CIRM’s clinical trial portfolio: Two teams tackle blindness, macular degeneration and retinitis pigmentosa

RPE precursor cells

Researchers seek to restore health to the retina in the back of the eye using cells such as these precursors of an area called the RPE.

More than seven million people in the US struggle to see. While most are not completely blind they have difficulty with, or simply can’t do, daily tasks most of us take for granted. CIRM has committed more than $100 million to 17 projects trying to solve this unmet medical need. Two of those projects have begun clinical trials testing cell therapies in patients. (Both were featured in the “Stem Cells in Your Face” video we released yesterday.)

The two diseases targeted by those therapies bookend the spectrum of patients impacted and their symptoms. Retinitis pigmentosa (RP) strikes young people, wiping out peripheral version first and only later attacking the central vision. Age related macular degeneration (AMD), the leading cause of blindness in the elderly, slowly erodes the central vision.

The RP team

Researcher Henry Klassen at the University of California, Irvine, was told as a kid he might have RP. He didn’t. Instead he has spent more than 25 years searching for cures for blindness, including RP. When asked about the dogged determination it has required to get to the point of the CIRM-funded clinical trial, he naturally fell into visual metaphors.

“It really has been difficult with many opportunities to lose the path, but I think I just had a singular vision of what was possible and when you see the possibility and you know it’s there, you feel this deep responsibility for acting even if other people aren’t seeing what you’re seeing.”

Klassen’s team has treated eight patients in the first part of the clinical trial, all with severe vision loss. If the monitoring of those patients shows the therapy to be safe the team should be given permission to treat a second group of patients, this time people with less progressed vision loss.


Rosie Barrero

The therapy involves injecting nerve stem cells into the fluid of the eye. There the cells release various proteins and factors that promote the health of the photo-receptors that become non-functional in RP.

Rosie Barrero lives with RP’s limitation every day. Although in hindsight she believes the progressive disease started as a young child, she was not diagnosed until the age of 26. Now, with three children of her own to help raise, she can only see shadows and shapes to maneuver, but can not recognize the faces of family and friends—something that can make some new acquaintances think she is a bit of a snob when she unknowingly ignores them.

“A cure for RP would mean independence for me. It would mean I would play a bigger role as a parent; I would do more things, I would help out more.”

Rosie and her husband German explained more about living with the disease in our “Spotlight” series. And at the same event, Klassen gave a more detailed description of the project.

Second team aims for AMD

A multi-center team lead by Mark Humayun and David Hinton at the University of Southern California and Dennis Clegg at the University of California, Santa Barbara, are the force behind the second CIRM-funded clinical trial . They developed an approach to treating dry AMD with stem cells fairly different from other teams around the world that are also in the midst of clinical trials. While the other groups generally inject cells from various sources directly into the eye, the California team combines cells with a synthetic scaffold to hold them in place in the eye.


Artist Virginia Doyle had to change her style of painting to adjust to the reduced vision of AMD. See her tell her story and hear more about the research in this short video.

Most of the clinical work in AMD seeks to replace a monolayer of cells under the retina that support that critical part of our eye where the photoreceptors reside. That layer of cells, called the Retinal Pigmented Epithelium (RPE) degenerates in AMD for unknown reasons and without its support structure the photoreceptors start to give out. Rather than hoping injected cells will find their way to where they need to be, the CIRM-funded team grows them on a thin synthetic scaffold. They then implant that three-by-five millimeter piece of plastic under the retina where it is needed.


Dennis Clegg

“We’ve designed the scaffold material—the little piece of plastic that we’re putting the cells on—to be very, very thin such that anything can move through it that needs to move through,” said UC Santa Barbara’s Dennis Clegg. “And there are a number of nutrients that are delivered to the RPE cells from the corriocapillaris, which is the system of blood vessels underneath.”

USC’s Humayan presented more detail about the science behind the project at one of our “Spotlight” presentations very early in the project in 2009, and his clinical collaborator at USC, David Hinton provided clinical perspective at the same session.

Others working on the goal

A collaborating team led by Pete Coffey in London has begun a clinical trial for the more aggressive wet form of AMD.  Coffey splits his time between University College London and UC Santa Barbara.

The clinical trial teams have formed companies or collaborated with corporate partners to manage the clinical trials and further development of the technology—something CIRM considers critical to moving therapies forward for patients. jCyte manages the RP work and Regenerative Patch Technologies manages the AMD project. Pfizer is involved with the London project.

Somewhere close to a dozen teams around the world are trying various forms of stem cell-based therapies to fill the huge patient need created by AMD. Clegg suggests this is not redundant but rather a great thing for patients:

“Sometimes I like to compare it to the beginning of the space program. There are a lot of ways you can build a rocket ship. We don’t know which one is going to get to the moon, but it’s worth trying all of these to see what works best for patients.”

