CIRM-Funded Scientists Make New Progress Toward Engineering a Human Esophagus

Creating tissues and organs from stem cells—often referred to as ‘tissue engineering’—is hard. But new research has discovered that the process may in fact be a little easier than we once thought, at least in some situations.

Engineered human esophageal tissue [Credit: The Saban Research Institute].

Engineered human esophageal tissue [Credit: The Saban Research Institute].

Last week, scientists at The Saban Research Institute of Children’s Hospital Los Angeles announced that the esophagus—the tube that transports food, liquid and saliva between the mouth and the stomach—can be grown inside animal models after injecting the right mix of early-stage, or ‘progenitor,’ esophageal cells.

These findings, published in the journal Tissue Engineering Part A, are an important step towards generating tissues and organs that have been damaged due to disease or—in some cases—never existed in the first place.

According to stem cell researcher Tracy Grikscheit, who led the CIRM-funded study, the researchers first implanted a biodegradable ‘scaffold’ into laboratory mice. They then injected human progenitor cells into the mice and watched as they first traveled to the correct location—and then began to grow. The ability to both migrate to the right location and differentiate into the right cell type, without the need for any external coaxing, is crucial if scientists are to successfully engineer such a critical type of tissue.

“Different progenitor cells can find the right ‘partner’ in order to grow into specific esophageal cell types—and without the need for [outside] growth factors,” explained Grikscheit in a news release. “This means that successful tissue engineering of the esophagus is simpler than we previously thought.”

Grikscheit, who is also a pediatric surgeon as Children’s Hospital Los Angeles, was particularly hopeful with how their findings might one day be used to treat children born with portions of the esophagus missing—as well as adults suffering from esophageal cancer, the fastest-growing cancer in the U.S.

“We have demonstrated that a simple and versatile, biodegradable polymer is sufficient for the growth of a tissue-engineered esophagus from human cells. This not only serves as a potential source of tissue, but also a source of knowledge—as there are no other robust models available for studying esophageal stem cell dynamics.”

Want to learn more about tissue engineering? Check out these video highlights from a recent CIRM Workshop on the field.

Stem cell stories that caught our eye: Some good news got a little overplayed on blindness and Alzheimer’s

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.

Stories on blindness show too much wide-eyed wonder. While our field got some very good news this week when Advanced Cell Technologies (ACT) published data on its first 18 patients treated for two blinding diseases, many of the news stories were a little too positive. The San Diego Union Tribune ran the story from Associated Press writer Maria Cheng who produced an appropriately measured piece. She led with the main point of this early-phase study—the cells implanted seem to be safe—and discussed “improved vision” in half the patients. She did not imply their sight came back to normal. Her third paragraph had a quote from a leading voice in the field Chris Mason of University College London:

“It’s a wonderful first step but it doesn’t prove that (stem cells) work.”

The ACT team implanted a type of cell called RPE cells made from embryonic stem cells. Those cells are damaged in the two forms of blindness tested in this trial, Stargardt’s macular dystrophy and age-related macular degeneration, the leading cause of blindness in the elderly. Some of the patients have been followed for three years after the cell transplants, which provides the best evidence to date that cells derived from embryonic stem cells can be safe. And some of the patients regained useful levels of vision, which with this small study you still have to consider other possible reasons for the improvement, but it is certainly a positive sign.

CIRM funds a team using a different approach to replacing the RPE cells in these patients and they expect to begin a clinical trial late this year

Stem cells create stronger bone with nanoparticles.   Getting a person’s own stem cells to repair bad breaks in their bones certainly seems more humane than hacking out a piece of healthy bone from some place else on their body and moving it to the damaged area. But our own stem cells often can’t mend anything more than minor breaks. So, a team from Keele University and the University of Nottingham in the U.K. laced magnetic nanoparticles with growth factors that stimulate stem cell growth and used external magnets to hold the particles at the site of injury after they were injected.

