Stem cell stories that caught our eye: good fat vs. bad fat, the black box of cell reprogramming and Parkinson’s

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.

One day a pill might turn bad fat into good fat. For a few years now several research teams have linked white fat to the bad health effects of fat and brown fat to more positive metabolism and to being leaner. Now, a team at the Harvard Stem Cell Institute has used stem cells in the laboratory as a screening tool to look for drugs that could cause the bad fat to turn into the good fat.

Brown fat derived from stem cells. Image courtesy of Harvard

Brown fat derived from stem cells. Image courtesy of Harvard

They have found two molecules that can prevent fat stem cells from becoming mature white fat and instead direct them to become brown fat. But those two molecules used as pills would likely have too many unintended side effects to become a treatment that would likely need to be taken long-term. So, despite some overblown headlines about a “pill to replace a treadmill,” don’t count on it anytime soon.

That treadmill line came from a story in the Harvard Gazette, but to the school’s credit they did follow-up with the needed caveats:

“The path from these findings to a safe and effective medication may not be easy, and the findings will have to be replicated by other research groups, as well as refined, before they could lead to a clinical treatment.”

Opening up the black box of reprogramming cells. Researchers around the world have been turning adult cells into embryonic-like stem cells ever since Shinya Yamanaka’s Nobel-prize winning work showing it was possible more than six years ago. But no one really knew how it works. And that lack of understanding has made it quite difficult to improve on the poor efficiency and mixed-results of the process.

This led 30 senior scientists at eight institutions around the world to launch a project in 2010 to create an extremely detailed map of all the switching on and off of genes over time during the weeks it takes to reprogram adult cells to become “pluripotent” stem cells. The effort, called Project Grandiose, reported its results this week in a series of three papers in the journal Nature Communications. The name comes in part from the massive size of the data sets involved. Files could not be sent electronically. The teams were shipping memory storage devices around the world by courier. The leader of the project, Andras Nagy of Mount Sinai Hospital in Toronto described the project in a review of the field in Nature:

“It was the first high-resolution analysis of change in cell state over time. I’m not shy about saying grandiose.”

That journal review provides the best history of reprogramming that I have read and it is written on a level that a lay science hobbyist could understand. It gives a good explanation for one of the surprise findings from Project Grandiose that got a little over-played in some coverage. That was discovery of a new type of pluripotent stem cell called F Class, not referring to Mercedes car lines, but rather the fact that the cell clusters in a lab dish look fuzzy. The process that creates them in the lab seems to be more efficient than traditional reprogramming.

The critical output of the international project is more practical. Researchers around the world now have myriad new ways to think about improving the production of reprogrammed stem cells. Ken Zaret of the University of Pennsylvania, and a long time toiler in the field told the author of the Nature review this work opens up options for more reliable sources of cells to be used in human medicine:

“The motivation of my research is to treat patients. Anything that helps push iPS cells into the clinic excites me.”

Stem cells from inside the nose treat Parkinson’s in rats. A type of stem cell found in tissue that in humans would be thrown out after sinus surgery was retrieved from rats and then injected into the parts of their brains that do not function properly in Parkinson’s disease (PD). After 12 weeks the cells had migrated to where they were needed and matured into the type of nerve cell needed to cure PD and improved the function of the animals.

The cells, called inferior turbinate stem cells, could be a way to use a patient’s own stem cells as therapy for PD and avoid issues of immune rejection of donor cells, which may or may not be an issue in the brain, but this would remove a layer of risk. The work by a team at the University of Bielefeld and Dresden University of Technology in Germany was published in the journal Stem Cells Translational Medicine and the Houston Chronicle picked up the journal’s press release.

Stem Cell Stories that Caught our Eye: Stem Cell Summit Roundup, Spinal Cords in a Dish and Stem Cell Tourism in the NFL

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.

Success at the World Stem Cell Summit. This week some of the biggest names in regenerative medicine descended upon San Antonio, Texas for the annual summit. Along with researchers from the world’s top universities, institutions and companies were members of CIRM, including CIRM President and CEO C. Randall Mills.

We’ve been publishing top highlights from the Summit all week here on the Stem Cellar. There’s also been detailed coverage in the local San Antonio press, including the local ABC station. And if you’d like to find out more about this year’s conference, be sure to visit @WSCSummit and #WSC14 on Twitter.

