Mini-Brains Help Unlock Autism’s Secrets

Some diseases like sickle cell anemia, an inherited blood disorder, can be traced to a single known genetic mutation. But other diseases like autism spectrum disorder (ASD), are so varied in their symptoms and severity that pinpointing the underlying cause is extremely complicated. People with autism typically have difficulties communicating with the world around them, unable to fully process both verbal and non-verbal language, and plagued by repetitive behaviors. Some rare forms of autism appear to be inherited but over 80% of cases are idiopathic, a fancy term for “we don’t know what causes it.”

Process for making organoid

Process for making organoid “mini-brains” from iPS cells derived from patient skin samples (image credit: Keval Tilva, wikipedia)

Last week, a research team at the Yale School of Medicine published data in Cell that appears to unveil some of the mystery behind autism. The scientists relied on induced pluripotent stem cells (iPS) derived from skin samples of people with severe forms of ASD. Rather than maturing the stem cells into a flat layer of brain cells, or neurons, on a plastic petri dish, the Yale team stirred the cells in a bioreactor. This technique allows the cells to mature in a small three-dimensional clump, which self organizes into so-called brain “organoids” or “mini-brains.” The structure of these mini-brains resembles the portions of the developing fetal human brain, the stage at which autism is thought to arise.

An analysis of the mini-brains found no underlying genetic mutations. Instead, the team identified genes involved with cell growth and neuron development that were turned on higher in the ASD vs. non-ASD mini-brains. A closer look at cell growth showed that inhibitory neurons, responsible for keeping nerve signals in check, were increased in number in the ASD mini-brains. Teasing out this discovery further pinpointed a protein, called FOXG1, which was responsible for the increased cell growth of the inhibitory neurons.

Fluorescent microscopy images of minibrain organoids derived from ASD patients (right) and unaffected family members (left). The red and green color indicate the increased presence of inhibitory neurons in the ASD minibrain (right). (Image credit: Mariani et al. Cell Volume 162, Issue 2, p375–390.

Fluorescent microscopy images of minibrain organoids derived from ASD patients (right) and unaffected family members (left). The red and green color indicate the increased presence of inhibitory neurons in the ASD minibrain (right). (Image credit: Mariani et al. Cell Volume 162, Issue 2, p375–390, Fig 4I.)

Here’s the interesting part if you’re still with me: of the four patient samples used in this study, higher levels of FOXG1 protein correlated with more severe ASD. And blocking the production of FOXG1 in the ASD mini-brains reduced the inhibitory neurons back to normal levels. Although this initial finding doesn’t directly link FOXG1 and autism, the results suggest a common disease mechanism: that autism may arise by over producing FOXG1 which in turn creates too many inhibitory neurons during brain development and somehow disrupts connections between neurons.

In an interview with The Scientist, CIRM-funded grantee Alysson Muotri of UCSD, who also studies autism using patient derived iPS cells, finds this possible commonality in ASD remarkable:

“These are patients with idiopathic autism that do not share any genetic causes, and yet the authors find phenotypes shared between their cells. That’s impressive. If someone had asked me, I would have said, ‘You won’t find anything in common, it’s probably going to be a mixed bag.’ But no . . . there seems to be key things that are dysregulated in all of them.”

Stem cell stories that caught our eye: fixing defects we got from mom, lung repair and staunching chronic nerve pain

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.

Two ways to clean up mitochondrial defects. Every student gets it drilled into them that we get half our genes from mom and half from dad, but that is not quite right. Mom’s egg contains a few genes outside the nucleus in the so-called powerhouse of the cell, the mitochondria that we inherit only from mom. The 13 little genes in that tiny organelle that are responsible for energy use can wreak havoc when they are mutated. Now, a multi-center team working in Oregon and California has developed two different ways to create stem cells that match the DNA of specific patients in everyway except those defective mitochondrial genes.

The various mitochondrial mutations tend to impact one body system more than others. The end goal for the current research is to turn those stem cells into healthy tissue that can be transplanted into the area most impacted by the disease in a specific patient. That remains some years away, but this is a huge step in providing therapies for this group of diseases.

