Harder, Better, Faster, Stronger: Scientists Work to Create Improved Immune System One Cell at a Time

The human immune system is the body’s best defense against invaders. But even our hardy immune systems can sometimes be outpaced by particularly dangerous bacteria, viruses or other pathogens, or even by cancer.

Salk Institute scientists have developed a new cellular reprogramming technique that could one day boost a weakened immune system.

Salk Institute scientists have developed a new cellular reprogramming technique that could one day boost a weakened immune system.

But what if we could give our immune system a boost when it needs it most? Last week scientists at the Salk Institute for Biological Sciences devised a new method of doing just that.

Reporting in the latest issue of the journal Stem Cells, Dr. Juan Carlos Izpisua Belmonte and his team announce a new method of creating—and then transplanting—white blood cells into laboratory mice. This new and improved method could have significant ramifications for how doctors attack the most relentless disease.

The authors achieved this transformation through the reprogramming of skin cells into white blood cells. This process builds on induced pluripotent stem cell, or iPS cell, technology, in which the introduction of a set of genes can effectively turn one cell type into another.

This Nobel prize-winning approach, while revolutionary, is still a many months’ long process. In this study, the Salk team found a way to shorten the cellular ‘reprogramming’ process from several months to just a few weeks.

“The process is quick and safe in mice,” said Izpisua Belmonte in a news release. “It circumvents long-standing obstacles that have plagued the reprogramming of human cells for therapeutic and regenerative purposes.”

Traditional reprogramming methods change one cell type, such as a skin cell, into a different cell type by first taking them back into a stem cell-like, or ‘pluripotent’ state. But here, the research team didn’t take the cells all the way back to pluripotency. Instead, they simply wiped the cell’s memory—and gave it a new one. As first author Dr. Ignacio Sancho-Martinez explained:

“We tell skin cells to forget what they are and become what we tell them to be—in this case, white blood cells. Only two biological molecules are needed to induce such cellular memory loss and to direct a new cell fate.”

This technique, which they dubbed ‘indirect lineage conversion,’ uses the molecule SOX2 to wipe the skin cell’s memory. They then use another molecule called miRNA 125b to reprogram the cell into a white blood cell.

These newly generated cells appear to engraft far better than cells derived from traditional iPS cell technology, opening the door to therapies that more effectively introduce these immune cells into the human body. As Sanchi-Martinez so eloquently stated:

“It is fair to say that the promise of stem cell transplantation is now closer to realization.”

Stem cell stories that caught our eye: first iPS clinical trial, cancer metabolism and magnates helping heal hearts

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.

First clinical trial with reprogrammed stem cells.
Today, a Japanese woman became the first patient to be treated with cells derived from reprogrammed iPS-type stem cells. The patient received cells matured into a type of cell damaged in the most common form of blindness, age-related macular degeneration.

Those cells, a normal part of the eye’s retina, were made from stem cells created from a skin sample donated by the patient several months ago. In the intervening time the resulting retinal cells have been tested in mice and monkeys to make sure they will not cause tumors. Because the cells have the same genes as the patient, researchers believe they may not be rejected by the patient’s immune system in the absence of immune suppressive drugs—the beauty of iPS technology.

Right now, that technology is much too cumbersome and time consuming to result in a broadly applicable therapy. But if this first clinical trial proves the immune system get-out-of-jail-free theory, it should intensify efforts to make iPS technology more efficient.

When Japanese authorities gave permission to treat the first patient earlier this week Popular Science provided an easy read version of the story and Nature News provided a bit more detail.

Cancer cells don’t handle their sugar well. Sugar has a bad rep these days. Now, it looks like manipulating sugar metabolism might lead to ways to better treat leukemia and perhaps, make therapies less toxic to normal cells. It turns out cancer cells are much more sensitive to changes in sugar level than normal blood stem cells or the intermediate cells that give rise the various branches of the blood system.

David Scadden at the Harvard Stem Cell Institute has long studied the role of the stem cell's environment in its function.

