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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Cancer Cells Mimic Blood Vessels to Colonize the Body’s Farthest Reaches

Scientists at Cold Spring Harbor Laboratory have just uncovered the latest dirty trick in the cancer playbook—one that spurs the cancer cells to spread throughout the body and evade treatment. But importantly, they believe they may have found a way to counter it.

Reporting today in the journal Nature, Cold Spring Harbor researchers describe how tumor cells can form tubular networks that mimic blood vessels. It is this mimicry, the team argues, that plays a key role in helping the cancer spread throughout the body—and a significant hurdle to successfully treating the disease.

Two adjacent sections of a mouse breast tumor. Tissue at left is stained so that normal blood vessels can be seen (black arrow). Extending from these vessels are blood filled channels (green arrows). On the right, the tissue is stained for a fluorescent protein expressed by the tumor cells. Here, blood-filled channels are actually formed by tumor cells in a process known as vascular mimicry. [Credit: Hannon Lab, CSHL]

Two adjacent sections of a mouse breast tumor. Tissue at left is stained so that normal blood vessels can be seen (black arrow). Extending from these vessels are blood filled channels (green arrows). On the right, the tissue is stained for a fluorescent protein expressed by the tumor cells. Here, blood-filled channels are actually formed by tumor cells in a process known as vascular mimicry. [Credit: Hannon Lab, CSHL]

Using mouse models of breast cancer, the team—led by Simon Knott—identified this phenomenon, called ‘vascular mimicry,’ and revealed that two genes, called Serpine2 and Slpi, were driving it. Made up of tumor cells literally stacked together, these tubular networks allowed oxygen and other nutrients to reach far-flung tumor cells throughout the body. This kept the tumor cells healthy, and helped them spread.

In today’s press release, Knott explained his initial reactions to this critical discovery:

“It’s very neat to watch and see cells evolve to have these capacities, but on the other hand it’s really scary to think that these cells are sitting there in people doing this.”

In laboratory experiments, the team found that boosting levels of Serpin2 and Slpi boosted the cancer’s ability to build these networks. Conversely, shutting down these two genes appeared to do the opposite. Knott argues that targeting the proteins that these two genes produce, as a way of shutting them off, may be a winning strategy:

“Targeting them might provide therapeutic benefits,” said Knott, “but we’re not sure yet.”

Indeed, research efforts over the past decade or more have tried to curb the production of these tubular networks of tumor cells, but with limited success. These drugs, called angiogenesis inhibitors, may not have worked as well as originally hoped because the underlying mechanism that creates this vascular mimicry—namely the genes Serpin2 and Slpi—was not targeted. Postdoctoral researcher Elvin Wagenblast, the paper’s first author, thinks they might have more success now:

“Maybe by targeting angiogenesis and also vascular mimicry at the same time we might actually have a better benefit in the clinic in the long run.”

This strategy is ultimately the goal of the team, but much work remains. Their most immediate next steps are to understand the process by which tumor cells pass through these tubular networks and infiltrate new areas of the body. But armed with this new-found knowledge of vascular mimicry, these and other researchers may be well on their way to outsmarting cancer, at least some of the time.

Building a Better Needle: CIRM-Funded Invention Gets Cells Into Brain More Safely, Efficiently

If NASA’s billion dollar Mars rovers deployed a bunch of dollar store party balloons to cushion the moment of impact, the mission would fail miserably. Likewise, the many years and millions of dollars spent on developing a stem cell-based therapy could be all for naught if the delivery of those precious cells into patients used cheap, inefficient tools.

That’s the subject of a recent TV interview with George Yu, who is CEO of Accurexa, a company that is developing and commercializing a novel syringe and needle device that could dramatically improve the delivery of cell therapies to the brain. The device was invented by UCSF neurosurgeon Daniel Lim with the support of a CIRM Tools and Technologies grant.

“So [Dr. Lim] participated in a phase 1 trial a few years ago where he was asked to deliver stem cell[-derived cells] to the brain and he didn’t really have adequate tools to do that, “ Yu explained in his interview with the New York-based finance and business TV program, New to the Street.

“The company that manufactured the stem cells spent millions of dollars in research but then they gave [Dr. Lim] a syringe and a needle that literally costs a couple of dollars. When he used that syringe and needle, which is a straight needle and injected those cells into the brain he actually saw a substantial amount of cells coming to the surface of the brain, which we call reflux, and that’s the reason he said there must be something better than this. And he applied for a grant, he got funded, and he invented the device. “

Not only does the standard straight syringe and needle cause a loss of transplanted cells due to reflux it also requires multiple injections in order to properly distribute the cell therapy in the brain. And with each injection, healthy brain tissue is damaged and increases the risk of stroke.