Currently, we have two ways of making stem cells that match the DNA of a patient, which hopefully result in transplantable cells that can avoid immune rejection. One is to reprogram adult tissue into induced pluripotent (iPS type) stem cells and the other uses the techniques called Somatic Cell Nuclear Transfer (SCNT), often called therapeutic cloning. The current research did both.

The team converted the SCNT stem cells into various needed tissues such as these nerve precursor cells.

The team converted the SCNT stem cells into various needed tissues such as these nerve precursor cells.

The iPS work relied on the fact that our tissues are mosaics because of the way mitochondria get passed on when cells divide. So not all cells show mitochondrial mutations in people with “mito disease” —how impacted families tend to refer to it, as I found out through a distant cousin with a child valiantly struggling with one form of the disease. Because each iPS stem cell line arises from one cell, the researchers could do DNA analysis on each cell line and sort for ones with few or no mutations, resulting in healthy stem cells, which could become healthy transplant tissue.

But for some patients, there are just too many mutations. For those the researchers inserted the DNA from the patient into a healthy donor egg containing healthy mitochondria using SCNT. The result: again healthy stem cells.

“To families with a loved one born with a mitochondrial disease waiting for a cure, today we can say that a cure is on the horizon,” explained co-senior author Shoukhrat Mitalipov at the Oregon Stem Cell Center in a story in Genetic Engineering News. “This critical first step toward treating these diseases using gene therapy will put us on the path to curing them and unlike unmatched tissue or organ donations, combined gene and cell therapy will allow us to create the patients’ own healthy tissue that will not be rejected by their bodies.”

ScienceDaily ran the Oregon press release, HealthCanal ran the press release from the Salk Institute in La Jolla home of the other co-senior author Juan Carlos Izpisua Belmonte, whose lab CIRM funds for other projects. And Reuters predictably did a piece with a bit more focus on the controversy around cloning. Nature published the research paper on Wednesday.

Stem cells to heal damaged lungs. Lung doctors dealing with emphysema, cystic fibrosis and other lung damage may soon take a page from the playbook of cancer doctors who transplant bone marrow stem cells. A team at Israel’s Weizmann Institute has tested a similar procedure in mice with damaged lungs and saw improved lung function

Transplanted lung cells continued to grow at six weeks (left) and 16 weeks (right).

Transplanted lung cells continued to grow at six weeks (left) and 16 weeks (right).

Stem cells are homebodies. They tend to hang out in their own special compartments we call the stem cell niche, and if infused elsewhere in the body will return home to the niche. Bone marrow transplants make use of that tendency in two ways. Doctors wipe out the stem cells in the niche so that there is room there when stem cells previously harvested from the patient or donor cells are infused after therapy.

The Weizmann team did this in the lungs by developing a method to clear out the lung stem cell niche and isolating a source of stem cells capable of generating new lung tissue that could be infused. They now need to perfect both parts of the procedure. ScienceDaily ran the institute’s press release.

Stem cells for chronic pain due to nerve damage. Neuropathy, damaged nerves caused by diabetes, chemotherapy or injury tends to cause pain that resists treatment. A team at Duke University in North Carolina has shown that while a routine pain pill might provide relief for a few hours, a single injection of stem cells provided relief for four to five weeks—in mice.

They used a type of stem cell found in bone marrow known to have anti-inflammatory properties called Bone Marrow Stromal Cells (BMSCs). They infused the cells directly into the spinal cavity in mice that had induced nerve damage. They found that one chemical released by the stem cells, TGF Beta1, was present in the spinal fluid of the treated animals at higher than normal levels. This finding becomes a target for further research to engineer the BMSCs so that they might be even better at relieving pain. ScienceNewsline picked up the Duke press release about the research published in the Journal of Clinical Investigation.

Giving stem cells the right physical cues produced micro hearts, maybe a tool to avoid birth defects

Heart defects, one of the leading types of birth defects, often result from drugs mom is taking, but we have not had a good model of developing fetal hearts to test drugs for these side effects. Now, a team at the University of California, Berkeley and the Gladstone Institutes has created micro heart chambers in a lab dish by providing the starting stem cells with the right physical cues. And they found these mini-hearts can predict birth defects.