Stem cell stories that caught our eye: making vocal cords, understanding our brain and the age of donor cells matters

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.

Tissue engineered vocal cords. A report from the University of Wisconsin that researchers there had grown new vocal cords got quite a bit of play in the media including this piece on the NBC News web site. It caught my attention not so much because of what they had created, but rather because of the vivid example it provides of cells having a memory of their role and their ability to communicate with each other to function in that role.

In the rather simple experiment, the team took vocal fold tissue from patients who had their larynxes removed for reasons other than cancer. They then used a solution to separate the tissue into individual cells and seeded those cells onto collagen scaffolding. Within 14 days they had fully formed tissue. One of the researchers stated in a phone briefing that the cells knew what they should be doing:

“They’re effectively talking to each other and producing the structural proteins that make this special tissue capable of vibration,” said Brian Frey.

The team transplanted the tissue into a larynx from a deceased dog and was able to demonstrate that the cells could make sound. In the artificial lab setting it evidently sounded a bit like a Kazoo, but the researchers maintained that if transplanted into a human it could easily sound like a voice.

Never ending quest to understand our brain. We’ve known for some time that the gene NeuroD1 plays a critical role in the early development of the brain. Now work by researchers at the Institute of Molecular Biology in Mainz, Germany report that this one gene seems to be the master switch to creating the brain.

Neurons using NeuroD1

Cells in which NeuroD1 is turned on are reprogrammed to become neurons. Cell nuclei are shown in blue and neurons are shown in red

They used several popular new techniques to track the activity of NeuroD1 in living tissue. They found it turned on a large number of genes that act to maintain cells’ trajectory to become nerves. Another indication of NeuroD1’s Svengali role came when they realized that even after it is turned off, the other genes stay active and keep driving cells to become more brain tissue.

“Our research has shown how a single factor, NeuroD1, has the capacity to change the epigenetic landscape of the cell, resulting in a gene expression program that directs the generation of neurons,” wrote the investigators in the EMBO Journal.

A story in Genetic Engineering News describes the potential impact this finding could have on understanding brain development as well as in figuring out how to repair brain damage.

Age of donor cells matters. Stem cells in older individuals just don’t do their jobs as well as those in younger people. Now a team at the Miller School of Medicine in Miami has provided clear evidence that this difference matters when selecting donor stem cells—at least in the mice in this study.

The study, published in Translational Research, looked at the ability of mesenchymal stem cells (MSCs) to protect lungs from injury. HealthCanal picked up the institution’s press release that quoted one of the researchers.

“Donor stem cells from younger mice were effective in preventing damage when infused into older mice at the same time as a disease-causing agent,” said Marilyn K. Glassberg. “However, donor MSCs from older mice had virtually no effect.”

The issue becomes key when debating the merits of autologous cells (from the patient themselves) versus allogeneic cells (from donors). This study adds weight to the side that says for older patients choose allogeneic—and make sure the donor is young.

Stem cell stories that caught our eye: three teams refine cell reprogramming, also stem cell tourism

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

Why stem cells in the lab don’t grow up right. A classic cartoon among stem cell fans shows a stem cell telling a daughter cell it can grow up to become anything, and in a living creature that is pretty much true. But in the lab those daughter cells often don’t behave and mature properly. This seems particularly true for stem cells made by reprogramming adult cells through the iPS cell technology.

Tissues, such as heart muscle grown in the lab from stem cells too often look and behave like heart tissue found in a growing embryo rather than like a mature adult. A team at Johns Hopkins decided the best way to solve this problem was to understand the differences between those heart tissues maturing in a lab and those grown naturally and to understand those differences at the molecular level. They looked at which molecular and genetic signaling pathways were turned on in each during development.

After studying 17,000 genes in 200 heart cell samples they found that the pathways in the lab-grown cells were like a map in which the roads don’t line up. Pathways that were supposed to be turned on were not and ones that were supposed to be blocked were open. In a university press release picked up by they explain that they now intend to look for ways to correct some of those misguided cellular pathways, in part by making the lab conditions better mimic normal growing conditions.

The result should be tissues grown for research that result in a more accurate model of disease and, potentially, better tissue for transplantation and repair.

Getting the cells needed faster. Pretty much everyone’s cell therapy wish list contains cells that genetically match the patient—to reduce the chance of immune system rejection—and often with the added feature of genetic modification to correct an in-born error. We have the technology to do this. You can use the iPS cell system to reprogram a patient’s adult cells into stem cells and use any number of gene modifying tools to correct the error. But the combined processes can take three months or more; time patients often don’t have.