The Branched Point Device allows a well distributed cell transplantation into the brain with just one injection site. (image credit: Stereotact Funct Neurosurg. 2013; 91(2): 92–103.)

The Branched Point Device allows a well distributed transplantation of cells into the brain with just one injection site. (image credit: Stereotact Funct Neurosurg. 2013; 91(2): 92–103.)

Lim’s invention, called a Branched Point Device, avoids both cell reflux and the need for multiple injections. Instead of coming straight out of the needle tip, the cells are delivered through an opening that’s positioned on the side of the needle. So rather than re-injecting the needle, it’s incrementally rotated to deliver the cells in a different direction. With the use of a catheter that pokes through the needle, the cells can be distributed around the needle at different depths in a radial pattern much like the branches of a tree.

Use of the device in clinical trials may soon become a reality based on Yu’s comments in the interview:

“We’ve mostly completed our testing and the design of the device and we’re in the late stage of preparing a 510k submission to the FDA. So we expect that to happen this year. And once it’s FDA approved we can potentially sell the device.”

And because CIRM funded the development of this invention, the State of California is entitled to share in licensing revenue arising from the invention. Better still, the use of the device in clinical trials could provide more consistent, reliable results and a faster path to approval for stem cell-based therapies for neurodegenerative diseases like Parkinson’s.

Mutation Morphs Mitochondria in Models of Parkinson’s Disease, CIRM-Funded Study Finds

There is no singular cause of Parkinson’s disease, but many—making this disease so difficult to understand and, as a result, treat. But now, researchers at the Buck Institute for Research on Aging have tracked down precisely how a genetic change, or mutation, can lead to a common form of the disease. The results, published last week in the journal Stem Cell Reports, point to new and improved strategies at tackling the underlying processes that lead to Parkinson’s.

Mitochondria from iPSC-derived neurons. On the left is a neuron derived from a healthy individual, while the image on the right shows a neuron derived from someone with the Park2 mutation, the most common mutation in Parkinson's disease (Credit: Akos Gerencser)

Mitochondria from iPSC-derived neurons. On the left is a neuron derived from a healthy individual, while the image on the right shows a neuron derived from someone with the Park2 mutation, the most common mutation in Parkinson’s disease (Credit: Akos Gerencser)

The debilitating symptoms of Parkinson’s—most notably stiffness and tremors that progress over time, making it difficult for patients to walk, write or perform other simple tasks—can in large part be linked to the death of neurons that secrete the hormone dopamine. Studies involving fruit flies in the lab had identified mitochondria, cellular ‘workhorses’ that churn out energy, as a key factor in neuronal death. But this hypothesis had not been tested using human cells.

Now, scientists at the Buck Institute have replicated the process in human cells, with the help of stem cells derived from patients suffering from Parkinson’s, a technique called induced pluripotent stem cell technology, or iPSC technology. These newly developed neurons exactly mimic the disease at the cellular level. This so-called ‘disease in a dish’ is one of the most promising applications of stem cell technology.

“If we can find existing drugs or develop new ones that prevent damage to the mitochondria we would have a potential treatment for PD,” said Dr. Xianmin Zeng, the study’s senior author, in a press release.

And by using this technology, the Buck Institute team confirmed that the same process that occurred in fruit fly cells also occurred in human cells. Specifically, the team found that a particular mutation in these cells, called Park2, altered both the structure and function of mitochondria inside each cell, setting off a chain reaction that leads to the neurons’ inability to produce dopamine and, ultimately, the death of the neuron itself.

This study, which was funded in part by a grant from CIRM, could be critical in the search for a cure for a disease that, as of yet, has none. Current treatment regimens aimed at slowing or reducing symptoms have had some success, but most begin to fail overtime—or come with significant negative side effects. The hope, says Zeng, is that iPSC technology can be the key to fast-tracking promising drugs that can actually target the disease’s underlying causes, and not just their overt symptoms. Hear more from Dr. Xianmin Zeng as she answers your questions about Parkinson’s disease and stem cell research:

Stem cell stories that caught our eye; converting bad fat to good, Parkinson’s and X-linked disease

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.

Which fat for you, white, brown or beige.
Those who read up on those pesky fat cells that accumulate in our bodies probably have heard about white fat and brown fat. White is the bad guy linked to obesity and diabetes and brown is the good guy that burns energy and fosters leanness. Add one more color. A team at the University of California, San Francisco, has isolated beige fat that can convert white to brown.

body fatThey now want to see if they can figure out the molecular mechanism behind this conversion to see if they can develop a therapy to combat obesity. I heard a presentation on similar work at the International Society for Stem Cell Research last June, and there were suggestions that the stem cell known to reside in fat may play a role, but no one seems to be sure.

The current research made it into Nature Medicine and ScienceDaily picked up the university’s press release, which quotes the senior researcher, Shingo Kajimura:

“This finding brings us another step closer to the goal of our laboratory, which is engineering fat cells to fight obesity. We are trying to learn how to convert white fat into brown fat, and until now, it had not been demonstrated that this recruitable form of brown fat is actually present in humans.”


A wonkish revelation on reprogrammed stem cells.
When Shinya Yamanaka first discovered how to reprogram adult cells into embryonic-like stem cells, the resulting iPS cells won him the Nobel Prize. But neither he nor anyone else knew exactly how this reprogramming actually happened. It was assumed that by adding genes that are normally only active during embryo development we were turning back the clock and letting the cells sort of start over.

Now, CIRM-funded researchers at Stanford have discovered the cells first go through a clearly identifiable intermediate state that does not have any of the markers of early stem cells, so called pluripotency genes. The leader of the team, Marius Wernig, described his surprise in a university press release picked up by HealthCanal:

“This was completely unexpected. It’s always been assumed that reprogramming is simply a matter of pushing mature cells backward along the developmental pathway. These cells would undergo two major changes: They’d turn off genes corresponding to their original identity, and begin to express pluripotency genes. Now we know there’s an intermediary state we’d never imagined before.”

The research, published in Nature, used a clever new technique that lets cells grow in individual tiny wells on a laboratory plate. Wernig hopes the finding will help his group and others find ways to improve reprogramming efficiency, which is commonly in single percentage points and rarely in the teens.

Chemical trick yields nerves needed in Parkinson’s.
It’s relatively easy to get stem cells to mature into nerves, but can be quite difficult sometimes to get them to grow into just the right kind of nerves. The dopamine-producing nerves needed in Parkinson’s disease turn out to be one of the difficult ones.

Now, a team from Brazil has used an approved drug to treat stem cells in the lab and get them to consistently mature into dopamine-producing nerves. What’s better, the cells survived and continued to produce dopamine for 15 months after being transplanted into mice. ScienceDaily picked up the press release from D’Or Institute for Research and Education.

The X chromosome and disease? Researchers have long sought answers to why when a disease gene resides on the X chromosome, it often causes more harm in boys than girls. A likely culprit is the process a developing embryo uses to shut down one of the two X chromosomes in females, and a team at Stanford thinks they have found a way to discover how.

The CIRM-funded team lead by Howard Chang used a new molecular tool to study in detail all the components of the cell involved in silencing one of the X chromosomes.

Calico cats are female due to X-chromosome silencing.

Calico cats are female due to X-chromosome silencing.

Researchers have known for some time that one particular genetic component, an RNA called Xist, plays a lead role. But Chang’s team discovered 80 different proteins it interacts with in order to completely shut down one X chromosome. They hope that learning more about the process will let researchers figure out how this selective silencing protects females from some of the mutations on the X chromosome.

The Stanford press release, picked up by HealthCanal, starts with a fun explanation of X silencing and how it can lead to calico female cats, but not males—sorry Garfield you don’t exist.

Breast Cancer Tumors Recruit Immune Cells to the Dark Side

We rely on our immune system to stave off all classes of disease—but what happens when the very system responsible for keeping us healthy turns to the dark side? In new research published today, scientists uncover new evidence that reveals how breast cancer tumors can actually recruit immune cells to spur the spread of disease.

Some forms of breast cancer tumors can actually turn the body's own immune system against itself.

Some forms of breast cancer tumors can actually turn the body’s own immune system against itself.

Breast cancer is one of the most common cancers, and if caught early, is highly treatable. In fact, the majority of deaths from breast cancer occur because the disease has been caught too late, having already spread to other parts of the body, a process called ‘metastasis.’ Recently, scientists discovered that women who have a heightened number of a particular type of immune cells, called ‘neutrophils,’ in their blood stream have a higher chance of their breast cancer metastasizing to other tissues. But they couldn’t figure out why.

Enter Karin de Visser, and her team at the Netherlands Cancer Institute, who announce today in the journal Nature the precise link between neutrophil immune cells and breast cancer metastasis.

They found that some types of breast tumors are particularly nefarious, sending out signals to the person’s immune system to speed up their production of neutrophils. And then they instruct these newly activated neutrophils to go rogue.

Rather than attack the tumor, these neutrophils turn on the immune system. They especially focus their efforts at blocking T cells—the type of immune cells whose job is normally to target and attack cancer cells. Further examination in mouse models of breast cancer revealed a particular protein, called interleukin 17 (or IL17) played a key role in this process. As Visser explained in today’s news release:

“We saw in our experiments that IL17 is crucial for the increased production of neutrophils. And not only that, it turns out that this is also the molecule that changes the behavior of the neutrophils, causing them to become T cell inhibitory.”