David Scadden at the Harvard Stem Cell Institute has long studied the role of the stem cell’s environment in its function.

A team led by old friend and colleague at the Harvard Stem Cell Institute, David Scadden, first looked at sugar metabolism in normal blood forming stem cells and their intermediate cells. They found that the parent stem cell and their direct offspring, those intermediate cells, behave differently when faced with various manipulations in sugar level, which makes sense since the intermediate cells are usually much more actively dividing.

But when they manipulated the genes of both types of cells to make them turn cancerous, the cancer cells from both were much more sensitive to changes in sugar metabolism. In a university press release picked up by ScienceCodex David said he hoped to interest drug companies in developing ways to exploit these differences to create better therapies.

Magnets and nanoparticles steer stem cells.
Getting stem cells to where they are needed to make a repair, and keeping them there is a major challenge. A team at Los Angeles’ Cedars-Sinai hospital that we fund (but not for this study) has taken an approach to this problem that is the equivalent of holding your pants up with a double set of button, a belt and suspenders.

Treating damaged hearts in rats they first loaded iron-containing nanoparticles with two types of antibodies, one that recognizes and homes to injured heart tissue and one that attracts healing stem cells. After infusing them into the animal’s blood stream, they placed a magnet over its heart to hold the iron nanoparticles near by. The iron provided the added benefit of letting the team track the cells via magnetic resonance imaging (MRI) to verify they did get to and stay where they were needed.

In a press release from the hospital picked up by ScienceDaily the lead researcher Eduardo Marban said:

“The result is a kind of molecular matchmaking,”

The study was published in Nature Communications and you can read about other work we fund in Marban’s lab trying to figure out once you get the stem cells to the heart exactly how do they create the repair.

Reprogrammed stem cells turned into white blood cells. We have written often about the difficulties of getting stem cells to create fully mature blood cells. Last week we talked about a Wisconsin team breaking the barrier for red blood cells. Now, a team at the Salk Institute is reporting success for white blood cells.

Starting with iPS-type stem cells they got the mature white cells via a two-step process. First they manipulated one gene called Sox2 to get the stem cells to become the right intermediate cells. Then they used a gene-regulating molecule called a micro-RNA to get the middleman cells to mature into white blood cells.

In a press release from the Salk, lead researcher Juan Carlos Izpisua Belmonte noted the clinical importance of the work:

“In terms of potential clinical applications, the hematopoietic system represents one of the most suitable tissues for stem cell-based therapies. . .”

The team published the research in the journal Stem Cells and the web portal BioSpace picked up the release.

Book on early spinal cord injury clinical trial. The title of a book on the first ever clinical trial using cells from embryonic stem cells kind of says it all: Inevitable Collision: The Inspiring Story that Brought Stem Cell Research to Conservative America.

Katy Sharify's experience in the first embryonic stem cell trial is featured in a new book and she discussed it in a video from a CIRM workshop.

Katy Sharify’s experience in the first embryonic stem cell trial is featured in a new book and she discussed it in a video from a CIRM workshop.

The book details the personal stories of the first and fifth patients in the spinal cord injury trial conducted by Geron. That company made the financial decision to end its stem cell product development in favor of its cancer products. But the spinal cord injury trial is now set to restart, modified to treat neck injuries instead of back injuries and at higher doses, through CIRM funding to the company that bought the Geron stem cell business, Asterias.

In a press release from the publisher, the book’s author explained her goal:

“Through this book I hope to bridge the gap between science and religion and raise awareness of the importance and power of stem cell research.”

The fifth patient in the Geron study, Katie Sharify, is featured in our “Stories of Hope” that have filled The Stem Cellar this week.

Don Gibbons

Disease in a Dish – That’s a Mouthful: Using Human Stem Cells to Find ALS Treatments

Saying “let’s put some shrimp on the barbie” will whet an Australian’s appetite for barbequed prawns but for an American it conjures up an odd image of placing shrimp on a Barbie doll. This sort of word play confusion doesn’t just happen across continents but also between scientists and the public.

Take “disease in a dish” for example. To a stem cell scientist, this phrase right away describes a powerful way to study human disease in the lab using a Nobel Prize winning technique called induced pluripotent stem cells (iPSC). But to a non-scientist it sounds like a scene from some disgusting sci-fi horror cooking show.

Our latest video Disease in a Dish: That’s a Mouthful takes a lighthearted approach to help clear up any head scratching over this phrase. Although it’s injected with humor, the video focuses on a dreadful disease: amyotrophic lateral sclerosis (ALS). Also known as Lou Gehrig’s disease, it’s a disorder in which nerve cells that control muscle movement die. There are no effective treatments and it’s always fatal, usually within 3 to 5 years after diagnosis.

To explain disease in a dish, the video summarizes a Science Translation Medicine publication of CIRM-funded research reported by the laboratory of Robert Baloh, M.D., Ph.D., director of Cedars-Sinai’s multidisciplinary ALS Program. In the study, skin cells from patients with an inherited form of ALS were used to create nerve cells in a petri dish that exhibit the same genetic defects found in the neurons of ALS patients. With this disease in a dish, the team identified a possible cause of the disease: the cells overproduce molecules causing a toxic buildup that affects neuron function. The researchers devised a way to block the toxic buildup, which may point to a new therapeutic strategy.

In a press release, Clive Svendsen, Ph.D., a co-author on the publication and director of the Cedars-Sinai Regenerative Medicine Institute had this perspective on the results:

“ALS may be the cruelest, most severe neurological disease, but I believe the stem cell approach used in this collaborative effort holds the key to unlocking the mysteries of this and other devastating disorders.”

The video is the pilot episode of Stem Cells in Your Face, which we hope will be an ongoing informational series that helps explain the latest advances toward stem cell-based therapies.

For more information about CIRM-funded ALS research, visit our ALS fact sheet.

CIRM Creativity Student Cindy Nguyen Goes “Beyond the Classroom”

This summer we’re sponsoring high school interns in stem cell labs throughout California as part of our annual Creativity Program. We asked those students to share their experiences through blog posts and videos.

Today in our final installment, we hear from Cindy Nguyen, who has been busy at Stanford University’s Beckman Center for Molecular and Genetic Medicine.

Beyond the Classroom

Cindy Nguyen

“And these are human induced pluripotent stem cells.”

I stood in awe. It was my first day in the lab, and I could not believe what I was seeing for the first time. I remembered reading about these “inner healers” in AP Biology class just a year ago and thinking about the endless possibilities of research that these induced pluripotent stem cells (iPSCs) could lead to. In a small classroom miles away from Stanford University, the existence of iPSCs seemed surreal and inaccessible. However, here I was standing before these cells, as one of the post-doctoral fellows of my lab was culturing them while describing their purpose.

Picking colonies at the bench.

Picking colonies at the bench.

One of the projects of my lab involves differentiating iPSCs into beating cardiomyocytes. It is almost unbelievable that fibroblasts could have their “biological clocks” rewounded and then be differentiated into pulsing heart cells so easily. I was reminded yet again of the incredible power of scientific research and all the open questions left to answer about iPSCs.

Spending the summer at a research laboratory at Stanford has given me the opportunity to become involved in life-changing research with access to everything I could ever need to conduct an investigation. Ranging from the thermal cycler to pipettes, all these commodities would be considered rare specialties in a high school biology classroom. I feel especially grateful to have the opportunity not only to conduct cutting-edge research in a lab on one of the most prestigious campuses in the country but also to learn about the world of research at my age.

Performing my first immunohistochemistry stain!

Performing my first immunohistochemistry stain!

