Stem cell stories that caught our eye: reversing aging, mature hearts, arthritic knees and tiny organs

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.

Young brain cells (top) show little of the molecule that impairs stem cell function (green) that is abundant in old cells (bottom).

Young brain cells (top) show little of the molecule that impairs stem cell function (green) that is abundant in old cells (bottom).

Making stem cells feels young again. Stem cells are supposed to rejuvenate our tissues, whether brain or muscle, and keep them functioning at their peak. But the aging process seems to poison the environment where stem cells reside and prevent them from getting the job done.

A CIRM-funded team at the University of California, Berkeley, has found a drug that can reverse the effect of aging and make the stem cells function better and in turn make tissues behave like younger versions of brain or muscle. Their previous work had shown that old tissues had much more of one growth factor, TGF-beta1, than young tissue. When the team, led by David Schaffer and Irina Conboy, blocked the activity of that growth factor with a cancer drug already in clinical trials they saw rejuvenated youthful tissue—in mice.

HealthCanal picked up the university’s press release, in which Schaffer described the broad effect of the treatment:

“We established that you can use a single small molecule to rescue essential function in not only aged brain tissue but aged muscle. That is good news, because if every tissue had a different molecular mechanism for aging, we wouldn’t be able to have a single intervention that rescues the function of multiple tissues.”

The team, however, noted that multiple molecular signals are in play in the aging stem cell’s environment and optimum intervention may require using more than one drug and getting the dosages just right. Conboy said that the task was to “recalibrate the environment to be youth-like.”

Maturing of the heart. Scientists can turn embryonic stem cells into most forms of adult tissue, but often those tissues don’t function like fully mature forms of the organ they are supposed to be. Now a consortium of researchers has identified a molecular switch that seems to be able to take stem cells and get them to form fully mature heart muscle.

In an interview with Genetic Engineering & Biotechnology News, senior author on the paper Hannele Ruohola-Baker of the University of Washington noted the breakthrough:

“Although we can now induce embryonic stem cells to become heart cells, getting them to mature to an adult-like state remains a significant challenge. We believe we’ve now found the master switch that drives the maturation process.”

The researchers found the molecular switch by studying many of the genetic switches called micro-RNAs in both young and old heart muscle cells. The one linked to helping stem cells mature interestingly is also involved in up-regulating metabolism and it makes sense that a supercharged metabolism would be valuable for fully functional heart muscle.

Some answers may be coming on stem cells and knees. While many clinics around the word offer to treat arthritic knees with stem cells taken from a patient’s own fat—often for large sums of money—very little data exist on the outcomes of those treatments. So, it was great to read this week that a European consortium is about to launch a large trial that should provide some quality data.

The ADIPOA-2 trial will enroll 150 patients in a randomized way so that the stem cell treatment can be compared to standard therapies, and the researchers will handle processing of the fat stem cells in a consistent way across clinics in four countries. It follows a phase 1 ADIPOA trial with 18 patients that showed promising results.

Frank Barry of the National University of Ireland Galway is coordinating the phase 2 trial and was quoted in the university’s press release picked up by HealthCanal:

“The results from ADIPOA’s first-in-man-trials were very encouraging and paved the way for another study to further test the safety and effectiveness on a wider scale. ADIPOA-2 is bringing together Europe’s leading scientific, clinical and technical expertise on this project.”

A lingering question remains about how long any benefit from the stem cell therapy will last. Some researchers have suggested that fat stem cells can only form soft cartilage like in your ear lobe and not the articular hard cartilage normally in your knee. So, it will take some years of follow-up to see if any new cartilage made by the stem cells can stand up to the beating of a good tennis match or hike up a mountain.

CIRM funds a research team at the University of Calirfornia, San Diego, that believe they have found a way to get embryonic stem cells, which are more versatile than fat stem cells, to form the hard articular cartilage.

Great hope in tiny little organs. For the past couple years one of the hottest areas of stem cell science has been growing stem cells in 3-D cultures in the lab and getting them to self organize into multi-tissue layers that mimic some function of one of our vital organs. It has been done for the eye, lung, liver, kidney and brain, but the first was the intestine, and the researcher behind the advance, Hans Clevers, dubbed them “organoids.”

The journal Nature just published a good Q&A interview with Clevers who works at the Hubrecht Institute Utrecht, the Netherlands. In it he describes how organoids will be a useful tool for drug screening and how his team is working on ways that organoids made from a patient’s own cells could be tested in the lab for sensitivity to specific cancer therapies.

Dying cells signal their moms, aka stem cells, to protect themselves so that they can make replacements cells.

