Cranking it Up to Eleven: Heightened Growth of Neural Stem Cells Linked to Autism-like Behavior

Autism is not one single disease but a suite of many, which is why researchers have long struggled to understand its underlying causes. Often referred to as the Autism Spectrum Disorders, autism has been linked to multiple genetic and environmental factors—different combinations of which can all result in autism or autistic-like behavior.

Could an unusual boost in neural stem cell growth during pregnancy be linked to autistim-like behavior in children?

Could an unusual boost in neural stem cell growth during pregnancy be linked to autitism-like behavior in children?

But as we first reported in last week’s Weekly Roundup, scientists at the University of California, Los Angeles (UCLA) have identified a new factor that can occur during pregnancy and that may be linked to the development of autism-like behavior. These results shed new light on a notoriously murky condition.

UCLA scientist Dr. Harley Kornblum led the study, which was published last week in the journal Stem Cell Reports.

In it, Kornblum and his team describe how inflammation in pregnant mice, known as ‘maternal inflammation’ caused a spike in the production of neural stem cells—cells that one day develop into mature brain cells, such as neurons and glia cells. This abnormal growth, the team argues, led to enlarged brains in the newborn mice and, importantly, autism-like behavior such as decreased vocalization and social behavior, as well as overall increase in anxiety and repetitive behaviors, such as grooming. As Kornblum explained in a news release:

“We have now shown that one way maternal inflammation could result in larger brains and, ultimately, autistic behavior is through the activation of the neural stem cells that reside in the brain of all developing and adult mammals.”

However, Kornblum notes that many environmental factors may cause inflammation during pregnancy—and the inflammation itself is not thought to directly cause autism.

“Autism is a complex group of disorders, with a variety of causes. Our study shows a potential way that maternal inflammation could be one of those contributing factors, even if it is not solely responsible, through interactions with known risk factors.”

These known risk factors include genetic mutations, such as those to a gene called PTEN, which have been shown to increase one’s risk for autism.

Further research by Kornblum’s team further clarified the connection between inflammation and neural stem cell overgrowth. Specifically, they noticed a series of chemical reactions, known as a molecular pathway, appeared to stimulate the growth of neural stem cells in the developing mice. The identification of pathways such as these are vital when exploring new types of therapies—because once you know the pathway’s role in disease, you can then figure out how to change it.

“The discovery of these mechanisms has identified new therapeutic targets for common autism-associated risk factors,” said Dr. Janel Le Belle, the paper’s lead author. “The molecular pathways that are involved in these processes are ones that can be manipulated and possibly even reversed pharmacologically.”

These findings also support previous clinical findings that the roots of autism likely begin in the womb and continue to develop after birth.

One key difference between this work and previous studies, however, was that most studies point to irregularities in the way that neurons are connected as a key factor that leads to autism. This study points to not just a network ‘dysregulation,’ but also perhaps an overabundance of neurons overall.

“Our hypothesis—that one potential means by which autism may develop is through an overproduction of cells in the brain, which then results in altered connectivity—is a new way of thinking about autism.”

Advances in the fields of stem cell biology and regenerative medicine have given new hope to families caring for autistic loved ones. Read more about one such family in our Stories of Hope series. You can also learn more about how CIRM-funded researchers are building our understanding of autism in our recent video: Reversing Autism in the Lab with help from Stem Cells and the Tooth Fairy.

Scientists Reach Yet Another Milestone towards Treating Type 1 Diabetes

There was a time when having type 1 diabetes was equivalent to a death sentence. Now, thanks to advances in science and medicine, the disease has shifted from deadly to chronic.

But this shift, doctors argue, is not good enough. The disease still poses significant health risks, such as blindness and loss of limbs, as the patients get older. There has been a renewed effort, therefore, to develop superior therapies—and those based on stem cell technology have shown significant promise.

Human stem cell-derived beta cells that have formed islet like clusters in a mouse. Cells were transplanted to the kidney capsule and photo was taken two weeks later by which time the beta cells are making insulin and have cured the mouse's diabetes. [Credit: Douglas Melton]

Human stem cell-derived beta cells that have formed islet like clusters in a mouse. Cells were transplanted to the kidney capsule and photo was taken two weeks later by which time the beta cells are making insulin and have cured the mouse’s diabetes. [Credit: Douglas Melton]

Indeed, CIRM-funded scientists at San Diego-based Viacyte, Inc. recently received FDA clearance to begin clinical trials of their VC-01 product candidate that delivers insulin via healthy beta cells contained in a permeable, credit card-sized pouch.