Researchers at the University of Wisconsin’s Morgridge Institute and the Murdoch Children’s Research Institute in Australia have sped up that process to just two weeks. They found a way to do the stem cell conversion and the genetic correction at the same time and used the trendy new gene-editing tool, CRISPR, which is faster and simpler than other methods. Wisconsin’s stem cell pioneer James Thompson commented on the work led by Sara Howden:

James Thompson

James Thompson

“If you want to conduct therapies using patient-specific iPS cells, the timeline makes it hard to accomplish. If you add correcting a genetic defect, it really looks like a non-starter. You have to make the cell line, characterize it, correct it, then differentiate it to the cells of interest. In this new approach, Dr. Howden succeeded in combining the reprogramming and the gene correction steps together using the new Cas9/CRISPR technology, greatly reducing the time required.”

Howden discussed the work with Australian Broadcasting Corp and her institute issued a press release. In the release she noted than when iPS-based therapies become a reality, the faster method will be critical for certain patients such as children with severe immune deficiency or people with rapidly deteriorating vision.

Skipping the stem cell step. A team at Guangzhou Medical University created unusually pure heart muscle cells directly from skin samples without first turning them into iPS type stem cells. This so-called “direct reprogramming” has been accomplished for a few years, but mostly in nerve tissue and with much less efficiency. This team got 80 percent pure heart muscle.

Heart muscle cells created with traditional iPS cell reprogramming

Heart muscle cells created with traditional iPS cell reprogramming

They also avoided one of the potential problems with iPS technology. Most often, the reprogramming happens using viruses to carry genetic factors into adult cells. The Chinese team used proteins to do the reprogramming, which are much less likely to leave lasting, and potentially cancer-causing, changes in the cells.

“While additional research is needed to fully understand the properties of these cells, the results suggest a potentially safer method to generate cardiac progenitor cells for use as a regenerative therapy after a heart attack,” said Anthony Atala, Editor-in-Chief of STEM CELLS Translational Medicine, which published the work and released a press release picked up by BioSpace.

The research team noted one bit of needed work that reflected back to the first item in this post. They need to see if the new heart cells function like mature native cells and can interact properly with native cells if transplanted.

Stemming stem cell tourism. A pair of medical ethicists, one from Rice University in Houston and one from Wake Forest University in North Carolina, published a call for reforms in how stem cell clinical trials are designed and regulated. They say our system should encourage people to get therapy in the U.S. at regulated clinics rather than go overseas or to seek out unproven therapies here.

“The current landscape of stem cell tourism should prompt a re-evaluation of current approaches to study cell-based interventions with respect to the design, initiation and conduct of U.S. clinical trials,” the authors wrote. “Stakeholders, including scientists, clinicians, regulators and patient advocates, need to work together to find a compromise to keep patients in the U.S. and within the clinical-trial process.”

The web portal MNT wrote an article on the paper based on a Rice press release. The piece notes that many of the same patients who came forward to secure state funding for stem cells like the voter initiative that created CIRM are now tired of waiting for therapies and are seeking out unproven therapies. The authors noted that the problems this causes, in addition to the risks for patients, include the lack of any systematic way to collect data on whether those therapies are really working.

“Policy should be aimed at bringing patients home and fostering responsible scientific research as well as access for patients,” they wrote. “This will require discussions about alternative approaches to the design and conduct of clinical trials as well as to how interventions are approved by the Food and Drug Administration.”

Stem cell stories that caught our eye: mini-brains in a dish, blood stem cells and state funded stem cell research

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.

Great review of brains in a dish. The veteran Associated Press science journalist Malcolm Ritter produced the most thorough overview I have seen of the recent spate of research projects that have grown “mini-brains” in lab dishes. He provides the perspective from the first report in 2013 to a recent, and as he noted, unconfirmed claim of a more complex ball of brain cells.

Alysson Muotri

Alysson Muotri

He uses CIRM grantee Alysson Muotri to discuss the value of modeling diseases with these pea-sized brains. In the case of this University of California, San Diego researcher that involves finding out how nerves in people with autism are different from those in other people. But Ritter does not leave the false impression that these very rudimentary clumps of cells—that each self-organize in slightly different ways—are functioning brains. He makes this point with great quote from Madeline Lancaster of the Medical Research Council in England:

“Lancaster compares the patchwork layout to an airplane that has one wing on top, a propeller at the back, the cockpit on the bottom and a wheel hanging off the side. ‘It can’t actually fly,’ she said. But ‘you can study each of the components individually and learn a lot about them.’”

