Stem cell stories that caught our eye: new ways to reprogram, shifting attitudes on tissue donation, and hockey legend’s miracle questioned

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.

Insulin-producing cells produced from skin. Starting with human skin cells a team at the University of Iowa has created iPS-type stem cells through genetic reprogramming and matured those stem cells into insulin-producing cells that successfully brought blood-sugar levels closer to normal when transplanted in mice.

University of Iowa researchers reprogrammed human skin cells to create iPS cells, which were then differentiated in a stepwise fashion to create insulin-producing cells. When these cells were transplanted into diabetic mice, the cells secreted insulin and reduced the blood sugar levels of the mice to normal or near-normal levels. The image shows the insulin-producing cells (right) and precursor cells (left). [Credit: University of Iowa]

University of Iowa researchers reprogrammed human skin cells to create iPS cells, which were then differentiated in a stepwise fashion to create insulin-producing cells. When these cells were transplanted into diabetic mice, the cells secreted insulin and reduced the blood sugar levels of the mice to normal or near-normal levels. The image shows the insulin-producing cells (right) and precursor cells (left).
[Credit: University of Iowa]

The cells did not completely restore blood-sugar levels to normal, but did point to the possibility of achieving that goal in the future, something the team leader Nicholas Zavazava noted in an article in the Des Moines Register, calling the work an “encouraging first step” toward a potential cure for diabetes.

The Register discussed the possibility of making personalized cells that match the genetics of the patient and avoiding the need for immune suppression. This has long been a goal with iPS cells, but increasingly the research community has turned to looking for options that would avoid immune rejection with donor cells that could be off-the-shelf and less expensive than making new cells for each patient.

Heart cells from reprogramming work in mice. Like several other teams, a group in Japan created beating heart cells from iPS-type stem cells. But they went the additional step of growing them into sheets of heart muscle that when transplanted into mice integrated into the animals own heart and beat to the same rhythm.

The team published the work in Cell Transplantation and the news agency AlianzaNews ran a story noting that it has previously been unclear if these cells would get in sync with the host heart muscle. The result provides hope this could be a route to repair hearts damaged by heart attack.

Patient attitudes on donating tissue. A University of Michigan study suggests most folks don’t care how you use body tissue they donate for research if you ask them about research generically. But their attitudes change when you ask about specific research, with positive responses increasing for only one type of research: stem cell research.

On the generic question, 69 percent said go for it, but when you mentioned the possibility of abortion research more than half said no and if told the cells might lead to commercial products 45 percent said nix. The team published their work in the Journal of the American Medical Association and HealthCanal picked up the university’s press release that quoted the lead researcher, Tom Tomlinson, on why paying attention to donor preference is so critical:

“Biobanks are becoming more and more important to health research, so it’s important to understand these concerns and how transparent these facilities need to be in the research they support.”

CIRM has begun building a bank of iPS-type stem cells made from tissue donated by people with one of 11 diseases. We went through a very detailed process to develop uniform informed consent forms to make sure the donors for our cell bank knew exactly how their cells could be used. Read more about the consent process here.

Mainstream media start to question hockey legend’s miracle. Finally some healthy skepticism has arrived. Hockey legend Gordie Howe’s recovery from a pair of strokes just before the holidays was treated by the general media as a true Christmas miracle. The scientific press tried to layer the coverage with some questions of what we don’t know about his case but not the mainstream media. The one exception I saw was Brad Fikes in the San Diego Union Tribune who had to rely on a couple of scientists who were openly speaking out at the time. We wrote about their concerns then as well.

Now two major outlets have raised questions in long pieces back-to-back yesterday and this morning. The Star in hockey-crazed Canada wrote the first piece and New York Magazine wrote today’s. Both raise serious questions about whether stem cells could have been the cause of Howe’s recovery and are valuable additions to the coverage.

