you could replace the nucleus of a frog’s egg with the nucleus from another cell and still get the egg to develop into a tadpole. And 22 events later, it ends in 2014 with the first use of using cloning techniques to create stem cells that matched an adult.

Stem cell stories that caught our eye: screening for cancer drugs for kids, better CRISPR gene editing and funding for chimeras

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 screen drugs for kids’ rare tumor.  A team at Johns Hopkins University in Baltimore has transformed stem cells into a particularly nasty form of pediatric brain cancer, medulloblastoma. They then used those cells to figure out what drugs might defeat the tumor and found one existing drug, approved for advanced breast cancer, that seemed to be a good candidate.

While about two-thirds of medulloblastoma patients do well with standard therapy, those in a class called “group 3” often do not survive. But the rarity of that condition, meant the researcher could not use what has become a common route to determining effective drugs: comparing the genetic profile of the cancer with the genetic profile of banks of cancer cells that have already have been tested against existing cancer drugs. There are not enough Group 3 samples in the banks to take that route.

So, the Hopkins team used a two-step process for the drug search. They first inserted genes associated with the Group 3 cancers into stem cells and let the cells begin to transform into tumors. After making sure their stem cell tumors genetically looked and behaved like medulloblastoma the researchers compared genetic “signatures” from those cells with the signatures of cells in the large databases of other cancers.

eric raabe hopkins

Raabe

“We wanted to find whether the cells we created matched any of these existing signatures, because if they did, then we would have some idea of what kinds of drugs are more or most likely to kill these cells,” said Eric Raabe in a university release posted by ScienceDaily. “We didn’t have to do the laborious screening to test 100,000 compounds against our own cells.”

Raabe suggested this system might work to create a short cut to finding best therapies for other rare tumors as well.

 

Combining tricks from two critters.  This article does not address stem cells directly, but rather a widely popular gene editing technique many hope to use with stem cell therapies, the system known as CRISPR.  But before that can happen, researchers need to figure out how to eliminate or minimize pesky “off-target” gene editing, when the genetic scissor slices the DNA in a spot that was not intended.

CRISPR technology borrows from bacteria. About 40 percent of bacteria immune systems use CRISPR’s genetic elements to recognize foreign genes such as phages, the viruses that can kill or tag along in bacteria. Scientists generally pair CRISPR’s ability to recognize specific gene segments, with great specificity, with the nuclease, or genetic scissor, called CAS9. But that scissor is not quite as precise. So, a team at Kobe University in Japan borrowed an immune system trick from a second critter, a sea lamprey, sometimes incorrectly called an eel. The result was a much more precise gene editing tool.

Lamprey

The lamprey gene editing tool they borrowed is based on an enzyme called a deaminase. The lamprey uses the enzyme to create breaks in the genes for its immune system’s antibodies in order to have a more diverse immune system able to recognize more outside pathogens. That deaminase tool turns out to go a long way toward making CRISPR precise enough to be considered for use in a therapy.

The Japanese work published in the journal Science, marks the second time researchers have recently published a way to use a deaminase tool to improve CRISPR. The prior work came from the lab of Harvard’s George Church, who is quoted extensively in an article about the latest study in The Scientist. Be warned, Church likes detail and this is a pretty technical article unless you are a science nerd like us at The Stem Cellar.

 

Animals with bits of human get green light.  A flurry of stories came out a few months ago when a reporter realized that while the National Institutes of Health (NIH) had a moratorium on creating chimeras—animal embryos that are partly human—CIRM was still funding the work. Now, NIH has announced plans to lift that moratorium with several safeguards in place to make sure certain projects that raise ethical issues don’t get approved. We are glad to have company in funding this potentially life-saving research.

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Researchers working in the area have two main goals. They want to create better models of human disease, and they want to grow human organs in animals such as pigs to alleviate the current shortage of donor organs and help the thousands of patients who die each year waiting for a donor.

NPR aired a story that did a good job describing the safeguards and the types of projects that would not be allowed. It quoted Carrie Wolinetz, the NIH associate director for science policy:

 “At the end of the day, we want to make sure this research progresses because it’s very important to our understanding of disease. It’s important to our mission to improve human health. But we also want to make sure there’s an extra set of eyes on these projects because they do have this ethical set of concerns associated with them.”

Forbes posted a story online that took great liberty with comparisons to science fiction, but had fun with it and in the end valued the potential for the work. And the public does have a chance to weigh in on the ethical issues as NIH has published a call for comments in the Federal Register.

