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.

Brain’s Own Activity Can Fuel Growth of Deadly Brain Tumors, CIRM-Funded Study Finds

Not all brain tumors are created equal—some are far more deadly than others. Among the most deadly is a type of tumor called high-grade glioma or HGG. Most distressingly, HGG’s are the leading cause of brain tumor death in both children and adults. And despite extraordinary progress in cancer research as a whole, survival rates for those diagnosed with an HGG have yet to improve.

shutterstock_30402241

But recent research from Stanford University scientists could one day help move the needle—and give renewed hope to the patients and their families affected by this devastating disease.

The study, published today in the journal Cell, found that one key driver for HGG’s deadly diagnosis is that the tumor can be stimulated to grow by the brain’s own neural activity—specifically the nerve activity in the brain’s cerebral cortex.

Michelle Monje, senior author of the study that was funded in part by two grants from CIRM, was initially surprised by these results, as they run counter to how most types of tumors grow. As she explained in today’s press release:

“We don’t think about bile production promoting liver cancer growth, or breathing promoting the growth of lung cancer. But we’ve shown that brain function is driving these brain cancers.”
 


By analyzing tumor cells extracted from HGG patients, and engrafting it onto mouse models in the lab, the researchers were able to pinpoint how the brain’s own activity was driving tumor growth.

The culprit: a protein called neuroligin-3 that appeared to be calling the shots. There are four distinct types of HGGs that affect the brain in vastly different ways—and have vastly different molecular and genetic characteristics. Interestingly, says Monje, neuroligin-3 played the same role in all of them.

What was so disturbing to the research team, says Monje, is that neuroligin-3 is an essential protein for overall brain development. Specifically, it helps maintain healthy growth and repair of brain tissue over time. In order to grow, HGG tumors hijack this critical protein.

The research team came to this conclusion after a series of experiments that delved deep into the molecular mechanisms that guide both brain activity and brain tumor development. They first employed a technique called optogenetics, whereby scientists use genetic manipulation to insert light-sensitive proteins into the brain cells, or neurons, of interest. This allowed scientists to activate these neurons—or deactivate them—at the ‘flick of a switch.’

When applying this technique to the tumor-engrafted mouse models, the team could then see that tumors grew significantly better when the neurons were switched on. The next step was to narrow it down to why. Additional biochemical analyses and testing on the mouse models confirmed that neuroligin-3 was being hijacked by the tumor to spur growth.

And when they dug deeper into the connection between neuroligin-3 and cancer, they found something even more disturbing. A detailed look at the Cancer Genome Atlas (a large public database of the genetics of human cancers), they found that HGG patients with higher levels of neuroligin-3 in their brain had shorter survival rates than those with lower levels of the same protein.

These results, while highlighting the particularly nefarious nature of this class of brain tumors, also presents enormous opportunity for researchers. Specifically, Monje hopes her team and others can find a way to block or nullify the presence of neuroligin-3 in the regions surrounding the tumor, creating a kind of barrier that can keep the size of the tumor in check. 


Molecular Trick Diminishes Appearance of Scars, Stanford Study Finds

Every scar tells a story, but that story may soon be coming to a close, as new research from Stanford University reveals clues to why scars form—and offers clues on how scarring could become a thing of the past.

Reported last week in the journal Science, the research team pinpointed the type of skin cell responsible for scarring and, importantly, also identified a molecule that, when activated, can actually prevent the skin cells from forming a scar. As one of the study’s senior authors Michael Longaker explained in a press release, the biomedical burden of scarring is vast.

Scars, both internal and external, present a significant biomedical burden.

Scars, both internal and external, present a significant biomedical burden.

“About 80 million incisions a year in this country heal with a scar, and that’s just on the skin alone,” said Longaker, who also co-directs Stanford’s Institute for Stem Cell Biology and Regenerative Medicine. “Internal scarring is responsible for many medical conditions, including liver cirrhosis, pulmonary fibrosis, intestinal adhesions and even the damage left behind after a heart attack.”

Scars are normally formed when a type of skin cell called a fibroblast secretes a protein called collagen at the injury site. Collagen acts like a biological Band-Aid that supports and stabilizes the damaged skin.