Just a few months before, I had felt unsure about my future prospects. I did not have the chance to explore what having a career in science really meant. My family had a very little idea of what research was like and was not sure if this would be a rewarding career. However, after this summer’s incredible internship, I am confident in diving into biological sciences in the future. This position has given me the opportunity to show my family the great work that scientific researchers do every day and how rewarding it can be. The ambiguity of lab research has dissolved, and my future choices seems that much clearer.

Stem Cell Stories that Caught our Eye: “Let it Grow” Goes Viral, Stroke Pilot Study, The Bowels of Human Stem Cells, Tumor ‘Safety Lock.’

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.

“Let it Grow” Goes Viral (and National!): Last week on The Stem Cellar we shared one of our favorite student videos from our annual Creativity Program. The video, a parody of the hit song from the movie Frozen, highlighted the outstanding creativity of a group of high school students from City of Hope in Los Angeles. And now, the song has made a splash nationwide—with coverage from ABC 7 Bay Area and even NBC New York!

Students from the City of Hope practice their routine for the group video

Students from the City of Hope practice their routine for the group video

Watch the full video on our YouTube page.

Stroke Pilot Study Shows Promise. Researchers at Imperial College London are currently testing whether stem cells extracted from a patient’s bone marrow can reverse the after effects of a stroke.

Reporting in this week’s Stem Cells Translational Medicine the team, lead by Dr. Soma Banjeree, describe their pilot study in which they collect a type of bone marrow stem cells called CD34+ cells. These cells can give rise to cells that make up the blood and the blood vessel lining. Earlier research suggested that treating stroke victims with these cells can improve recovery after a stroke—not because they replace the brain cells lost during a stroke, but because they release a chemical that triggers brain cells to grow. So the team decided to take the next step with a pilot study of five individuals.

As reported in a recent news release, this initial pilot study was only designed to test the safety of the procedure. But in a surprising twist, all patients in the study also showed significant improvement over a period of six months post-treatment. Even more astonishing, three of the patients (who had suffered one of the most severe forms of stroke) were living assistance-free. But since the first six months after injury is a time when many patients see improved function, these results need to be tested in a controlled trial where not all patients receive the cells

Immediate next steps include using advancing imaging techniques to more closely monitor what exactly happens in the brain after the patients are treated.

Want to learn more about using stem cells to treat stroke? Check out our Stroke Fact Sheet.

Deep in the Bowels of Stem Cell Behavior. Another research advance from UK scientists—this time at Queen Mary University of London researchers—announces important new insight into the behavior of adult stem cells that reside in the human gastro-intestinal tract (which includes the stomach and intestines). As described in a news release, this study, which examined the stem cells in the bowels of healthy individuals, as well as cells from early-stage tumors, points to key differences in their behaviors. The results, published this week in the journal Cell Reports, point to a potential link between stem cell behavior and the development of some forms of cancer.

By measuring the timing and frequency of mutations as they occur over time in aging stem cells, the research team, led by senior author Dr. Trevor Graham, found a key difference in stem cell behaviors between healthy individuals, and those with tumors.

In the healthy bowel, there is a relative stasis in the number of stem cells at any given time. But in cancer, that delicate balance—called a ‘stem cell niche’—appears to get thrown out of whack. There appears to be an increased number of cells, paired with more intense competition. And while these results are preliminary, they mark the first time this complex stem cell behavior has been studied in humans. According to Graham:

“Unearthing how stem cells behave within the human bowel is a big step forward for stem cell research. We now want to use the methods developed in this study to understand how stem cells behave inside bowel cancer, so we can increase our understanding of how bowel cancer grows. This will hopefully shed more light on how we can prevent bowel cancer—the fourth most common cancer in the UK.”

Finding the ‘Safety Lock’ Against Tumor Growth. It’s one of the greatest risks when transplanting stem cells: the possibility that the transplanted cells will grow out of control and form tumors.

But now, scientists from Keio University School of Medicine in Japan have devised an ingenious method that could negate this risk.

Reporting in the latest issue of Cell Transplantation and summarized in a news release, Dr. Masaya Nakamura and his team describe how they transplanted stem cells into the spinal columns of laboratory mice.