Stem cells maturing into nerve produce a compound that speeds the process

Getting pluripotent stem cells—those early stage stem cells that can make any tissue—to actually make the cell type you want can be quite tricky. I have written before that it takes a village to raise a stem cell because they respond to everything around them from the physical pressure and rigidity of their environment to any number of already present or added chemical factors. Now, a CIRM-funded team at the University of California, Los Angeles, has shown they respond to a compound made in the maturation process itself.

As stem cells mature into specific tissue their metabolism speeds up and they convert sugar to energy more efficiently. In the process they produce compounds, various so-called metabolites, and it turns out those metabolites can be part of a feedback loop that speeds the maturation process. In particular, the UCLA team looked at the metabolite alpha-ketoglutarate and when they added it to it to stem cells in the process of turning into nerve cells in a dish, the process proceeded more quickly.

 

UCLA metabolite video

Lead researcher Tara TeSlaa describes the work in a video

Prior research had shown alpha-ketoglutarate gets involved in regulating gene activity. The Los Angeles researchers did some testing and determined that the metabolite was indeed turning off genes needed to keep the stem cells in a stem cell state and turning on genes needed to mature the cells into nerves.

 “Until very recently, metabolites have been overlooked as a way to help pluripotent stem cells differentiate,” said Michael Teitell, the senior author on the study in a university press release. “This work helps to change that view.”

The research published in Cell Metabolism showed a five to 40 percent improvement in the rate that cells matured into desired tissues. These results were based on lab cultures that already had the standard factors used to grow nerve cells, but also contained added alpha-ketoglutarate to see what a little extra of the metabolite would do. While they were looking only at nerve cells in this experiment, they speculated that the same metabolite would have similar effects in lab cultures using standard factors for growing other cell types.

The team now plans to try to determine exactly which genes the metabolite regulates. Every tidbit of information on how cells mature into desired tissues, makes it more likely we will be able to efficiently make those tissues to repair and replace tissues damaged by disease for patients in need.

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: 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.

Stem cell stories that caught our eye: heart repair, a culprit in schizophrenia, 3-parent embryos and funding for young scientists

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.

Chemicals give stem cells heart.  Coaxing stem cells into improving the function of failing hearts has proven quite difficult. Many trials have used a type of stem cell found in fat and bone marrow, called mesenchymal stem cells, to release factors believed to reduce scarring after a heart attack and improve the growth of new blood vessels to nourish the damaged area. But they have produced spotty and only modest positive results. CIRM funds a team at Capricor that uses related cells, but retrieved from heart tissue and believed to release factors that are more efficient in fostering repair—the results are still pending.

Get-Over-Heartbreak-Step-08 This week a Belgian company, using technology developed by the Mayo Clinic in Minnesota, announced positive results for a third option. They start with the stem cells from bone marrow, but in the lab treat them with a cocktail of chemicals that take them part way down the path to becoming heart muscle—into cells called cardiac progenitors. Having shown safety and initial signs of benefit in Phase 1 and 2 trials in Europe, the company Celyad launched the first part of a Phase 3 trial in 2012 and released the results this week.

The company’s research team found that, as with many breakthrough therapies, the most important aspect of early trials is defining which patients are most likely to benefit. The results did not show a benefit for the entire patient group lumped together, but did show significant gain for the 60 percent who fit a certain profile of symptoms at the start of the study. Twin Cities Business wrote about the research that originated in its home state, quoting the lead researcher with OLV Hospital in Belgium, Jozef Bartunek:

 “The results seen for a large clinically relevant number of the patients are groundbreaking,” adding that the results would direct the selection of patients for the second part of the trial to be conducted in the U.S.

The fundamental work done by researchers at Mayo discovered the mechanisms that drive an embryonic stem cell to become heart cells and used that information to develop the cocktail of chemicals that can turn ordinary adult stem cells into cardiac progenitors.

 

Stem cell model fingers culprit in brain. We were all taught the dogma about the path from genes to our tissues: DNA to RNA to protein. And we learned that two types of RNA did the heavy lifting in this transition from genetic recipe to functioning tissue. But RNAs have turned out to be a much more complex family of genetic players, with several types regulating genes rather than coding for any specific function. Some of the most active of these are the micoRNAs with more than 2,000 identified.

A CIRM-funded team at the Salk Institute in La Jolla has fingered one microRNA, miR-19, as playing a role in the faulty wiring seen among nerves in patients with schizophrenia. We always have a few nerve progenitor cells maturing into nerves. But the team found that when they altered the levels of miR-19 the new nerves did not migrate to where they were needed. So, the researchers made iPS type stem cells from patients with schizophrenia, matured them into nerves and looked at miR-19 levels and found them elevated. They also showed the nerve cells did not migrate properly.