In this study, which was funded in part by a grant from CIRM, Longaker, along with co-first authors Yuval Rinkevich and Graham Walmsley, as well as co-senior author and Institute Director Irving Weissman, focused their efforts on a type of fibroblast that appeared to play a role in the earliest stages of wound healing.

This type of fibroblast stands out because it secretes a particular protein called engrailed, which initial experiments revealed was responsible for laying down layers of collagen during healing. In laboratory experiments in mouse embryos, the researchers labeled these so-called ‘engrailed-positive fibroblast cells,’ or EPF cells, with a green fluorescent dye. This helped the team track how the cells behaved as the mouse embryo developed.

Interestingly, these cells were also engineered to self-destruct—activated with the application of diphtheria toxin—so the team could monitor what would happen in the absence of EPF cells entirely.

Their results revealed strong evidence that EPF cells were critical for scar formation. The scarring process was so tied to these EPF cells that when the team administered the toxin to shut them down, scarring reduced significantly.

Six days later the team found continued differences between mice with deactivated EPF cells, and a group of controls. Indeed, the experimental group had repaired skin that more closely resembled uninjured skin, rather than the distinctive scarring pattern that normally occurs.

Further examination of EPF cells’ precise function revealed a protein called CD26 and that blocking EPF’s production of CD26 had the same effect as shutting off EPF cells entirely. Wounds treated with a CD26 inhibitor had scars that covered only 5% of the original injury site, as opposed to 30%.

Pharmaceutical companies Merck and Novartis have already manufactured two types of CD26 inhibitor, originally developed to treat Type II diabetes, which could be modified to block CD26 production during wound healing—a prospect that the research team is examining more closely.

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.

A new approach to killing blood cancer

It’s not often that you get a therapy named after you, particularly one that has so much promise for helping to save lives. So when researchers at the University of California, San Diego Moore’s Cancer Center named the treatment Cirmtuzumab after us it’s understandable we should feel just a little pride. After all, we provided the funding and support needed to develop it.

Now Cirmtuzumab is being used in a clinical trial to treat chronic lymphocytic leukemia (CLL) a deadly blood cancer. Cirmtuzumab is a monoclonal antibody drug and is designed to attach itself to a protein called ROR1 that CLL cells need to survive and spread. The idea is that if you block ROR1, you can block the growth of the cancer.

Ivanhoe Broadcasting, a company that syndicates medical stories to TV stations around the US, recently featured this trial. You can see that report here.

kipps2013Dr. Thomas Kipps, who is heading the trial, told Ivanhoe that CLL is an important disease to target:

“This is the most common adult leukemia in western societies. We have early data now to suggest this antibody may be effective at preventing the relapse and metastasis of cancer.”

It’s always encouraging when a promising therapy moves out of the lab and into clinical trials. Reaching this point is the culmination of years, sometimes decades, of hard work and while this is an important milestone, it’s just the first step in a long journey. But now we get to put it to the test and see if it will work in people.

If it does, then that will be something to be truly proud of.

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.

CIRM-Funded Scientists Build a Better Neuron; Gain New Insight into Motor Neuron Disease

Each individual muscle in our body—no matter how large or how small—is controlled by several types of motor neurons. Damage to one or more types of these neurons can give rise to some of the most devastating motor neuron diseases, many of which have no cure. But now, stem cell scientists at UCLA have manufactured a way to efficiently generate motor neuron subtypes from stem cells, thus providing an improved system with which to study these crucial cells.

“Motor neuron diseases are complex and have no cure; currently we can only provide limited treatments that help patients with some symptoms,” said senior author Bennett Novitch, in a news release. “The results from our study present an effective approach for generating specific motor neuron populations from embryonic stem cells to enhance our understanding of motor neuron development and disease.”

Normally, motor neurons work by transmitting signals between the brain and the body’s muscles. When that connection is severed, the individual loses the ability to control individual muscle movement. This is what happens in the case of amyotrophic lateral sclerosis, or ALS, also known as Lou Gehrig’s disease.