Ritter also discusses the broader trend of creating various miniature “organoids” in the lab including a quote from CIRM grantee at the University of California, San Francisco, Arnold Kriegstein:

This overall approach “is a major change in the paradigm in terms of doing research with human tissues rather than animal tissues that are substitutes. … It’s truly spectacular.” Organoids “are poised to make a major impact on the understanding of disease, and also human development.”

Unfortunately, this AP piece did not get as broad a pick up as the wire service often achieves. But here is the version from the Seattle Times.

Throw out the textbook on blood stem cells. A new study suggests that the textbook roadmap showing blood stem cells slowly going down various paths to eventually produce specific adult blood cells may be like a faulty GPS system. In this case that voice saying “redirect” is the renown stem cell scientist John Dick of the University of Toronto.

plateletsDick’s research team showed that very early in the process the daughter cell of the stem cell is already committed to a specific adult cell, for instance a red blood cell or a platelet needed for clotting. Low cell counts for one of those cell is the most common cause for patients needing transfusions. Now, with these cell-specific progenitor cells discovered, it may be easier to generate those adult cells for therapy. The discovery will also help the research community better understand many blood disorders.

“Our discovery means we will be able to understand far better a wide variety of human blood disorders and diseases – from anemia, where there are not enough blood cells, to leukemia, where there are too many blood cells,” said Dick in a press release from the University affiliated Princess Margaret Cancer Center. “Think of it as moving from the old world of black-and-white television into the new world of high definition.”

The journal Science published the study today.

The power of states to fund stem cells. The Daily Beast published a good review of state efforts to fund stem cell research with the slightly mischievous title, “George W., Father of Stem-Cell Revolution.” It recounts how several states stepped into the breach after then President George W. Bush restricted stem cell research. The story originally ran in Kaiser Health News under a more subdued headline.


The article states that today seven states offer some level of stem cell research funding. And the author asserts that as an engine for generating economic development and local scientific prestige “stem cell research for many states appears to be worth the investment.” We have to agree.

The story does retell some of the early criticisms of CIRM, but goes on to discuss some of our reforms and quotes our new president C. Randal Mills on the “systems-based agency” he is creating:

“We’re setting up continuous paths to move basic research to clinical trials. It’s like a train moving down a track, where each grant is the link to the next step down the line.”

The piece ends with a great forward-looking quote from Jakub Tolar, head of the University of Minnesota’s Stem Cell Institute:

“We started on drugs a hundred years ago. Then we went to monoclonal antibodies—biological. We are now getting ready to use cells as a third way of doing medicine. We are at a historical sweet spot.”

Stem cell stories that caught our eye: Fertility after chemo, blood shortages, modeling kidney disease and “good” stress

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.

Fertility restoration after chemo—Maybe. A research paper presented at the American Society of Reproductive Medicine annual meeting in Baltimore this week got considerable attention on the web because it suggested women who had lost their fertility due to cancer chemotherapy could have it restored.

A team of Egyptian and US scientists, led by Sarah Mohamed of Mansoura Medical School in Egypt injected bone marrow mesenchymal stem cells directly into the ovaries of mice that had received chemotherapy. They saw restoration of function in the ovaries and the mice were also able to become pregnant and give birth to healthy pups.

While this is potentially exciting news, the stories tended to have headlines that were way too positive. This was a mouse study presented at a meeting, which has some peer review, but not nearly as rigorous as the review that happens before a journal publication. Much more research needs to verify this report before the thousands of women rendered infertile by their cancer therapy can consider baring children again.

The British paper The Telegraph, which had one of the most hyped headlines, also provided some good caveats for readers who stuck with the story to the end:

“Theoretically if you are regenerating the ovary you should be getting better quality eggs,” said Geoffrey Trew of Hammersmith Hospital in London. “Clearly we’re not there yet, and it’s good that the researchers are not over-claiming their findings, but it’s a great proof of concept.”

Potential way to end blood shortages. With the holiday season just a month away, another season is approaching for hospitals; a time of blood shortages as regular donors get too busy and distracted to roll up their sleeves. A team at Dana Farber Cancer Institute and Children’s Hospital, Boston, may have developed a way to eliminate those shortages. They used a gene editing technique to triple the number of red blood cells stem cells make. A major advance given the oxygen carrying capacity of red cells is the main reason for transfusions.

Previous studies had shown a certain gene, when active in the stem cells, resulted in lower numbers of red cells. So they used a genetic technique called RNA interference to turn that gene off. The resulting stem cells produced three times as many red cells as usual.

“We know that if we can make these cells, and improve upon the process, hopefully future blood shortages will not be a problem at all,” lead researcher Vijay Sankaran told Alice Park at Time.