 “This is one of the first links between an individual microRNA and a specific process in the brain or a brain disorder,” said senior author Rusty Gage, in an institute press release posted by trueviralnews.

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Over expressing the microRNA miR-19 resulted in new nerves migrating and branching abnormally (right) compared to untreated cells (left)

 

Profile of 3-parent pioneer.  No matter where you stand on the ethics of the “three-parent” fertilization technique that has been much in the news this year, you will enjoy reading Karen Weintraub’s well researched and well written piece about the leading pioneer in the field, Shoukhrat Mitalipov in STAT this morning.

 

Mitalipov-2

Pioneer Mitalipov

The technique focuses on the 37 genes that reside in our cells’ mitochondria rather than in the cells’ nucleus. We only inherit those genes from our moms because we only get the mitochondria in mom’s egg. So, when a woman has a disease-causing mutation in one of those genes, she could have a healthy child that mostly matched her genetic makeup if she could just swap out her mitochondria for someone else’s. That is exactly what the new technique accomplishes.

So far, it has only been tried in monkeys, the oldest of those offspring are now 7 but they are males. The first female is just 4 and since monkeys don’t reproduce until age 6 or 7, and the FDA wants to see how her babies fare, it will be some time before the procedure gets the green light to move forward in humans. None of the 3-parent monkeys show any health issues so far.

Karen’s piece paints a detailed account of the research’s protractors and detractors, as well putting a human face on the man leading the charge. As someone who reads regular posts from a cousin with a child struggling from “Mito” disease, I am rooting for this protagonist.

 

Funding challenge for young stem cell scientists.  A new study in the journal Cell Stem Cell quantifies a lament you hear anytime you are around young researchers, they have a hard time competing with older researchers in the field. The author of the report, Misty Heggeness from the National Institutes of Health, was quoted in news outlets including the San Diego Union Tribune and the blog Science 2.0 on a related issue that should set off alarm bells. If young people are not attracted to the field or fail to stay in the field, at the same time established scientists are nearing retirement age, we could end up with a gap in the research workforce in a few years.

 “From a policy and leadership perspective, one needs to understand what the near future year implications of an aging workforce are. If a system discourages younger cohorts from staying and is heavily composed of older cohorts who will exit the workforce in the near term, who will replace them?”

Part of the problem young researchers have seems to be baked into the current system. Young researchers compete fairly well with older ones on individual applications, but older researchers have the resources to file a lot more applications.  They have more personnel in their labs, freeing them up to write applications, and that personnel also produces the preliminary data that are often needed to even meet application requirements.

The Union Trib piece pointed out that older and younger stem cell scientists are both doing better with funding in California because of CIRM.

Stem cell stories that caught our eye: growing muscle, new blood vessels and pacemakers and Tommy John surgery

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.

Better way to grow muscle.  The specialized stem cells responsible for repairing muscle, the satellite cells, have always been difficult to grow in large quantities in the lab. They have a strong natural hankering to mature into muscle. Researchers have not been able to keep them in their stem cell state in the lab and that prevents creating enough of them for effective therapies for diseases like muscular dystrophy.

new muscle Kodaira

New muscle fibers in green grown in mice from satellite stem cells

A team at the National Institute of Neuroscience in Kodaira, Japan, published what seems to be a simple solution to the problem. In a press release from the publisher of the Journal of Neuromuscular Diseases posted by Science Daily they reported that adding just one protein to satellite cells allowed them to grow indefinitely in the lab and expand to the point they could provide a meaningful transplant that resulted in muscle repair in mice.

 “This research enables us to get one step closer to the optimal culture conditions for muscle stem cells,” said Shin’ichi Takeda from the institute.

The protein they used, leukemia inhibitory factor, and its downstream impacts on other genes is now the subject of their ongoing research.

 

Regenerating heart vessels. A CIRM funded team at Sanford Burnham Prebys Medical Discovery Institute (SBP) in San Diego and at Stanford University have shown that repressing a single gene can encourage the formation of new blood vessels in the heart. Creating those new conduits for oxygen after a heart attack could reduce damage to the heart muscle and prevent development of heart failure.

Building new blood vessels requires coordination of several growth factors and clinical trials evaluating individual factors have resulted in failure. The SBP team found that a single gene repressed all those needed factors and blocking it could let them do their job and create new blood vessels.

Mark Mercola

Mark Mercola

“We found that a protein called RBPJ serves as the master controller of genes that regulate blood vessel growth in the adult heart,” said senior author Mark Mercola, a professor at SBP and at Stanford, in an institute press release. “RBPJ acts as a brake on the formation of new blood vessels. Our findings suggest that drugs designed to block RBPJ may promote new blood supplies and improve heart attack outcomes.”