Different types of cells required to make functioning heart tissue show up as different colors here.

Different types of cells required to make functioning heart tissue show up as different colors here.

As we have written before, it takes a neighborhood to raise a stem cell into a wanted adult cell. While most lab cultures maturing stem cells into adult tissue are flat, the developing fetal heart grows in an environment with many physical cues, both chemical and pressure. The Berkeley team added a chemical layer to the cell culture dish and etched it to provide added physical cues. The result produced both connective tissue and heart muscle that were organized into micro heart chambers that could beat.

“We believe it is the first example illustrating the process of a developing human heart chamber in vitro,” said Kevin Healy, co-senior author of the study at UC Berkeley. “This technology could help us quickly screen for drugs likely to generate cardiac birth defects, and guide decisions about which drugs are dangerous during pregnancy.”

The team took the added step of testing a drug known to cause birth defects, thalidomide. When the stem cells were growing with the drug added to the culture, they did not develop into the same micro chambers.

The Berkeley bioengineers started with stem cells reprogrammed from adult skin tissue in the CIRM-funded lab of Bruce Conklin at the Gladstone, the other co-senior author on the paper. These iPS-type stem cells were essential to the project.

“The fact that we used patient-derived human pluripotent stem cells in our work represents a sea change in the field,” said Healy. “Previous studies of cardiac micro-tissues primarily used harvested rat cardiomyocytes, which is an imperfect model for human disease.”

 

Berkeley issued a press release on the work and Popular Science wrote a piece on it complete with a fun embedded video of the beating tissue. The journal Nature Communication ran the original research publication today.

Stem cell stories that caught our eye: correcting cystic fibrosis gene, improving IVF outcome, growing bone and Dolly

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.

Cystic Fibrosis gene corrected in stem cells. A team at the University of Texas Medical School at Houston corrected the defective gene that causes cystic fibrosis in stem cells made from the skin of cystic fibrosis patients. In the long term the advance could make it possible to grow new lungs for patients with genes that match their own—with one life-saving exception—and therefore avoid immune rejection. But, the short-term outcome will be a model for the disease that provides tools for evaluating potential new drug therapies.

“We’ve created stem cells corrected for the cystic fibrosis mutation that potentially could be utilized therapeutically for patients,” said Brian Davis the study’s senior author in a university press release. “While much work remains, it is possible that these cells could one day be used as a form of cell therapy.”

The researchers made the genetic correction in the stem cells using the molecular scissors known as zing finger nucleases. Essentially they cut out the bad gene and pasted in the correct version.

Stem cell researchers boost IVF. Given all the ethical issues raised in the early years of embryonic stem cell research it is nice to be able to report on work in the field that can boost the chances of creating a new life through in vitro fertilization (IVF). Building on earlier work at Stanford a CIRM-funded team there has developed a way to detect chromosome abnormalities in the embryo within 30 hours of fertilization.

Chromosomal abnormalities account for a high percent of the 60 to 70 percent of implanted embryos that end up in miscarriage. But traditional methods can’t detect those chromosomal errors until day five or six and clinicians have found that embryos implant best three to four days post fertilization. This new technique should allow doctors to implant only the embryos most likely to survive.

“A failed IVF attempt takes an emotional toll on a woman who is anticipating a pregnancy as well as a financial toll on families, with a single IVF treatment costing thousands and thousands of dollars per cycle. Our findings also bring hope to couples who are struggling to start a family and wish to avoid the selection and transfer of embryos with unknown or poor potential for implantation,” explained Shawn Chavez who led the team and has since moved to Oregon Health Sciences University.

The study, which used recent advanced technology in non-invasive imaging, was described in a press release from Oregon.

Fun TED-Ed video shows how to grow bone. Medical Daily published a story this week about a team that had released a TED-Ed video earlier this month on how to grow a replacement bone on the lab. The embedded video provides a great primer on how we normally grow and repair bone in our bodies and how that knowledge can inform efforts to grow bone in the lab.

