Stem cell stories that caught our eye: diabetes, Down Syndrome and the long road to gene therapy

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

Role of blood vessels in diabetes. I have been a skeptic of the few reports that have come out suggesting mesenchymal stem cells, the second type of stem cell found in bone marrow, can be used to treat Type 1 diabetes. But a new study in the journal Diabetes has erased a bit of that skepticism. It provides a plausible rational for why those cells might provide some benefit. A team from the University of Missouri found that when a patient’s immune system attacks their insulin-producing Beta cells it also attacks the blood vessels that nourish those key cells. They report that transplanted bone marrow cells were able to induce new blood vessel growth and that in turn fostered the Beta cells to replenish themselves. They do not claim the stem cells became Beta cells. Because mesenchymal stem cells are proven to foster blood vessel growth and not the growth of endocrine tissue that would be needed for Beta cells, they offer a reasonable scenario. This online news article is a little over the top using words like “cure,” but it does give the basics of what the team has done and found.

Down syndrome defects at the cell level. We often write about the power in creating disease-in-a-dish models of genetic diseases by reprogramming skin cells from a patient to become the stem cells known as iPS cells. But this research into Down Syndrome is a particularly fine example of what those cells can tell us. They found that the nerves grown from cells with the genetic defect produced 40 percent fewer synapses—the connections nerves use to communicate with each other. Those cells also had an unusual number of active genes that are usually only turned on when cells are under a type of chemical stress called oxidative stress. The lower number of synapses could explain part of the cognitive deficit seen in many of these individuals, and the chemical stress could explain the premature aging most experience as this article notes. Understanding these underlying causes often points to potential therapies to ameliorate the disease. Here’s a story about that work.

BMT—the original stem cell transplant. Discussions about stem cell therapy often overlook the fact that stem cell therapies have been in the clinic for more than 30 years in the form of bone marrow transplants (BMT) for patients with blood cancers. In the early years, BMT was a quite dangerous procedure reserved for patients with no other option. Researchers and clinicians have constantly refined it over the years and the outcomes have improved dramatically to the point that it is now presented to many patients as one of multiple options. The Journal of Clinical Oncology just published a good review of the progress, which is discussed in this press release from the National Marrow Donor Program.

The long road to gene therapy. Observers often compare the novelty and hurdles to successful gene therapy to those being experienced by the stem cell field as it moves beyond bone marrow transplants. I actually think these comparisons are usually over done. I really don’t think it will take as long to get an approved second generation stem cell therapy as it did for the first gene therapy approved (in Europe) just in the past year. This press release from the publisher Mary Ann Liebert highlights two articles in its journals this month from pioneers in gene therapy detailing the many ups and downs of that field. Even if stem cell therapies only have a fraction of these issues, the article provides a good reminder of what could be. (Unlike many articles from this publisher, these pieces are not behind a pay wall.)

History of the ties between IVF and stem cells science. ABC TV, in this case the Australian Broadcasting Corp, has aired and posted a half hour interview with Alan Trounson, who is not only our president, but also one of the pioneers of in vitro fertilization and one of the earliest folks from that field to make the connection and move to stem cell research. The interview provides a nice history of the two fields and Alan’s rich and divergent career.


California stem cell bank will save time, speed research

Early this year our Governing Board approved funding for nine awards to create a stem cell bank to be located at the Buck Institute for Research on Aging just north of San Francisco (here’s our press release).

The San Francisco Chronicle’s Erin Allday recently wrote about the bank, which will eventually contain 9,000 stem cell lines generated from tissue donated by 3,000 people with with known diseases like Alzheimer’s disease, autism, hepatitis, forms of blindness and heart disease, among others. It will also include embryonic stem cells and stem cells generated from people without known diseases. The stem cells will then be a resource scientists can use to model diseases in the lab.

Allday quoted CIRM science officer Uta Greishammer:

“The intent for these cells is research. They’re for understanding better how diseases work. They’re for discovering new targets for drug developers, and the cells might be used to screen for new drugs. If these cells lead to a new drug and a new treatment that would of course be fantastic.”

Worldwide, scientists are making use of technology developed in 2007 to reprogram adult cells contained in skin or blood into an embryonic-like form. When the skin or blood comes from people with known diseases, the resulting cells can then be used to better understand those diseases in the lab (we’ve written about these disease-in-a-dish studies).

The current problem is that scientists are generating their lines in different ways making it hard for two labs to compare their results, not to mention the process of generating the lines takes time that could be better spent doing research. We wrote about this problem in the 2011 annual report:

CIRM’s solution to this laboratory logjam takes the form of a three-part initiative. The first part will bank cells created by CIRM grantees and make them easily accessible to California scientists and their collaborating partners worldwide. The other two portions focus on creating new disease-specific cell lines that are proving valuable in understanding diseases, and identifying new therapies. Creating this centralized resource to handle the distribution, the paperwork and the creation of new lines will allow scientists to keep their focus on what is most important—using those cells to develop new therapies.

CIRM’s initiative includes an award to Cellular Dynamics International (CDI), which will be responsible for taking all the tissue from donors and generating the cell lines. This means that scientists will be studying cells created the same way and can compare their results across different labs. Those cells will be stored and distributed through an award to Coriell Institute for Medical Research, which is developing the new facility at the Buck.

There’s more information on our website about each of the awards that make up this initiative. We’ll be writing more about how the bank is progressing over the coming months.


Does the immune system hold the key to re-growing limbs? Ask the axolotl

The axolotl’s ability to regrow limbs make it widely studied by scientists hoping to understand regeneration and perhaps mimic the process for healing injuries in people. (Photo: wikimedia commons)

Yes, it’s true; the axolotl is an oddly adorable salamander but it is its ability to regrow complex structures like the legs, tail, retina and spinal cord after injury that fascinate researchers. Unlocking the mysteries of regeneration in the axolotl may some day help point the way to therapeutic strategies for tissue regeneration in humans. And in the May 20th issue of the Proceedings of the National Academy of Science, a research team from the Australian Regenerative Medicine Institute reports on progress toward that goal: they demonstrate that a specific white blood cell, the macrophage, is critical for the axolotl’s ability to regrow its limbs.

When you hear “white blood cells” you might think “fighting off a bad cold” and probably not “re-growing limbs”. The macrophage, which literally means “big eater”, does in fact act as a first line of defense against foreign invaders. They travel the body devouring viruses and bacteria and then pour out signaling proteins that sound the alarm to the other cells of the immune system. But macrophages have many more functions such as wound healing in which they help clear out dead cells and support cell growth for restoring tissue.

Wound healing and tissue regeneration are thought to use similar mechanisms. So in this study, the researchers removed macrophages from the axolotl and then amputated a limb. The result: in all cases, no new limbs. When the scientists added macrophages back and amputated more of the limb, that limb regenerated normally. This confirmed that macrophages are required for this remarkable process.

So what’s the difference in macrophage function between mammalian wound healing and amphibian limb regeneration that might explain the axolotl’s superior abilities?

The researchers found that in the first 24 hours after amputation, macrophages secrete proteins that both activate and inhibit the immune system. In wound healing, on the other hand, macrophages are known to secrete activator proteins for several days and then later they release proteins that help slow down the immune response. The authors speculate that stepping on both the accelerator and the brake of the immune system creates the right cellular conditions to kick-start the regeneration process.

Despite these intriguing results, re-growing a severed human foot is a long ways off. Still, as James Godwin, the paper’s first author, said in an interview with The Scientist:

This really gives us somewhere to look for what might be secreted into the wound environment that allows for regeneration.

At CIRM, we’re big fans of this type of fundamental developmental biology research. CIRM grantees like Gage Crump of USC, who has a New Faculty award to study regeneration of facial bones in the zebrafish, are deconstructing how nature builds tissues to help inform the development of stem cell-based therapies that will repair our bodies after injury or illness.

Here’s a 30 second video of Dr. Crump explaining his regeneration research:


Early phase stem cell trials show promise in stroke and blindness

Blurring at the center of vision in macular degeneration

The very first time a potential therapy gets tested in people it’s part of what’s called a phase 1 trial, which is very small and is mostly just testing to make sure the drug, cells or device are even safe. Until the start of a trial the potential therapy has generally only been tested in lab animals, which can be quite different from humans.

With that caveat in mind, there’s some hopeful news coming out of a phase 1 trials testing stem cell-based approaches to treating stroke and blindness.

The stroke trial in Scotland is testing a type of neural stem cell to see if it can help people who have had strokes recover function. People in the trial are reporting better grip strength and more coordination. That said, because it’s such a small trial there’s no way of knowing whether some of the improvements would have happened anyway—people do improve over time after a stroke.

A story in the Telegraph quotes Clare Walton from the Stroke Association talking about the results:

“We are very excited about this trial. However, we are currently at the beginning of a very long road and significant further development is needed before stem cell therapy can be regarded as a possible treatment.”

This trial is testing a type of neural stem cell injected directly into the place where the stroke happened. Other groups are working toward trials with other types of stem cells or ways of delivering those cells to the brain. Our stroke fact sheet has more about stem cell research for stroke, including a list of all awards we fund.

Two other trials, led by Advanced Cell Technology, are showing very early positive signs. Both trials are testing cells derived from embryonic stem cells to see if they can replace the function of cells lost in the back of the eye in people with macular degeneration or Stargardt’s macular dystrophy. Macular degeneration is the leading cause of blindness. In very preliminary results, one person went from being effectively blind to having 20/40 vision.

A story in New Scientist quotes Gary Rabin, chief executive officer of Advanced Cell Technology

“There’s a guy walking around who was blind, but now can see. With that sort of vision, you can have a driver’s licence.”

As with the stroke results, it’s too early to know if the cells are responsible for the change, work long-term or are safe. That’s the point of starting slow with phase 1 trials before working up to trials that include more people and will give a better indication of whether the treatment works.

There’s more information about stem cell research for blindness on our fact sheet, including information about our funding for forms of blindness. The groups are testing different type of cells or ways of implanting those cells in the eye to see which approach is most effective for treating various forms blindness.


Karl Deisseroth profile: using light to control neurons, understand brain diseases

Image from the NIH

Nature ran a great profile of our grantee Karl Deisseroth, who has a New Faculty Award to develop ways of controlling neurons derived from stem cells. He’s the Stanford bioengineer who recently made such a splash with his see-through brain (that’s the technology on display in this most awesome video ever).

Deisseroth’s career path changed during a medical school rotation in psychiatry:

“Everything changed when I did my psychiatry rotation. A person can be right in front of you who looks intact, not obviously injured, and yet their brain is constructing for them a completely different reality. At the same time I saw how deep the suffering was.”

His work since then reflects that interest in understanding and treating diseases of the brain. Many stem cell projects involve maturing stem cells in a lab dish to become a type of neuron that goes awry in particular diseases. These studies–called disease-in-a-dish–have been effective for learning how diseases form and beginning to develop drugs, but Deisseroth told Nature that he wanted to understand those functions in the context of the whole brain. That’s easier said than done, given that studying an actual functioning brain is hardly straightforward.

That’s where the bioengineering comes in.

Deisseroth and his collaborators found a way of getting neurons to incorporate a type of protein from algae that is sensitive to light. Researchers can then use a certain wavelength of light to essentially turn those cells on and off. As part of his New Faculty Award, he and his team used the technology to, among other things, understand which neurons should be stimulated to reduce symptoms of Parkinson’s disease. The technique, called optogenetics, was named Method of the Year in 2011. (Bruce Goldman at Stanford wrote a remarkably understandable story about this complicated technique and its discovery.)

In his public description of his New Faculty Award, Deisseroth wrote:

This process of “stem cell differentiation” is slow, costly, laborious, variable, prone to error and contamination, and ultimately rate-limiting in the long road leading to clinical translation.

Although his work hasn’t eliminated all of those barriers, it’s a significant step toward the ultimate goal of developing stem cell therapies for the types of diseases that first turned his attention to understanding the brain.


Alan Trounson on stem cell progress, new clinics and the pace of research

CIRM President Alan Trounson

Patt Morrison of the L.A. Times had a wide-ranging conversation with CIRM President Alan Trounson, which appears in today’s paper. The conversation included cell lines generated from cloning, personal attacks during his work developing IVF technology and conflicts of interest, among other topics.

One of the things they discussed was the alpha clinic initiative, which will come before our Governing Board in July. The idea is to set up a network of clinics in California to deliver stem cell-based therapies. Trounson says:

It will make California a go-to place for stem cell therapies. I want to make sure it’s part of our medical fabric.

About the pace of research, Trounson had this to say:

I think we’re way ahead of what people predicted. Nevertheless, it takes a lot of time to do this. I think we’re hurrying carefully.

I was also rather fond of what Trounson (who is Australian) had to say about life in California:

[My colleagues] always say, “You’ve got the best job in the world. How did California do this?” That’s California. California is a can-do place, and when they want something, they stand up and do it. Many of [my colleagues] want to come to California. It’s just a wonderful place. You could sail it off the coast of America and it would be the most wonderful country in the world.

Read the full article for more on the money California will get from patents that come out of CIRM-funded research and scientific progress to-date.