 The team published their work in Cell Stem Cell and a press release from Dana Farber provides a bit more detail.

A mini-kidney (1mm diameter) grown from a patient's stem cells.

A mini-kidney (1mm diameter) grown from a patient’s stem cells.

Mini-kidneys mimic disease. Kidneys were once considered too complex for these early days of using stem cells to create organs. But creating mini-kidneys in the lab has turned out to be much easier than researcher thought. Stem cells, when given the right signals in the lab, self organize into organoids with the various components of kidneys as a few teams around the world have demonstrated over the past year.

But now, a team at Harvard and Brigham and Women’s Hospital has taken these mini organoids to a new level. They have used genetic engineering to model two debilitating kidney diseases in a dish. They used the popular gene editing technique CRISPR to give the stem cells the ability to create organoids that mimic polycystic kidney disease and glomerulonephritis.

“Mutation of a single gene results in changes in kidney structures associated with human disease, thereby allowing better understand of the disease and serving as models to develop therapeutic agents to treat these diseases,” explained senior author Joseph Bonventre of Brigham and Women’s.

The lead author on the study, Benjamin Freedman is now at the University of Washington, which put out a press release on the work picked up by MedicalXpress.

 Stem Cells can benefit from stress. The Huffington Post picked up a Q&A piece on stress that originally appeared in Berkeley Wellness. While detractors of the “Peoples’ Republic of Berkeley” might assume any article in that publication on stress would be long on psychology and short on hard science, they would be wrong.

The Q&A with University of California, Berkeley’s Daniela Kaufer features her work looking at the impact of stress on the stem cells in the brains of rats. It turns out short-term stress can actually enhance the proliferation of stem cells and in turn the number of new nerve cells they produce, which we wrote about based on her early results.

“The stress response is designed to help us react when something potentially threatening happens, to help us deal with it and learn from it. Our research shows that moderate, short-lived stress can improve alertness and performance and boost memory.”

However, she notes that chronic stress suppresses stem cell growth and the generation of new nerve cells. And being a Berkeley publication, the last question does get around to yoga for managing stress.

Stem cell stories that caught our eye: sleepy stem cells, pig organ donors, therapy in the womb and dementia

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 rested stem cell is a better stem cell. A bone marrow stem cell donor who has a sleep deficit of as little as four hours results in stem cells that, when injected into a recipient, lose as much as 50 percent of their normal ability. When transplanted, they don’t migrate to where they belong in the bone marrow as well and they produce fewer of the desired new immune system cells. A CIRM-funded team at Stanford worked with mice in the current study, but suggest in a university press release that their findings could have implications for human patients.

“Considering how little attention we typically pay to sleep in the hospital setting, this finding is troubling,” said Asya Rolls, a former postdoctoral scholar at Stanford now at Israeli Institute of Technology. “We go to all this trouble to find a matching donor, but this research suggests that if the donor is not well-rested it can impact the outcome of the transplantation. However, it’s heartening to think that this is not an insurmountable obstacle; a short period of recovery sleep before transplant can restore the donor’s cells’ ability to function normally.”

The team published their work in Nature Communications and the Bioscience Technology web portal picked up the release.

Genetically cleaned up pigs as organ donors. Since pigs have organs similar in size and function to humans, they are often discussed as possible organ donors to overcome the acute organ shortage. One problem: pig cells are full of PERVs—that is porcine endogenous retroviruses. Those viruses, normally inactive for many generations in the pigs, can be activated if transplanted into people. So, the pig donor idea got put on the back burner after some early work in the 1990s uncovered the problem.


Now, a team in the lab of one my favorite faculty members when I was at Harvard, George Church, has inactivated all 62 PERVs in living pig cells. They used the hot new technology called CRISPR that Church helped to refine. The CRISPR gene-editing tool usually requires a separate molecule for each gene to be edited, but the team was able to use just one identifier molecule because all the PERVs come from one long-ago ancestor and share common DNA.

This major advance will not result in pig hearts for humans on its own. Researchers have to find ways to alter certain of the pig’s own genes that produce proteins that could result in immune system rejection of the organs in humans. Making that gene modification in a way that still results in a living pig will be much more difficult. The research got considerable coverage including in the New York Times and in Genetic Engineering and Biotechnology News.

Clinical trial to use stem cells in the womb. Researchers at Sweden’s Karolinska Institute will begin a clinical trial in January to determine if injecting stem cells into a fetus known to carry the genetic defect for “brittle bone” disease can result in a healthier child. The injection will be at 20 to 34 weeks of pregnancy and be repeated every six months for the child’s first two years of life. Fifteen babies will be treated in the womb and another 15 will begin injections after birth to try to determine if early intervention makes a difference.