In particular, the story walks through a scenario of a patient with a bone defect too large for our normal repair mechanisms to patch up. It describes how scientist can take stem cells from fat, use 3D printers to mold a scaffold the exact shape of the defect, and culture the stem cells on the scaffold in the lab to create the needed bone.

The video and story reflect the work of New York-based company EpiBone and its tissue engineer CEO Nina Tandon.

Happy birthday Dolly (the sheep). July 5 marked the 19th anniversary of the first cloned mammal, Dolly the sheep in Scotland. For fans of the history of science, MotherBoard gives a good brief history of the resulting kerfuffle and a reminder that Dolly was not very healthy and the procedure was not and is not ready to produce cloned human.

Dolly's taxidermied remains are in a museum in Scotland. She died after only six years, about half the normal life expectancy.

Dolly’s taxidermied remains are in a museum in Scotland. She died after only six years, about half the normal life expectancy.

Parkinson’s blog explains the science behind turning skin cells into a model for the disease

When my colleagues and I write about new advances in stem cell science we often rely on what I refer to as the Sydney Harris method of explaining the science. One of the cartoonist’s most reproduced drawings shows a researcher writing a series of steps on a chalk board with one in the middle being “then a miracle happens.”

Alex was diagnosed with Parkinson's at age 36. His skin cells became a model for the disease.

Alex was diagnosed with Parkinson’s at age 36. His skin cells became a model for the disease.

Our goal usually centers on helping our readers understand an advance and how it moves the field forward, not describing how the scientist actually knows what he or she is reporting. For anyone who wants to get inside the science, particularly about reprogramming skin cells to be stem cells, which we write about often, I suggest a visit to “Alex’s Skin Cell Blog.” A patient with young-onset Parkinson’s disease, it chronicles turning Alex’s skin cells into a model for the disease.

The research takes place at the Parkinson’s Institute in Sunnyvale and the blog features a conversation between Alex and researchers there. Most of the columns feature a CIRM-funded graduate student Lauren Pijanowski, and more recently, Birgitt Schuele.

They explain in pretty understandable pros and illustrations how scientists know things like: were they successful in getting the skin cells to become stem cells; how they make sure the reprogramming process does not damage the cells; and how they keep Alex’s cells alive in a tissue bank. In the most recent, Birgitt explains the use of fluorescent markers to identify cells that have become true stem cells.

This resource could be extremely valuable to teachers, but can also be fun for the simply science curious. For a wealth of more basics on stem cells for teachers, students or the science curious, also check out our high school curriculum.

Not all reprogrammed stem cells are the same—an eye-catching example

Scientists can take any adult tissue whether skin, blood or nerve and use genetic factors to reprogram them into embryonic-like stem cells. But the Nobel Prize-winning technique does not produce stem cells with equal ability to mature into various tissues needed to repair damage from disease or injury.

A team at St. Jude Children’s Research Hospital recently showed that stem cells made from a type of nerve in the eye produced retinal cells more efficiently than stem cells made from skin. The finding fits well with a few years of evidence that reprogrammed stem cells, called iPSCs (induced pluripotent stem cells), retain some memory of what they were before they were reprogrammed into stem cells.

Retinal cells grown from stem cells.

Retinal cells grown from stem cells.

The research, published in Cell Stem Cell, took the extra step to identify one factor that allowed the eye nerve cells to remember their origin. Adult cells develop changes in the structure around the genes called epigenetic markers. Those markers help regulate whether the genes are turned on or off. The St. Jude’s team found one specific epigenetic switch that contributed to the nerve-derived stem cells’ memory.

They used a new technique they developed called STEM-RET that let them quantify how good various stem cells are at creating retinal cells. Then they looked for epigenetic fingerprints to use as markers for isolating those cells. Michael Dyer, who led the team, explained the value of finding and sorting stem cells with particular traits in a press release picked up by ScienceNewsline:

 

“Such fingerprints would tell researchers which stem cell lines would most likely be effective in making retinal cells, bone marrow cells or other types of mature cells for therapeutic purposes.”