 The authors also suggested that RBPJ itself might be beneficial in cancer if it can inhibit the new blood vessels tumors need to thrive.

 

Bionic patch as pacemaker.  Chemists at Harvard have designed nanoscale electronic scaffolds that can be seeded with heart cells and are able to conduct current to detect irregular heart rhythms and potentially send out electrical signals to correct them.

 “Rather than simply implanting an engineered patch built on a passive scaffold, our works suggests it will be possible to surgically implant an innervated patch that would now be able to monitor and subtly adjust its performance,” said Charles Lieber the senior author in a university press release posted by Phys.Org. The research was published in Nature Nanotechnology

 With its electronics built into the patch that is integrated into the heart, Lieber suggested the bionic patch could detect heart rhythm problems sooner than traditional pace makers. Another use for the patch he suggested could be to screen potential drugs.

 

Alternate to Tommy John in pictures. Sports fans generally have a vague idea of what Tommy John surgery is. First performed on baseball pitcher Tommy John of the LA Dodgers in 1974, the surgery replaces a torn elbow tendon with one from another part of the body.  A number of baseball players in the past couple years have made headlines because they sought out an alternative to this invasive procedure using stem cells.

The players sometimes improve, but with their high-priced team doctors also demanding extensive physical therapy and other interventions, we don’t really know how much of the improvement is due to the stem cells.  I am not aware of controlled clinical trials looking at the alternative therapy.

LA Angels Andrew HeaneyBut given how much it is in the news, I thought it would be good to share this excellent info-graphic from the LA Times explaining exactly what happens with the stem cell version of the Tommy John procedure. The Times posted the graphic yesterday, and then today, papers around the country ran stories that the most recent famous recipient of the cells, Los Angeles Angels lefthander Andrew Heaney, was going to have the old-fashioned surgery today because the stem cell treatment did not work in this case.

There may be some individuals, likely those with only partial tears who might benefit from this stem cell procedure that uses a type of stem cell that is not likely to replace tendons, but can release factors that summons the body’s natural healing apparatus to do a better job.  But until more formal clinical trials are conducted, it will be hard for     doctors to know who would and would not benefit.

Presentations at ISSCR that caught our eye: Stem cell clinical trials expand as work to improve our understanding of just how they work goes on in parallel

In a special edition of our weekly roundup, here are some highlights from just the first two days of the four-day annual meeting of the International Society for Stem Cell Research

 Seeing stem cells from both sides now. As the biggest gathering of stem cell researchers each year, the annual meeting of the International Society for Stem Cell Research offers a chance to catch up on progress across the complete spectrum of research, from fundamental exploration in the lab to clinical trials. This year’s meeting in San Francisco offers more advances toward the clinic than ever before, but it also shows a cadre of basic researchers struggling to understand what is really going on at the genetic and molecular level with some of the biggest breakthroughs of the past few years. It is a bit like the opening verse of Joni Mitchell’s song “Both Sides Now” in which she laments that even after seeing clouds as beautiful patterns and as blocks to the sun she does not really know clouds at all.

Yamanaka at ISSCR 2016

Nobelist Shinya Yamanaka at the annual ISSCR meeting

Nothing captured that spirit better than the opening talk on the second day by Nobel Prize winner Shinya Yamanaka who maintains labs at Kyoto University in Japan and at the Gladstone institutes here in San Francisco, about a mile from the site of the meeting. This year marks the 10th anniversary of his Nobel-winning discovery that you can use genetic factors to reprogram adult cells into embryonic-like stem cells called iPS cells. Even as his institute is supplying the cells for the first ever clinical trial using iPS, in this case in the blinding disease called macular degeneration, he spent much of his talk discussing his ongoing basic research trying to understand what really goes on in that reprogramming process, and why so many cells are refractory to reprogramming with only a few percent in most experiments becoming stem cells.

Before launching into his ongoing basic research—some of it from a research thread he began to unravel as a postdoc at the Gladstone—he told an enlightening tale of how he had been reprogrammed as a scientist.  He said that he went from a a basic researcher just working in his lab to someone who spent much of their time talking to government officials, bankers and donors. But he noted that like our cells, part of him was refractory to reprogramming and he still liked getting into the lab to do the basic research needed to understand the creation of iPS cells and make it it faster and more efficient, which is critical to any future role for the cells at the other end of the research pipeline—treating patients in need.

 

It takes a neighborhood. As usual much of the basic science revolved around the lab recipes needed to keep stem cells in the stem cell state in the lab, or how to efficiently direct them to become a specific type of adult tissue. On the latter there was also considerable work presented on how to get around the fact that too often the adult cells created from stem cells are not fully mature and function more like those tissues would in the fetus than they should in an adult patient.

Fiona Watt of Kings College London presented her work on studying the one “organ” that is easier to study in humans than mice: the skin hair follicle. In the furry critters the hair follicles are too close together to easily isolate individual ones. With our sparser covering it is easy to study single hair follicles, which serve as the niche that houses skin stem cells until they are needed to replenish or repair our outer barrier. In recent years, when trying to understand how stem cells stay stem cells or decide to mature into specific tissue, researchers have increasingly turned their attention to the niches all over the body that stem cells call home. They are finding that there are many facets to these homes—physical, chemical and genetic—that like any neighborhood, impact how a stem cell grows up.

Watt opened by paying tribute to a pioneer in the field who died this past year, Harvard Med School’s Howard Green, who was always a treat to interview when I was there, and who pioneered single cell analysis in skin four decades ago. Watt’s work tries to break down the various components of the skin stem cell niche in the lab to see how each contributes to cell fate. She looked at the extracellular matrix, the scaffold that holds cells in place, and found a link between the size of the hole in the scaffold and cells remaining stem cells. She also found difference between soft and hard scaffolds. She noted other factors such as the type of cell that lives next door and the oxygen level all impact the cell decisions.

She suggested that these determinants of cell fate are likely consistent across stem cell niches throughout the body and will be critical to more efficiently producing replacement tissues to help patients.

 

Jumping from A to C, skipping B.  Two researchers followed Watt who are trying to develop ways to skip the step of turning adult cells in to iPS-type stem cells and instead convert them directly into the desired tissue needed for repair. Stanford’s Marius Wernig, who cited funding from CIRM and the New York Stem Cell Foundation, reported on his work trying to improve his breakthrough from a few years ago in which he converted skin into nerve with just one genetic factor. He is investigating the underlying structures of our DNA to try to understand why only 20 percent of cells make the desired conversion. He is finding some answers but has more to ferret out.

 

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Malin Parmar

Then Malin Parmar of Sweden’s Lund University went into more detail on the fetal cell and stem cell transplant trials she is working with in Parkinson’s disease that she described at our public symposium earlier in the week. But she closed with work that she thinks could be the ultimate best solution to the disease.  Finding genetic factors that can convert other nerve cells directly into the dopamine-producing nerve cells lost in patients with the disease. She started with Wernig’s recipe and added a genetic factor known to drive cells to become dopamine nerves. She succeeded in turning brain cells called glial cells into dopamine nerves inside the brains of mice and showed they made the needed connections to other brain cells. But the work is still some years from getting to patients.

 

The complexities of the heart.  Yesterday afternoon five researchers presented different ways to figure out how to use stem cells to repair or replace a very complex organ, the heart. Shen Ding from Gladstone, who has pioneered the concept of using chemical instead of genetic factors to reprogram cells, presented his latest work in which he used that technique to grow partially mature heart cells in the lab, transplanted them into mice and saw them mature into tissue that improved heart function in a model of heart attack. He said his next experiments will involve finding a way to deliver the chemicals directly into the damaged heart to try to get the reprogramming done in the living animal.

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Stephanie Protze, of the McEwen Centre for Regenerative Medicine in Toronto, presented work on another component of the heart, the pace maker cells that ensure any new muscle cell beats at the right speed.  She described a recipe to drive stem cells to become pace maker cells, but there was a glitch. They beat at 150 beats per minute, which is the fetal rate not the adult rate. So, once again the field ran into the block of creating only partially mature tissue.

Tamer Mohamed, also of the Gladstone, presented work using chemicals to convert heart scar tissue to functional heart muscle. His work tweaked an earlier recipe that resulted in fewer than one percent of cells converting to a procedure that resulted in 30 percent. In the mouse model he saw improved heart function and reduced scarring.

University of Pittsburgh’s Lei Yang presented work on a very big, long-term goal for the field: producing a complete replacement heart. Like several other teams, his group started with a mouse donor heart and used detergents to wash away the cells so that all that was left was the scaffold of that extracellular matrix mentioned above.  He then seeded the scaffold with heart cells derived from iPS cells and let them mature.  The work resulted in what he called “beating heart constructs.”  Some of the cells beat with needed synchronicity and some did not.

All in all, the meeting exudes measured confidence. The field is clearly making rapid strides toward understanding stem cells well enough to create meaningful therapies.  However, it is ripe for what is called “reverse translation,” which is taking the findings of early clinical trials  that don’t perform quite as well as desired, and going back to  the lab to figure out how to make them better.