I love the name for stem cells in Spanish, células madre, or mother cell. It seems appropriate that the sons and daughters of our stem cells send a warning to mom to protect herself when they are under attack. Specifically, a team at the University of Washington reported Monday in Nature Communications, that when cells die from radiation or chemotherapy, they send a chemical signal that causes the nearby stem cells to flip a genetic switch that prevents them from dying.

This ability helps our bodies recover from cancer treatment, but it could also be one reason so many cancers return. While we want our normal stem cells to retain the ability to replace damaged tissue, that benefit may come with an unwanted corollary. The closely related cancer stem cells that can generate new tumors may have the same ability.

The researchers found that dying cells release a protein that binds to a receptor on the surface of stem cells. That in turn triggers the stem cells to produce a genetic tool that switches off a key gene that would normally tell the stem cells to die because of damage to their DNA caused by the therapy.

Having survived the programmed cell death normally triggered by DNA damage, the stem cells have time to repair their DNA and go on to reproduce healthy tissue. This pathway—the protein released by the dying cell to the genetic switch in the stem cell—could also become a target for cancer therapy. It could provide a way to prevent the cancer-initiating stem cell from surviving the chemotherapy or radiation.

A press release from the university quoted one of the researchers on the therapeutic potential:

“There are very similar genes and proteins in human cancers that are likely playing the same role of protecting the tumor-initiating cells from destruction. As a result, the tumor-initiating cells survive and the cancers return. By targeting these factors, perhaps by blocking [the stem cell surface] receptors, it may be possible to block the protective signal from the daughter cells, and thereby allow programmed cell death to proceed in the [cancer] stem cells and prevent cancer.”

Stem cell stories that caught our eye: a new type of stem cell, stomach cancer and babies—stem cell assisted and gene altered

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.

New type of stem cell easier to grow, more versatile. Both the professional scientific media and the lay science media devoted considerable ink and electrons this week to the announcement of a new type of stem cell—and not just any stem cell, a pluripotent one, so it is capable of making all our tissues. On first blush it appears to be easier to grow in the lab, possibly safer to use clinically, and potentially able to generate whole replacement organs.

The newly found stem cells (shown in green) integrating into a mouse embryo.

The newly found stem cells (shown in green) integrating into a mouse embryo.

How a team at the Salk Institute made the discovery was perhaps best described in the institute’s press release picked up by HealthCanal. They sought to isolate stem cells from a developing embryo after the embryo had started to organize itself spatially into compartments that would later become different parts of the body. By doing this they found a type of stem cell that was on the cusp of maturing into specific tissue, but was still pluripotent. Using various genetic markers they verified that these new cells are indeed different from embryonic stem cells isolated at a particular time in development.

The Scientist did the best job of explaining why these cells might be better for research and why they might be safer clinically. They used outside experts, including Harvard stem cell guru George Daly and CIRM-grantee from the University of California, Davis, Paul Knoepfler, to explain why. Paul described the cells this way:

“[They] fit nicely into a broader concept that there are going to be ‘intermediate state’ stem cells that don’t fit so easily into binary, black-and-white ways of classifying [pluripotent cells].”

The Verge did the best job of describing the most far-reaching potential of the new cells. Unlike earlier types of human pluripotent cells, these human stem cells, when transplanted into a mouse embryo could differentiate into all three layers of tissue that give rise to the developing embryo. This ability to perform the full pluripotent repertoire in another species—creating so called chimeras—raises the possibility of growing full human replacement organs in animals, such as pigs. The publication quotes CIRM science officer Uta Grieshammer explaining the history of the work in the field that lead up to this latest finding.

Stem cells boost success in in vitro fertilization.  Veteran stem cell reporter and book author Alice Park wrote about a breakthrough in Time this week that could make it much easier for older women to become pregnant using in vitro fertilization. The new technique uses the premise that one reason older women’s eggs seem less likely to produce a viable embryo is they are tired—the mitochondria, the tiny organs that provide power to cells, just don’t have it in them to get the job done.

The first baby was born with the assistance of the new procedure in Canada last month. The process takes a small sample of the mother-to-be’s ovarian tissue, isolates egg stem cells from it, extracts the mitochondria from those immature cells and then injects them into the woman’s mature, but tired eggs. Park reports that eight women are currently pregnant using the technique. She quotes the president of the American Society of Reproductive Medicine on the potential of the procedure:

“We could be on the cusp of something incredibly important. Something that is really going to pan out to be revolutionary.”

But being the good reporter that she is, Park also quotes experts that note no one has done comparison studies to see if the process really is more successful than other techniques.

Why bug linked to ulcers may cause cancer. The discovery of the link between the bacteria H. pylori and stomach ulcers is one of my favorite tales of the scientific process. When Australian scientists Barry Marshall and Robin Warren first proposed the link in the early 1980s no one believed them. It took Marshall intentionally swallowing a batch of the bacteria, getting ulcers, treating the infection, and the ulcers resolving, before the skeptics let up. They went on to win the Nobel Prize in 1995 and an entire subsequent generation of surgeons no longer learned a standard procedure used for decades to repair stomach ulcers.

In the decades since, research has produced hints that undiagnosed H. pylori infection may also be linked to stomach cancer, but no one knew why. Now, a team at Stanford has fingered a likely path from bacteria to cancer. It turns out the bacteria interacts directly with stomach stem cells, causing them to divide more rapidly than normal.

They found this latest link through another interesting turn of scientific process. They did not feel like they could ethically take samples from healthy individuals’ stomachs, so they used tissue discarded after gastric bypass surgeries performed to treat obesity. In those samples they found that H. pylori clustered at the bottom of tiny glands where stomach stem cells reside. In samples positive for the bacteria, the stem cells were activated and dividing abnormally. HealthCanal picked up the university’s press release on the work.

Rational balanced discussion on gene-edited babies.   Wired produced the most thoughtful piece I have read on the controversy over creating gene-edited babies since the ruckus erupted April 18 when a group of Chinese scientists published a report that they had edited the genes of human eggs. Nick Stockton wrote about the diversity of opinion in the scientific community, but most importantly, about the fact this is not imminent. A lot of lab work lies between now and the ability to create designer babies. Here is one particular well-written caveat:

“Figuring out the efficacy and safety of embryonic gene editing means years and years of research. Boring research. Lab-coated shoulders hunched over petri dishes full of zebrafish DNA. Graduate students staring at chromatographs until their eyes ache.”

He discusses the fears of genetic errors and the opportunity to layer today’s existing inequality with a topping of genetic elitism. But he also discusses the potential to cure horrible genetic diseases and the possibility that all those strained graduate student eyes might bring down the cost to where the genetic fixes might be available to everyone, not just the well heeled.

The piece is worth the read. As he says in his closing paragraph, “be afraid, be hopeful, and above all be educated.”

Genes + Cells: Stem Cells deliver genes as “drugs” & hope for ALS

This month a lab animal will become the initial patient in the final steps in Clive Svendsen’s 15-year quest to provide the first meaningful therapy for people with ALS, also known as Lou Gehrig’s disease. If that animal and subsequent ones in this required study have good results—no side effects from the treatment—Svendsen plans to take that data to the Food and Drug Administration in November to seek approval to begin a human clinical trial.

Clive Svendsen has been on a 15-year quest to develop an ALS therapy

Clive Svendsen has been on a 15-year quest to develop an ALS therapy

A native of England, Svendsen first started trying to merge gene therapy and stem cell therapy at Cambridge working with Parkinson’s disease. But after moving to the University of Wisconsin in 2000 and being approached by the ALS Association he switched to ALS. He has continued the work since moving to Cedars-Sinai in Los Angeles in 2010 where he receives CIRM funds to do the necessary animal tests as well as for the first human trial.

By contrast, Nanci Ryder’s voyage with ALS has only been a few short months. Since being diagnosed with the disease in August 2014 she has thrown herself into learning about it. “The only power I have ever felt over the adversity of a life threatening disease is knowledge.” She has also enlisted the help of many of the celebrity actor-clients of her public relations firm to advocate for ALS research funding, even though she knows the research may not move fast enough to help her.

A previous ALS stem cell trial shows the ups and downs faced by advocates for this stubborn fast-progressing and ultimately fatal disease. Largely conducted at the University of Michigan and Emory University that trial had provided one of the early hints of success with a potential stem cell therapy. But a subsequent larger trial did not achieve the results it was hoped it would produce.

Svendsen argues that trial has provided valuable insights, proven that you can put stem cells in the spinal cord and provides some rational as to why his team may have greater success. The Cedars team uses a different type of cell and boosts those cells’ performance with an added copy of a gene that makes a protein known to protect the type of nerves destroyed in ALS.

The earlier trial used cells from the spinal cord; Svendsen’s team uses cells from the brain’s cortex. In both cases the cells were recovered from discarded fetal tissue, but the cells from the cortex migrate better after transplantation and are more likely to spread out and have an impact on a greater area. Both teams transplant middleman cells that are part way down the path between stem cells and mature adult cells. But those stem/progenitor cells from the two teams mature into different adult nerve tissue. The ones from the spinal cord mostly become nerve cells called interneurons, while those from the cortex being used at Cedars all transform into astrocytes, the cells that protect nerves. Astrocytes have been shown to go bad in ALS and it is their malfunction that puts the body on a deadly path to paralysis.

In addition to potentially replacing the nerves’ valuable damaged support cells Svendsen hopes to boost the chances for therapeutic success by making the cells a drug delivery vehicle. The drug of choice: a growth factor called GDNF known to enhance the survival of many types of nerves. Both of the cell types used in ALS so far produce small quantities of GDNF, but the Cedars team wants to crank up that production.

That’s where the gene therapy comes into play. The Cedars team uses a modified lentivirus as a delivery vehicle to carry the GDNF gene into the stem cells. They have shown that half of the stem cells end up having copies of the gene and make the protective elixir. Once transplanted, the cells continue to pump out GDNF into the damaged area—helping the patient’s own neurons survive and function.

As Svendsen and his colleagues complete the last tests needed to get permission to test their one-two-punch cells in humans, they are already working on a key refinement. They would like to be able to regulate when and for how long the therapeutic gene is turned on—to actually make the protective protein on demand. This could be key if any side effects develop. Using a trick that other gene therapy experts have used, they plan to further modify the genetic manipulation so that the gene is only turned on in the presence of the antibiotic doxycycline. So, taking a pill could activate the gene.

After 15 years of intense effort, you can hear the excitement in Svendsen’s voice when he talks about the possibility of beginning a clinical trial later this year. He has all the additional processes in place and says, “we will begin recruiting patients the first week we have approval.”

[May is ALS Awareness month if you want to find out more about how you can help fight the disease visit the ALS Goldenwest chapter website]

Thrust into ALS Advocacy

A publicist for big-name stars, Nanci Ryder found herself thrust into ALS advocacy after her diagnosis last summer.

A publicist for big-name stars, Nanci Ryder found herself thrust into ALS advocacy after her diagnosis last summer.

I have always had a fascination for medicine, and thanks to the Internet, I’ve become a tireless researcher. Having already faced breast cancer a decade ago, the only power I have ever felt over the adversity of a life-threatening illness is knowledge. When I was diagnosed in August 2014 with bulbar ALS, I had to know the specifics of the disease. But more importantly, I had to know who was at the forefront fighting it.

Having spent my entire professional career providing public relations counsel to hundreds of actors and entertainers, I was no stranger to the value of their influence in bringing attention to far-ranging issues, and ALS would be no exception. I had seen what my longtime client Michael J. Fox was able to do for Parkinson’s research and I was determined to follow his example. With the support of clients past and present, Renee Zellweger, Reese Witherspoon, Emmy Rossum and many others, I immediately decided I would commit my energies to support awareness efforts that would translate into additional funding for research.

I met Clive Svendsen through the Cedar Sinai ALS program. I had read about his research in gene therapy and later toured his lab with my friend and ALS advocate, Courteney Cox. We were both very excited by the promise of his research. While there are no cures, I was admittedly daunted when I discovered I was not a candidate for any of the gene therapy clinical trials since my ALS (bulbar) began in the brain, and not in the spine as in 99% of cases.

We cannot always derive the benefits of our efforts for ourselves, but we can help others. That is my life’s path.

Nanci Ryder

Genes + Cells: Stem Cells Deliver Genetic Punch

Bad luck stalked the early years of gene therapy. The pioneering research revealed it is difficult to manipulate a patient’s genes both efficiently and safely. Today, after more than two decades of tireless labor in the lab, nearly 2,000 gene therapy trials have been conducted or are approved, with many of the most promising using stem cells to carry the genetic tricks.

CIRM is providing $110 million in funds for nine projects that have made it into the clinic—or hope to get there soon—by marrying the power of gene manipulation and stem cells. We have several other projects combing the two therapy tools in earlier stages of development.

The first gene therapy trial in the U.S. in 1990 sought to cure Severe Combined Immune Deficiency (SCID), or ‘bubble-baby disease,” and produced modest success. But it did not last. The gene-modified cells did not stick around. Much tinkering ensued to create better ways of getting the desired therapeutic gene into cells, but one of those new tools resulted in the death of a patient in a clinical trial in 1999. That death of Jesse Gelsinger led the Food and Drug Administration to suspend several ongoing clinical trials. Then the 2003 death of a SCID patient from leukemia, believed to have been caused by another gene delivery approach, further dampened the field.

But researchers who see great potential for treating unmet medical needs are not easily dissuaded. The pioneers of gene therapy studied why the deaths occurred and found gene delivery tools that would not go down those same unsafe paths. They discovered ways to get the genes expressed by cells efficiently and longterm. CIRM grantee at the University of California, Los Angeles (UCLA), Don Kohn was helping lead the charge in the early days; despite setbacks he stuck with it, and last year announced that 18 kids had been cured of SCID using stem cells modified to produce the protein missing in the disease. He has just launched a clinical trial hoping to vanquish sickle cell anemia in the same way.

CIRM clinical projects combining stem cells and gene manipulation fall into three categories:

    1. Genetic fix when someone is born with a mutated copy of a gene.
    2. Gene modification to alter stem cells to give them a desired trait.
    3. Gene insertion as drug delivery to give cells a boost of a naturally occurring protein.

Both of the CIRM genetic fix projects seek to rectify errors in the gene for hemoglobin, the protein that our red blood cells use to carry oxygen. Kohn explains his work to provide a working copy of a hemoglobin gene in sickle cell patient’s blood-forming stem cells in our “Stem Cells in Your Face” video series.

Sangamo’s clinical trial won’t be correcting the defective hemoglobin gene in Beta Thalassemia patients directly, but instead will edit the patient’s genes to turn on the gene for fetal hemoglobin that is not normally active as an adult. The company’s team has shown that this gene can produce enough of the protein to end the patients’ need for constant blood transfusions, which up until now has been the only way for them to get healthy red blood cells.

Genetically modifying stem cells to give them desired traits comes in many forms. The two HIV/AIDS projects both seek to alter patients’ blood-forming stem cells so that they produce T cells that are immune to infection by the virus. City of Hope scientists, working with Sangamo, devised a way to alter a protein on the surface of T cells, called a receptor that the virus uses like a door to gain entry into the cells. It is like taking away the key so the virus can’t get in. The Calimmune team doubled down on door security. They are altering two different receptors the virus uses for entry.

Both of the cancer projects seek to alter blood-forming stem cells so that they produce immune system cells that are better targeted to killing a patient’s specific tumor.

Gene insertion to act as a “drug” delivery system also has diverse applications. The Huntington’s disease project uses a type of stem cell found in bone marrow called a mesenchymal stem cell (MSC) to deliver a nerve growth factor that has been shown to be protective of nerves facing the type of damage seen in Huntington’s.

The ALS project starts with cells called neural progenitors, “teenaged” cells that are only part way along the path of maturity between a nerve stem cell and the final adult brain cells. Once transplanted the cells should have a two-pronged benefit. They mature specifically into astrocytes, the initial brain cell to go bad in ALS, and the added gene will produce a growth factor that has been shown to be protective of the damage seen in ALS—a different growth factor than the one used in the Huntington’s research.

In limb ischemia, poor blood circulation and severe pain results from clogged blood vessels, so therapies that stimulate growth of new vessels make sense. A growth factor called VEGF has long been known to do this, but when doctors tried injecting it into aching legs it didn’t stick around long enough to do any good. MSCs are also known to stimulate blood vessel growth and have shown some benefit when transplanted into patients with limb ischemia. If that benefit could be ratcheted up patients could gain significant pain relief. The UC Davis team hopes to transplant MSCs that have an extra copy of the VEGF gene so they stimulate vessel growth through two paths.

The marriage of gene therapy and stem cell therapy seems likely to produce a number of live-happily-ever-after therapies.

Stem cell stories that caught our eye: spina bifida, review of heart clinical trials, tracking cells and cell switches

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.

Stem cells boost fetal surgery for spina bifida. Fetal surgery to correct the spinal defect that causes spina bifida has revolutionized treatment for the debilitating birth defect in the past few years. But for one of the researchers who pioneered the surgery it was only a half fulfilled hope. While the surgery let most of the treated kids grow up without cognitive deficits it did not improve their ability to walk.

spina_bifida-webNow that researcher, Diana Farmer at the University of California, Davis, has found a way to complete the job. Though it has only been used in an animal model so far, she found that when you engineer a stem cell patch that you insert into the gap before you push the protruding spinal cord back in its place during surgery, the animals are able to walk within a few hours of birth.

Specifically, she used a type of stem cell found in the placenta that has been shown to protect nerves. She incased those cells in a gel and placed them on a scaffold to hold them in place after transplant. All six lambs that had surgery plus the cell transplant walked. None of the ones who just had surgery did.

“Fetal surgery provided hope that most children with spina bifida would be able to live without (brain) shunts,” Farmer said. “Now, we need to complete that process and find out if they can also live without wheelchairs.”

CIRM awarded Farmer’s team funds in March to carry this work forward and prepare it for a possible clinical trial. The animal study appeared in Stem Cells Translational Medicine this week and the university’s press release was picked up by HealthCanal.

Thorough, digestible review of heart trials. Kerry Grens, writing in The Scientist, has produced the most complete and understandable review of the clinical trials using stem cells to treat heart disease that I have read. More important she provides significant detail about the three large Phase 3 trials that are ongoing that could provide make-or-break outcomes for using bone marrow stem cells for patients developing heart failure.

The bulk of the piece focuses on research using various types of mesenchymal stem cells found in bone marrow. All three of the late stage clinical trials use those cells, two use cells from the patient’s own marrow and one uses cells from donors. Grens uses a broad spectrum of the research community describe what we currently know about how those cells may work and more importantly, what we don’t know. The experts provide a good point-counter-point on why there are so many clinical trials when we don’t really know those stem cells’ “method of action,” why they might make someone’s heart stronger.

However she leads and ends with work CIRM funds at Cedars-Sinai and Capricor Therapeutics in Los Angeles. That work uses cells derived from the heart called cardiosphere-derived cells. Early trials suggested these cells might be better at reducing scar tissue and triggering regrowth of heart muscle. Those cells are currently being tested in a Phase 2 study to try to get a better handle on exactly what their benefit might be.

Monitoring stem cells after transplants. Early attempts to use stem cells as therapies have been hampered by an inability to see where the cells go after transplant and if they stay the desired location and function. A team at Stanford has used some ingenious new technologies to get over this hurdle, at least in laboratory animals.

Using a homegrown technology that recently won a major innovation prize for a Stanford colleague, optogenetics, the team was able to selectively activate the transplanted cells. Then they used the older technology, functional Magnetic Resonance Imaging (fMRI), to see if the cells were working. Because cell transplants in the brain have led to some of the most difficult to interpret results in humans, they chose to work with nerve stem cells transplanted into the brains of rats. The work was partially funded by CIRM.

Starting with iPS type stem cells made from Parkinson’s patients’ skin, they inserted a gene for a protein that is sensitive to certain wavelengths of light. They then matured those cells into nerve stem cells and implanted them along with a tube that could transmit the right wavelength of light. Over the course of many months they measured the activity of the cells via fMRI with and without the light stimulation. Because the fMRI measures blood flow it by default detects active nerve cells that require more nutrients from blood than inactive cells. Senior researcher, Jin Hyung Lee described the value of this imaging in the university’s press release picked up by HealthCanal:

“If we can watch the new cells’ behaviors for weeks and months after we’ve transplanted them, we can learn — much more quickly and in a guided way rather than a trial-and-error fashion — what kind of cells to put in, exactly where to put them, and how.”

Understanding cell’s switchboard may speed therapy. Cells function by switching genes on and off. Learning which switches to hit to maximize stem cells’ ability to multiply and mature into desired cell types has occupied a significant part of the stem cell research community for years. Now, a team at the Salk Institute has shown that two known genetic switches pack an additive punch when working together.

Both those signaling processes, one called Wnt and one called Activin, are needed for stem cells to mature into specific adult tissue. The Salk team led by Kathy Jones found that when working together the two signals activate some 200 genes. Wnt seems to load the cellular equipment needed for copying the cells and Activin increases the speed and efficiency of the process. In an institute press release picked up by Science Newsline, Jones discussed the practical implications of the finding:

“Now we understand stem cell differentiation at a much finer level by seeing how these cellular signals transmit their effects in the cells. Understanding these details is important for developing more robust stem cell protocols and optimizing the efficiency of stem cell therapies.”

Stem cell stories that caught our eye: multiple sclerosis, virus genes in embryos and preventing cancer’s spread to the brain

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.

Drugs activate brain stem cells in MS. We have frequently written that in some situations our own stem cells may do a better job at repairing the body than transplanted cells. A team at Case Western in Cleveland has done just that with lab and animal models of Multiple Sclerosis (MS). Even better, they did it with drugs that are already approved for other uses.

They used a steroid, clobetasol, and an antifungal, miconazole, to get a type of stem cell found in the brain to more effectively produce the myelin sheets that protect our nerves and that get destroyed in MS. But in a story in Science Blog the researchers cautioned that patients should not go ask a doctor to inject those drugs. They are currently used only as topical agents on the skin and no one knows what they would do internally in people.

“Off-label use of the current forms of these drugs is more likely to increase other health concerns than alleviate multiple sclerosis symptoms. We are working tirelessly to ready a safe and effective drug for clinical use,” said Paul Tesar who led the study.”

Specifically, the team worked with stem cells called oligodendrocyte progenitor cells. Growing them in the lab they tested hundreds of approved drugs to see if any would nudge those cells into producing myelin. They found these two and tested them in a mouse model of MS and saw improved function in the mice. They are now looking to test other drugs hoping to find one safe for internal use in humans.

Viral genes active in early embryos. Virus genes, mostly left over from infections of our ancestors thousands of years ago, make up some eight percent of the genetic material in our chromosomes. In general those genes just sit there and don’t do anything. But a CIRM funded team at Stanford has found that in the early days of embryo development some of them become quite active.

In fact, they seem to commandeer the growing embryo’s cellular machinery to produce whole virus particles that the researchers detected in the interior of the cells. What they could not determine is whether that activity is benign or somehow directs the development of the embryo—or might be the virus reasserting its parasitic ways.

“It’s both fascinating and a little creepy,” said Joanna Wysocka, the senior author on the study that appeared this week in Nature. “We’ve discovered that a specific class of viruses that invaded the human genome during recent evolution becomes reactivated in the early development of the human embryo, leading to the presence of viral-like particles and proteins in the human cells.”

In the press release, Stanford’s Krista Conger does a nice job of laying out some of the prior research about the origins and nature of all the viral genes hidden amongst our DNA. The release, picked up by HealthCanal makes it clear the finding raises more questions than it provides answers. Edward Grow, the graduate student who was first author on the paper put it this way:

“Does the virus selfishly benefit by switching itself on in these early embryonic cells? Or is the embryo instead commandeering the viral proteins to protect itself? Can they both benefit? That’s possible, but we don’t really know.”

Stem cells with multiple genetic tricks fight cancer. Breast cancer wreaks the most havoc when it spreads and about a third of the time it spreads to the brain. To fight that insidious spread a team a Massachusetts General Hospital and the Harvard Stem Cell Institute has rigged nerve stem cells with multiple genetic tricks to prevent breast cancer cells from growing after they get to the brain.

Certain types of nerve stem cells are naturally attracted to tumors. So the team led by Khalid Shah genetically manipulated those stem cells to express a gene called TRAIL. That gene produces a protein that activates a receptor on the surface of cancer cells that causes them to self-destruct. Then to make sure those stem cells did not stick around and multiply when they are no longer needed, the researchers added another gene that made them susceptible to a common antiviral drug. That drug could be given once the cells had done their work of delivering the suicide note to the cancer cells and the stem cells themselves would then be eliminated.

A press release on the work from MGH was picked up by ScienceNewsline and quoted Shah on the significance of the findings:

“Our results are the first to provide insight into ways of targeting brain metastases with stem-cell-directed molecules that specifically induce the death of tumor cells and then eliminating the therapeutic stem cells.”

In order to measure their results the team started with yet another genetic trick. They wanted to make sure the loaded stem cells were getting to the tumors. So, before they injected breast cancer cells into the carotid arteries in the necks of mice, they modified the cells so that they would express fluorescent markers. That glow could be tracked allowing the researchers to monitor the disappearance of the cancer cells.

This mouse work is obviously many steps away from use in humans, but it provides an ingenious path to follow.

International stem cell group offers much needed guidance for patients and families

Yesterday the International Society for Stem Cell Research launched a greatly expanded website for the public. While the site, “Closer Look at Stem Cells,” offers a broad overview of stem cell science, the group launched it out of concern stem cell treatments are being marketed by clinics around the world without appropriate oversight and patient protections in place.

closer look webThe design for the new site provides easy navigation that quickly gets you to brief outlines and opportunities for a bit more information one click down. Most important, the detail page often includes a bright yellow warning icon with messages like this:

“View clinics that offer the same cell treatment for a wide variety of conditions or diseases with extreme caution. Be wary of claims that stem cells will somehow just know where to go and what to do to treat a specific condition.”

I could buy several rounds at the pub if I had a dollar for every time I said something like that to a desperate patient or family member who called CIRM with questions.

With quick reads like “Nine things to know about stem cell treatments,” as well as a more in-depth patient handbook the site provides ample opportunities to get the level of information any individual wants. It offers clear explanations for the different phases of clinical trials and what to expect if you enter a clinical trial.

A task force of society members and staff produced the new site. The chair of the task force, Megan Munsie from Stem Cells Australia, noted some of the concerns that triggered the effort in the organization’s press release:

“Promising clinical trials are underway for many diseases and conditions, but most stem cell-based treatments are still in the future. We hope that the website will foster interest and excitement in the science, but also an understanding of the current limitations of stem cells as medicine and a healthy skepticism of clinics selling treatments.”

Hope mixed with a good dose of skepticism is always a good approach to a new field of science. Our web site also offers advice for things to consider if a person is contemplating going to a clinic offering an unproven therapy outside of a clinical trial.

Stem cell stories that caught our eye: iPS cells guide ALS trial, genetic link to hearing loss and easier to use stem cell

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.

An ALS clinical trial with a twist.
It is well known that the disease we call ALS, or Lou Gehrig’s Disease, behaves differently in different people, so it makes sense that a potential medication might help some people more than others. Now a collaborative group in the North East wants to use iPS-type stem cells to predict who will respond to a medication at the outset of a clinical trial.

The drug to be tested is already used to calm hyper excitable nerves in people with epilepsy. Hyper excitable nerves also seem to play a role in ALS, at least in some patients. So the team, lead by a researcher at Massachusetts General Hospital with others from Harvard, the Northeast ALS Consortium and GlaxoSmithKline, will reprogram the patients’ blood cells to be iPS type stem cells and grow them into nerve cells in the lab and test their response to the drug, Retigabine.

The ALS Association is providing part of the funding for the effort, and the association’s chief scientist, Lucie Bruijn noted the unique nature of this effort in the association’s press release picked up by Bloomberg.

“This powerful collaboration of leaders in the fields of stem cells, clinical neurology, ALS research and GSK will be the first time that lab data from patient derived stem cells with disease-specific properties that respond to drugs have formed the basis for a clinical trial.”

Do stem cells prefer wearing a coat? One of our grantees and the editor of the journal Stem Cells, Jan Nolta, likes to refer to mesenchymal stem cells as little ambulances that run around the body delivering first aid supplies. These cells found in bone marrow and fat are being tested in many different disease, but in most cases they are not expected to actually make repairs themselves. Instead researchers use them to deliver a variety of protein factors that trigger various components of the body’s natural healing machinery.

Mesenchymal stem cells captured in microcapsules

Mesenchymal stem cells captured in microcapsules

One problem is the cells often do not stick around very long delivering their needed medical supplies. A team at Cornell University in New York thinks they may have found a way to improve the performance of these stem cells, by giving them a coat. By enclosing the stem cells in a capsule the cells stay in place better and more effectively help wounds heal, at least in the lab model the team used.

The university’s press release was picked up by Medical Design Technology.

Noise plus bad genes bad for hearing. Some people can spend years of Saturday nights attending loud rock concerts and have no issue with their hearing. Others end up constantly adjusting the battery on their hearing aids. A CIRM-funded team at the University of Southern California thinks they have fingered a genetic explanation for the difference.

Hearing is a complex process involving many components, which has resulted in no clear answers from previous attempts to find genetic links to hearing loss. The USC team performed a more complex analysis known as a GWAS, genome-wide association study. The result provided strong evidence that variations in the gene Nox3, which is normally turned on only in the inner ear, account for the differences in susceptibility.

Researchers now have a clear target to look for opportunities for prevention and therapy. Futurity picked up the University’s press release.

Accident creates new type of stem cell.
Much of the work with embryonic stem cells centers on figuring out what proteins and other factors to expose them to in order to get them to mature into a desired type of cell. One such attempt at the University of Missouri resulted in creating a new type of stem cell that may be easier to work with than embryonic stem cells (ESCs).

They call their new cells BMP-primed stem cells because one of the various factors they were adding to their ESCs in a lab dish was Bone Morphogenetic Protein. Michael Roberts, the leader of the team, described the potential value of the new stem cells in an article in Genetic Engineering & Biotechnology News:

“These new cells, which we call BMP-primed stem cells, are much more robust and easily manipulated than standard embryonic stem cells. BMP-primed cells represent a transitional stage of development between embryonic stem cells and their ultimate developmental fate, whether that is placenta cells, or skin cells or brain cells.”

For hardcore biologyphiles, the new cells offer a chance to better understand the early stages of embryo development. ESCs can form any part of the body but they cannot form the placenta and other early tissues needed to support the embryo. The BMP-primed stem cells can. So they may yield some long-sought answers about what determines cell fate in the early days after fertilization and perhaps some practical information on diseases related to the placenta like pre-eclampsia.