The team also used a 3-D culture technique that seemed more efficient than standard cell cultures. Considering that many current processes for making a desired cell type for transplant are not sufficiently efficient for broad therapeutic use, these types of practical advances could be exactly what the field needs to reach mainstream clinical care.

CIRM funds several projects looking to treat blindness caused by retinal disease.

Hed: Stem cell stories that caught our eye: the why’s of heart failure, harnessing stem cells’ repair kits and growing 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.

Stem cell model sheds light on heat failure. Pretty much everyone who has heart failure due to cardiomyopathy—where the heart muscle doesn’t work as effectively as it should—or has a condition that could lead there, is taking a beta blocker. The beta-andrenergic pathway, a key molecular pathway in the heart, dysfunctions in patients with cardiomyopathy and we have never known exactly why. We just know these drugs help.

Now, a team at Stanford led by Joseph Wu has used skin samples from patients and normal subjects to create reprogrammed iPS type stem cells, grown them into heart muscle, and compared them at a very fine-tuned molecular level.

Some patients have a mutation in a protein called TNNT2 in heart muscle fibers, which regulates muscle contraction. So, one thing they looked at was the impact of that mutation. Wu’s team followed the actions triggered by this mutation and found they lead to the beta-andrenergic pathway. Wu explained the value he sees in this fundamental understanding of the disease in a Stanford press release:

“As a cardiologist, I feel this basic research study is very clinically relevant. The beta-andrenergic pathway is a major pharmaceutical target for many cardiac conditions. This study confirms that iPS-cell-derived cardiomyocytes can help us understand biologically important pathways at a molecular level, which can aid in drug screening.”

CIRM did not fund this project but we do fund other projects in Wu’s lab including one to advance the use of iPS cells as models of heart disease, one using tissue engineering to repair damaged areas of the heart and one using embryonic stem cells to generate new heart muscle.

Harnessing stem cells’ repair kits. Stem cells repair tissue in multiple ways, but primarily by maturing into cells that replace damaged ones or by excreting various chemicals that give marching orders to neighboring cells to get busy and make the repairs. Those chemicals, collectively called paracrine factors, get excreted by the stem cells in vessels known as exosomes. So, a team at Temple University in Philadelphia decided to try injecting just the exosomes, rather than whole stem cells to repair heart damage. It seemed to work pretty well in mice.

Stem cells release exosomes, tiny vessels that act as repair kits.

Stem cells release exosomes, tiny vessels that act as repair kits.


After treatment with the exosomes, mice with induced heart attacks showed fewer heart cells dying, less scar tissue, more development of new blood vessels and a stronger heart function. The head of the Temple team, Raj Kishore, described the result in a university press release distributed by EuekaAlert:

“You can robustly increase the heart’s ability to repair itself without using the stem cells themselves. Our work shows a unique way to regenerate the heart using secreted vesicles from embryonic stem cells.”

The team went on to isolate a specific regulatory chemical that was among the most abundant in the exosomes. That compound, a type of RNA, produced much of the same results when administered by itself to the mice—intriguing results for further study.

Good primer on using stem cells to grow organs. The Wisconsin State Journal ran a nice primer in both video and prose about what would theoretically go into building a replacement organ from stem cells and some of the basic stem cell principals involved. The piece is part of a series the paper produces with the Morgridge Institute at the University of Wisconsin. This one features an interview with Michael Treiman of Epic Systems:

“The biggest challenge right now is that we can push a stem cell to be a particular type of cell, but in a tissue there’s multiple cells. And an organ like your heart or brain isn’t just made of one cell type; it’s made of many cell types working together.”

Stem cell stories that caught our eye: Spinal cord injury, secret of creating complex tissue, mini brains in a dish and funding

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.

Monkey trial provides some hope for spinal cord injury. Stem cell treatments have made many mice and rats walk again after spinal cord injury, but moving from those rodents to human has been a slow process. Their immune systems and nervous systems are very different from ours. So, it was good to read this week that a team at Japan’s Keio University reported success in monkeys with systems much more like ours.