The Swedish team gave the therapy to two people some years ago, with one now 13 years old and doing better than most with the genetic disorder that results in most patients suffering dozens of fractures during what is often a shortened life span. But since the disorder presents so differently in each patient, the team felt a clinical trial was needed to determine the impact of in utero therapy.

They will be injecting the cells known as mesenchymal stem cells derived from donated fetal tissue. The upcoming trial for the disease formally known as osteogenesis imperfecta was widely covered including in London’s Daily Star and in the industry newsletter FierceBiotech.

Neural stem cells (green) migrate throughout a brain and mature into astrocytes (red).

Neural stem cells (green) migrate throughout a brain and mature into astrocytes (red).

Stem cells and Lewy body dementia. The second leading cause of dementia, after Alzheimer’s disease, carries the acronym DLB for Dementia with Lewy Bodies and a team at the University of California, Irvine, thinks they may have a way to improve the lives of people with DLB. They injected nerve stem cells into mice with a form of DLB and saw improvements in both motor function and cognitive skills.

When the Irvine team looked at the effects of the treatment on the brains of the mice they determined that much of the impact came from the stem cells releasing a protective growth factor Brain-Derived Neurotrophic Factor (BDNF). They found benefit on both of the two types of nerve most affected by DLB, dopamine-making nerves and glutamate-making nerves.

“Our experiments revealed that neural stem cells can enhance the function of both dopamine-and glutamate-producing neurons, coaxing the brain cells to connect and communicate more appropriately. This, in turn, facilitates the recovery of both motor and cognitive function,” said lead researcher Natalie Goldberg in a university press release.

To further test the role of BDNF the team injected the growth factor by itself and saw improvement in motor skill but only very limited gain in cognitive skills. So, the stem cells clearly had a role beyond carrying the BDNF pill bottle.

Mesa talk a reminder the immune system is a two-way street


The second day of the three-day Stem Cell Meeting on the Mesa in La Jolla always ends with a public lecture. This year that slot featured no-longer-rising-star, but rather risen star, Jennifer Elisseeff, of Johns Hopkins. She provided a powerful reminder of the power of interdisciplinary research teams. Her career has always mingled cell biology, chemistry and engineering, but the highlight of her talk required her to take a sabbatical and learn more about immunology.

Jennifer Elisseeff

Jennifer Elisseeff

As director of the Hopkins’ Translational Tissue Engineering Center she has worked on complex tissue replacements for several areas of the body, with extensive work in knee damage and in and around the eye. She concentrates on the interplay of nature and nurture at the cellular level. In essence she looks at the dynamics of what genes are turned on in a cell and the role of the surrounding materials. When this is at work in a tissue-engineered implant it involves the interplay between cells and some sort of scaffold to hold them in place. In addition she finds added nuance to this exchange when mixing synthetic and natural scaffold materials.

“We are learning how these material talk to each other in a dish, but we need to know how this relates to what happens in the body.”

What surprised her in her findings was the powerful role of immune cells summonsed to an implant. Often times, in cell therapies the immune system is cast as a bad actor just working to reject the foreign cells. She found that one type of immune cell in particular, the macrophage, has two modes of operation. It can have a damaging inflammatory response or a reparative response. The toggle that can switch the macrophages from one form to the other turns out to be another immune cell, a particular type of T cell called a CD4.

Elisseeff called for the research community to become active in a sub-discipline Regenerative Immunology. She said that if we can empower the immune system’s beneficial affects, we can dramatically improve the value of tissue implants. She briefly described a study in which she enlisted the right T cells in mice to direct the macrophages to a reparative response. The result: tissue implants produced a better muscle repair.

CIRM co-sponsors the Mesa meeting along with the Alliance for Regenerative Medicine and the Sanford Consortium for Regenerative Medicine. The latter hosted the public talk in the auditorium named in honor of Duane Roth, the former vice chair of our board who died in a tragic bike accident a few years ago. He would have been proud of the standing-room only crowd and of Elisseeff’s admonishment for various fields to work together early with an aim to accelerate getting products to patients.

A call for scientists to speak out for Stem Cell Awareness Day

SCAD campaign

The International Society for Stem Cell Research (ISSCR) and the journal Cell Stem Cell, are asking stem cell scientists to take part in a social media campaign with the hashtag #AStemCellScientistBecause between October 1 and October 14.

“We want to share with the world our pride and excitement to be a part of a worldwide effort to transform human health,” the association states on a web page created for the event, calling the effort a “campaign to give a voice to the scientists behind the research.”

ISSCR suggests several ways to take part:

  • Tweet a brief statement about why you entered the field,
  • Record a 10-20 second video to accompany the Tweet,
  • Talk to peers about taking part,
  • Share and retweet favorites posts.

The journal’s October issue will include an article with contributions from all the first authors of papers in the issue stating why they entered the field as well as contributions from other authors in the issue.

As always, CIRM is facilitating getting researchers we fund into high school classrooms on October 14th to give guest lectures. We expect to reach more than 50 classrooms including several school-wide assemblies this year.

Several institutions in California will be hosting special events to commemorate Stem Cell Day this month. And if you are across the border, the MaRS center in Toronto is hosting the children’s museum exhibit we helped develop, “Super Cells: The Power of Stem Cells.”

All the events con be found at

Stem cell stories that caught our eye: better heart muscle, first patient with eye cell patch, brain cross talk and gut bugs

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.

Growing better heart muscle in the lab. While researchers have been able to grow beating heart cells from stem cells in a dish for many years, those beating blobs of cells have not looked or acted much like the long strong muscle fibers found in a normal heart. A team at Stanford, with collaborators at the Gladstone Institutes have spent much of the past five years looking for ways to make lab-grown heart muscle more like the real thing.

Heart muscle matured from stem cells functions better when grown in long, thin shapes.

Heart muscle matured from stem cells functions better when grown in long, thin shapes.

They published a couple of solutions in the Proceedings of the National Academy of Sciences this week. One of the keys was to make the stem cells feel more like they are in their natural environment, which is full of physical tension. When they grew the stem cells on substrates that provided that type of tension they got stronger heart muscle better able to beat in a synchronized rhythm. They also found that stem cells grown in long, narrow chambers produced heart muscle closer in appearance and function to the narrow muscle fibers found in normal hearts.

The press release, written by our former colleague Amy Adams who now works for the University, was picked up by Medical Express.

First patient in trial for blindness. Doctors at the Moorfields Eye Hospital in London have used specialized eye cells derived from embryonic stem cells and grown on a synthetic scaffold to try to reverse blindness caused by age-related macular degeneration(AMD). Prior clinical trials have injected similar cells but without the supporting structure of the patch to hold them in place.

Also, prior trials have aimed to halt the progressive loss of vision in the dry form of macular degeneration. This trial is trying to reverse damage already done by the wet form of AMD. Each of the groups use embryonic stem cells and first mature the cells into a type of cell found in the back of the eye’s retina, retinal pigmented epithelium (RPE) cells.

“The reason we are very excited is that we have been able to create these very specific cells and we have been able to transfer them to the patient,” lead researcher Lyndon Da Cruz told a writer for the Huffington Post. “It’s the combination of being able to create the cells that are missing and demonstrate that we can safely transplant them.”

CIRM funds a team at the University of Southern California and the University of California, Santa Barbara that has collaborated with the London team and plans to use a similar patch system on a trial set to begin in the next few weeks.

The London news got broad pick up in the media, including this BBC Video.

Cross-talk in the brain linked to success. The National Institutes of Health issued a press release this week describing two early results of its major Brain Initiative. One team from the University of California, San Francisco, provided an explanation about why primate brains are so much bigger than other mammals, and a team from Oxford and Washington University in St. Louis mapped cross talk between different parts of the brain to various personality traits.

The second group collected data on 280 measures such as IQ, language performance, rule-breaking behavior and anger that they mined from the initiative’s Connectome Project. Their analysis of 461 people found a strong correlation to sections of the brain talking to each other when in a resting state and positive personality and demographic traits. Those included high performance on memory tests, life satisfaction, years of education and income.

The UCSF team showed that brain stem cells during early development produce as much as 1,000-fold more neurons in primates than in lower mammals. More important, they isolated a reason for this strong performance. As the brain gets bigger the stem cells don’t have to continually migrate greater distance from their homes, called the stem cell niche. Instead they seem to pack their bags and take the niche with them.

“It is great to see data from large investments like the Human Connectome Project and the BRAIN Initiative result in such interesting science so quickly,” said Greg Farber of the National Institute of Mental Health in the release.

Have to agree.

The interplay of bugs and genes in our gut. The consumer press spends a considerable amount of time talking about the bacteria in our digestive tract, and now a team a Baylor College of Medicine in Houston has produced some data that suggests these microbial cohabitants of our bodies, called the microbiome, become important early in our development.

In research published in the journal Genome Biology and in a press release picked up by Medical Express, the researchers showed that the microbiome in mice during the period they are nursing helps determine which genes are turned on or turned off, and those settings, called epigenetics, follow the mice through their adult life. Specifically, they found that the gut microbiome impacted the function of gut stem cells that we rely on to replace the lining of our digestive system approximately every four days.

“This promises some exciting opportunities to understand how we might be able to tailor one’s microbiome exposure during infancy to maximize health and reduce gastrointestinal disease throughout life,” said one member of the team, Robert Waterland.

Three teams empower patients’ immune systems to oust cancer

Immuno-oncology is all the rage now in biotech publications, with due cause. It is producing some pretty impressive results in patients who failed other therapies. Most of what gets written about involves strengthening or unlocking the action of one immune cell, the T cell. But our immune systems are armed with many types of ammunition; we have multiple kinds of cells that can initiate or follow through in getting rid of unwanted invaders or cancers. CIRM funds three clinical trials that test these lesser-traveled routes to juicing up our immune response to cancer.

Robert Dillman has worked to bring immune therapy to cancer patients for 25 years.

Robert Dillman has worked to bring immune therapy to cancer patients for 25 years.

While this field is hot now, it is not new. It has been elusive; researchers have tried for decades to harness our multi-talented immune system in the war on cancer. One of those researchers, Robert Dillman, who has been working on it for 25 years, now leads a CIRM-funded clinical trial in Phase 3, which is the last leg in a long journey to having a therapy approved for any patient with metastatic melanoma.

Another CIRM-funded team is also in a Phase 3 trial, in this case a therapy for the brain cancer glioblastoma developed by ImmunoCellular Therapeutics. The third CIRM-funded team at Stanford is in the middle of an early phase trial testing for safety and early signs of effectiveness with a therapy that could become an off-the-shelf therapy for many different cancers.

25-year effort getting results

Dillman now works for Caladrius Biosciences, the company conducting the Phase 3 trial in many medical centers around the U.S. He heads the clinical trial team funded by CIRM to conduct the California portion of the trial. But he has been working on the concept behind the therapy since the 1990s, most of the time at Hoag Hospital in Orange County. His mom was diagnosed with cancer when he was 14, and she died of the disease when he was an undergraduate at Stanford. His entire career has been focused on immuno-oncology.

The current effort uses a part of the immune system called dendritic cells that are derived from the patient’s blood. A patient’s tumor cells from a cell line and their dendritic cells are exposed to each other in a lab culture flask. What dendritic cells are really good at is gobbling up the cancer cells, then presenting pieces of the destroyed cancer cells to the immune cells responsible for getting rid of tumors. So, when given back to the patient the dendritic cells present the cancer bits, or antigens, like road maps to the immune cells that can then seek out and kill the cancer stem cells. The company produced a great video explaining the process.

Unlike most of the other immunotherapies that generally only present or target one CSC antigen, the Caladrius strategy presents a multitude of CSC antigens through the dendritic cells. The therapy has been associated with minimal side effects and theoretically should be more effective than other therapeutic cancer vaccine approaches. With so many specific targets, the cells are less likely to cause immune attack on healthy cells and more likely to find all the renegade tumor cells. This therapy is also a bit slower acting, which is actually a good thing. Many of the other immune therapies trigger such a strong immune response, they cause flu like symptoms that sometimes require the therapy to be halted. The dendritic cell therapy has few side effects reported so far.

Caladrius plans to conduct the trial at 32 locations, with 20 of them recruiting patients currently. The first patient was dosed in June, and a total of 250

Norm Beegun was treated in an earlier phase of the Caladrius trial.

Norm Beegun was treated in an earlier phase of the Caladrius trial.

patients will be randomly selected to get the therapy or not, with two thirds getting the therapy. The researchers plan to review the interim results as early as the end of 2017.

One patient from the earlier phase trials of the therapy, Norm Beegun, believes he definitely benefited from the treatment and told his story to our board in May.

Other approaches to ousting cancer

The CIRM-funded team at Stanford began an early phase trial in August 2014 using an antibody that blocks a receptor on the surface of CSCs called CD47. One of the researchers on the team, Irving Weissman, has dubbed that gene the “don’t eat me gene(video)” because it tells the immune system cells responsible for getting rid of tumors to not do their job. When CD47 is blocked, the immune system cells called macrophages are able to destroy—in essence eat—the CSCs.

The initial study primarily seeks to determine safety and the best dose for moving forward. It is enrolling patients with advanced-stage solid tumors. So far 12 patients have been treated with five different doses, and the team continues to screen patients for higher doses to be treated in the coming months. The trial is open only at Stanford Cancer Center under the leadership of Branimir Sikic.

The team at ImmunoCellular plans to enroll 400 brain cancer patients at 120 clinical trial sites around the U.S., Canada and Europe. They are also developing a way to turn a patient’s dendritic cells into a vaccine that helps the immune system target cancer stem cells.