And now, scientists at Harvard University have announced a technique for producing mass quantities of mature beta cells from embryonic stem cells in the lab. The findings, published today in the journal Cell, offer additional hope for the millions of patients and their families looking for a better way to treat their condition.

The team’s ability to generate billions of healthy beta cells—cells within the pancreas that produce insulin in order to maintain normal glucose levels—has a particular significance to the study’s senior author and co-scientific director of the Harvard Stem Cell Institute, Dr. Doug Melton. 23 years ago, his infant son Sam was diagnosed with type 1 diabetes and since that time Melton has dedicated his career to finding better therapies for his son and the millions like him. Melton’s daughter, Emma, has also been diagnosed with the disease.

Type 1 diabetes is an autoimmune disorder in which the body’s immune system systematically targets and destroys the pancreas’ insulin-producing beta cells.

In this study, the team took human embryonic stem cells and transformed them into healthy beta cells. They then transplanted them into mice that had been modified to mimic the signs of diabetes. After closely monitoring the mice for several weeks, they found that their diabetes was essentially ‘cured.’ Said Melton:

“You never know for sure that something like this is going to work until you’ve tested it numerous ways. We’ve given these cells three separate challenges with glucose in mice and they’ve responded appropriately; that was really exciting.”

The researchers are undergoing additional pre-clinical studies in animal models, including non-human primates, with the hopes that the 150 million cells required for transplantation are also protected from the body’s immune system, and not destroyed.

Melton’s team is collaborating with Medical Engineer Dr. Daniel G. Anderson at MIT to develop a protective implantation device for transplantation. Said Anderson of Melton’s work:

“There is no question that the ability to generate glucose-responsive, human beta cells through controlled differentiation of stem cells will accelerate the development of new therapeutics. In particular, this advance opens the doors to an essentially limitless supply of tissue for diabetic patients awaiting cell therapy.”

World’s largest pharmaceutical company signs deal with ViaCyte supporting stem cell therapy for type 1 diabetes

It’s been a good week for ViaCyte, a good week for us here at the stem cell agency and potentially a great week for people with type 1 diabetes.

Earlier this week ViaCyte announced they have been given approval to start a clinical trial for their new approach to treating type 1 diabetes. Then today they announced that they have signed an agreement with Janssen Research & Development LLC and its affiliated investment fund, Johnson & Johnson Development Corporation (JJDC).

ViaCyte's President & CEO, Paul Laikind

ViaCyte’s President & CEO, Paul Laikind

Under this new agreement Janssen and JJDC will provide ViaCyte with $20 million with a future right to consider a longer-term transaction related to the product candidate that ViaCyte is developing for type 1 diabetes.

The agreement is a big deal because Janssen is a division of Johnson & Johnson, which just happens to be the largest pharmaceutical company in the world (they were also ranked the world’s most respected company by Barron’s Magazine in 2008, not a bad reputation to have). Companies like this have traditionally been shy about jumping into the stem cell arena, as they wanted to be sure that they had a good chance to see a return on any investment they made. Not surprising really. You don’t get to be as successful as they are by throwing your money away.

The fact that they have decided that ViaCyte is a good investment reflects on the quality of the company, the years of hard work the people at ViaCyte have put in developing their therapy, and the impressive pre-clinical evidence that it works. It also reflects the fact that we helped fund the project, investing almost $40 million in the program, and get it to this point

In a news release we issued about the announcement our President and CEO, C. Randal Mills, said:

“This is excellent news as it demonstrates that pharmaceutical companies are recognizing stem cell therapies hold tremendous promise and need to be part of their development portfolio,” says C. Randal Mills, Ph.D., President and CEO of the stem cell agency. “This kind of serious financial commitment from industry is vital in helping get promising therapies like this through all the phases of clinical trials and, most importantly, to the patients in need.”

What’s nice is that this is not just a one-off deal. This is the third time this year that a large company has stepped in to make a deal with a company that we are funding.

In January Capricor Therapeutics signed a deal with Janssen Biotech that could ultimately be worth almost $340 million for its work using stem cells to treat people who have had a heart attack. The same month Sangamo, who we are funding to develop a treatment for beta-thalassemia, signed a potential $320 million agreement with Biogen Idec.

As Randy Mills said:

“Our goal at CIRM is to do everything we can to accelerate the development of successful therapies for people in need,” says Mills. “These kinds of agreements and investments help us do that, not only by adding an extra layer of funding for development, but also by validating the scientific and commercial potential of regenerative medicine.”

It’s great news for ViaCyte. It’s confirmation for us that we have been investing our money well in a promising therapy. But most of all it’s encouraging for anyone with type 1 diabetes, giving them a sense of hope that a new treatment could be on the horizon.

Stem Cell Stories that Caught our Eye: “Let it Grow” Goes Viral, Stroke Pilot Study, The Bowels of Human Stem Cells, Tumor ‘Safety Lock.’

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.

“Let it Grow” Goes Viral (and National!): Last week on The Stem Cellar we shared one of our favorite student videos from our annual Creativity Program. The video, a parody of the hit song from the movie Frozen, highlighted the outstanding creativity of a group of high school students from City of Hope in Los Angeles. And now, the song has made a splash nationwide—with coverage from ABC 7 Bay Area and even NBC New York!

Students from the City of Hope practice their routine for the group video

Students from the City of Hope practice their routine for the group video

Watch the full video on our YouTube page.

Stroke Pilot Study Shows Promise. Researchers at Imperial College London are currently testing whether stem cells extracted from a patient’s bone marrow can reverse the after effects of a stroke.

Reporting in this week’s Stem Cells Translational Medicine the team, lead by Dr. Soma Banjeree, describe their pilot study in which they collect a type of bone marrow stem cells called CD34+ cells. These cells can give rise to cells that make up the blood and the blood vessel lining. Earlier research suggested that treating stroke victims with these cells can improve recovery after a stroke—not because they replace the brain cells lost during a stroke, but because they release a chemical that triggers brain cells to grow. So the team decided to take the next step with a pilot study of five individuals.

As reported in a recent news release, this initial pilot study was only designed to test the safety of the procedure. But in a surprising twist, all patients in the study also showed significant improvement over a period of six months post-treatment. Even more astonishing, three of the patients (who had suffered one of the most severe forms of stroke) were living assistance-free. But since the first six months after injury is a time when many patients see improved function, these results need to be tested in a controlled trial where not all patients receive the cells

Immediate next steps include using advancing imaging techniques to more closely monitor what exactly happens in the brain after the patients are treated.

Want to learn more about using stem cells to treat stroke? Check out our Stroke Fact Sheet.

Deep in the Bowels of Stem Cell Behavior. Another research advance from UK scientists—this time at Queen Mary University of London researchers—announces important new insight into the behavior of adult stem cells that reside in the human gastro-intestinal tract (which includes the stomach and intestines). As described in a news release, this study, which examined the stem cells in the bowels of healthy individuals, as well as cells from early-stage tumors, points to key differences in their behaviors. The results, published this week in the journal Cell Reports, point to a potential link between stem cell behavior and the development of some forms of cancer.

By measuring the timing and frequency of mutations as they occur over time in aging stem cells, the research team, led by senior author Dr. Trevor Graham, found a key difference in stem cell behaviors between healthy individuals, and those with tumors.

In the healthy bowel, there is a relative stasis in the number of stem cells at any given time. But in cancer, that delicate balance—called a ‘stem cell niche’—appears to get thrown out of whack. There appears to be an increased number of cells, paired with more intense competition. And while these results are preliminary, they mark the first time this complex stem cell behavior has been studied in humans. According to Graham:

“Unearthing how stem cells behave within the human bowel is a big step forward for stem cell research. We now want to use the methods developed in this study to understand how stem cells behave inside bowel cancer, so we can increase our understanding of how bowel cancer grows. This will hopefully shed more light on how we can prevent bowel cancer—the fourth most common cancer in the UK.”

Finding the ‘Safety Lock’ Against Tumor Growth. It’s one of the greatest risks when transplanting stem cells: the possibility that the transplanted cells will grow out of control and form tumors.

But now, scientists from Keio University School of Medicine in Japan have devised an ingenious method that could negate this risk.

Reporting in the latest issue of Cell Transplantation and summarized in a news release, Dr. Masaya Nakamura and his team describe how they transplanted stem cells into the spinal columns of laboratory mice.

And here’s where they switched things up. During the transplantation itself, all mice were receiving immunosuppressant drugs. But then they halted the immunosuppressants in half the mice post-transplantation.

Withdrawing the drugs post-transplantation, according to the team’s findings, had the interesting effect of eliminating the tumor risk, as compared to the group who remained on the drugs. Confirmed with bioluminescent imaging that tracked the implanted cells in both sets of mice, these findings suggest that it in fact may be possible to finely tweak the body’s immune response after stem-cell transplantation.