CIRM grantees at UCSD use stem cell injections to improve spinal cord injuries in rats

A three-dimensional, reconstructed magnetic resonance image (upper) shows a cavity caused by a spinal injury nearly filled with grafted neural stem cells, colored green. The lower image depicts neuronal outgrowth from transplanted human neurons (green) and development of putative contacts (yellow dots) with host neurons (blue).

CIRM grantees at University of California, San Diego have found that injections of stem cells help rats with acute spinal cord injuries.

The group, whose findings were published in the May 28, 2013 online issue of Stem Cell Research & Therapy, injected human neural stem cells into the animals three days after injury. In a press release from UCSD, the scientists say that eight weeks later the animals were able to control their paws better after receiving the injections and had less muscle spasticity.

They quote Martin Marsala, who led the work:

“Grafted spinal stem cells are rich source of different growth factors which can have a neuroprotective effect and can promote sprouting of nerve fibers of the host neurons. We have also demonstrated that grafted neurons can develop contacts with the host neurons and, to some extent, restore the connectivity between centers, above and below the injury, which are involved in motor and sensory processing.”

The animals in this study had to have their immune systems suppressed to prevent them from rejecting the injected cells. The scientists say they are hoping to start a small phase 1 trial testing these cells in people with spinal cord injuries, and they’d also like to try creating neural stem cells by reprogramming the patient’s own cells. Those cells would avoid the need for immune-suppressing drugs.

CIRM funds several teams of researchers exploring different ways of using stem cells to treat spinal cord injury. You can see the full list of those awards on our spinal cord injury fact sheet. The teams are testing different types of stem cells and different approaches to injecting those cells to see which is most effective at healing the injury.


CIRM Funding: Martin Marsala (RM1-01720)

ResearchBlogging.orgvan Gorp, S., Leerink, M., Kakinohana, O., Platoshyn, O., Santucci, C., Galik, J., Joosten, E., Hruska-Plochan, M., Goldberg, D., Marsala, S., Johe, K., Ciacci, J., & Marsala, M. (2013). Amelioration of motor/sensory dysfunction and spasticity in a rat model of acute lumbar spinal cord injury by human neural stem cell transplantation Stem Cell Research & Therapy, 4 (5) DOI: 10.1186/scrt209

Stem cell stories that caught our eye: ups and downs of cloning, another windpipe, and the value of fat

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.

Roller coaster ride for a breakthrough. News that scientists in Oregon had finally made embryonic stem cells from cloned embryos ricocheted around the globe last week. Then for a time this week, claims of data inconsistencies called those results into question. By the time the dust settled late yesterday it looked like the errors were not major and were not likely to impact the validity of the scientific claims (both the author and Cell, which published the paper, say they are investigating). The stem cells they produced still need to be genetically analyzed by an outside lab, but it seems likely this long-sought milestone has been met. CNN online did a nice review of the events to date.

Printing a wind pipe. The most recent regenerative medicine story to go viral was the heart-warming tale of the Ohio boy who received a new windpipe made by a 3-D printer. The procedure, performed by a team at the University of Michigan, occurred last year and the boy, now 16 months old, is doing very well. The plastic windpipe will slowly dissolve over three years and be replaced by his own tissue, which is being laid down with help from his naturally circulating stem cells. The piece by the Associated Press’ lead science writer got the widest play.

And my colleague blogged about the procedure here putting it into perspective with the larger evolving field of tissue engineering.

Fat stem cells’ value goes up—maybe. The stem cells that can be isolated from fat are very similar to one of the two types of stem cells found in bone marrow. Those are mesenchymal stem cells, which can form fat, bone, cartilage, and other connective tissues. While there are a few clinical trials using mesenchymal stem cells to repair those tissues, more often, teams seeking to use them clinically are trying to harness a different skill they possess. They can modulate our immune response, which often results in reduced inflammation. But researchers have been divided on whether it is better to use mesenchymal cells harvested from bone or fat for this role. Now a Dutch team has published an article in the journal Stem Cells Translational Medicine that suggests stem cells from fat may secrete more of the factors that regulate inflammation than stem cells from bone. Here’s more about that work. CIRM has financially supported the start-up of this important journal for the past three years. I am proud to have written the request-for-proposals that resulted SCTM, which seems to be attracting important research. But like all new finding, this one needs to be replicated by other labs.

States picking up the slack in funding. When the Bush administration placed restrictions on much of embryonic stem cell research, California led the charge in filling the gap at the state level. But other states joined us, most significantly New York, Connecticut and Maryland. Although those restrictions have been lifted, federal budget cuts have made this state funding increasingly critical to keeping the field moving. Maryland became a formal collaborative funding partner with CIRM a few years ago. CIRM now has 22 collaborative agreements with countries, states and foundations around world, which you can review here. These arrangements allow the best scientist anywhere to work together leveraging the intellectual and financial resources of both California and the partner organization. And we think these arrangements accelerate the movement of potential therapies to the clinic. Maryland just announced its most recent round of grants here, which include a partnership with Stanford’s Roel Nusse. He does fascinating fundamental work that helps us learn how cells decide to become different types of tissue. A colleague wrote about his most recent research paper here.


Attracting the brightest, and saying goodbye to the best: Farewell to Claire Pomeroy

Dr. Claire Pomeroy, Dean of the UC Davis Medical School, receiving her proclamation at her final CIRM Board meeting

I’m never bored at our Board meetings. There’s always something fascinating going on, and this time was no exception. I’m not just talking about the fact that at our meeting this week the Board approved $36 million in funding to lure six of the top stem cell researchers in the world to California. Those researchers won’t just be bringing their brains and their ideas, in many cases they’ll be bringing world-class support staff too. Just another example of how we are helping make California the global leader in stem cell research.

Nor am I talking about the Board approving a $6.37 million award to Sangamo BioSciences to help fund research that will hopefully result in a clinical trial for a promising new treatment for beta-thalassemia – a potentially deadly blood disorder.

You can read about both of those in our news release.

But perhaps the most memorable moment of Thursday’s meeting was the heartfelt farewell that the Board gave to Dr. Claire Pomeroy, who is stepping down after nine years. She is leaving to become President of the Lasker Foundation.

Dr. Pomeroy is the Vice Chancellor for Human Health Sciences at UC Davis and Dean of the UC Davis School of Medicine. She is also an expert in infectious diseases and a professor of internal medicine and microbiology and immunology. But in saying goodbye to Dr. Pomeroy the word that came up most was “beloved.”

Vice Chair Sen. Art Torres said: “in all my years in Sacramento I never saw anyone as beloved as you. Your compassion and expertise and integrity made you someone everyone loved.”

Board Chair Jonathan Thomas said she really helped him when he first joined the stem cell agency, calling her “a great colleague and a great counselor.”

Patient advocate Judy Roberson said “you dream big, work hard and are courageous” and that because of her unswerving devotion to funding research into currently incurable diseases she had “taken so many people from hopeless to hopeful.”

Dr. Pomeroy thanked her colleagues on the Board for their support and encouragement saying: “I look back on the last 9 years and I have learnt so much about a field of medicine that didn’t even exist when I was in medical school. And I learned it here, in public, with you, about an approach that could change the face of medicine.”

Dr. Pomeroy ended by thanking the patients and patient advocates, saying: “they are the reason why we do this. And one day, when we announce cures, we will all be able to stand up and say that we were part of it, together.”

She will be missed, but her legacy and her impact on all that we do will live on.


Doctors use 3D printer to create windpipe and save baby’s life

The words “breakthrough” and “revolutionary” are overused in the media for many stories, and particularly for medical ones, but it’s hard not to search for something powerful and descriptive when you hear how doctors in Ohio used a 3D printer to create a new windpipe that saved the life of a baby boy. (Here’s a story about the work.)

The child was born with a birth defect that meant his airway kept collapsing, causing his breathing, and even his heart, to stop. Without intervention he would have died.

Doctors at the hospital where the baby was being treated reached out to researchers at the University of Michigan for help. Those researchers used computer-guided lasers and a 3D printer to create a tiny tube that would act like a splint inside the boy’s windpipe, providing the support it needed to not collapse and to function normally. Because this was the first time anything like this had been done they needed special approval from the Food and Drug Administration to implant it, but after they did the boy responded beautifully. He was 3 months old at the time of the surgery. Today he is 19 months old, has been able to leave the hospital and has not had any breathing problems since then.

This work was described in the latest issue of the New England Journal of Medicine

This follows another recent story about a 2-year old girl who was given an artificial windpipe created, in part, from her own stem cells. These are examples of how the field of regenerative medicine is pioneering approaches to treating life-threatening conditions. While these are truly remarkable they are still, in some senses, experimental therapies. They went ahead because without them these children would have died. To make sure these are safe approaches for others we still need to do a lot of research and study.

Nonetheless there is no mistaking the excitement that stories like this generate. It’s part of the field of tissue-engineering, an area of research that seeks to develop new tools and methods for the replacement, or regeneration of human organs and tissues. It’s an area that we are actively involved in funding – here is a video that explores the field and the hopes for this approach.