It worked nicely in laboratory models as reported in the journal Stem Cells Translational Medicine, and reported on the web site benzinga. Now comes the hard step of proving it is safe to test in humans

Stem cells might end chronic shortage of blood platelets. Blood platelets—a staple of cancer therapy because they get depleted by chemotherapy and radiation—too often are in short supply. They can only set on the shelf for five days after a donation. If we could generate them from stem cells, they could be made on demand, but you’d have to make many different versions to match various peoples’ blood type. The latter has been a bit of a moot point since no one has been able to make clinical grade platelets from stem cells.

plateletsA paper published today by Advanced Cell Technologies may have solved the platelet production hurdle and the immune matching all at once. (ACT is having a good week.) They produced platelets in large quantities from reprogrammed iPS type stem cells without using any of the ingredients that make many iPS cells unusable for human therapy. And before they made the platelets, they deleted the gene in the stem cells responsible for the bulk of immune rejection. So, they may have created a so-called “universal” donor.

They published their method in Stem Cell Reports and Reuters picked up their press release. Let’s see if the claims hold up.

Alzheimer’s in a dish—for the second time. My old colleagues at Harvard got a little more credit than they deserved this week. Numerous outlets, including the Boston Globe, picked up a piece by The New York Times’ Gina Kolata crediting them with creating a model of Alzheimer’s in a lab dish for the first time. This was actually done by CIRM-grantee Lawrence Goldstein at the University of California, San Diego, a couple years ago.

But there were some significant differences in what the teams did do. Goldstein’s lab created iPS type stem cells from skin samples of patients who had a genetic form of the disease. They matured those into nerve cells and did see increased secretion of the two proteins, tau and amyloid-beta, found in the nerves of Alzheimer’s patients. But they did not see those proteins turn into the plaques and tangles thought to wreak havoc in the disease. The Harvard team did, which they attributed, in part, to growing the cells in a 3-dimensional gel that let the nerves grow more like they would normally.

The Harvard team, however, started with embryonic stem cells, matured them into nerves, and then artificially introduced the Alzheimer’s-associated gene. They have already begun using the model system to screen existing drugs for candidates that might be able to clear or prevent the plaques and tangles. But they introduced the gene in such a way the nerve cells over express the disease gene, so it is not certain the model will accurately predict successful therapies in patients.

Don Gibbons

UCLA Study Suggests New Way to Mend a Broken Heart

When you suffer a heart attack, your heart-muscle cells become deprived of oxygen. Without oxygen, the cells soon whither and die—and are entombed within scar tissue. And once these cells die, they can’t be brought back to life.

But maybe—just maybe—there is another way to build new heart muscle. And if there is, scientists like Dr. Arjun Deb at the University of California, Los Angeles (UCLA), are hot on the trail to find it.

Scar forming cells (in red) in a region of the injured heart expressing blood vessel cell marker in green and thus appearing yellow (see arrows). This study observed that approximately a third of the scar-forming cells in the injured region of the heart adopted "blood vessel" cell-like characteristics. [Credit: Dr. Arjun Deb/Nature]

Scar forming cells (in red) in a region of the injured heart expressing blood vessel cell marker in green and thus appearing yellow (see arrows). This study observed that approximately a third of the scar-forming cells in the injured region of the heart adopted “blood vessel” cell-like characteristics. [Credit: Dr. Arjun Deb/Nature]

Published yesterday in the journal Nature, Deb and his team at UCLA’s Eli & Edythe Broad Center for Regenerative Medicine and Stem Cell Research have found some scar-forming cells in the heart have the ability to become blood vessel-forming cells—if given the proper chemical ‘boost.’

“It is well known that increasing the number of blood vessels in the injured heart following a heart attack improves its ability to heal,” said Deb. “We know that scar tissue in the heart is associated with poor prognosis. Reversing or preventing scar tissue from forming has been one of the major challenges in cardiovascular medicine.”

Tackling the ever-growing problem in heart disease can seem an almost insurmountable task. While heart disease claims more lives worldwide than any other disease, advances in modern medicine in recent decades mean that more and more people are surviving heart attacks, and living with what’s called ‘heart failure,’ for their hearts can no longer beat at full capacity, and they have trouble taking long walks or even going up a flight of stairs.

Transforming this scar tissue into functioning heart muscle has therefore been the focus of many research teams, including CIRM grantees such as Drs. Deepak Srivastava and Eduardo Marbán, who have each tackled the problem from different angles. Late last year, treatment first designed by Marbán and developed by Capricor Therapeutics got the green light for a Phase 2 Clinical Trial.

In this study, Deb and his team focused on scar-forming cells, called fibroblasts, and blood-vessel forming cells, called endothelial cells. Previously, experiments in mice revealed that many fibroblasts literally transformed into endothelial cells—and helped contribute to blood vessel formation in the injured area of the heart. The team noted this phenomenon has been called the mesenchymal-endothelial transition, or MEndoT.

In this study, the researchers identified the molecular mechanism behind MEndoT—and further identified a small molecule that can enhance this transition, thus boosting the formation of blood vessels in the injured heart. This study bolsters the idea of focusing on the creation of blood vessels as a way to help reverse damage caused by a heart attack. Said Deb:

“Our findings suggest the possibility of coaxing scar-forming cells in the heart to change their identity into blood vessel-forming cells, which could potentially be a useful approach to better heart repair.”

The Nose Knows: Stem Cells are Vital Players in Brain Circuits Responsible for Smell

Ah, the smell of coffee! You can thank your olfactory bulb.

Ah, the smell of coffee! You can thank your olfactory bulb.

Ah, the mouth-watering scent of freshly baked bread and the intense aroma of roasted coffee beans. You can thank nerve cells in the front of your brain — in direct contact with your nasal passages — that convert odor molecules in the air into brain signals and generate your perception of those wonderful smells.

Loss of the sense of smell is often one of the earliest symptoms in people stricken with brain disorders such as Parkinson’s and Alzheimer’s. So the study of this part of the brain called the olfactory bulb, that’s responsible for smell perception, is an attractive area of research that could help provide insights into fundamental brain function and its connection to neurodegenerative diseases. Last week, scientists at the National Institutes of Health (NIH) moved the field a step forward by reporting in the Journal of Neuroscience that brain stem cells play a vital role in sustaining the proper brain cell circuitry in the olfactory bulb.

Studies in adult mice have shown that brain stem cells deep inside the brain have the uncanny ability to travel to the olfactory bulb, transform into nerve cells, and set up appropriate circuits with surrounding nerve cells. The NIH team had previously demonstrated that when a nostril is plugged for 20 days in these mouse studies, depriving the olfactory system of stimulation, the nerve cell connections scatter and become very disorganized. But after removing the plug for 40 days the proper connections and patterns are re-established.

The brain stem cells uncanny ability to migrate through the thin rostral stream, transform in to neurons, and make the right connections with surrounding neurons in the olfactory bulb, the large structure in the upper right. (Image credit:  Belluscio Lab, NINDS).

Newly born nerve cells migrate along a thin path and connect up with surrounding nerve cells in the olfactory bulb, the large structure in the upper right. (Image credit: Belluscio Lab, NINDS).

In the current study, the team used genetic engineering techniques to precisely remove only those brain stem cells in adult mice that transform into the olfactory nerve cells. Again when a nostril was plugged the nerve cell connections were disrupted. But this time when the brain stem cells were eliminated and the nose plug removed, the nerve cell connections remained disorganized. This result reveals that the system relies on a replenishing supply of brain stem cells. As senior author Leonardo Belluscio, Ph.D. states in a NIH press release:

“We found that without the introduction of the new neurons, the system could not recover from its disrupted state.”

Even when the brain stem cells were eliminated in mice that were not given the nose block, a deterioration of the olfactory bulb nerve cell network was still observed by the research team. These results turn scientists’ understanding of brain circuits on its head: rather than being mostly stable structures, in this case the olfactory brain circuits appear unstable by default and must continually receive new neurons (from stem cells) to not only restore disrupted connections but also to preserve stable circuits.

Dr. Belluscio reflected on these intriguing results and its implications for neurologic disease:

“This is an exciting area of science. I believe the olfactory system is very sensitive to changes in neural activity and given its connection to other brain regions, it could lend insight into the relationship between olfactory loss and many brain disorders.”

To hear more from Dr. Belluscio about these results, watch this video interview. And for more about the role of stem cells in adult brain circuitry, watch this seminar by UCSF researcher and CIRM grantee Arturo Alvarez-Buylla, PhD.

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.”

These Are the Cells You’re Looking for: Scientists Devise New Way to Extract Bone-Making Stem Cells from Fat

Buried within our fat tissue are stashes of stem cells—a hidden reservoir of cells that, if given the right cues, can transform into cells that make up bone, cartilage or fat. These cells therefore represent a much-needed store for regenerative therapies that rebuild bone or cartilage lost to disease or injury.

Finding cells that have bone-making potential is more efficiently done by looking at the genes they express (in this case, ALPL) than at proteins on their surface. The bone matrix being produced by cells is stained red in samples of cells that do not express ALPL (left), those that do express ALPL (right). [Credit: Darling lab/Brown University]

Finding cells that have bone-making potential is more efficiently done by looking at the genes they express (in this case, ALPL) than at proteins on their surface. The bone matrix being produced by cells is stained red in samples of cells that do not express ALPL (left), those that do express ALPL (right). The center image shows both types of cells prior to sorting [Credit: Darling lab/Brown University]

The only problem with these tucked-away cellular reservoirs, however, is identifying them and getting them out.

But now, researchers at Brown University have devised a unique method of identifying, extracting and then cultivating these bone-producing stem cells. Their results, published today in the journal Stem Cell Research & Therapy, seem to offer a much-needed alternative resource for growing bone.

Traditional methods attempting to locate and extract these stem cells focused on proteins that reside on the surface of the cells. Find the proteins, scientists reasoned, and you’ve found the cell.

Unfortunately, that method was not fool proof, and many argued that it wasn’t finding all the cells that reside in the fat tissue. So Brown scientists, led by Dr. Eric Darling found an alternative.

They knew that a gene called ALPL is an indicator of bone-making cells. If the gene is switched on, the cell has the potential to make bone. If it’s switched off, it does not. So Darling and his team devised a fluorescent marker, or tag, that stuck to the cells with activated ALPL. They then used a special machine to sort the cells: those that glowed went into one bucket, those that did not went into the other.

To prove that these ALPL-activated cells were indeed capable of becoming bone and cartilage, they then cultivated them for several weeks in a petri dish. Not only did they transform into the right cell types—they did so in greater numbers than cells extracted using traditional methods.

Hetal Marble, a graduate student in Darling’s lab and the paper’s first author, argues that tagging genes—rather than surface proteins—in order to distinguish and weed out cell types represents an important paradigm shift in the field. As he stated in a press release:

“Approaches like this allow us to isolate all the cells that are capable of doing what we want, whether they fit the archetype of what a stem cell is or is not. The paradigm shift is thinking about isolating populations that are able to achieve an end point rather than isolating populations that fit a strictly defined archetype.”

While their method is both precise and accurate, there is one drawback: it is slow.

Currently, it takes four days to tag, extract and cultivate the bone-making cells. In the future, the team hopes they can shorten this time frame so that they could perform the required steps within a single surgical session. As Darling stated:

“If you can take a patient into the OR, isolate a bunch of their cells, sort them and put them back in—that’s ideally where we’d like to go with this.”

Stem cell stories that caught our eye: heart disease, blindness and replacement teeth

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.

Review looks at approaches to blindness.
The Scientist published a nice lay level overview of various teams’ work to use stem cells to cure blindness. The bulk of the story covers age-related macular degeneration, the most common form of blindness in the elderly, with six approaches discussed and compared including the CIRM-funded California Project to Cure Blindness.

Dennis Clegg, one member of the California project team, was featured in a story posted by his university

The piece smartly includes an overview of the reasons eye diseases make up a disproportionate number of early stem cell trials using stem cells from sources other than bone marrow. Many in the field view it as the perfect target for early therapies where safety will be a main concern. It is a confined space so the cells are less likely to roam; it is small so fewer cells will be needed; and it has reduced immune activity so less likely to reject new cells.

The author describes three approaches to using cells derived from embryonic stem cells, one using iPS-type stem cells, one using fetal-derived nerve stem cells and one using cells from umbilical cord blood. An ophthalmologist from the University of Wisconsin who was not associated with any of the trials offered a fair assessment:

“We’re pushing the boundaries of this technology. And as such, we expect there to be probably more bumps in the road than smooth parts.”