The solution then, was clear: block the connection, or pathway, between IL17 and neutrophils, and you can thwart the tumor’s efforts. And when Visser and her team, including first author and postdoctoral researcher Seth Coffelt, did this they saw a significant improvement. When the IL17-neutrophil pathway was blocked in the mouse models, the tumors failed to spread at the same rate.

“What’s notable is that blocking the IL17-neutrophil route prevented the development of metastases, but did not affect the primary tumor,” Visser added. “So this could be a promising strategy to prevent the tumor from spreading.”

The researchers are cautious about focusing their efforts on blocking neutrophils, however, as these cells are in and of themselves important to stave off infections. A breast cancer patient with neutrophil levels that were too low would be at risk for developing a whole host of infections from dangerous pathogens. As such, the research team argues that focusing on ways to block IL17 is the best option.

Just last month, the FDA approved an anti-IL17 based therapy to treat psoriasis. This therapy, or others like it, could be harnessed to treat aggressive breast cancers. Says Visser:

“It would be very interesting to investigate whether these already existing drugs are beneficial for breast cancer patients. It may be possible to turn these traitors of the immune system back towards the good side and prevent their ability to promote breast cancer metastasis.”

Stem cell stories that caught our eye; creating bone, turning data into sound, cord blood and path of a stem cell star

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.

A better ratio of bone to fat
. Most of us at any age would prefer a little less fat and older folks, particularly ones plagued by the bone loss of osteoporosis, could use a bit more bone. Since both types of tissues come from mesenchymal stem cells (MSCs) a team at the University of Miami decided to look for chemical triggers that tells those stem cells whether to become fat or bone.

They found an enzyme that seems to do just that. In mice that were born with a mutation in the gene for that enzyme they saw increased bone growth, less fat production and a leaner body mass. HealthCanal picked up the university’s press release that quoted the leader of the team Joshua Hare:

“The production of bone could have a profound effect on the quality of life for the aging population.”

He goes on to note that there are many hurdles to cross before this becomes a therapeutic reality, but the current work points to lots of potential.

Path to becoming a star stem cell scientist. D, the city magazine for Dallas, published a lengthy—nearly 4,000-word—feature on Sean Morrison, one of the undisputed leaders of our field. While it starts out talking about his latest role of creating a multi-pronged center for innovation at

Sean Morrison

Sean Morrison

Children’s Medical Center Dallas and UT Southwestern, it spends most of its words on how he got there.

It’s fun reading how someone gets into a field as new as stem cell science and what keeps them in the field. Initially, for him it seems to originate from an immense curiosity about what was not known about the powerful little stem cells.

“Fifteen years ago, there was nothing known at the molecular level about how stem cells replicate. And I really felt it was a fundamental question in biology to understand. It was a question that was central to a lot of important issues, because the ability of stem cells to self-renew is critical to form your tissues throughout development, to maintain your tissues throughout adulthood.”

There is also a good retelling of Morrison’s role in the protracted and hard-fought battle to make embryonic stem cell research legal during his years in Michigan. He started working on the campaign to overturn the ban in 2006 and in 2008 the voters agreed. The article makes a compelling case for something I have advocated for years: scientists need to practice speaking for the public and get out and do it.

Turning stem cell data into sound. Interpreting scientific data through sound, sonification, is a bit trendy now. But the concept is quite old. Think of the Geiger counter and the speed of the click changing based on the level of radiation.

Researchers tend to consider sonification when dealing with large data sets that have some level of repetitive component. Following the differentiation of a large number of stem cells as they mature into different types of tissue could lend itself to the genre and a team at Cardiff University in Scotland reports they have succeeded. In doing just that.

HealthCanal picked up the university’s piece talking about the project. Unfortunately it does a very poor job of explaining how the process actually works. I did find this piece on ocean microbes that describes the concept of sonification of data pretty well.

Cord blood poised for greater use. I get very uncomfortable when friends ask for medical advice around stem cells. I usually try to give a lay of the land that comes short of direct advice. A common question centers on the value of paying the annual storage fees to freeze their baby’s cord blood. To which, I typically say that for current uses the value is marginal, but for the uses that could come in five to 10 years, it could be quite significant.

So, it was not surprising to read a headline on a Scientific American Blog last December reading “Vast Majority of Life-Saving Cord Blood Sits Unused.” But it was also fun to read a well-documented counter point guest blog on the site this morning by our former President, Alan Trounson. He suggested a better headline would be: “Vast Majority of Life-Saving Cord Blood Sits Poised for Discovery.”

He details how cord blood has become a valuable research tool and lists some of the FDA-approved clinical trials that could greatly expand the indication of cord blood therapy. While some of those trials will likely produce negative results, some will succeed and they all will start to show how to turn those frozen vials into a more valuable resource.