The experiment was “controlled.” They compared treated and non-treated animals and saw a significant difference in mobility between the two groups. Bloomberg picked up the release from the journal that published the work Stem Cells Translational Medicine, which quoted the study author Hideyuki Okano:

“An animal in the control group, for example, could not raise her hands up to head height at 12 weeks after injury when motor function almost plateaus. On the other hand, at the same point in time a transplanted animal was able to jump successfully and run so fast it was difficult for us to catch her. She could also grip a pen at 3 cm. above head-height.”

But the work requires some caveats. They treated all animals at exactly 14-days post injury, a window considered optimal for having initial inflammation subside and scar tissue not yet formed. Also, the researchers inflicted bruises not more severe damage to the spinal cord. Most patients with spinal cord injury are chronic, long past the 14-day window, and have damage to their spinal cords more severe than these animals.

The researchers started with embryonic stem cells and matured them into nerve progenitor cells, which they injected into the monkeys. While this process can yield plentiful cells for therapy the researchers acknowledged that much more research is needed before they can help the vast majority of spinal cord injuries with more severe and older injuries. CIRM funds a clinical trial using cells derived from embryonic stem cells to treat more complex spinal injuries, but it is just getting underway.

Clues to creating complex tissues. These days getting stem cells to form a single type of tissue, nerve or skin for example, is almost routine, with the remaining hurdle being purity. But getting stem cells to form complex tissues with multiple types of cells, while done a few times, still gets folks attention. For the most part, this is because we don’t know the cell-to-cell interactions required to form complex tissues. A CIRM-funded team at the University of California, San Diego, thinks they have part of the answer.

They studied something called the neurovascular unit, made up of blood vessels, smooth muscle and nerves that regulate heart rate, blood flow and breathing, among other basic functions. Using a lab model they showed how the different cell types come together to form the vital regulatory tissue. San Diego Newscape posted a piece on the work, quoting the study’s senor author David Cheresh:

“This new model allows us to follow the fate of distinct cell types during development, as they work cooperatively, in a way that we can’t in intact embryos, individual cell lines or mouse models. And if we’re ever going to use stem cells to develop new organ systems, we need to know how different cell types come together to form complex and functional structures such as the neurovascular unit.”

And a brainy example.   Prior research has created small brain “organoids” that started with stem cells and self assembled in a lab dish to create layers of nerves and support cells, but the cells did not interact much like normal brain tissue. Now, a team at Stanford has developed “cortex-like spheroids” with different types of cells that talk to each other.

Nerves and supporting cells form layers and organize like in the developing brain

Nerves and supporting cells form layers and organize like in the developing brain

In the new cortex spheres the nerves are healthier with a better network of the natural supporting cells called glial cells. The cells form layers that interact with each other like in our brains as we are developing.

A program at the National Institutes of Health (NIH) focusing on using stem cells to create models of disease in the lab funded the work. Thomas Insel, Director of the NIH’s National Institute of Mental Health described the importance of the current work in a press release from the institute picked up by HealthCanal:

 

“There’s been amazing progress in this field over the past few years. The cortex spheroids grow to a state in which they express functional connectivity, allowing for modeling and understanding of mental illnesses. They do not even begin to approach the complexity of a whole human brain. But that is not exactly what we need to study disorders of brain circuitry.“

The release starts with a fun lede imagining the day when a patient tormented by mental illness could have a model of their disease grown in a dish and researchers could genetically engineer better brain circuits for the patient. Certainly not just around the corner, but not far fetched.

States economic gain from funding research. The very niched web cite Governing posted a piece that appears to be largely from a conference in Washington D.C. hosted by the Greater Phoenix Economic Council. It quotes several experts speaking about the opportunity for states to gain economic advantage by funding research.

The piece notes some well documented examples of federal government spending on research spawning industries—think Silicon Valley. Then it talks about some more recent state examples including the California initiative that created CIRM.

One speaker, Mark Muro of the Brookings Institute said that we are in a new era now and states may not be able to fund research through their general tax revenue. He said:

“It may be the state becoming part of a consortium or working with Fortune 500 companies, or going to voters with a general obligation bond vote. I think we’re heading for a new complexity.”

Since CIRM was created through a vote for bonds, guess we have to agree.

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.

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: