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.



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.


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.

Stem cell stories that caught our eye: hearts with nerve, keeping adult stem cells as stem cells and lab models for the inner ear and pituitary

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.

Hearts with nerve.  When trying to heal a damaged heart you can’t just worry about the heart muscle, you also need to pay attention to the nerves that tell the muscle what to do. A team at John Hopkins has grown nerves from stem cells in the lab that connect to heart cells growing in the same dish, a key step to making the two tissues collaborate where you need them.

Specifically, the team grew sympathetic nerves—a name that never made much sense to me, but basically refers to all those nerves that function without us thinking about their role, like breathing and heartbeat. Faulty sympathetic nerves lead to several diseases including high blood pressure. While it will likely be many years before this work leads to lab-grown heart muscle and nerves teaming up in actual patients, using nerves grown from stem cells made from patients, teams can begin studying those diseases in the lab now.

The researchers published their work in Cell Stem Cell, and ScienceDaily posted the university’s press release. Much of the work involved what has become classic in stem cell research, trying many different combinations of growth factors applied at different moments in time until they arrived at just the right recipe to end up with sympathetic nerves.



Lab grown inner ear structure (Indiana University)

Inner ear grown in a dish.  Researchers at Children’s Hospital, Boston, and Indiana University have succeeded in growing a sac-like tissue that contains the inner ear organs responsible for balance. Starting with mouse embryonic stem cells, the resulting one millimeter structure contained functioning sensory hair cells critical to hearing.

Jeffrey Holt of Children’s said, in the hospital’s Vector blog, that he hopes to use the lab model of the inner ear to test potential therapies for balance disorders he sees in children coming to the facility. The lab-grown tissues seem to behave like the real thing, responding to mechanical stimuli by producing tiny electrical currents. The team published its research in Nature Communications.


Getting adult stem cells to stay stem cells.  While pluripotent stem cells like embryonic stem cells can generally be grown in the lab indefinitely, most stem cells from adult tissue eventually mature into specific adult tissue and loose the stem cell property of being able to renew themselves. Researchers at Harvard and Massachusetts General Hospital (MGH) developed a process that keeps adult stem cells from maturing into specific tissue. This could eventually help teams scaling up production of potential therapies but can already speed up and reduce the cost of much of the research getting to that point.

The MGH team worked with airway stem cells, which have been particularly hard to maintain in the lab and require constant collection of new cells that can require invasive procedures such as bronchoscopy. This has made diseases such as asthma and COPD hard to study using stem cell models of disease, which are generally more accurate than animal models.

They started by looking at what internal cellular signaling pathways were active in cells that were maturing into specific tissue but that were not active in the stem cells. They found two such pathways and developed ways to shut down those cell signals. That in turn kept cell in the stem cell state and allowed them to be grown in large quantities in the lab. They were even able to do this with the few airway stem cells that patients cough up when collecting a sputum sample. This would greatly simplify stem cell collection for researchers and patients.

“We also found that the same methodology works for many tissues of the body — from the skin to the esophagus to mammary glands. Many of these organ tissues cannot currently be cultured, so it remains to be seen whether scientists in these areas will be able to grow stem cells from samples acquired from other minimally invasive procedures, including the collection of secretions. If all this becomes possible, it would represent a big step forward for personalized medical approaches to disease,” said Jayaraj Rajagopal, senior author on the paper published in Cell Stem Cell in an MGH press release posted by ScienceDaily


Tunable pituitary tissue. While prior research has reported creating tiny pituitary organoids in a dish, those tissues were not very precise in what hormones they produce. Given the fact that the pituitary gland secretes hormones for growth, reproduction and the stress response, and patients with pituitary disease have varying deficiencies in specific hormones, random production of various hormones isn’t likely to be effective treatment.


Pituitary cells grown from stem cells

Now a team at the Sloan Kettering Institute for Cancer Research led by Lorenz Studer has developed a system of adjusting two factors used to drive stem cells to become pituitary tissue. This system results in adjustable proportions of the tissue that produces different hormones. That way you can get more or less of the various hormones that a patient may need.

When transplanted into rats, the lab grown tissue succeeded in secreting multiple hormones and causing appropriate responses in the animals. Bastian Zimmer, the first author on the paper in Stem Cell Reports, suggested the technique could be used to generate specific cell types for patients with different types of hypopituitarism.

“For the broad application of stem cell-derived pituitary cells in the future, cell replacement therapy may need to be customized to the specific needs of a given patient population,” Zimmer said in a release provided by the journal and posted by MedicalXpress.

Patient advocates a small but mighty force at BIO meeting

Patient Advocacy Pavilion at BIO2016

Patient Advocacy Pavilion at BIO2016

A few hundred patient advocates operating from a small sub-section carved out of three cavernous exhibit halls could easily get lost amid the 16,000 scientists and business folks attending the BIO International meeting in San Francisco last week. But their voice was heard as they made great use of the meeting to remind companies developing therapies that they are the end user. They are the reason why the companies exist.

Talking to many advocates representing their constituents from the tiny two-foot by one-foot shelves and a stool they were each given within the advocate zone a couple of consensus points came through. The meeting provided incredibly valuable contacts for the patient advocates, and the attitudes of the companies are changing.

 “We want to make people aware that family caregivers are making care decisions,” said Mark Gibbons of the Caregiver Action Network. “It has been wonderful having companies reach out to us rather than us making cold calls on them.”

Bill Remak of the California Chronic Care Coalition had similar thoughts on the changing attitude, but on a different aspect of the patient-company interface:

 “This has been a very good meeting; we made really good contacts and had great discussions on business models, pricing and making products accessible to patients. The mentality is changing to more concern on patient access.”

We had a lengthy discussion with Sean Elkins, chief science officer, and Allison Moore, CEO, of the Hereditary Neuropathy Foundation. They fight the battle to get therapies to their constituents on two fronts: The battle to get funding for the research as well as the added barrier of working with orphan diseases. They represent folks with Charcot-Marie-Tooth (CMT) disease and a half dozen related neurologic conditions. And while a prevalence of one in 2,500 makes it one of the more common orphan diseases, they have no treatments, and still have a hard time getting some company’s attention.

Allison Moore

Allison Moore and Sean Elkins

As a result, they initiate many research projects themselves with their own donor-derived funds and federal grants. In one effort they developed an assay for whether existing drug compounds could impact the nerves of patients with CMT. They have been testing many existing compounds and finding a few candidate therapies. But Elkins lamented on Twitter that he wished the drug companies would train their exhibit staff better about rare diseases. “When you approach some of them and say you have tested some of their products in an orphan disease they act like a deer in the headlights.”

His colleague, Moore, noted their efforts to take the bull by the horns and bring in the next generation of scientist/business people to tackle their diseases. “The highlight of the meeting for us has been meeting with former academics starting companies who are excited about the prospect of working on something new.”

Moore’s own story highlighted the dedication evident among the advocates at the meeting. She is a patient herself and not just a foundation executive. She worked the meeting so hard that by the third day she had bandages on both legs to cover the blisters from the braces that allow her to walk despite the underlying illness.

Everyone working the patient advocate zone at the meeting seemed pleased to have the chance to make connections that might one day make things a bit better for their constituents. This was the first time attending for the team from the California Chronic Care Coalition and the group’s CEO, Liz Helms, was exuberant in stating their time was well spent:

 “This meeting was over the top valuable; everything we expected and more.”

Stem cell stories that caught our eye: hopeful stroke data, new target for muscular dystrophy and a rave from Silicon Valley

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.

Stroke study offers hope.  The dogma in stroke recovery says six months after the event patients will have recovered as much as they ever will. A research team at Stanford and the University of Pittsburg may have proven that wrong. They injected mesenchymal stem cells (MSCs) from donor bone marrow directly into the brains of 18 patients and saw significant improvement in the patients’ mobility.

Gary Steinberg, the lead researcher at Stanford where 12 of the patients were treated, offered appropriate caution in a university release stating that more and bigger clinical trials will be needed to verify these results:

“This was just a single trial, and a small one. It was designed primarily to test the procedure’s safety. But patients improved by several standard measures, and their improvement was not only statistically significant, but clinically meaningful. Their ability to move around has recovered visibly. That’s unprecedented.”


At least one patient was able to abandon her wheel chair

At least one patient was able to abandon here wheel chair.

News outlets around the world ran the story including CNBC and Hufffington Post, which included an interview with Sonia Olea Coontz who had one of the more dramatic recoveries. Like most of the patients, Coontz was more than a year out from her stroke and generally considered unable to regain any lost function, but after the injection her right arm and leg “woke up” in her words.

The team used MSCs from two donors that had been modified to enhance their ability to secrete factors that can foster the innate healing ability of the brain. Steinberg noted that the stem cells did not stay in the brain for much more than a month. But, during that time they seem to have done something pretty amazing. Can’t wait to see if the team repeats this result in a planned 156-patient trial.


 Stem cell decisions and muscular dystrophy. While most muscle repair relies on a type of stem cell that can only become muscle, a second type of stem cell that can become muscle or fat also has a role and might provide a way to intervene in the muscle wasting of muscular dystrophy. A team at Rockefeller University in New York City has found a gene that can direct those cells, called pericytes and PICs, to preferentially become muscle.

Previous work had shown that the loss of the protein laminin was associated with some forms of muscular dystrophy and that injecting it directly into the muscle of mice did alleviate some of their muscular dystrophy. But laminin does not migrate from the injection site so in humans would require far too many injections. So the Rockefeller researchers looked to see how laminin affects the activity of genes—whether they are turned on or off—in those special stem cells. They found one gene in particular, gpihbp1, that when forced on could result in the stem cells making much more muscle.

 “Our data suggests that gpihbp1 could be a novel target for the treatment of muscular dystrophy,” said team leader Sidney Strickland in an article posted by Scicasts.

 The researchers published their work in the journal Nature Communications.


Silicon Valley leader pushes stem cells. Eric Schmidt, former CEO of Google and current executive chairman of its parent company Alphabet, told The Economic Club of New York this week that America needs to concentrate on transformative big ideas, and he included stem cell science among those.

Google's Eric SchmidtWhen he talked about tackling important problems with science and technology he cited 3D printing of buildings and using stem cells to grow body parts as examples. In an article on he said he is seeing an “incredible revolution in medicine and this incredible revolution that’s going on in knowledge.”

When the interviewer, Charlie Rose, asked him whether, if he was starting over today, if he would go into computer science or biology, he answered with an anecdote about a computer scientist who went into biology marrying the two.


Stem cell stories that caught our eye: reducing radiation damage, making good cartilage, watching muscle repair and bar coding 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.

A bomb blastaStem cells key to reducing radiation damage. With the anniversary of Hiroshima and President Obama’s historic visit to the site all over the news this week, it was nice to read about research that could result in many more people surviving a major radiation event—either from a power plant accident or the unthinkable repeat of history.

Much of the life-threatening damage that occurs early after radiation exposure happens in the gut, so a way to reduce that damage could buy time for other medical care. A team at the University of Texas Medical Branch at Galveston has discovered a drug that activates stem cells in the gut, which help maintain a healthy population of crypt cells that can repair gut damage.

A single injection of the small protein drug in mice significantly increased their survival, even if it was given 24 hours after exposure to radiation. The researchers published their work in the journal Laboratory Investigation and in a story written for MedicalNewsToday the lead author, Carla Kantara suggested the role the drug might have:

 “The current results suggest that the peptide may be an effective emergency nuclear countermeasure that could be delivered within 24 hours after exposure to increase survival and delay mortality, giving victims time to reach facilities for advanced medical treatment.”

The small protein, or peptide, named TP508, has already been tested in humans for diabetic foot ulcers so could be tested in humans fairly quickly.


Making good cartilage for your knees. Rarely a week goes by that I don’t tell a desperate osteoarthritis patient with painful knees that I am treating my own rotten knees with physical therapy until we learn how to use stem cells to make the right kind of cartilage needed for lasting knee repair. So, I was thrilled to read this week that the National Institutes of Health awarded Case Western Reserve University in Cleveland $6.7 million to develop a center to create standardized systems for monitoring stem cells as they convert into cartilage and for evaluating the resulting cartilage.

ear_wakeforest There are a couple problems with existing attempts to use stem cells for knee and other cartilage repair. First not all cartilage is equal and too often stem cells form the soft kind like in your earlobe, not the hard kind needed to protect knees. Also, it has been hard to generate enough cells to replace the entire area that tends to be eroded away in osteoarthritis, one of the leading causes of disability.

The new center, which will be available to researchers anywhere in the world, will develop tools for them to measure four things:

  • which genes are turned on or off as stem cells take the many steps toward becoming various forms of cartilage;
  • predict the best makeup of the extracellular matrix, the support structures outside cells that help them organize as they become a specific tissue;
  • evaluate the biochemical environment around the cells that helps direct their growth;
  • measure the mechanical properties of the resulting cartilage—is it more like the ear or the knee.

NewsWise posted the university’s press release


Damaged muscle grabs stem cells.  All our tissues have varying skills in self repair. Muscles generally get pretty high marks in that department, but we don’t really know how they do it. A team at Australia’s Monash University used the transparent Zebra fish and fancy microscopes to actually watch the process.

When they injured mature muscle cells they saw those cells send out projections that actually grabbed nearby muscle stem cells, which regenerated the damaged muscle. They published their findings in Science, the university issued a press release and a news site for Western Australia, WAtoday wrote a story quoting the lead researcher Peter Currie:

 “A significant finding is that the wound site itself plays a pivotal role in coordinating the repair of damaged tissue. If that response could be sped up, we are going to get better, or more timely, regeneration and healing.”

The online publication posted four beautiful florescent images of the cells in action.


muscle stem cells Monash

Muscle stem cells in action

“Bar coding” cells points to better transplants.  A team at the University of Southern California, partially funded by CIRM, developed a way genetically “bar code” stem cells so they can be tracked after transplant. In this case they watched the behavior of blood-forming stem cells and found the dose of cells transplanted had a significant impact on what the cells became as they matured.

The general dogma has blood stem cells producing all the various types of cells in our blood system including all the immune cells needed by cancer patients after certain therapies. But the USC tracking showed that only 20 to 30 percent of the stem cells displayed this do-it-all behavior. The type of immune cells created by the remaining 70 to 80 percent varied depending on whether there was a low dose of cells or a high dose, which can be critical to the effectiveness of the transplant.

 “The dose of transplanted bone marrow has strong and lasting effects on how HSCs specialize and coordinate their behavior,” said Rong Lu, senior author, in a USC press release posted by ScienceDaily. “This suggests that altering transplantation dose could be a tool for improving outcomes for patients — promoting bone marrow engraftment, reducing the risk of infection and ultimately saving lives.”

Free public event will detail the many ways stem cells are used in clinical trials today

The hundreds of active stem cell clinical trials being run in the US, and indeed around the world, provide ample evidence that our favorite cells are truly multi-talented. There are so many different ways researchers are using them to develop therapies we would be hard-pressed to name them all. However, most fall into five general categories that will be discussed at a free public symposium CIRM is co-hosting in conjunction with the International Society for Stem Cell Research during its annual meeting in San Francisco.

Moscone at dusk

San Francisco’s Moscone Center is close to BART and Muni public transit

The free public event will run from 6:00 to 7:30 on Tuesday evening June 21 at the Moscone West convention center, room 2009, on the corner of Howard and Fourth streets in San Francisco. After a brief overview, four researchers will describe active clinical trials and how stem cells provide hope for therapies in different diseases.  The last half hour will be open for general questions from the audience.

All the details are at a special page on EventBright where you can register to attend. The evening will start with Bruce Conklin of the Gladstone Institutes providing an overview of the many ways to use stem cells, including his own work using them to create laboratory models of heart disease. Then:

  • Malin Parmar of Sweden’s Lund University will discuss a Parkinson’s disease trial where stem cells are used to replace vital brain cells destroyed by the disease;
  • Donald Kohn of the University of California, Los Angeles, will provide details of two trials that combine stem cells and gene therapy, one for sickle cell anemia and one for severe combined immune deficiency, also called Bubble Baby disease;
  • Henry Klassen of University of California, Irvine, will talk about using progenitor stem cells to deliver factors that can protect the photoreceptors in the eyes of patients who have a blinding condition;
  • Catriona Jamieson of the University of California, San Diego will describe the bad boy of the stem cell world, the cancer stem cell, and clinical trials she is conducting to attack those cells.

While some of the hundreds of current stem cell clinical trials will not produce the desired impact on their target diseases, they will all make strides toward learning how to optimize the great potential of stem cell therapies.

Right now CIRM is funding 16 different clinical trials in diseases as varied as HIV/AIDS and type 1 diabetes. Over the next 5 years we hope to add another 50 clinical trials to that list. The field of regenerative medicine is advancing. This event is a chance for you to understand the progress, and the challenges, that we face in bringing potentially life-changing, even life-saving therapies to the people who need it the most, the patients.

In the Stem Cellar: making better blood stem cells, a heart guard, iPS model points to ALS drug and tracking 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.

Major step in creating blood stem cells. If you track stem cells in any online news search, your feed perpetually will have numerous posts about attempts to find a bone marrow stem cell match for a desperate cancer patient. The power of those cells to reconstitute a person’s immune system after aggressive therapy saves the lives of thousands of cancer patients every year, but too many patients still die waiting to find an immunologically compatible donor.

Since pluripotent stem cells, both embryonic and iPS cells, can create any cell type in the body, they should be able to produce the needed blood forming stem cells. But that feat has been one of the toughest to accomplish in the young history of stem cell science. Blood stem cells created from pluripotent cells don’t self-renew like they should and don’t take up residence in the bone marrow properly. A CIRM-funded team at the University of California, Los Angeles, has made a major stride toward making this possible.

The team, led by Hanna Mikkola, started by looking at what genes were turned on in blood stem cells they created in the lab compared to natural ones. They pinpointed one set of genes, the HOXA genes, that is linked to the ability to self-renew. Next, they found that mimicking the effects of retinoic acid, a derivative of vitamin A, can turn on the HOXA genes.

 “Inducing retinoic acid activity at a very specific time in cell development makes our lab-created cells more similar to the real hematopoietic stem cells found in the body,” said Diana Dou, a graduate student in Mikkola’s lab in a UCLA press release.

While this is one major hurdle leaped, the team acknowledges they have more work to do before they can create lab-grown blood stem cell that fully match the functions of natural blood stem cells.


Turned-off gene protects hearts.  When Nobel Prize winner Shinya Yamanaka reprogrammed skin cells into embryonic-like iPS cells, he activated four genes that are very involved in embryo development, but have been assumed to be inactive in adults. Researchers at the University of Virginia published data overturning that dogma, and more importantly suggested that one of those genes, Oct4, is not just active in adults, it protects people from heart disease.

They found that Oct4 plays a role in the formation of atherosclerotic plaque. When that plaque buildup in arteries ruptures it causes heart attacks and strokes.  But Oct4 instructs smooth muscle cells to create protective fibrous caps that make the plaques less likely to rupture. The team leader, Gary Owen, speculated that Oct4 might also be involved in other aspects of the body’s effort to repair damage and heal wounds.

 “Finding a way to augment the expression of this gene in adult cells may have profound implications for promoting health and possibly reversing some of the detrimental effects with ageing,” said Owen in a story in Scicasts adapted from a university press release.

The researchers are now looking for ways to selectively activate Oct4 for therapeutic purposes.



Nerves grown from iPS cells

Stem cell model leads to potential ALS drug.  In amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease) motor nerves that allow all forms of movement die off. But, some nerves seem to be resistant to this damage. Researchers at Sweden’s Karolinska Institute and at the University of Milan in Italy have found that a specific nerve growth factor can protect motor nerves from ALS.

That factor, insulin-like growth factor 2 (IGF-2), was able to rescue human motor nerves grown in the lab from iPS-type stem cells made by reprogramming skin of ALS patients. The researchers then provided IGF-2 to mice with ALS-like disease through gene therapy and the animals lived longer than without the growth factor.

 “We can see that motor neurons are preserved and that IGF-2 treatment causes the axons to regenerate and recreate vital connections with muscles that were previously lost,” said Karolinska’s Eva Hedlund in a press release posted by MedicalXpress.

 Prior attempts to treat ALS patients with a related compound, IGF-1, by injecting it under the skin failed.  The current team suggests that direct delivery to motor nerves via gene therapy could provide a better outcome.


Labeling and tracking stem cells.  Numerous studies have shown stem cells grown in the lab function more like normal stem cells the closer the lab environment comes to mimicking the natural environment where the cells would grow in the body. Using that strategy a team at Carnegie Mellon University in Pittsburg succeeded in loading stem cells with an FDA-approved iron nanoparticle that will allow them to track the cells after transplant.


MSCs with iron nanoparticles

MSCs labeled with iron nanoparticles

They focused on a type of stem cell found in bone marrow, mesenchymal stem cells (MSCs), which are being used in more than half of the 600+ active stem cell clinical trials. To date, MSC trials have produced a very mixed bag of results, with much of the poorer outcomes attributed to the cells not going to, and staying, where they are needed.  So this tracking technique could help develop strategies to improve those outcomes.

Up to this point, researchers could not get the tracking agent into cells without using an agent to help get the particles across the cell membrane and those agents tend to disrupt the normal cell function. But, in their normal environment cells will engulf small particles on their own.  So the Carnegie team added other cells types found in bone marrow to their lab cultures, the MSCs felt more at home, and took up the nanoparticles. A neat little trick written up in a university press release posted at Science Daily.

Stem cell stories that caught our eye: Zika virus and brain stem cells, new guidelines, re-growing tails and better iPS 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.

Three more studies on Zika and brain stem cells. It’s heartening to see how quickly the scientific community has reacted to the recent Zika virus epidemic. They have already completed and published dozens of research projects. And science journals have responded by not only speeding up their often slow process to get results published, but also some are removing pay walls to ease disseminating the data.

After a pair of studies earlier this month showed how the virus could impact brain stem cells in mini human brain “organoids” in the lab, three studies this week showed how the virus does its damage in animal models. A colleague wrote two blog posts on the human mini-brain studies, one revealing the entry point the virus uses to enter brain stem cells and the other finding the virus negatively impacts the ability of brain stem cells to specialize into mature brain.


Zika in placenta Wash U

Zika virus (red) in a mouse placenta (Washington U.)

While those organoids can tell us a lot, they don’t show what happened when the fetus matures, so the new mouse models provided the first conclusive link between infection and microcephaly—the small brains seen in children born following their mother’s infection with the virus. But the three studies muddied the water a bit on the cause of the reduced brain size. One suggested that damage to the placenta could have reduced blood flow to the developing fetus. The other studies showed that the virus does indeed infect brain stem cells, but one suggested that the bulk of the damage from the virus occurs later in pregnancy acting directly on mature nerve cells, not the stem cells.

The papers in Cell from Washington University in St. Louis, in Nature, from the University of California, San Diego and in Cell Stem Cell from the Chinese Academy of Science got wide media coverage. Genetic Engineering News and Science Magazine did some of the most thorough reporting and Newsweek wrote a piece a bit easier to understand.


Stem cell research guidelines.  When an august scientific body issues guidelines for its work, the public generally either ignores it or never hears about it. That paradigm shifted a bit this week when the International Society for Stem Cell Research issued revised guidelines for numerous aspects of regenerative medicine research and practice. A large part of the difference probably resulted from the group self-cautioning its members to avoid hype and not oversell their results.

The Bloomberg business wire issued a story with the headline, “Stop Hyping Stem Cell Science, Say Stem Cell Scientists.” Four scientific journals simultaneously published various reviews of the guidelines including one in Science authored by five members of the 25-person committee that drafted them. That piece carried the title, “Confronting Stem Cell Hype.”

One of the authors, Tim Caulfield of the University of Alberta, acknowledged changing the discourse in the field will not be easy:

 “Because the forces that twist how science is communicated are complex, systemic, and interrelated, correcting for science hype will not be easy.”

Beyond the hype, the guidelines address several important issues in our field calling for:

  • a process to review all embryo research, not just when the embryo is destined to be a source of stem cells;
  • support for laboratory research on genetically modifying sperm, eggs and embryos, but banning such techniques for clinical use at this time;
  • defining proper research and clinical use of techniques to swap out healthy mitochondria, for defective ones in cells;
  • allowing compensation for women who donate eggs for research within certain defined parameters
  • creating robust standards for evaluating the outcome of stem cell clinical trials.


Just a few switches to regrow a tail.  Many lizards and amphibians regrow their tails with ease, but prior research has shown a great many genes get turned on to make it happen. Now, a team at Arizona State University has shown that just three genetic switches orchestrate much of that gene activity.

arizona_green anole lizard

Green Anole lizard (Arizona State U.)

The tiny genetic components called microRNAs turn out to be very powerful on-off switches for genes and can control many different genes at the same time.

 “Since microRNAs are able to control a large number of genes at the same time, like an orchestra conductor leading the musicians, we hypothesized that they had to play a role in regeneration,” said senior author Kenro Kusumi in a story in Bioscience Technology.

 The group hopes their research will lead to ways to get tissue regeneration in humans for repairing damage such as spinal cord injury or worn knee cartilage.


Making better iPS cells.  Although we have known for a decade the basics of how to turn an adult cell into an embryonic-like stem cell, iPS cells, virtually that entire time researchers have sought ways to make them even more like embryonic stem cells. Too often iPS cells retain memory of the adult cell they came from and stubbornly refuse to turn into certain other types of tissue.

Researchers at the University of Pennsylvania have shed light on this stubborness using an emerging field called “3D epigenetics.”  Epigenetics looks at the various controls that turn genes on and off, but it traditionally cannot take into account the effect of DNA folding that puts genes next to each other adding a layer of regulation based on juxtaposition.  They found that in some iPS cells the DNA folding looked more like mature cells than embryonic stem cells, but that by manipulating the way the cells were grown they could modify that folding.

 “Our observations are important because they suggest that, if we can push the 3-D genome conformation of cells that we are turning into iPS cells to be closer to that of embryonic stem cells, then we can possibly generate iPS cells that match gold-standard pluripotent stem cells more rapidly and efficiently,” said graduate student Jonathan Beagan in a university press release.

Stem cell stories that caught our eye: two-week old embryos in the lab, gene edited disease model, recipe for bone and cancer milestone

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.

Two-week embryos grabbed headlines. I have rarely seen as many online news outlets pick up a basic science story as happened this week with the news that an international team had nearly doubled the time it is possible to keep an embryo alive in a lab dish. While the research has tremendous potential to improve the chances couples can bring a new life into their families, the bulk of the coverage focused on the ethical issues surrounding the research embryo itself.


Imaris Snapshot

Molecular markers highlight various parts of a 12-day old embryo

After countless national and international confabs in the late 1970s and into the 1980s, research organizations around the world adopted the policy that no one would grow an embryo in the lab beyond 14 days. That is the point the “primitive streak” develops marking the first time cells within the embryo adopt individual identities. But the rule required no enforcement because no one knew how to coax an embryo into growing beyond nine days, and few could get them even to grow seven.

That changed this week, when the team led by Ali Brivanlou at Rockefeller University got embryos to grow to 13 days. They followed a procedure developed by a team colleague in Cambridge, UK, in mice reported earlier. They basically made the embryos feel more at home. They tested many different chemicals to add to the lab dish to optimize growth and gave the embryos a rigid structure more like a uterine wall.

They successfully mimicked implantation, the key step when the few-day-old embryo attaches to the uterus. Failure in this critical step is a key cause of infertility, but we have never been able to find out how it happens, and what little we do know suggests the mouse model for that step is not a good one for looking at human fertility.

 “This portion of human development was a complete black box,” said Brivanlou in a university press release picked up by many outlets including Bioscience Technology. She later added: “With this work, we can really appreciate the differences between human and mouse, and across all mammals. Because of the variations between species, what we learn in model systems is not necessarily relevant to our own development, and these results provide crucial information we couldn’t learn elsewhere.”

Because of that incredible potential value in this work, the journal Nature that published the research paper also ran a commentary about the current 14-day limit on growing embryos in the lab. It does not call for changing the policy at this time, but it does suggest the conversation–likely to be long–about whether the benefits of this work outweigh the ethical trip wires should begin soon.

The Washington Post wrote one of the most balanced pieces discussing both sides of the issue.


A mightier disease-in-a-dish model.  We frequently write about using iPS type stem cells to model diseases. Usually this involves getting a skin sample from a patient with a genetically-linked disease, converting it to stem cells and then growing the nerve or other tissue impacted by the disease. But you can also mimic the disease by genetically modifying normal stem cells to have specific mutations. This allows you to start to sorting out the role of individual genes in diseases linked to multiple genes.


Neurons from stem cells_TessierLavigne_neurons

Nerves grown from stem cells

One problem with the latter had been that gene editing techniques, particularly the wildly popular CRISPR-Cas9 method, usually edit both strands of DNA, but many disease mutations can do their damage with only a single incorrect gene, so-called heterozygous mutations. Now, another Rockefeller University team, this one led by the University’s president Marc Tessier-Lavigne, developed a way to make the CRISPR edit much more specific and only impact one strand of DNA.

HealthCanal picked up the university’s press release about the work published in Nature. The specific gene editing in this reports involved mutations linked to Alzheimer’s disease.


bone-scaffold Hopkins

Printed jaw

A better recipe for bone. Researchers trying to grow new tissue are finding the make-up of the scaffold you use can be more important than the stem cells you put on the structure. A Johns Hopkins team recently reported an improved recipe for making a scaffold for growing bone. Their formula: 30 percent pulverized natural bone and the remainder a special plastic with the mixture extruded using a 3D printer.

 “Bone powder contains structural proteins native to the body plus pro-bone growth factors that help immature stem cells mature into bone cells,” said Hopkins’ Warren Grayson. “It also adds roughness to the PCL (plastic), which helps the cells grip and reinforces the message of the growth factors.”

MDTmag posted the university press release about the research published in ACS Biomaterials Science & Engineering.


Licensing moved cancer therapy forward.  We at CIRM are always thrilled when one of our projects hurdles a milestone toward becoming a widely available therapy. One such critical move was announced last month and picked up this week by HealthCanal.

 Oncternal Therapeutics licensed the antibody drug named for our agency, Cirmtuzumab, for further testing of its ability to fight leukemia, and potentially other cancers. The antibody selectively targets a protein on cancer stem cells, ROR1, which has the unwieldy full name “receptor-tyrosine kinase-like orphan receptor 1.” The license also includes rights to other drugs that might be developed targeting ROR1.

University of California, San Diego, which developed Cirmtuzumab, has begun a clinical trial but has not got to a point where it can report results. We covered it in more detail in our series CIRM Fights Cancer.

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

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


Untreated (top) and treated nerves

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

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

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

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


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

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

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


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

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

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



Wenbin Deng of UC Davis

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

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


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

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

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

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