These images reveal the significance of the 'Foxp1 effect.' The Foxp1 transcription factor is crucial to the normal growth and function of motor neurons involved in limb-movement.

These images reveal the significance of the ‘Foxp1 effect.’ The Foxp1 transcription factor is crucial to the normal growth and function of motor neurons involved in limb-movement.

Recent efforts had focused on ways to use stem cell biology to grow motor neurons in the lab. However, such efforts to generate a specific type of motor neuron, called limb-innervating motor neurons, have not been successful. This motor-neuron subtype is particularly affected in ALS, as it supplies nerves to the arms and legs—the regions usually most affected by this deadly disease.

In this study, published this week in Nature Communications, Novitch and his team, including first author Katrina Adams, worked to develop a better method to produce limb-innervating motor neurons. Previous efforts had only had a success rate of about 3 percent. But Novitch and Adams were able to boost that number five-fold, to 20 percent.

Specifically, the UCLA team—using both mouse and human embryonic stem cells—used a technique called ‘transcriptional programming,’ in order to coax these stem cells into become fully functional, limb-innervating motor neurons.

In this approach, which was funded in part by a grant from CIRM, the team added a single transcription factor (a type of protein that regulates gene function), which would then guide the stem cell towards becoming the right type of motor neuron. Here, Novitch, Adams and the team used the Foxp1 transcription factor to do the job.

Normally, Foxp1 is found in healthy, functioning limb-innervating motor neurons. But in stem cell-derived motor neurons, Foxp1 was missing. So the team reasoned that Foxp1 might actually be the key factor to successfully growing these neurons.

Their initial tests of this theory, in which they inserted Foxp1 into a developing chicken spinal cord (a widely used model for neurological research), were far more successful. This result, which is not usually seen with most unmodified stem-cell-derived motor neurons, illustrates the important role played by Foxp1.

The most immediate implications of this research is that now scientists can now use this method to conduct more robust studies that enhance the understanding of how these cells work and, importantly, what happens when things go awry.

Gene Therapy Beats Half-Matched Stem Cell Transplant in Side-by-Side Comparison to Treat ‘Bubble Baby’ Disease

If you are born with Severe Combined Immunodeficiency (SCID), your childhood is anything but normal. You don’t get to play with other kids, or be held by your parents. You can’t even breathe the same air. And, without treatment, you probably won’t live past your first year.

The bubble boy.  Born in 1971 with SCID, David Vetter lived in a sterile bubble to avoid outside germs that could kill him. He died in 1984 at 12 due to complications from a bone marrow transplant. [Credit: Baylor College of Medicine Archives]

The bubble boy. Born in 1971 with SCID, David Vetter lived in a sterile bubble to avoid outside germs that could kill him. He died in 1984 at 12 due to complications from a bone marrow transplant. [Credit: Baylor College of Medicine Archives]

This is the reality of SCID, also called “Bubble Baby” disease, a term coined in the 1970s when the only way to manage the disease was isolating the child in a super clean environment to avoid exposure to germs. The only way to treat the disorder was with a fully matched stem cell transplant from a bone marrow donor, ideally from a sibling. But as you may have guessed, finding a match is extraordinarily rare. Until recently, the next best option was a ‘half-match’ transplant—usually from a parent. But now, scientists are exploring a third, potentially advantageous option: gene therapy. Late last year, we wrote about a promising clinical trial from UCLA researcher (and CIRM Grantee) Donald Kohn, whose team effectively ‘cured’ SCID in 18 children with the help of gene therapy. Experts still consider a fully matched stem cell transplant to be the gold standard of treatment for SCID. But are the second-tier contenders—gene therapy and half-matched transplant—both equally as effective? Until recently, no one had direct comparison. That all changes today, as scientists at the Necker Children’s Hospital in Paris compare in the journal Blood, for the first time, half-matched transplants and gene therapy—to see which approach comes out on top. The study’s lead author, Fabien Touzot, explained the importance of comparing these two methods:

“To ensure that we are providing the best alternative therapy possible, we wanted to compare outcomes among infants treated with gene therapy and infants receiving partial matched transplants.”