A heart of gold, nanoparticles that is.
Most teams using scaffolds seeded with cells to create patches to strengthen damaged hearts start with animal material to create the scaffold, which can cause immune problems. An Israeli group has developed a way to use a patient’s own fat tissue to create these scaffolds. But that left the remaining problem of getting cells in a scaffold to beat in unison with the native heart. They found that by lacing the scaffold with gold nanoparticles they could create an effective conduction system for the heart’s electrical signals.

A story in ScienceDaily quotes the lead researcher Tal Dvir:

“The result was that the nonimmunogenic hybrid patch contracted nicely due to the nanoparticles, transferring electrical signals much faster and more efficiently than non-modified scaffolds.”

If you read the story parts of it are a little overwrought. The headline, “A Heartbeat away? Hybrid patch could replace transplants,” pushes credibility on two fronts. The first half suggests this therapy is imminent, rather than the reality of years away. Patches could only replace the need for transplants. They could never work as well as a full new heart, but since we only need partial function in our heart to live relatively OK, and they might be safer than a transplant they might replace the need.

Could teeth be first complex organ stem cell success? The Seattle Times did a pretty thorough story about why the tooth might be the first complex organ replaced via stem cells and regenerative medicine. While it is a complex organ with multiple layers, a blood system and a nervous system, it does not have moveable parts and we understand each part better than with other major organs.

The paper starts with a good reminder of just how far dental hygiene has come, with few elderly people needing dentures today—leaving the need for new teeth, suggests the author, to people such as hockey players.

A CIRM-funded team is investigating various ways to build a new tooth.

Even the Tea Party would like this regulation.
We have roughly as many genes as a frog, but are much more complicated. Our higher function evolved in part by making our genes more highly regulated. A CIRM-funded team now reports that this particularly applies to our “jumping genes,” and no that does not have anything to do with jumping frogs.

The work focuses on transposons, bits of our DNA that literally move around, or jump, between our functional genes and change how they are turned on or off. We also have evolved a set of genes to control the jumping genes, and the researchers at the University of California, Santa Cruz, suggest that evolution has been a never ending tug of war between the jumping genes and the genes that are supposed to control them.

HealthCanal ran the university’s press release, which quotes lead researcher Sofie Salama:

“We have basically the same 20,000 protein-coding genes as a frog, yet our genome is much more complicated, with more layers of gene regulation. This study helps explain how that came about.”

Don Gibbons

The sparrow’s dying song: a possible path toward natural, stem cell-based repair of human brain diseases

Songbird research? How the heck could studying tweeting birds lead to advancements in human health?

At a first glance, biological research in other organisms like bacteria, yeast, flies, mice and birds can seem frivolous and a waste of taxpayer money. Yet it’s astonishing how we humans share very similar if not identical functions at a cellular level with our fellow creatures on Earth. So unraveling underlying biological processes in less complex animals is essential to better understanding human biology and to finding possible paths for treating human disease.

Gambel's White-crown sparrow: could its song unlock methods for repairing the brain? (photo courtesy Lip Kee, wikimedia commons)

Gambel’s White-crown sparrow: could its song unlock methods for repairing the brain? (photo courtesy Lip Kee, wikimedia commons)

Case in point: research published in the Journal of Neuroscience last week suggests that studying brain stem cells in song birds could one day lead to methods for naturally repairing neurodegenerative disorders such as Alzheimer’s disease in humans.

The University of Washington team behind the report studies the seasonal song behavior of Gambel’s white-crown sparrows. During the spring breeding season, the population of cells in the sparrow’s brain that are responsible for singing double in number. This cell growth helps the bird to be at its peak singing performance for attracting mates and staking its territory. As breeding season recedes, these brain cells die away naturally and the sparrow’s song, no longer needed, deteriorates. When the next spring arrives the brain cells will grow again.

Audio tracing's of the sparrow's song show its degradation after breeding season each year. (T. Larson/Univ. of Washington)

Audio tracings of the sparrow’s song show its degradation after breeding season each year. (image: T. Larson/Univ. of Washington)

The team’s fascinating discovery is that the dying brain cells themselves appear to provide a signal that tells brain stem cells to multiply for the next breeding season. The scientific term for the cell die-off is called programmed cell death, or apoptosis (pronounced A-POP-TOE-SIS). There are chemicals available to block apoptosis signals. And when the research team administered these anti-apoptosis chemicals at the end of the breeding season, there was a significant reduction in newly dividing brain stem cells. This result shows that new brain stem cell growth depends on the death of brain cells associated with song.

The next step in the project is to identify the signal from the dying cells that stimulates new brain stem cell growth. Once identified, that signal could be harnessed to naturally stimulate new brain stem growth to help repair the loss of brain cells seen in aging, Parkinson’s or Alzheimer’s disease.

As he mentions in a university news story, Dr. Eliot Brenowitz, the senior author of the report, is optimistic about their prospects:

“There’s no reason to think what goes on in a bird brain doesn’t also go on in mammal brains, in human brains. As far as we know, the molecules are the same, the pathways are the same, the hormones are the same. That’s the ultimate purpose of all this, to identify these molecular mechanisms that will be of use in repairing human brains.”

To learn about CIRM-funded projects related to neurodegenerative disorders, visit our Alzheimer’s and Parkinson’s online fact sheets.

Stem cell stories that caught our eye: heart disease, premature infants and incontinence

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.

Decoding heart health and genetics in Asians. A study from CIRM grantee Joseph Wu at Stanford may point the way to using stem cells to solve problems caused by too many drugs being tested predominantly on white males. Ethnic variations to drug response too often get ignored in current clinical trials.

The Stanford team has used iPS type stem cells to create a disease-in-a-dish model of a genetic mutation that effects 500 million people, but mostly East Asians. The mutation disables the metabolic protein called ALDH2 and results in increased risk of heart disease and increases the risk of death after a heart attack. By growing heart muscle from stem cells made from the skin of patients with the mutation his team found that the defect alters the way the heart cells react to stress.

Wu suggests that drug companies one day may keep banks of iPS cells from various ethnic groups to see how their responses to drugs differ. Science Daily ran the university’s press release.

Stem cells may treat gut disease in premies.
A laundry list of medical challenges confronts premature babies, but few are as deadly as the intestinal disease that goes by the name NEC, or necrotizing enterocolitis. It strikes with no notice and can kill within hours.

140925100256-largeA team at the University of Ohio reports they have developed what may be a two-pronged attack on the disease. First, they found a biomarker that can predict which infants might develop NEC, and second they have tested stem cells for treating the intestinal damage done by the disease. In an animal model they found that a type of stem cell found in bone marrow, mesenchymal stem cells, can reduce the inflammation that causes the damage and that neural stem cells can repair the nerve connections disrupted by the inflammation.

While this explanation sounds straight forward, getting to that potential intervention was anything but a simple path. The university wrote an extensive feature detailing the many years and many steps the research team took to unravel this who-done-it that involves the gut’s extensive “brain” and immune system. Science Daily picked up the piece.

We recently posted a video about a project we fund using stem cells to develop a treatment for irritable bowel disease.

Fat stem cells tested in incontinence. For far too many older women laughing and coughing can lead to embarrassing bladder leaks. Several groups are working with various types of stem cells to try to strengthen the urinary sphincter and help patients lead a more normal life. A team at Cleveland Clinic now reports some positive results using the most easily accessed form of stem cells, those in fat.

They harvested patients’ own fat stems cells, grew them in the lab for three weeks and then mixed them with a collagen gel from cows to hold them in place before injecting them into the sphincter. Three of five patients passed “the cough test” after one year. Good results, but clearly more work needs to be done to yield more uniform results. Stem Cells Translational Medicine published the research and issued this press release.

Some researcher suspect starting with an earlier stage, more versatile stem cell might yield better results. One of our grantees is developing cells to treat incontinence starting with reprogrammed iPS type stem cells.

New course looks at where fact and fiction overlap. I am a big fan of almost any effort to blend science and the arts. A professor at the University of Southern California seems to agree. CIRM grantee Gage Crump will be teaching a course next spring about science fiction and stem cells.

The university says the course, Stem Cells: Fact and Fiction, will range from babies born with three biological parents to regrown body parts. The course will explore the current state of stem cell biology as it closes the gap between reality and the sci fi visions of authors such as Margaret Atwood and Philip K. Dick. Crump describes it as:

“a mad scientist type of course, where we go through some real science but also [think] about what’s the future of science.”

Don Gibbons