Extending the Lease: Stanford Scientists Turn Back Clock on Aging Cells

In the end, all living things—even the cells in our bodies—must die. But what if we could delay the inevitable, even just for a bit? What new scientific advances could come as a result?

Stanford scientists have found a way to temporarily extend the life of an aging cell.

Stanford scientists have found a way to temporarily extend the life of an aging cell.

In research published this week in the FASEB Journal, scientists at the Stanford University School of Medicine have devised a new method that gives aging DNA a molecular facelift.

The procedure, developed by Stanford Stem Cell Scientist Helen Blau and her team at the Baxter Laboratory for Stem Cell Biology, physically lengthens the telomeres—the caps on the ends of chromosomes that protect the cell from the effects of aging.

When born, all cells contain chromosomes capped with telomeres. But during each round of cell division, those telomeres shrink. Eventually, the telomeres shorten to such an extent that the chromosomes can no longer replicate at the rate they once could. For the cell, this is the beginning of the end.

The link between telomeres and cellular aging has been an intense focus in recent years, including the subject of the 2009 Nobel Prize in Physiology or Medicine. Extending the lifespan of cells by preventing—or reversing— the shortening of telomeres can not only boost cell division during laboratory studies, but can also lead to new therapeutic strategies to treat age-related diseases.

“Now we have found a way to lengthen human telomeres… turning back the internal clock in these cells by the equivalent of many years of human life,” explained Blau in a press release. “This greatly increases the number of cells available for studies such as drug testing or disease modeling.”

The method Blau and her team describe involves the use of a modified bit of RNA that boosts the production of the protein telomerase. Telomerase is normally present in high levels in stem cells, but drops off once the cells mature. Blau’s modified RNA gives the aging cells a shot of telomerase, after which they begin behaving like cells half their age. But only for about 48 hours, after which they begin to degrade again.

The temporary nature of this change, say the researchers, offers significant advantages. On the biological level, it means that the treated cells won’t begin dividing out of control indefinitely, minimizing the risk of tumor formation. The study’s first author John Ramunas offers up some additional pluses to their method:

“Existing methods of extending telomeres act slowly, whereas our method acts over just a few days to reverse telomere shortening that occurs over more than a decade of normal aging. This suggests that a treatment using our method could be brief and infrequent.”

Indeed, the genetic disease Duchenne muscular dystrophy is in part characterized by abnormally short telomeres. Blau reasons that their discovery could lead to better treatments for this disease. Their immediate future steps involve testing their method in a variety of cell types. Said Blau:

“We’re working to understand more about the differences among cell types, and how we can overcome those differences to allow this approach to be more universally successful.”

Hear more about stem cells and muscular dystrophy in our recent Spotlight on Disease featuring Helen Blau:

Scientists Develop Colorful Cell-Imaging Technique

Proteins are the helmsmen of the cell. They drive the essential processes that keep cells alive, keep them healthy and keep them functioning. And in recent years scientists have discovered that proteins rarely act alone.

In fact, so-called ‘protein-protein interactions’ are now known to drive the vast majority of cellular functions. But figuring out exactly how they do so has proven difficult.

Luckily, scientists now have a way to see these interactions—in a dazzling array of Technicolor.

As described in today’s issue of Nature Methods, Robert Campbell and his team at the University of Alberta have announced a new way to visualize protein-protein interactions, by converting these interactions into changes in color. This technique could be employed across a variety of disciplines, helping scientists understand normal processes in the cell—and observe the molecular changes that occur when those processes go awry.

“With this development,” explained Campbell in a news release, “we can immediately image activity happening at the cellular level, offering an alternative to existing methods for detecting and imaging of protein-protein interactions in live cells.”

Called FPX, Campbell’s method links a change in a protein-protein interaction to a color. As seen in the video below, every time the interaction changes, a color change—from red to green, and back to red again—is visible.

The FPX method is based on previously published work by Campbell and others, which found that green and red fluorescent proteins could both be inserted into a single cell so that the protein could be red or green—but not both at the same time. So, the team was able to construct biosensors that changed color in response to changes in protein-protein interactions.

In this study, the researchers have essentially given scientists a powerful tool to help them understand how even the smallest molecular changes can lead to significant changes in the health of the cell.

According to Campbell:

“It will be immediately relevant to many areas of fundamental cell biology research and practical applications such as drug discovery. Ultimately, it will help researchers achieve breakthroughs in a wide variety of areas in the life sciences, such as neuroscience, diabetes and cancer.”

Scientists Send Rodents to Space; Test New Therapy to Prevent Bone Loss

In just a few months, 40 very special rodents will embark upon the journey of a lifetime.

shutterstock_200932226

Today UCLA scientists are announcing the start of a project that will test a new therapy that has the potential to slow, halt or even reverse bone loss due to disease or injury.

With grant funding from the Center for the Advancement of Science in Space (CASIS), a team of stem cell scientists led by UCLA professor of orthopedic surgery Chia Soo will send 40 rodents to the International Space Station (ISS). Living under microgravity conditions for two months, these rodents will begin to undergo bone loss—thus closely mimicking the conditions of bone loss, known as osteoporosis, seen in humans back on Earth.

At that point, the rodents will be injected with a molecule called NELL-1. Discovered by Soo’s UCLA colleague Kang Ting, this molecule has been shown in early tests to spur bone growth. In this new set of experiments on the ISS, the researchers hope to test the ability of NELL-1 to spur bone growth in the rodents.

The team is optimistic that NELL-1 could really be key to transforming how doctors treat bone loss. Said Ting in a news release:

“NELL-1 holds tremendous hope, not only for preventing bone loss but one day even restoring healthy bone. For patients who are bed-bound and suffering from bone loss, it could be life-changing.”

“Besides testing the limits of NELL-1’s robust bone-producing efforts, this mission will provide new insights about bone biology and could uncover important clues for curing diseases such as osteoporosis,” added Ben Wu, a UCLA bioengineer responsible for initially modifying NELL-1 to make it useful for treating bone loss.

The UCLA team will oversee ground operations while the experiments will be performed by NASA scientists on the ISS and coordinated by CASIS.

These experiments are important not only for developing new therapies to treat gradual bone loss, such as osteoporosis, which normally affects the elderly, but also those who have bone loss due to trauma or injury—including bone loss due to extended microgravity conditions, a persistent problem for astronauts living on the ISS. Said Soo:

“This research has enormous translational application for astronauts in space flight and for patients on Earth who have osteoporosis or other bone-loss problems from disease, illness or trauma.”

UC Davis Surgeons Begin Clinical Trial that Tests New Way to Deliver Stem Cells; Heal Bone Fractures

Each year, approximately 8.9 million people worldwide will suffer a bone fracture. Many of these fractures heal with the help of traditional methods, but for some, the road to recovery is far more difficult.

shutterstock_243407335

After exhausting traditional treatments—such as surgically implanted pins or plates, bed rest and injections to spur bone growth—these patients can undergo a special type of stem cell transplant that directs stem cells extracted from the bone marrow to the fracture site to speed healing.

This procedure has its drawbacks, however. For example, the act of extracting cells from one’s own bone marrow and then injecting them into the fracture site requires two very painful surgical procedures: one to extract the cells, and another to implant them. Recovery times for each procedure, especially in older patients, can be significant.

Enter a team of surgeons at UC Davis. Who last week announced a ‘proof-of-concept’ clinical trial to test a device that can extract and isolate stem cells far more efficiently than before—and allow surgeons to implant the cells into the fracture in just a single surgery.

As described in HealthCanal, he procedure makes use of a reamer-irrigator-aspirator system, or RIA, that normally processes wastewater during bone drilling surgery. As its name implies, this wastewater was thought to be useless. But recent research has revealed that it is chock-full of stem cells.

The problem was that the stem cells were so diluted within the wastewater that they couldn’t be used. Luckily, a device recently developed by Sacramento-based SynGen, Inc., was able to quickly and efficiently extract the cells in high-enough concentrations to then be implanted into the patient. Instead of having to undergo two procedures—the patient now only has to undergo one.

“The device’s small size and rapid capabilities allow autologous stem cell transplantation to take place during a single operation in the operation room rather than requiring two procedures separated over a period of weeks,” said UC Davis surgeon Mark Lee, who is leading the clinical trial. “This is a dramatic difference that promises to make a real impact on healing and patient recovery.”

Hear more from Lee about how stem cells can be used to heal bone fractures in our 2012 Spotlight on Disease.

In living color: new imaging technique tracks traveling stem cells

Before blood stem cells can mature, before they can grow and multiply into the red blood cells that feed our organs, or the white blood cells that protect us from pathogens, they must go on a journey.

A blood stem cell en route to taking root in a zebrafish. [Credit: Boston Children's Hospital]

A blood stem cell en route to taking root in a zebrafish. [Credit:
Boston Children’s Hospital]

This journey, which takes place in the developing embryo, moves blood stem cells from their place of origin to where they will take root to grow and mature. That this journey happened was well known to scientists, but precisely how it happened remained shrouded in darkness.

But now, for the first time, scientists at Boston Children’s Hospital have literally shone a light on the entire process. In so doing, they have opened the door to improving surgical procedures that also rely on the movement of blood cells—such as bone marrow transplants, which are in essence stem cell transplants.

Reporting in today’s issue of the journal Cell, Boston Children’s senior investigator Leonard Zon and his team developed a way to visually track the trip that blood stem cells take in the developing embryo. As described in today’s news release, the same process that guides blood stem cells to the right place also occurs during a bone marrow transplant. The similarities between the two, therefore, could lead to more successful bone marrow transplants. According to the study’s co-first author Owen Tamplin:

“Stem cell and bone marrow transplants are still very much a black box—cells are introduced into a patient and later on we can measure recovery of the blood system, but what happens in between can’t be seen. Now we have a system where we can actually watch that middle step.”

And in the following video, Zon describes exactly how they did it:

As outlined in the above video, Zon and his team developed a transparent version of the zebrafish, a tiny model organism that is often used by scientists to study embryonic development. They then labeled blood stem cells in this transparent fish with a special fluorescent dye, so that the cells glowed green. And finally, with the help of both confocal and electron microscopy, they sat back and watched the blood stem cell take root in what’s called its niche—in beautiful Technicolor.

“Nobody’s ever visualized live how a stem cell interacts with its niche,” explained Zon. “This is the first time we get a very high-resolution view of the process.”

Further experiments found that the process in zebrafish closely resembled the process in mice—an indication that the same basic system could exist for humans.

With that possibility in mind, Zon and his team already have a lead on a way to improve the success of human bone marrow transplants. In chemical screening experiments, the team identified a chemical compound called lycorine that boosts the interaction between the zebrafish blood stem cell and its niche—thus promoting the number of blood stem cells as the embryo matures.

Does the lycorine compound (or an equivalent) exist to boost blood stem cells in mice? Or even in humans? That remains to be seen. But with the help of the imaging technology used by Zon and the Boston Children’s team—they have a good chance of being able to see it.

2015 Golden Globes shines light on Alzheimer’s and ALS with acting awards

In between the one-liners, surprise presenters and bottomless champagne, something remarkable happened at last night’s 72nd Golden Globe Awards.

26 awards were given last night to the best in film and television. But two in particular were especially meaningful.

Julianne Moore plays a professor grappling with Alzheimer's in Still Alice [Credit: Sony Pictures Classics]

Julianne Moore plays a professor grappling with Alzheimer’s in Still Alice [Credit: Sony Pictures Classics]

I am referring, of course, to Julianne Moore and Eddie Redmayne, who each took home awards in the lead acting categories for their portrayals of two individuals suffering from neurodegenerative diseases. Their wins not only solidified them as front-runners for the Academy Awards ceremony next month, but also gave millions of viewers a deeply intimate look at two unforgiving illnesses.

Eddie Redmayne as Stephen Hawking in The Theory of Everything [Credit: Focus Features]

Eddie Redmayne as Stephen Hawking in The Theory of Everything [Credit: Focus Features]

Renowned actress Julianne Moore was the first of the two to receive her award, winning for her role as Alice Howland, a Columbia linguistics professor diagnosed with Early-Onset Alzheimer’s disease, in the film Still Alice.

And later in the program the Globes honored Eddie Redmayne for his brilliant portrayal of Professor Stephen Hawking—a long-time sufferer of the motor neuron disease ALS—in the biopic The Theory of Everything.

These two films were particularly poignant for those in the Alzheimer’s and ALS communities—as they reveal in stark, sometimes disturbing detail, how these diseases wreak havoc on the brain and nervous system. In preparation for their roles, each spent several months speaking with patients and clinicians who see and live with the diseases every day.

For example, Moore spoke with women who—like her character Alice—were living with Early-Onset Alzheimer’s, giving her first-hand knowledge of not only how the disease affects them, but also how their families are affected.

Meanwhile, Redmayne spent significant time with Hawking himself, learning about his unique experience as a long-time ALS patient. In interviews Redmayne has said that Hawking was often present during filming. The time the two individuals spent with each other clearly paid off, and had a remarkable impact on the actor.

“It is a great privilege for me to be in this room,” Redmayne said during his Golden Globe acceptance speech. “Getting to spend time with Stephen Hawking … was one of the great, great honors of my life.”

The fact that the two lead acting awards put spotlight on these diseases was not lost on the patient advocacy communities. For example, Maria Shriver tweeted shortly after the awards ceremony:

Shriver Tweet

Shriver’s statement underscores the stark reality of awareness, or lack thereof, for neurodegenerative diseases. Here at CIRM, we are laser focused on supporting ground-breaking work in regenerative medicine that can slow, halt or even reverse these conditions. We are hopeful that these two actors’ stellar performances can help put a human face on conditions that are all too-often reduced to numbers.

This hope has thus far translated to these films’ audiences. For example, said one review of Still Alice from the New York Post:

Still Alice … presents a disease that can devastate any family, anywhere, with unsparing truth and great compassion.”

Read more about how regenerative medicine can change the face of Alzheimer’s and ALS on our Stories of Hope.

Multitasking molecule repairs damaged nerve cells, scientists discover in ‘stunning’ research breakthrough

Every molecule in the body has a job to do—everything from maintaining healthy cell functions to removing dead or decaying cells requires a coordinated series of molecular switches to complete. There’s a lot we know about what these molecules do, but even more that we are still discovering.

The PSR-1 molecule, which normally clears out dead or dying nerve cells, has also been observed trying to repair them.

The PSR-1 molecule, which normally clears out dead or dying nerve cells, has also been observed trying to repair them.

And as reported in a pair of studies published this week in Nature and Nature Communications, a molecule that has long been known to clear out dying or damaged nerve cells also—amazingly—tries to heal them.

The molecule at the heart of these studies is called phophatidylserine receptor, or PSR-1 for short. PSR-1’s main job had been to target and remove cells that were dead or dying—a sort of cellular ‘cleanup crew.’

Some cells die because they’ve reached the end of their life cycle and are scheduled for destruction, a programmed cell death known as apoptosis. Other cells die because they have been damaged by disease or injury. In this study, scientists at the University of Colorado, Boulder and the University of Queensland (UQ) in Brisbane, Australia, discovered that not only does PSR-1 clear out dead cells, it tries to save the ones that haven’t quite kicked the bucket.

Specifically, the team observed PSR-1 literally reconnecting nerve fibers, known as axons, which had broken due to injury.

“I would call this an unexpected and somewhat stunning finding,” said one of the study’s lead authors Ding Xue in a news release. “This is the first time a molecule involved in apoptosis has been found to have the ability to repair severed axons, and we believe it has great therapeutic potential.”

Professor Ding Xue of the University of Colorado Boulder. [Credit: Casey A. Cass, University of Colorado]

Professor Ding Xue of the University of Colorado Boulder. [Credit: Casey A. Cass, University of Colorado]

Injuries to nerve cells that reside in the brain or spinal cord are particularly distressing because once damaged, the cells can’t be repaired. As a result, many research groups have looked to innovative ways of coaxing the cells to repair themselves. Xue and Hilliard see the potential of PSR-1 to be involved in such a strategy.

“This will open new avenues to try and exploit this knowledge in other systems closer to human physiology and hopefully move toward solving injuries,” said Hilliard.

The discovery of PSR-1’s role in axon repair is based off a key difference between cells undergoing programmed cell death and those that are dying due to injury.

During apoptosis, cells release a beacon to alert PSR-1 that they’re ready for removal. But when a nerve cell is injured, it sends out a distress signal. Explained Xue:

“The moment there is a cut to the nerve cell we see…a signal to PSR-1 molecules in the other part of the nerve that essentially says ‘I am in danger, come and save me.’”

While these experiments were performed in the model organism C. elegans (a small worm often used in this sort of research), the researchers are optimistic that a similar process is taking place in human nerve cells.

“Whether human PSR has the capacity to repair injured axons is still unknown. But I think our new research findings will spur a number of research groups to chase this question.”

Scientists identify gene that causes good protein to turn bad

shutterstock_200363513

There exists a protein that, most of the time, helps keep the growth of cancer cells in check. But every so often it does the opposite—with potentially deadly consequences.

But now, researchers have discovered precisely why this protein, known as TGF-beta, can perform such an abrupt about-face. The results, published today in the journal Science Signaling, shed light on potential therapies that can succeed where others have failed—and attack the most aggressive forms of cancer.

TGF-beta is a type of tumor suppressor, a protein that normally keeps cells from growing, dividing and multiplying too quickly, which is how most tumors originate. But scientists have long observed that in many forms of cancer, TGF-beta has switched sides: it becomes a tumor promoter fostering the out-of-control growth of cells.

In this study, scientists at the University of Michigan Comprehensive Cancer Center have figured out that a gene called Bub1 seems to be pulling the strings—essentially flipping the switch on TGF-beta. The finding that Bub1 played such an important role in regulating TGF-beta caught the team completely off guard. According to the paper’s senior author Alnawaz Rehemtulla:

“Bub1 is well-known for its role in cell division. But this is the first study that links it to TGF-beta. We think this may explain the paradox of TGF-beta as a tumor promoter and a tumor suppressor.”

The team reached this conclusion by screening gene candidates against lung cancer and breast cancer cells. After screening over 700 genes, they narrowed down the potential gene to Bub1.

Further experiments revealed that Bub1 physically binds to TGF-beta, turning it to a tumor promoter in the process. And when the team prevented Bub1 from binding to TFG-beta, essentially blocking it, TGF-beta never turned sides.

These initial results have left the research team optimistic, in large part because Bub1 is known to be active, or ‘expressed,’ in so many forms of cancer. So, if they can find a way to block Bub1 in one type of cancer, they may be able to do so with other types.

Even at this early stage, the team has developed a compound that could block Bub1. Initial lab tests show that this so-called Bub1 ‘inhibitor’ could shut off the gene without affecting surrounding regions. Said Rehemtulla:

“When you look at gene expression in cancer, Bub1 is in the top five…. But we never knew why. Now that we have that link, we’re a step closer to shutting down this cycle.”