And here’s where they switched things up. During the transplantation itself, all mice were receiving immunosuppressant drugs. But then they halted the immunosuppressants in half the mice post-transplantation.

Withdrawing the drugs post-transplantation, according to the team’s findings, had the interesting effect of eliminating the tumor risk, as compared to the group who remained on the drugs. Confirmed with bioluminescent imaging that tracked the implanted cells in both sets of mice, these findings suggest that it in fact may be possible to finely tweak the body’s immune response after stem-cell transplantation.

Want to learn more about stem cells and tumor risk? Check out this recent video from CIRM Grantee Dr. Paul Knoepfler: Paul Knoepfler Talks About the Tendency of Embryonic Stem Cells to Form Tumors.

Grafted Stem Cells Snake through Spinal Cord, CIRM-Funded Study Finds

New research lends increasing support to the notion that paralysis may not be so permanent after all.

Scientists at the University of California, San Diego have generated stem cells that, when grafted onto the injured spines of rats—traverse through the injury sites, coupling with nerve cells hidden beneath the damaged tissue. These results, published today in the journal Neuron, are a critical next step towards using stem cell-technology to reverse spinal cord injury—a condition that has long been considered irreversible.

The extension of human axons into host adult rat white matter and gray matter three months after spinal cord injury. [Credit: UCSD School of Medicine

The extension of human axons into host adult rat white matter and gray matter three months after spinal cord injury. [Credit: UCSD School of Medicine]

This research team, led by CIRM grantee Dr. Mark Tuszynski, generated stem cells from the skin cells of an adult human male. These so-called induced pluripotent stem cells, or iPS cells, then had the ability to transform into virtually any cell type. With a bit of coaxing, the team transformed them one more time—into early-stage neurons—and grafted them onto the injured rats. After monitoring the animals over a period of three months, what they began to see astonished them.

The most amazing changes came from the cells’ axons—long, spindly projections that connect neurons to each other, allowing them to communicate through transmission of electrical signals. Much to their surprise, the team saw these iPS cell-derived axons began to grow—some extending across the animals’ entire central nervous system.

But it wasn’t just the fact that the axons grew that excited researchers—it’s where they went. They began to pierce through the spinal injury sites, penetrating scar tissue and grey matter and forming connections with existing rat neurons that had been entombed inside. Even more incredibly, the native rat axons began to do the same—growing and piercing through the iPS cell grafts to form connections of their own.

As Tuszynski explained in a news release:

“These findings indicate that intrinsic neuron mechanisms readily overcome the barriers created by a spinal cord injury to extend many axons over very long distances, and that these capabilities persist even in neurons that have been reprogrammed.”

The results of this study are encouraging, say the research team, though they do raise a few questions about the underlying signaling mechanisms that are guiding these axons to grow and become intertwined. Tuszynski elaborated:

“The enormous outgrowth of axons to many regions of the spinal cord and even deeply into the brain raises questions of possible side effects if axons are mis-targeted. We also need to learn if the new connections formed by axons are stable over time, and if implanted human neural stem cells are maturing on a human time frame—months to years—or more rapidly.”

The researchers are now exploring whether using different types of stem cells, such as embryonic stem cells, would yield similar results. Once they hone in on the best method, they hope to take their findings further down the path towards clinical trials.

“Ninety-five percent of human clinical trials fail,” explained Tuszynski. “We want to determine as best we can the optimal cell type and best method for human translation so that we can move ahead rationally and, with some luck, successfully.”

Stem cell stories that caught our eye: better cell reprogramming, heart failure and false claims for stem cells

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

Improving the efficiency of creating stem cell lines.
Ever since researchers first learned to reprogram adult cells to behave like embryonic stem cells in 2007 teams have tried to do it better. The earliest reprogramming resulted in less than one percent of cells converting to the stem cell state. Many years and many reprogramming recipes later some teams have got that up to a few percent, but usually still in the single digits. CIRM-funded researchers at the University of California, San Francisco, have uncovered a path that could yield dramatic increases in efficiency in creating these stem cells. They stepped back to look at what genetic factors were acting as brakes on the reprogramming and have now mapped out multiple brake points that could be inhibited to improve the production of stem cells. HealthCanal ran the university’s press release based on the journal publication in Cell.

Does source of adult cells matter for iPS-type stem cells. When researchers turn adult tissue into embryonic-like iPS cells, they know that the reprogrammed stem cells retain some memory of the type of adult tissue they were, whether it was skin, brain or heart. So, a CIRM-funded team at Stanford set out to do a series of experiments to see if that mattered. They created iPS cells from heart tissue and from skin cells. And initially, there was a difference. The stem cells made from heart more readily matured into heart muscle than those from skin, but over time, as the cells grew in the lab the difference abated. Both types of cells began to function like normal heart muscle. Stanford’s Scope blog wrote about this and a companion paper that were published this week in the Journal of the American College of Cardiology.

Heart progenitor cells, the middlemen between stem cells and adult heart muscle, shown here in green and infected with coxsackie vurus.

Heart progenitor cells, the middlemen between stem cells and adult heart muscle, shown here in green and infected with coxsackie vurus.

Viral heart failure link may be via stem cells
. Our hearts are one of our poorest performing organs when it comes to repairing themselves. The liver does it well. The lining of our guts does it well—the heart not so much. Scientists generally attribute this to the very small number of stem cells we retain in our hearts. If you lose those few, you are in deep trouble. While there are many reasons for heart failure, we have known that a high percent of those who develop this weakening of the heart’s ability to pump blood have signs of having been infected with the coxsackie virus. Researchers at San Diego State University have found out a possible reason why. The virus appears to selectively seek out and destroy the heart stem cells and middlemen progenitor cells. HealthCanal ran the university’s press release based on work published this week in PLOS Pathogens.

Review talks about reality of stem cells in sports.
Over the past year, there has been a parade of headlines about athletes getting their sports injuries treated with stem cells. The EuroStemCell collaborative has published online a great review of the reasons why stem cells might work for some of those conditions, and might not. The piece dutifully starts by noting that none of these treatments have been approved for general use because none have had sufficient testing. Taking muscle, cartilage, tendon and bone repair individually the authors discuss what research has been done and what it shows. In general, the results have not been great, in large part because we haven’t yet figured out what is the best type of cell for each injury and the best way to deliver it.

False claims in stem cell for plastic surgery. CIRM-grantee Michael Longaker at Stanford has called out his fellow plastic surgeons to lead the charge in evaluating the uses of stem cells in cosmetic procedures. In an article in the journal Plastic and Reconstructive Surgery he describes research he did into 50 clinics that showed up in a google search offering stem cell face lifts. While they were claiming to inject age-reversing stem cells, he suggests they were doing no more than the established practice of injecting fat to smooth out wrinkles. While fat does have a few stem cells in it, he could find no evidence that the clinics had the necessary equipment to isolate those cells, and even if they did, there is scant research into whether those stem cells could have any impact. Popular Science and ScienceNewsline both ran stories about the journal article this week.

Don Gibbons

Stem Cells become Tool to Screen for Drugs; Fight Dangerous Heart Infections.

A Stanford study adds a powerful example to our growing list of diseases that have yielded their secrets to iPS-type stem cells grown in a dish. These “disease-in-a-dish” models have become one of the most rapidly growing areas of stem cell science. But this time they did not start with skin from a patient with a genetic disease and see how that genetic defect manifests in cells in a dish. Instead they started with normal tissue and looked at how the resulting cells reacted to viral infection.

They were looking at a nasty heart infection called viral myocarditis, which can begin to cause damage to heart muscle within hours and often leads to death. Existing antiviral drugs have only a modest impact on reducing these infections. So even though there is an urgent need to find better drugs, animal models have not proven very useful and there is no ready supply of human heart tissue for lab study.

To create a ready supply of human heart tissue Joseph Wu’s CIRM-funded team at Stanford started with skin samples from three healthy donors, reprogrammed them into iPS cells and then matured those into heart muscle tissue. Then they took one of the main culprits of this infection, coxsackievirus, and labeled it with a fluorescent marker so they could track its activity in the heart cells.

They were able to verify that the virus infected the cells in a dish just as they do in normal heart tissue. And when they tried treating the cells with four existing antiviral drugs they saw the same modest decrease in the rate of infected cells seen in patients. For one of the drugs that had been shown to cause some heart toxicity, they also saw some damage to the cells in the dish.

They propose that their model can now be used to screen thousands of compounds for potentially more effective and safer drugs. They published their results in Circulation Research July 15.

DISCUSSing iPSC Derivation

Geoff Lomax is CIRM’s Senior Officer for Medical and Ethical Standards. He has been working in the implementation of CIRM’s iPSC Banking Program.

The ability to create high-quality stem cell lines depends, in part, on the generosity of donors. For example, CIRM is sponsoring an induced pluripotent stem cell bank (iPSC bank) that will eventually contain 9,000 stem cell lines. Each of these lines will be generated from tissue donated by 3,000 people suffering from known diseases such as Alzheimer’s disease, autism, hepatitis, blindness, heart disease—and many more. You can learn more about this important initiative here.


In other countries there are similar initiatives like the one sponsored by CIRM.

We also believe that our donors should have accurate information about how their donated materials will be used, so CIRM has developed variety of tools designed to educate donors. For example, each donor must go through a process called “informed consent” where they are told the details of how iPSC’s are derived and preserved in a bank. We discuss this effort here. In the context of the CIRM bank, new donors are being recruited under ethically and scientifically optimal conditions—where they can be fully informed as to how their cells will be used and how their contribution will spur stem cell research.

There are, however, existing libraries of cell and tissues that have inherent scientific value. For example, they may represent a rare or “orphan” disease. Or, they may be essential for tracking the progress of a patient’s disease over time. These collections have also been developed with the consent of the donor or patient, but, at the time of collection, iPSCs may not have even existed. One question that frequently arises is: can these cells be used for iPSC derivation, research and banking? It is not an abstract concern; CIRM and others often get questions about the adequacy of donor consent for precisely this purpose.

In 2013, CIRM, the NIH and the International Stem Cell Forum (ISCF)/McGill University formed the DISCUSS Project (Deriving Induced Stem Cells Using Stored Specimens) to engage the boarder research community on this issue. Rosario Isasi, a project collaborator from ISCF/McGill University, said that her research tells us that investigators around the world are asking the same questions about use of existing cell lines. To help inform researchers, we started by publishing a report on this very subject. The report included nine points to consider when answering the question of whether existing cell libraries can be used for iPSC research.

We followed this initial effort with a series of meetings and workshops to get reactions to our proposed points to consider. The process culminated with a workshop in March where researchers from around world provided recommendations to the DISCUSS team. Sara Hull, a project collaborator from the NIH, noted that the international perspectives were key to producing a greatly improved product. A major workshop theme was the importance of having an effective management system in place, making sure that the cells are used in a way that is consistent with the donor consent. Participants described a number of specific mechanisms that should be used by the research community to ensure cells are used appropriately. Participants emphasized that having effective systems in place to manage cells and iPSC lines in accordance with donors wishes serves to build trust.

Our workshop report elaborates on specific steps researchers and stem cell banks should take to ensure cell lines are used appropriately. The report also includes a revised set of points to consider based on comments received from meetings and workshops.

The DISCUSS Team looks forward to working with the research community to develop consensus for the responsible use of donated materials in stem cell research.

Geoff Lomax

Stem Cell Stories that Caught our Eye: Multiple Sclerosis, Diabetes, Cornea Repair and of Course, New Stem Cells too Good to be True

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.

Buddy system gets stem cells to stick around. The type of stem cell most likely to be used in a clinical trial today is the mesenchymal stem cell (MSC) found in fat and bone marrow. It is also the type of stem cell most likely to produce vaguely positive or downright disappointing results. In most situations they die within a few days of being transplanted, so the only impact they can have is from the various protein signals they secrete that may trigger the body’s own natural healing processes. They never live up to their stem cell potential to form new adult tissue. A team at Harvard looked at their natural environment and found they most often live near a second type of cell called an endothelial colony-forming cell. When the team transplanted the two cells together they found the MSCs survived for weeks and matured into appropriate adult tissue. Genetic Engineering & Biotechnology News had a nice interview with members of the team about their work that appeared this week in the Proceedings of the National Academy of Sciences.

Fat cells (yellow) descended from transplanted stem cells (green) inside a mouse 28 days after co-transplantation with “buddy cells”  [Courtesy Children’s Hospital]

Fat cells (yellow) descended from transplanted stem cells (green) inside a mouse 28 days after co-transplantation with “buddy cells”
[Courtesy Children’s Hospital]

Master switch for creating brain insulation.
Researchers know how to take a skin cell from a patient, turn it into an iPS type stem cell and then turn those cells into the type of intermediate cell that can become the myelin that insulates our nerves and is lost in Multiple Sclerosis. The problem: the process takes way too long to be a feasible therapy. To get enough of these middleman cells called oligodendrocyte progenitors for a therapy can take as much as a year. Neural stem cells naturally mature into multiple intermediate cells, but prefer to become the progenitors for neurons, which would not help an MS patient. A team at the University of Buffalo looked to see what genetic switches were active in neuron progenitors versus those for myelin. They found that just one of these switches could push the early nerve stem cells to the myelin middlemen. That genetic factor, SOX10, instantly becomes a candidate for a path to a more efficient therapy. Again, Genetic Engineering & Biotechnology News did the best of several write-ups of this work that was published in the Proceedings of the National Academy of Sciences.

You can read about CIRM’s projects working on a cure for MS on our Multiple Sclerosis Fact Sheet.

Can gut be taught to make insulin. Earlier work at Columbia University had shown that in mice you can turn off a single gene and get normal gut cells to secrete insulin and to do so in response to sugar in the bloodstream. Now the team has made the often difficult transition of moving from mouse results to humans, or in this case human gut cells in a dish. They matured human stem cells into gut tissue and then shut down the one gene. The resulting cells produced insulin in response to sugar in their environment. The research published in Nature Communication got coverage on a few sites including HealthDay.

Early success in cornea repair poised to get even better. One of the stem cell field’s early successes has been work pioneered in Italy using a type of stem cell found in the cornea of the eye. When a patient has the cornea of one eye damaged they harvest these cells, called limbal stem cells, from the healthy eye and transplant them to the damaged eye. It often works quite well, but not always and the success has been correlated with how many actual limbal stem cells are among the cells transplanted. It has been difficult to sort out and purify the stem cells until now. A team from three Harvard affiliated hospitals has found a marker that let them transplant purer human limbal stem cells into mice and they saw consistent regrowth of damaged corneas. RedOrbit wrote up the research that was published in Nature.

STAP stem cell retraction everywhere. When Japanese and American researchers published a new, simple method for creating stem cells in January it got way more news coverage than an unconfirmed and unconventional piece of research should have. Most of that coverage failed to include the caveat that the work needed to be replicated to confirm the findings. In less than six months, the research community quickly reported repeated failures to replicate the work and more recently found outright errors in the published papers. When the journal that published the work, Nature, formally retracted the papers this week it was good to see that this “oops-ignore-our-first-article” seemed to get equal play. To show the reach of this news, I have included the Associated Press version from the tiny Logansport Pharos Tribune, which averages about 12 pages a day and is the closest real newspaper to the tiny Indiana town where I grew up.

Don Gibbons