Scientists have found a way to grow spinal cords from embryonic stem cells in a petri dish. [Credit: Abigail Tucker/ MRC Centre for Developmental Neurobiology/ Wellcome Images.]

Scientists have found a way to grow spinal cords from embryonic stem cells in a petri dish. [Credit: Abigail Tucker/ MRC Centre for Developmental Neurobiology/ Wellcome Images.]

Growing Spinal Cords in the Lab. Tissue engineering, the process of using stem cells to build new tissues and organs, has been the Holy Grail for regenerative medicine. And while there has been some progress with engineering some organs, others—especially the spinal cord—have proven far more difficult. This is because the biodegradable scaffolding cannot be made correctly to grow complex and intricately connected nerve cells.

But now, a research team in Germany has grown complete spinal cords in the lab, pointing to a new strategy for treating those with irreparable spinal cord injuries.

As reported in The Guardian this week, Andrea Meinhardt of the Dresden University of Technology and her colleagues worked around the problem of scaffolding by employing a new method called self-directed morphogenesis, first developed by the late Yoshiki Sasai. According to The Guardian‘s Mo Costandi:

“Self-directed morphogenesis is a method for growing embryonic stem cells in a three-dimensional suspension. Cells grown in this way can, when fed the right combination of signaling molecules, go through the motions of development and organize themselves to form complex tissues such as eyes, glands and bits of brain.”

While preliminary, this research offers immense promise towards the ultimate goal: reversing the devastating effects of spinal cord injuries.

Stem Cells and the NFL. Despite the best efforts of experts, stem cell tourism continues to proliferate. A new study published this week in 2014 World Stem Cell Report (a special supplement to Stem Cells and Development) describes the latest example of people seeking unproven stem cell treatments: this time in the NFL.

New research from Rice University is suggesting that some NFL players are seeking out unproven stem cell treatments—oftentimes traveling abroad without fully understanding the risks. This poses serious problems not only for players but also for the NFL as a whole. As Co-lead author Kirsten Matthews elaborated in a news release:

“With the rise of new and unproven stem cell treatments, the NFL faces a daunting task of trying to better understand and regulate the use of these therapies in order to protect the health of its players.”

Specifically, 12 NFL players are known to have received unproven treatments at some point during the last five years, including star quarterback Peyton Manning who we’ve blogged about before The authors caution that high-profile players broadcasting that they are receiving these unproven therapies could influence regular patients who are also desperate for cures.

In order to fix this growing problem, the authors recommend the NFL review and investigate these unproven stem cell treatments with the help of an independent committee of medical professionals. Finally, they suggest that the NFL could support stem cell research here in the United States—so that proven, effective stem cell-based treatments could more quickly enter the clinic.

Using stem cells paves new approach to treating a blistering skin disease

Imagine a child not being able to run or jump or just roll around, for fear that any movement could strip away their skin and leave them with open, painful wounds. That’s what life is like for children with a nasty genetic disease called epidermolysis bullosa or EB. The slightest touch can cause their skin to peel off. People with the disease often die in their late teens or early 20’s from skin cancer, caused by repeated cycles of skin wounding and healing.

Now Stanford researchers, funded by the stem cell agency, have found a way to correct the faulty gene and grow healthy skin, a technique that could completely change the lives of children with EB. This new approach, which the researchers call “therapeutic reprogramming”, is reported in the journal Science Translational Medicine

In the study the researchers took skin cells from patients with EB and reprogrammed them to become induced pluripotent stem (iPS) cells that have the ability to become any of the other cells in the body. They then replaced the faulty gene that caused that particular form of EB and then turned the cells into keratinocytes, the cells that make up most of our outer layer of skin. When they grafted these cells onto the back of laboratory mice they grew into normal human skin.

In a news release about the work, Dr. Anthony Oro, one of the senior authors of the paper, says the work represents a completely different approach to treating EB.

“Normally, treatment has been confined to surgical approaches to repair damaged skin, or medical approaches to prevent and repair damage. But by replacing the faulty gene with a correct version in stem cells, and then converting those corrected stem cells to keratinocytes, we have the possibility of achieving a permanent fix — replacing damaged areas with healthy, perfectly matched skin grafts.”

One of the key words in that quote is “healthy”. Because the skin cells that they got from the patient probably already included some that had a skin cancer-causing mutation, the researchers carefully screened the cells to make sure they removed any that looked suspicious.

Oro says tests showed the resulting skin from these iPS cells was very similar to human skin made from normal keratinocytes.

“The most difficult part of this procedure is to show not just that you can make keratinocytes from the corrected stem cells, but that you can then use them to make graftable skin. What we’d love to do is to be able to give patients healthy skin grafts on the areas that they bang a lot, such as hands and feet and elbows — those places that don’t heal well. That alone would significantly improve our patients’ lives. We don’t know how long these grafts might last in humans; we may need some improvements. But I think we’re getting very close.”

Having seen that this works in mice the team are now eager to see if they can replicate their results in people. With CIRM support they have already been working with the Food and Drug Administration (FDA) to pave the way for that to happen. Dr. Marius Wernig, one of the senior authors of the paper, says that focus on patients is driving their work:

“CIRM made sure that we were always keeping in mind the need to translate our results to the clinic. Now we’ve shown that this approach that we call ‘therapeutic reprogramming’ works well with human cells. We can indeed take skin cells from people with epidermolysis bullosa, convert them to iPS cells, replace the faulty collagen 7 gene with a new copy, and then finally convert these cells to keratinocytes to generate human skin. It is almost like a fountain of youth that, in principle, produces an endless supply of new, healthy skin from a patient’s own cells.”

10 Years/10 Therapies: 10 Years after its Founding CIRM will have 10 Therapies Approved for Clinical Trials

In 2004, when 59 percent of California voters approved the creation of CIRM, our state embarked on an unprecedented experiment: providing concentrated funding to a new, promising area of research. The goal: accelerate the process of getting therapies to patients, especially those with unmet medical needs.

Having 10 potential treatments expected to be approved for clinical trials by the end of this year is no small feat. Indeed, it is viewed by many in the industry as a clear acceleration of the normal pace of discovery. Here are our first 10 treatments to be approved for testing in patients.

HIV/AIDS. The company Calimmune is genetically modifying patients’ own blood-forming stem cells so that they can produce immune cells—the ones normally destroyed by the virus—that cannot be infected by the virus. It is hoped this will allow the patients to clear their systems of the virus, effectively curing the disease.

Spinal cord injury patient advocate Katie Sharify is optimistic about the latest clinical trial led by Asterias Biotherapeutics.

Spinal cord injury patient advocate Katie Sharify is optimistic about the clinical trial led by Asterias Biotherapeutics.

Spinal Cord Injury. The company Asterias Biotherapeutics uses cells derived from embryonic stem cells to heal the spinal cord at the site of injury. They mature the stem cells into cells called oligodendrocyte precursor cells that are injected at the site of injury where it is hoped they can repair the insulating layer, called myelin, that normally protects the nerves in the spinal cord.

Heart Disease. The company Capricor is using donor cells derived from heart stem cells to treat patients developing heart failure after a heart attack. In early studies the cells appear to reduce scar tissue, promote blood vessel growth and improve heart function.

Solid Tumors. A team at the University of California, Los Angeles, has developed a drug that seeks out and destroys cancer stem cells, which are considered by many to be the reason cancers resist treatment and recur. It is believed that eliminating the cancer stem cells may lead to long-term cures.

Leukemia. A team at the University of California, San Diego, is using a protein called an antibody to target cancer stem cells. The antibody senses and attaches to a protein on the surface of cancer stem cells. That disables the protein, which slows the growth of the leukemia and makes it more vulnerable to other anti-cancer drugs.

Sickle Cell Anemia. A team at the University of California, Los Angeles, is genetically modifying a patient’s own blood stem cells so they will produce a correct version of hemoglobin, the oxygen carrying protein that is mutated in these patients, which causes an abnormal sickle-like shape to the red blood cells. These misshapen cells lead to dangerous blood clots and debilitating pain The genetically modified stem cells will be given back to the patient to create a new sickle cell-free blood supply.

Solid Tumors. A team at Stanford University is using a molecule known as an antibody to target cancer stem cells. This antibody can recognize a protein the cancer stem cells carry on their cell surface. The cancer cells use that protein to evade the component of our immune system that routinely destroys tumors. By disabling this protein the team hopes to empower the body’s own immune system to attack and destroy the cancer stem cells.

Diabetes. The company Viacyte is growing cells in a permeable pouch that when implanted under the skin can sense blood sugar and produce the levels of insulin needed to eliminate the symptoms of diabetes. They start with embryonic stem cells, mature them part way to becoming pancreas tissues and insert them into the permeable pouch. When transplanted in the patient, the cells fully develop into the cells needed for proper metabolism of sugar and restore it to a healthy level.

HIV/AIDS. A team at The City of Hope is genetically modifying patients’ own blood-forming stem cells so that they can produce immune cells—the ones normally destroyed by the virus—that cannot be infected by the virus. It is hoped this will allow the patients to clear their systems of the virus, effectively curing the disease

Blindness. A team at the University of Southern California is using cells derived from embryonic stem cell and a scaffold to replace cells damaged in Age-related Macular Degeneration (AMD), the leading cause of blindness in the elderly. The therapy starts with embryonic stem cells that have been matured into a type of cell lost in AMD and places them on a single layer synthetic scaffold. This sheet of cells is inserted surgically into the back of the eye to replace the damaged cells that are needed to maintain healthy photoreceptors in the retina.

More Than Meets the Eye: Protein that Keeps Cancer in Check also Plays Direct Role in Stem Cell Biology, a Stanford Study Finds.

Here’s a startling fact: the retinoblastoma protein —Rb, for short — is defective or missing in nearly all cancers.

Rb is called a tumor suppressor because it prevents excessive cell growth by acting as a crucial traffic stop for the cell cycle, a process that controls the timing for a cell to divide and multiply. Without a working Rb protein, that traffic barrier on cell division is effectively removed, allowing unrestricted cell growth and a path towards cancer.

Retinoblastoma - a known road block to cancer growth also inhibits a stem cell's capacity to change into any cell type

Retinoblastoma – a known road block to cancer growth also inhibits a stem cell’s capacity to change into any cell type

The Rb gene was cloned over two decades ago and its link to cancer has been known for years. But today in Cell Stem Cell, CIRM-funded scientists at Stanford University report an unexpected finding: Rb protein also inhibits a stem cell’s pluripotency, or it’s capacity to become any type of cell in the body. Julien Sage, a senior author of the report, described this new facet to Rb in a press release:

“We were very surprised to see that retinoblastoma directly connects control of the cell cycle with pluripotency. This is a completely new idea as to how retinoblastoma functions.”

The research team uncovered Rb’s versatility in experiments using the induced pluripotent stem cell (iPS) technique in which adult cells, such as a skin, are reprogrammed to an embryonic stem cell-like state that, in turn, can be transformed into any cell type.

Creating iPS cells is notoriously slow and inefficient. However, the Stanford scientists found that cells without Rb were much easier and faster to convert to iPS than cells with normal Rb. And when Rb protein levels in the cells were boosted, it was much more difficult to make the iPS cells — suggesting that the presence of Rb was encouraging the skin cells to remain skin and to resist reprogramming into an iPS cell. As Marius Wernig, the other senior author, sums it up:

“The loss of Rb appears to directly change a cell’s identity. Without the protein, the cell is much more developmentally fluid and is easier to reprogram into an iPS cell.”

And Dr. Sage further points out that:

“The process of creating iPS cells from fully differentiated, or specialized, cells is in many ways very similar to what happens when a cell becomes cancerous.”

So now that the team has established the Rb protein’s direct link between stem cell and cancer biology, they stand at unique vantage point to gain new insights on the inner workings of both, such as better iPS methods and new cancer therapy targets.

To hear about more aspects of Marius Wernig’s research, watch his 30 second elevator pitch below:

Creating a Genetic Model for Autism, with a Little Help from the Tooth Fairy

One of the most complex aspects of autism is that it is not one disease—but many. Known more accurately as the autism spectrum disorder, or ASD, experts have long been trying to tease apart the various ways in which the condition manifests in children, with limited success.

But now, using the latest stem cell technology, scientists at the University of California, San Diego (UCSD) have identified a gene associated with Rett Syndrome—a rare form of autism almost exclusively seen in girls. And in so doing, the team has made the startling discovery that the many types of autism may be linked by common molecular pathways.

The research team, led by UCSD Professor and CIRM grantee Alysson Muotri, explained in a news release how induced pluripotent stem cell, or iPS cell, technology was used to pinpoint a gene associated with Rett Syndrome:

“One can take advantage of genomics to map all mutant genes in the patient and then use their own iPS cells to measure the impact of mutations in relevant cell types. Moreover, the study of brain cells derived from these iPS cells can reveal potential therapeutic drugs tailored to the individual. It is the rise of personalized medicine for mental and neurological disorder.”

iPS cell technology—a process by which scientists transform adult skin cells back into embryonic-like stem cells, after which they can be coaxed into maturing into virtually any type of cell—is a promising way to model diseases at the cellular level. But in order to truly understand what is happening in the brains of people with autism, Muotri and his team needed more samples from autistic individuals—on the order of hundreds or even thousands.

The Tooth Fairy Project allows scientists to gather large quantities of cells from autistic individuals for genomic analysis—simply asking parents to send in a discarded baby tooth.

The Tooth Fairy Project allows scientists to gather large quantities of cells from autistic individuals for genomic analysis—simply by asking parents to send in a discarded baby tooth.

Luckily, Muotri had a little help from the Tooth Fairy.

Or, more accurately, the Tooth Fairy Project, in which parents register for a “Fairy Tooth Kit” that lets them send a discarded baby tooth of their autistic child to researchers. Housed within each baby tooth are cells that can be transformed—with iPS cell technology—into neurons, thus giving the researchers a massive sample size with which to study.

Interestingly, the findings presented here come from the very first tooth to be sent to Muotri. Specifically, the team identified a mutation in the gene TRPC6 was present in children with autism. Additional experiments in animal models revealed that the TRPC6 mutation was indeed associated with abnormal brain cell development and function.

And for their next trick, the team found a way to reverse the mutation’s damaging effects.

By treating the cells with the chemical hyperforin, they were able to restore some normal function to the neurons—offering up a potential therapeutic strategy for treating ASD patients who harbor the TRPC6 mutation.

Drilling down even further, the team found that mutations in another gene called MeCP2, which causes Rett Syndrome, also set off a genetic domino effect that alters the normal function of the TRPC6 gene. Thus connecting this syndrome with other, non-syndromic types of autism.

“Taken together, these findings suggest that TRPC6 is a novel predisposing gene for ASD that may act in a multiple-hit model,” said Muotri. “This is the first study to use iPS cell-derived human neurons to model non-syndromic ASD and illustrate the potential of modeling genetically complex sporadic diseases using such cells.”

Find out more about how stem cell research could help solve the mysteries behind autism in our Autism Fact Sheet.

CIRM Scientists Discover Key to Blood Cells’ Building Blocks

Our bodies generate new blood cells—both red and white blood cells—each and every day. But reproducing that feat in a petri dish has proven far more difficult.

Pictured: sections from zebrafish embryos. Blood vessels are labeled in red, the protein complex that regulates inflammation green and cell nuclei in blue. The arrowhead indicates a potential HSC. The image at bottom right combines all channels. [Credit: UC San Diego School of Medicine]

Pictured: sections from zebrafish embryos. Blood vessels are labeled in red, the protein complex that regulates inflammation green and cell nuclei in blue. The arrowhead indicates a potential HSC. The image at bottom right combines all channels.
[Credit: UC San Diego School of Medicine]

But now, scientists have identified the missing ingredient to producing hematopoietic stem cells, or HSC’s—the type of stem cell that gives rise to all blood and immune cells in the body. The results, published last week in the journal Cell, describe how a newly discovered protein plays a key role in generating HSC’s in the developing embryo—giving scientists a more complete recipe to reproduce these cells in the lab.

The research, which was led by University of California, San Diego (UCSD) professor David Traver and supported by a grant from CIRM, offers renewed hope for the possibility of generating patient-specific blood or immune cells using induced pluripotent stem cell (iPS cell) technology.

As Traver explained in last week’s news release:

“The development of some mature cell lineages from iPS cells, such as cardiac or neural, has been reasonably straightforward, but not with HSCs. This is likely due, at least in part, to not fully understanding all the factors used by the embryo to generate HSCs.”

Indeed, the ability to generate HSCs has long challenged scientists, as outlined in a CIRM workshop from last year. But now, says Traver, they have found a crucial piece to the puzzle.

Specifically, the researchers investigated a signaling protein called tumor necrosis factor alpha—or TNFα for short— a protein known to be important for regulating inflammation and immunity. Previous research by this study’s first author, Raquel Espin-Palazon, and others also discovered it was related to the healthy function of blood vessels during embryonic development.

In this study, Traver, Espin-Palazon and the UCSD drilled down even further—and found that TNFα was required for the normal development of HSCs in the embryo. This surprised the research team, as the young embryo is generally considered to be sterile—with no need for a protein normally charged with regulating immune response to be switched on. Explained Traver:

“There was no expectation that pro-inflammatory signaling would be active at this time or in the blood-forming regions.”

While preliminary, establishing this relationship between TNFα and HSC formation will be a boon to researchers looking for new ways to generate large quantities of healthy, patient-specific red and white blood cells for those patients who so desperately need them.

Learn more about how stem cell technology could help treat blood diseases in our Thalassemia Fact Sheet.

Stem Cell Stories that Caught our Eye: Skin Cells to Brain Cells in One Fell Swoop, #WeAreResearch Goes Viral, and Genes Helps Stem Cells Fight Disease

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.

Building a Better Brain Cell. Thanks to advances in stem cell biology, scientists have found ways to turn adult cells, such as skin cells, back into cells that closely resemble embryonic stem cells. They can then coax them into becoming virtually any cell in the body.

But scientists have more recently begun to devise ways to change cells from one type into another without first having to go back to a stem cell-like state. And now, a team from Washington University in St. Louis has done exactly that.

As reported this week in New Scientist, researcher Andrew Yoo and his team used microRNAs—a type of ‘signaling molecule’—to reprogram adult human skin cells into medium spiny neurons(MSNs), the type of brain cell involved in the deadly neurodegenerative condition, Huntington’s disease.

“Within four weeks the skin cells had changed into MSNs. When put into the brains of mice, the cells survived for at least six months and made connections with the native tissue,” explained New Scientist’s Clare Wilson.

This process, called ‘transdifferentiation,’ has the potential to serve as a faster, potentially safer alternative to creating stem cells.

#WeAreResearch Puts a Face on Science. The latest research breakthroughs often focus on the science itself, and deservedly so. But exactly who performed that research, the close-knit team who spent many hours at the lab bench and together worked to solve a key scientific problem, can sometimes get lost in the shuffle.

#WeAreResearch submission from The Thomson Lab at the University of California, San Francisco. This lab uses optogenetics, and RNAseq to probe cell fate decisions.

#WeAreResearch submission from The Thomson Lab at the University of California, San Francisco. This lab uses optogenetics, and RNAseq to probe cell fate decisions.

Enter #WeAreResearch, a new campaign led by the American Society for Cell Biology (ASCB) that seeks to show off science’s more ‘human side.’

Many California-based stem cell teams have participated—including CIRM grantee Larry Goldstein and his lab!

Check out the entire collection of submissions and, if you’re a member of a lab, submit your own. Prizes await the best submissions—so now’s your chance to get creative.

New Genes Help Stem Cells Fight Infection. Finally, UCLA scientists have discovered how stem cells ‘team up’ with a newly discovered set of genes in order to stave off infection.

Reporting in the latest issue of the journal Current Biology, and summarized in a UCLA news release, Julian Martinez-Agosto and his team describe how two genes—adorably named Yorkie and Scalloped—set in motion a series of events, a molecular Rube Goldberg device, that transforms stem cells into a type of immune system cell.

Importantly, the team found that without these genes, the wrong kind of cell gets made—meaning that these genes play a central role in the body’s healthy immune response.

Mapping out the complex signaling patterns that exist between genes and cells is crucial as researchers try and find ways to, in this case, improve the body’s immune response by manipulating them.

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