Want to learn more about stem cells and tumor risk? Check out this recent video from CIRM Grantee Dr. Paul Knoepfler: Paul Knoepfler Talks About the Tendency of Embryonic Stem Cells to Form Tumors.

A Glimpse Inside the Cellular Universe: Scientists Track the Growth of an Organism, One Cell at a Time

Trying to keep tabs on how an organism grows from a single fertilized egg into an embryo, cell by cell, is hard work. So hard in fact, that no one’s quite figured out how to do it.

Digital fruit fly embryo, reconstructed from live imaging data recorded with a SiMView light-sheet microscope. Each colored circle in the image shows one of the embryo's cells, and the corresponding tail indicates that cell's movement over a short time interval at around 3 hours post-fertilization [Credit: Kristin Branson, Fernando Amat, Bill Lemon and Philipp Keller (HHMI/Janelia Research Campus)]

Digital fruit fly embryo, reconstructed from live imaging data recorded with a SiMView light-sheet microscope. Each colored circle in the image shows one of the embryo’s cells, and the corresponding tail indicates that cell’s movement over a short time interval at around 3 hours post-fertilization
[Credit: Kristin Branson, Fernando Amat, Bill Lemon and Philipp Keller (HHMI/Janelia Research Campus)]

The problem, as researchers have lamented, is that there’s just too much happening—all at the same time—for the human eye to parse through all the data, even with the aid of the most powerful microscopes.

But now, scientists at the Howard Hughes Medical Institute (HHMI) have devised a high-tech shortcut: a new computational program that measures in real-time the three-dimensional development of each individual cell in a developing fetus.

This program stands to revolutionize how scientists understand the microscopic cellular ‘universe.’ As lead author, HHMI Group Leader Dr. Philipp Keller, explained in a news release:

“We wanted to reconstruct the elemental building plan of animals, tracking each cell from very early development until the late stages, so that we know everything that has happened in terms of cell movement and cell division.”

This technique, which is described in the latest issue of the journal Nature Methods, was built upon Keller’s 2012 development of a something called SiMView, a one-of-a-kind microscope that can capture precise 3D images of cells over a period of hours or even days.

But this was only the first step. Since the development of SiMView, Keller has been working on improving the system so that it could be used more broadly and over the course an organism’s development as an embryo. Specifically, Keller had sought to use this technique to look at how specific parts of the body develop—cell by cell. As Keller elaborated:

“In particular, we wanted to understand how the nervous system forms. Ultimately, we could like to collect the developmental history of every cell in the nervous system and link that information to the cell’s final function.”

In collecting and analyzing these vast datasets, researchers would then be well-poised to understand underlying molecular mechanisms of nervous system diseases.

Keller and his team have been looking for ways to both capture and analyze the vast amount of data hidden within each cell as it grows, matures and divides, with limited success—even the SiMView system was only active at a much smaller scale than what the team desired. One of the main issues is that as the cells in the embryo grow and divide, they become densely packed. They also shift around constantly, making tracking incredibly difficult to view.

The solution, Keller said, was to simplify the data. First, they clustered groups of 3D pixels called ‘voxels’ together into larger units, called ‘supervoxels.’ Next, they programmed the software to recognize the nuclei of each cell within the supervoxels. Then, using high-speed microscopy, they could capture images in a very quick sequence—so quick that individual cells wouldn’t be able to move out of the frame.

In this way, they are able to gather about 95% of all available data, a far higher number than that achieved by traditional methods. For the remaining 5%, the team employed even more complex algorithms to sort through the data. The end result, Keller says, is a wealth of knowledge that reveals more than many ever thought possible. According to Keller:

“You know the path, you know where it is at a certain time point. You know it divided from a certain point, you know the daughter cells, you know what mother cell it came from.”

In the early tests, the team studied the cellular ‘lineages’ of 295 early-stage nerve cells, called neuroblasts. Interestingly, they were not only able to trace these lineages in their entirety, but they could also predict their behavior later in their lifespan based on how they behaved early on.

The software, which is free and readily available to interested researchers, can be applied to a wide variety of data types—including different organisms and different microscopes.

This development stands to potentially become highly valuable to the stem cell research community. Increasingly, stem cell scientists are finding that in order to drive stem cells towards a desired adult tissue efficiently and completely, they need to try to recreate the stem cells’ natural environment. This should make it easier to build the right cellular “Neighborhood,” and help foster the transition from basic research into effective therapies.