So the team monitored a group of 14 SCID children who had been treated with gene therapy, and compared them to another group of 13 who had received the half-matched transplant. And the differences were staggering. Children in the gene therapy group showed an immune system vastly improved compared to the half-matched transplant group. In fact, in the six months following treatment, T-cell counts (an indicator of overall immune system health) rose to almost normal levels in more than 75% of the gene therapy patients. In the transplant group, that number was just over 25%. The gene therapy patients also showed better resilience against infections and had far fewer infection-related hospitalizations—all indictors that gene therapy may in fact be superior to a half-matched transplant. This is encouraging news say researchers. Finding a fully matched stem cell donor is incredibly rare. Gene therapy could then give countless families of SCID patients hope that their children could lead comparatively normal, healthy lives. “Our analysis suggests that gene therapy can put these incredibly sick children on the road to defending themselves against infection faster than a half-matched transplant,” explained Touzot. “These results suggest that for patients without a fully matched stem cell donor, gene therapy is the next-best approach.” Hear more about how gene therapy could revolutionize treatment strategies for SCID in our recent interview with Donald Kohn:

Stem cell stories that caught our eye: Hair stem cells, amniotic fluid cells for repair and fixing kids’ faulty genes

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.

With hair, lose a few to grow more.
A team at the University of Southern California has shown that if you pull out a couple hundred hairs in just the right pattern you could trigger a thousand or more hairs to grow. It is the latest example of several we have written about that show stem cells react very acutely to their environment.

The researcher had known that hair follicle injury affects the adjacent environment and that environment can influence hair growth. They teamed up with a University of California, Irvine, expert on “quorum sensing,” a field that the USC press release defined as “how a system responds to stimuli that affects some, but not all members”. They tested various patterns of hair follicle damage caused by plucking hairs on the back of a mouse. They eventually found the pattern and spacing that turned the 200 hairs loss into a thousand-strand gain.

The stem cells that reside at the base of hair follicles are a common tool for studying stem cell behavior because they are easy to get at. And while this work could eventually produce real cosmetic benefits for folks follicularly challenged like myself, the real payoff could come from finding similar quorum affects in stem cells in other organs, which the senior researcher, Cheng-Ming Chuong, notes in the release picked up by Epoch Times:

“The implication of the work is that parallel processes may also exist in the physiological or pathogenic processes of other organs, although they are not as easily observed as hair regeneration.”

Baby’s amniotic fluid as source of repairs. The amniotic fluid that surrounds a growing baby carries cells shed by the fetus that doctors use to diagnose problems, but it also has some valuable stem cells, actually a few types of stem cells. Even though those cells are characteristically adult stem cells, because they have recently crossed the line from embryo to adult, they seem to be more versatile than adult stem cells, and since they match the baby could be the perfect cell for repairing birth defects.

Mature blood vessels form after two weeks in a mouse, with red blood cells flowing at the bottom right.

Mature blood vessels form after two weeks in a mouse, with red blood cells flowing at the bottom right.

Scientists at Rice University and Texas Children’s hospital have reported that when you seed those stem cells into the gel scaffolds commonly used for tissue engineering, the resulting tissues do a better job of growing blood vessels. And without the nutrients brought by new vessels, repair tissues will not survive. They now hope to use this new technique in their ongoing efforts to grow heart muscle patches for children born with heart defects.

The university’s press release was picked up by ScienceDaily. It looks like the fluid and cells normally thrown away after a prenatal test, might become a valuable resource.

Genetically correcting childhood disease.
Last week Stanford organized a multi-day symposium called Childx with an impressive array of speakers from around the world talking about how to improve child health. It ended with a special session on the rapid advances being made by combining stem cell science and gene therapy.

“It’s not just science fiction anymore,” Stanford’s Matthew Porteus, told the audience. “We can correct mutations that cause childhood disease.”

The university’s Scope blog summed up the session in a post this week. It discusses progress in sickle cell anemia, severe combined immune deficiency (SCID) and epidermolysis bullosa, among others. The piece also has a voice from industry cautioning that many hurdles remain before any of these therapies can be scaled up to broad use.

But my email this morning had a potent reminder that enough scientists are getting on this bandwagon to make it happen. The subject line of a sales pitch was “Boost transduction with 20 % off Lentiviral Particles,” which referred to the viral units used to carry genes into cells hoping they with take up residence there and function, aka transduction.

CIRM has bet big on this avenue of research investing more than $110 million in nine projects that combine stem cells and gene manipulation and are either in the clinic or soon will be. We will be launching a new series of posts on “Genes + Cells” next week.

Stem Cell Scientists Reconstruct Disease in a Dish; Gain Insight into Deadly Form of Bone Cancer

The life of someone with Li-Fraumeni Syndrome (LFS) is not a pleasant one. A rare genetic disorder that usually runs in families, this syndrome is characterized by heightened risk of developing cancer—multiple types of cancer—at a very young age.

People with LFS, as the syndrome is often called, are especially susceptible to osteosarcoma, a form of bone cancer that most often affects children. Despite numerous research advances, survival rates for this type of cancer have not improved in over 40 years.

shutterstock_142552177 But according to new research from Mount Sinai Hospital and School of Medicine, the prognosis for these patients may not be so dire in a few years.

Reporting today in the journal Cell, researchers describe how they used a revolutionary type of stem cell technology to recreate LFS in a dish and, in so doing, have uncovered the series of molecular triggers that cause people with LFS to have such high incidence of osteosarcoma.

The scientists, led by senior author Ihor Lemischka, utilized induced pluripotent stem cells, or iPSCs, to model LFS—and osteosarcoma—at the cellular level.

Discovered in 2006 by Japanese scientist Shinya Yamanaka, iPSC technology allows scientists to reprogram adult skin cells into embryonic-like stem cells, which can then be turned into virtually any cell in the body. In the case of a genetic disorder, such as LFS, scientists can transform skin cells from someone with the disorder into bone cells and grow them in the lab. These cells will then have the same genetic makeup as that of the original patient, thus creating a ‘disease in a dish.’ We have written often about these models being used for various diseases, particularly neurological ones, but not cancer.

“Our study is among the first to use induced pluripotent stem cells as the foundation of a model for cancer,” said lead author and Mount Sinai postdoctoral fellow Dung-Fang Lee in today’s press release.

The team’s research centered on the protein p53. P53 normally acts as a tumor suppressor, keeping cell divisions in check so as not to divide out of control and morph into early-stage tumors. Previous research had revealed that 70% of people with LFS have a specific mutation in the gene that encodes p53. Using this knowledge and with the help of the iPSC technology, the team shed much-needed light on a molecular link between LFS and bone cancer. According to Lee:

“This model, when combined with a rare genetic disease, revealed for the first time how a protein known to prevent tumor growth in most cases, p53, may instead drive bone cancer when genetic changes cause too much of it to be made in the wrong place.”

Specifically, the team discovered that the ultimate culprit of LFS bone cancer is an overactive p53 gene. Too much p53, it turns out, reduces the amount of another gene, called H19. This then leads to a decrease in the protein decorin. Decorin normally acts to help stem cells mature into healthy, bone-making cells, known as osteoblasts. Without it, the stem cells can’t mature. They instead divide over and over again, out of control, and ultimately cause the growth of dangerous tumors.

But those out of control cells can become a target for therapy, say researchers. In fact, the team found that artificially boosting H19 levels could have a positive effect.

“Our experiments showed that restoring H19 expression hindered by too much p53 restored “protective differentiation” of osteoblasts to counter events of tumor growth early on in bone cancer,” said Lemischka.

And, because mutations in p53 have been linked to other forms of bone cancer, the team is optimistic that these preliminary results will be able to guide treatment for bone cancer patients—whether they have LFS or not. Added Lemischka:

“The work has implications for the future treatment or prevention of LFS-associated osteosarcoma, and possibly for all forms of bone cancer driven by p53 mutations, with H19 and p53 established now as potential targets for future drugs.”

Learn more about how scientists are using stem cell technology to model disease in a dish in our special video series: Stem Cells In Your Face: