Stem Cell Stories that Caught our Eye: finding the perfect match, imaging stem cells and understanding gene activity

Here are the stem cell stories that caught our eye this week. Enjoy!

LAPD officer in search of the perfect match.

LAPD Officer Matthew Medina with his wife, Angelee, and their daughters Sadie and Cassiah. (Family photo)

This week, the San Diego Union-Tribune featured a story that tugs at your heart strings about an LAPD officer in desperate need of a bone marrow transplant. Matthew Medina is a 40-year-old man who was diagnosed earlier this year with aplastic anemia, a rare disorder that prevents the bone marrow from producing enough blood cells and platelets. Patients with this disorder are prone to chronic fatigue and are at higher risk for infection and uncontrolled bleeding.

Matthew needs a bone marrow transplant to replace his diseased bone marrow with healthy marrow from a donor, but so far, he has yet to find a match. Part of the reason for this difficulty is the lack of diversity in the national bone marrow registry, which has over 25 million registered donors, the majority of which are white Americans of European decent. As a Filipino, Matthew has a 40% chance of finding a perfect match in the national registry compared to a 75% chance if he were white. An even more unsettling fact is that Filipinos make up less than 1% of donors on the national registry.

Matthew has a sister, but unfortunately, she wasn’t a match. For now, Matthew is being kept alive with blood transfusions at his home in Bellflower while he waits for good news. With the support of his family and friends, the hope is that he won’t have to wait for long. Already 1000 people in his local community have signed up to be bone marrow donors.

On a larger scale, organizations like A3M and Mixed Marrow are hoping to help patients like Matthew by increasing the diversity of the national bone marrow registry. A3M specifically recruits Asian donors while Mixed Match focuses on people with multi-ethnic backgrounds. Ayumi Nagata, a recruitment manager at A3M, said their main challenge is making healthy people realize the importance of being a bone marrow donor.

“They could be the cure for someone’s cancer or other disease and save their life. How often do we have that kind of opportunity?”

An algorithm that makes it easier to see stem cell development.

To understand how certain organs like the brain develop, scientists rely on advanced technologies that can track individual stem cells and monitor their fate as they mature into more specialized cells. Scientists can observe stem cell development with fluorescent proteins that light up when a stem cell expresses specific transcription factors that help decide the cell’s fate. Using a time-lapse microscope, these fluorescent stem cells can easily be identified and tracked throughout their lifetime.

But the pictures don’t always come out crystal clear. Just as a dirty camera lens makes for a dirty picture, images produced by time-lapse microscopy images can be plagued by shadows, artifacts and lighting inconsistencies, making it difficult to observe the orchestrated expression of transcription factors involved in a stem cell’s development.

This week in the journal Nature Communications, a team of scientists from Germany reported a solution that gives a clear view of stem cell development. The team developed a computer algorithm called BaSiC that acts like a filter and removes the background noise from time-lapse images of individual cells. Unlike previous algorithms, BaSiC requires fewer reference images to make its corrections.

The software BaSiC improves microscope images. (Credit: Tingying Peng / TUM/HMGU)

In coverage by Phys.org, author Dr. Tingying Peng explained the advantages of their algorithm,

“Contrary to other programs, BaSiC can correct changes in the background of time-lapse videos. This makes it a valuable tool for stem cell researchers who want to detect the appearance of specific transcription factors early on.”

The team proved that BaSiC is an effective image correcting tool by using it to study the development of hematopoietic or blood stem cells. They took time-lapse videos of blood stem cells over six days and observed that the stem cells chose between two developmental tracks that produced different types of mature blood cells. Using BaSiC, they found that blood stem cells that specialized into white blood cells expressed the transcription factor Pu.1 while the stem cells that specialized into red blood cells did not. Without the algorithm, they didn’t see this difference.

Senior author on the study, Dr. Nassir Navab, concluded by highlighting the importance of their technology and sharing his team’s vision for the future.

“Using BaSiC, we were able to make important decision factors visible that would otherwise have been drowned out by noise. The long-term goal of this research is to facilitate influencing the development of stem cells in a targeted manner, for example to cultivate new heart muscle cells for heat-attack patients. The novel possibilities for observation are bringing us a step closer to this goal.”

Silenced vs active genes: it’s like oil and water (Todd Dubicoff)

The DNA from just one of your cells would be an astounding six feet in length if stretched out end to end. To fit into a nucleus that is a mere 4/10,000th of an inch in diameter, DNA’s double helical structure is organized into intricate twists within twists with the help of proteins called histones.

Together the DNA and histones are called chromatin. And it turns out that chromatin isn’t just for stuffing all that genetic material into a tiny space. The amount of DNA folding also affects the regulation of genes. Areas of chromatin that are less densely packed are more accessible to DNA-binding proteins called transcription factors that activate gene activity. Other regions, called heterochromatin, are compacted which leads to silencing of genes because transcription factors are shut out.

But there’s a wrinkle in this story. More recently, scientists have shown that large proteins are able to wriggle their way into heterochromatin while smaller proteins cannot. So, there must be additional factors at play. This week, a CIRM-funded research project published in Nature provides a possible explanation.

Liquid-like fusion of heterochromatin protein 1a droplets is shown in the embryo of a fruit fly. (Credit: Amy Strom/Berkeley Lab)

Examining the nuclei of fruit fly embryos, a UC Berkeley research team report that various regions of heterochromatin coalesce into liquid droplets which physically separates them from regions where gene activity is high. This phenomenon, called phase-phase separation, is what causes oil droplets to fuse together when added to water. Lead author Dr. Amy Strom explained the novelty of this finding and its implications in a press release:

“We are excited about these findings because they explain a mystery that’s existed in the field for a decade. That is, if compaction [of chromatin] controls access to silenced [DNA] sequences, how are other large proteins still able to get in? Chromatin organization by phase separation means that proteins are targeted to one liquid or the other based not on size, but on other physical traits, like charge, flexibility, and interaction partners.”

Phase-phase separation can also affect other cell components, and problems with it have been linked to neurological disorders like dementia. In diseases like Alzheimer’s and Huntington’s, proteins aggregate causing them to become more solid than liquid over time. Strom is excited about how phase-phase separation insights could lead to novel therapeutic strategies:

“If we can better understand what causes aggregation, and how to keep things more liquid, we might have a chance to combat these types of disease.”

Cancer-causing mutations in blood stem cells may also link to heart disease

Whether we read about it in the news or hear it from our doctor, when we think about the causes of heart disease it’s usually some combination of inheriting bad genes from our parents and making poor life style choices like smoking or eating a diet high in fat and cholesterol. But in a fascinating research published yesterday in the New England Journal of Medicine, scientists show evidence that in some people, heart disease may develop much in the same way that a blood cancer does; that is, through a gradual, lifetime accumulation of mutations in hematopoietic cells, or blood stem cells.

This surprising discovery began as a project, published in 2014, aimed at early detection of blood cancers in the general population. This earlier study focused on the line of evidence that cells don’t become cancerous overnight but rather progress slowly as we age. So, in the case of a blood cancer, or leukemia, a blood stem cell can acquire a mutation that transforms the cell into a pre-cancerous state. When that stem cell multiplies it creates “clones” of the blood stem cell that had the cancer-initiating mutation. It’s only after additional genetic insults that these stem cells become full blown cancers.

The research team, composed of scientists from Brigham and Women’s Hospital as well as the Broad Institute of Harvard and MIT, examined DNA sequences from blood samples of over 17,000 people who didn’t have blood cancer. They analyzed these samples, specifically looking at 160 genes that are often mutated in blood cancer. The results from the 2014 study showed that mutations in these genes in people 40 years and under were few and far between. Interestingly, the frequency noticeably increased in older folks with those 10% over 70 years of age carrying the mutations.

Most of these so-called “clonal hematopoiesis of indeterminate potential”, or CHIP, mutations occurred in three genes called DNMT3A, TET2, and ASXL1. While these mutations were indeed associated with a 10-fold higher risk of blood cancer, the team also saw an unexpected correlation: people with these mutations had a 40% higher overall risk of dying due to other causes compared to those who did not carry the mutations. They pinpointed heart disease as one primary cause of the increased mortality risk.

The current follow-up study not only sought to confirm this correlation between the mutations and heart disease but also show the mutations cause the increased risk. This time around, the team looked for the mutations in a group of four different populations totaling over 8000 people. Again, they saw a correlation between the mutations and the risk of heart disease or a heart attack later in life. One of the team leads, Dr. Sekar Kathiresan from the Broad Institute, talked about his team’s reaction to these results in a Time Magazine interview:

Sekar Kathiresan, Photo: Broad Institute

“We were fully expecting not to find anything here. But the odds of having an early heart attack are four-fold higher among younger people with CHIP mutations.”

 

To show a causal link, they turned to mouse studies. They collected bone marrow stem cells from mice engineered to lack Tet2, one of the three genes that when mutated had been associated with increased risk of heart disease. The bone marrow cells were then transplanted into mice which are prone to have increased blood cholesterol and symptoms of heart disease. The presence of these cells that lacked Tet2 led to increased hardening of major arteries – a precursor to clogged blood vessels, heart disease and heart attacks – compared to mice that received normal bone marrow cells.

Though more work remains, Kathiresan thinks these current results offer some tantalizing therapeutic possibilities:

“This is a totally different type of risk factor than hypertension or hypercholestserolemia [high blood cholesterol] or smoking. And since it’s a totally different risk factor that works through a different mechanism, it may lead to new treatment opportunities very different from the ones we have for heart disease at present.”

Humacyte Receives Prestigious Technology Pioneer Award for Kidney Failure Treatment

This month, a CIRM-funded company called Humacyte was named one of the World Economic Forum’s 30 Technology Pioneers for 2017. This prestigious award “recognizes early-stage companies from around the world that are involved in the design, development and deployment of new technologies and innovations, and are poised to have a significant impact on business and society.”

Humacyte is a North Carolina-based company that’s developing a promising human-tissue based treatment for kidney failure. They’ve developed a technology to manufacture a bioengineered human vein that they hope will improve kidney function in patients with end stage kidney disease and patients on hemodialysis. We’ve blogged about their exciting technology previously on the Stem Cellar (here).

The technology is fascinating. The first step involves stimulating human smooth muscle cells from donor tissue to develop into tubular vessels. After the vessels are made, the cells are removed, leaving a 3D extracellular matrix structure composed of molecules secreted by the cells. This decellularized tube-like structure is called a human acellular vessels or HAV.

Human acellular vessel (HAV) from Humacyte.

The HAV is then implanted under a patient’s skin, where it recruits the patient’s own stem cells to migrate into the HAV and develop into vascular smooth muscle cells that line the insides of actual blood vessels. For patients with kidney failure, HAVs provide vascular access for hemodialysis, the process of collecting and filtering a patient’s blood through an artificial kidney and then returning “clean” blood back to the body. It would provide an alternative to the current procedures that insert a plastic tube called a shunt into the patient’s vein. Shunts can cause infection, blood clots, and can also be rejected by a patient’s immune system.

In July of 2016, CIRM awarded Humacyte almost $10 million to launch a Phase 3 trial in California to test their bioengineered blood vessels in patients with kidney failure. Since launching the trial, Humacyte received Regenerative Medicine Advanced Therapy or RMAT designation from the US Food and Drug Administration in March of this year. This designation is a sign that the FDA sees promise in Humacyte’s stem cell-based therapy and “will help facilitate the efficient development and expedited review of the HAV for vascular access to patients in need of life-sustaining hemodialysis.”

Humacyte’s technology has wide-ranging applications beyond treating kidney disease, including peripheral arterial disease, “repairing or replacing damaged arteries, coronary artery bypass surgery, and vascular trauma.” Other key benefits of this technology are that HAVs can be designed on demand and can be stored for later use without fear of a rapidly degrading shelf-life.

In a recent Humacyte news release, Carrie Cox, Chair and CEO of Humacyte, commented on her company’s purpose and vision to help patients.

“Keeping patient care at its core, Humacyte’s scientific discoveries are designed to create ‘off-the-shelf,’ or ready to use, bioengineered blood vessels. Today these conduits are being investigated clinically for patients undergoing kidney dialysis who require vascular access and for patients with peripheral arterial disease. However, this technology may be extended into a range of vascular applications in the future, with the potential for better clinical outcomes and lower healthcare costs. Our vision is to make a meaningful impact in healthcare by advancing innovation in regenerative medicine to produce life-sustaining improvements for patients with vascular disease.”

The potential impact that Humacyte’s technology could have for patients with unmet medical needs was compelling enough to earn the company a coveted spot in the World Economic Forum’s Technology Pioneer community. This recognition will likely foster new partnerships and collaborations to further advance Humacyte’s technology down the clinical pipeline. Fulvia Montresor, Head of Technology Pioneers at the World Economic Forum, concluded in a news release.

“We welcome Humacyte in this group of extraordinary pioneers. We hope that thanks to this selection, the World Economic Forum can facilitate greater collaboration with business leaders, governments, civil society and other relevant individuals to accelerate the development of technological solutions to the world’s greatest challenges.”

According to coverage by North Carolina Biotechnology Center, Humacyte and the other Technology Pioneers will be honored at the “Summer Davos” World Economic Forum Annual Meeting of the New Champions later this month in China. You can learn more about this meeting here.


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World Sickle Cell Day: A View from the Front Line

June 19th is World Sickle Cell Day. Sickle cell disease is an inherited blood disorder that causes normally round red blood cells to take on an abnormal sickle shape, resulting in clogged arteries, severe pain, increased risk of stroke and reduced life expectancy. To mark the occasion we asked Nancy M. Rene to write a guest blog for us. Nancy is certainly qualified; she is the grandmother of a child with sickle cell disease, and the co-founder of Axis Advocacy, a non-profit advocating for those with sickle cell disease and their families.

Nancy ReneOn this World Sickle Cell Day, 2017, we can look back to the trailblazers in the fight against Sickle Cell Disease.  More than 40 years ago, the Black Panther Party established the People’s Free Medical Clinics in several cities across the country. One of the functions of these free clinics: to screen people for sickle cell disease and sickle cell trait. This life-saving screening began  in 1971.

Around that same time, President Richard Nixon allocated $10 million to begin the National Sickle Cell Anemia Control Act. This included counseling and screening, educational activities, and money for research.

In the early part of the twentieth century, most children with sickle cell died before their fifth birthday. With newborn screening available nationwide, the use of penicillin to prevent common infections, and the finding that hydroxyurea was useful in fighting the disease, life expectancy began to improve.

For much of the twentieth century, people with sickle cell disease felt that they were fighting the fight alone, knowledgeable doctors were scarce and insurance was often denied.

Making progress

As we moved into the twenty-first century, patients and families found they had some powerful allies. The National Institutes of Health (NIH), Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA) joined the battle.  In 2016 the NIH held its tenth annual international conference on sickle cell disease that featured speakers from all over the world.  Participants were able to learn about best practices in Europe, Africa, India, and South America.

Sickle Cell centers at Howard University, the Foundation for Sickle Cell Disease Research, and other major universities across the country are pointing the way to the best that medicine has to offer.

Last year, the prestigious American Society of Hematology (ASH) launched an initiative to improve understanding and treatment of sickle cell disease.  Their four-point plan includes education, training, advocacy, and expanding its global reach.

Just last month, May 2017, the FDA looked at Endari, developed by Emmaus Medical in Torrance, California.  It is the first drug specifically developed for sickle cell disease to go through the FDA’s approval process. We should have a decision on whether or not the drug goes to market in July.

The progress that had been made up to the beginning of the twenty-first century was basically about alleviating the symptoms of the disease: the sickling, the organ damage and the pervasive anemia. But a cure was still elusive.

But in 2004, California’s Stem Cell Agency, CIRM, was created and it was as if the gates had opened.

Researchers had a new source of funding to enable  them to work on Sickle Cell Disease and many other chronic debilitating diseases at the cellular level. Scientists like Donald Kohn at UCLA, were able to research gene editing and find ways to use autologous bone marrow transplants to actually cure people with sickle cell. While some children with sickle cell have been cured with traditional bone marrow transplants, these transplants must come from a matched donor, and for most patients, a matched donor is simply not available. CIRM has provided the support needed so that researchers are closing in on the cure. They are able to share strategies with doctors and researchers throughout the world

And finally, support from the federal government came with the passage of the Affordable Care Act and adequate funding for the NIH, CDC, the Health Resources and Services Administration (HRSA), and FDA.

Going backwards

And yet, here we are, World Sickle Cell Day, 2017.

Will this be a case of one step forward two steps back?

Are we really going back to the time when people with Sickle Cell Disease could not get health insurance because sickle cell is a pre-existing condition, to the time when there was little money and no interest in research or professional training, to a time when patients and their families were fighting this fight alone?

For all of those with chronic disease, it’s as if we are living a very bad dream.

Time to wake up

For me, I want to wake up from that dream.  I want to look forward to a future where patients and families, where Joseph and Tiffany and Marissa and Ken and Marcus and all the others, will no longer have to worry about getting well-informed, professional treatment for their disease.

Where patients will no longer fear going to the Emergency Room

Where doctors and researchers have the funding they need to support them in their work toward the cure,

Where all children, those here in the United States along with those in Africa, India, and South America, will have access to treatments that can free them from pain and organ damage of sickle cell disease.

And where all people with this disease can be cured.

Stories that caught our eye: An antibody that could make stem cell research safer; scientists prepare for clinical trial for Parkinson’s disease; and the stem cell scientist running for Congress

Antibody to make stem cells safer:

There is an old Chinese proverb that states: ‘What seems like a blessing could be a curse’. In some ways that proverb could apply to stem cells. For example, pluripotent stem cells have the extraordinary ability to turn into many other kinds of cells, giving researchers a tool to repair damaged organs and tissues. But that same ability to turn into other kinds of cells means that a pluripotent stem cell could also turn into a cancerous one, endangering someone’s life.

A*STAR

Researchers at the A*STAR Bioprocessing Technology Institute: Photo courtesy A*STAR

Now researchers at the Agency for Science, Technology and Research (A*STAR) in Singapore may have found a way to stop that happening.

When you change, or differentiate, stem cells into other kinds of cells there will always be some of the original material that didn’t make the transformation. Those cells could turn into tumors called teratomas. Scientists have long sought for a way to identify pluripotent cells that haven’t differentiated, without harming the ones that have.

The team at A*STAR injected mice with embryonic stem cells to generate antibodies. They then tested the ability of the different antibodies to destroy pluripotent stem cells. They found one, they called A1, that did just that; killing pluripotent cells but leaving other cells unharmed.

Further study showed that A1 worked by attaching itself to specific molecules that are only found on the surface of pluripotent cells.

In an article on Phys.Org Andre Choo, the leader of the team, says this gives them a tool to get rid of the undifferentiated cells that could potentially cause problems:

“That was quite exciting because it now gives us a view of the mechanism that is responsible for the cell-killing effect.”

Reviving hope for Parkinson’s patients:

In the 1980’s and 1990’s scientists transplanted fetal tissue into the brains of people with Parkinson’s disease. They hoped the cells in the tissue would replace the dopamine-producing cells destroyed by Parkinson’s, and stop the progression of the disease.

For some patients the transplants worked well. For some they produced unwanted side effects. But for most they had little discernible effect. The disappointing results pretty much brought the field to a halt for more than a decade.

But now researchers are getting ready to try again, and a news story on NPR explained why they think things could turn out differently this time.

tabar-viviane

Viviane Tabar, MD; Photo courtesy Memorial Sloan Kettering Cancer Center

Viviane Tabar, a stem cell researcher at Memorial Sloan Kettering Cancer Center in New York, says in the past the transplanted tissue contained a mixture of cells:

“What you were placing in the patient was just a soup of brain. It did not have only the dopamine neurons, which exist in the tissue, but also several different types of cells.”

This time Tabar and her husband, Lorenz Studer, are using only cells that have been turned into the kind of cell destroyed by the disease. She says that will, hopefully, make all the difference:

“So you are confident that everything you are putting in the patient’s brain will consist of  the right type of cell.”

Tabar and Studer are now ready to apply to the Food and Drug Administration (FDA) for permission to try their approach out in a clinical trial. They hope that could start as early as next year.

Hans runs for Congress:

Keirstead

Hans Keirstead: Photo courtesy Orange County Register

Hans Keirstead is a name familiar to many in the stem cell field. Now it could become familiar to a lot of people in the political arena too, because Keirstead has announced he’s planning to run for Congress.

Keirstead is considered by some to be a pioneer in stem cell research. A CIRM grant helped him develop a treatment for spinal cord injury.  That work is now in a clinical trial being run by Asterias. We reported on encouraging results from that trial earlier this week.

Over the years the companies he has founded – focused on ovarian, skin and brain cancer – have made him millions of dollars.

Now he says it’s time to turn his sights to a different stage, Congress. Keirstead has announced he is going to challenge 18-term Orange County Republican Dana Rohrabacher.

In an article in the Los Angeles Times, Keirstead says his science and business acumen will prove important assets in his bid for the seat:

“I’ve come to realize more acutely than ever before the deficits in Congress and how my profile can actually benefit Congress. I’d like to do what I’m doing but on a larger stage — and I think Congress provides that, provides a forum for doing the greater good.”

 

 

 

 

 

 

 

 

 

Nine months in, stem cell-based therapy for spinal cord injury continues to improve paralyzed patients’ lives

If you’ve been following the Stem Cellar blog this year, then you must be as encouraged as we are with Asterias Biotherapeutics’ CIRM-funded clinical trial, which is testing an embryonic stem cell-based therapy for spinal cord injury.

astopc1Over many months, we’ve covered the company’s string of positive announcements that their cell therapy product – called AST-OPC1 – appears safe, is doing what is it’s supposed to after injection into the damaged spinal cord, and shows signs of restoring upper body function at 3 and 6 months after treatment. We’ve also written about first-hand accounts from some of the clinical trial participants who describe their remarkable recoveries.

That streak of good news continues today with Asterias’ early morning press release. The announcement summarizes 9-month results for a group of six patients who received an injection of 10 million AST-OPC1 cells 2 to 4 weeks after their injury (this particular trial is not testing the therapy on those with less recent injuries). In a nut shell, their improvements in arm, hand and finger movement seen at the earlier time points have persisted and even gotten better at 9 months.

Two motors levels = a higher quality of life
These participants sustained severe spinal cord injuries in the neck, leading to a loss of feeling and movement in their body from the neck down. To quantify the results of the cell therapy, researchers refer to “motor levels” of improvement. These levels correspond to an increasing number of motor, or movement, abilities. For a spinal cord injury victim paralyzed from the neck down, recovering two motor levels of function can mean the difference between needing 24-hour a day home care versus dressing, feeding and bathing themselves. The impact of this level of improvement cannot be overstated. As mentioned in the press release, regaining these abilities, “can result in lower healthcare costs, significant improvements in quality of life, increased ability to engage in activities of daily living, and increased independence.”

asterias9mo_results

9-month follow-up results of Asterias’ spinal cord injury trial. Patients treated with stem cell-based therapy (green line) have greater movement recovery compared to historical data from 62 untreated patients (Blue dotted line). Image: Asterias Biotherapeutics.

With the new 9-month follow-up data, the clinical researchers have confirmed that 3 out of the 6 (50%) patients show two motor levels of improvement. This result is up from 2 of 6 patients at the earlier time points. And all six patients have at least one motor level of improvement up through 9 months post-treatment. Now, make no mistake, spontaneous recovery from spinal cord injuries does occur. But historical data collected from 62 untreated patients show that only 29% reached two motor levels of improvement after 12-months.

As you can imagine, the Asterias team is optimistic about these latest results. Here’s what Chief Medical Officer, Dr. Edward Wirth had to say:

Edward-Wirth

Edward Wirth
Photo: Asterias

“The new efficacy results show that previously reported meaningful improvements in arm, hand and finger function in the 10 million cell cohort treated with AST-OPC1 cells have been maintained and in some patients have been further enhanced even 9 months following dosing. We are increasingly encouraged by these continued positive results, which are remarkable compared with spontaneous recovery rates observed in a closely matched untreated patient population.”

Equally encouraging is the therapy’s steady safety profile with no serious adverse events reported through the 9-month follow up.

Looking ahead
Dr. Jane Lebkowski, Asterias’ President of R&D and Chief Scientific Officer, will be presenting these data today during the International Society for Stem Cell Research (ISSCR) 2017 Annual Meeting held in Boston. Asterias expects to share more results later this fall after all six patients complete their 12-month follow-up visit.

The clinical trial is also treating another group of patients with a maximum dose of 20 million cells. The hope is that this cohort will show even more effectiveness.

For the sake of the more than 17,000 people who are incapacitated by a severe spinal cord injury each year, let’s hope the streak of good news continues.

Baseball’s loss is CIRM’s gain as Stanford’s Linda Boxer is appointed to Stem Cell Agency Board

Boxer

Dr. Linda Boxer: Photo courtesy Stanford University

One of the things that fascinates me is finding out how people end up in the job they have, the job they love. It is rare that the direction they started out on is the one they end on. Usually, people take several different paths, some intended, some unintended, to get to where they want to be.

A case in point is Dr. Linda Boxer, a renowned and respected researcher and physician at the Stanford School of Medicine, and now the newest member of the CIRM Board (you can read all about that in our news release).

In Dr. Boxer’s case, her original career path was a million miles from working with California’s stem cell agency:

“The first career choice that I recall as a young child was professional baseball—growing up in Minnesota, I was a huge Twins fan—I did learn fairly quickly that this was not likely to be a career that was available for a girl, and it wasn’t clear what one did after that career ended at a relatively young age.”

Fortunately for us she became interested in science.

“I have always been curious about how things work—science classes in grade school were fascinating to me. I was given a chemistry kit as a birthday gift, and I was amazed at what happened when different chemicals were mixed together: color changes, precipitates forming, gas bubbles, explosions (small ones, of course).

Then when we studied biology in middle school, I was fascinated by what one could observe with a microscope and became very interested in trying to understand how living organisms work.

It was an easy decision to plan a career in science.  The tougher decision came in college when I had planned to apply to graduate school and earn a PhD, but I was also interested in human health and disease and thought that perhaps going to medical school made more sense.  Fortunately, one of my faculty advisors told me about combined MD/PhD programs, and that choice seemed perfect for me.”

Along the way she says she got a lot of help and support from her colleagues. Now she wants to do the same for others:

“Mentors are incredibly important at every career stage.  I have been fortunate to have been mentored by some dedicated scientists and physicians.  Interestingly, they have all been men.  There were really very few women available as mentors at the time—of course, that has changed for the better now.  It never occurred to me then that gender made a difference, and I just looked for mentors who had successful careers as scientists and physicians and who could provide advice to someone more junior.

One of the aspects of my role now that I enjoy the most is mentoring junior faculty and trainees.  I don’t think one can have too many mentors—different mentors can help with different aspects of one’s life and career.  I think it is very important for established scientists to give back and to help develop the next generation of physicians and scientists.”

Dr. Boxer is already well known to everyone at CIRM, having served as the “alternate” on the Board for Stanford’s Dr. Lloyd Minor. But her appointment by State Controller Betty Yee makes her the “official” Board member for Stanford. She brings a valuable perspective as both a scientist and a physician.

The Minnesota Twins lost out when she decided to pursue a career in science. We’re glad she did.

 

Stories that caught our eye: color me stem cells, delivering cell therapy with nanomagnets, and stem cell decisions

Nanomagnets: the future of targeted stem cell therapies? Your blood vessels are made up of tightly-packed endothelial cells. This barrier poses some big challenges for the delivery of drugs via the blood. While small molecules are able make their way through the small gaps in the blood vessel walls, larger drug molecules, including proteins and cells, are not able to penetrate the vessel to get therapies to diseased areas.

This week, researchers at Rice University report in Nature Communications on an ingenious technique using tiny magnets that may overcome this drug delivery problem.

170608072913_1_900x600

At left, the nanoparticles are evenly distributed among the microtubules that help give the cells their shape. At right, after a magnetic field is applied, the nanoparticles are pulled toward one end of the cells and change their shapes. Credit: Laboratory of Biomolecular Engineering and Nanomedicine/Rice University

Initial studies showed that adding magnetic nanoparticles to the endothelial cells and then applying a magnetic field affected the cells’ internal scaffolding, called microtubules. These structures are responsible for maintaining the tight cell to cell connections. The team took the studies a step further by growing the cells in specialized petri dishes containing tiny, tube-shaped channels. Applying a magnetic field to the cells caused the cell-cell junctions to form gaps, making the blood vessel structures leaky. Simply turning off the magnetic field closed up the gaps within a few hours.

Though a lot of research remains, the team aims to apply this on-demand induction of cell leakiness along with adding the magnetic nanoparticles to stem cell therapy products to help target the treatment to specific area. In a press release, team leader Dr. Gang Bao spoke about possible applications to arthritis therapy:

“The problem is how to accumulate therapeutic stem cells around the knee and keep them there. After injecting the nanoparticle-infused cells, we want to put an array of magnets around the knee to attract them.”

To differentiate or not differentiate: new insights During the body’s development, stem cells must differentiate, or specialize, into functional cells – like liver, heart, brain. But once that specialization occurs, the cells lose their pluripotency, or the ability to become any type of cell. So, stem cells must balance the need to differentiate with the need to make copies of itself to maintain an adequate supply of stem cells to complete the development process. And even after a fully formed baby is born, it’s still critical for adult stem cells to balance the need to regenerate damaged tissue versus stashing away a pool of stem cells in various organs for future regeneration and replacement of damaged or diseased tissues.

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Visualizing activation of Nanog gene activity (bright green spot) within cell nucleus. 
Image: Courtesy of Bony De Kumar, Ph.D., and Robb Krumlauf, Ph.D., Stowers Institute for Medical Research

A report this week in the Proceedings of the National Academy of Sciences finds evidence that the two separate processes – differentiation and pluripotency – directly communicate with each other as way to ensure a proper balance between the two states.

The study, carried out by researchers at Stowers Institute for Medical Research in Kansas City, Missouri, focused on the regulation of two genes: Nanog and Hox. Nanog is critical for maintaining a stem cell’s ability to become a specialized cell type. In fact, it’s one of the four genes initially used to reprogram adult cells back into induced pluripotent stem cells. The Hox gene family is responsible for generating a blueprint of the body plan in a developing embryo. Basically, the pattern of Hox gene activity helps generate the body plan, basically predetermining where the various body parts and organs will form.

Now, both Nanog and Hox proteins act by binding to DNA and turning on a cascade of other genes that ultimately maintain pluripotency or promote differentiation. By examining these other genes, the researchers were surprised to find that both Nanog and Hox were bound to both the pluripotency and differentiation genes. They also found that Nanog and Hox can directly inhibit each other. Taken together, these results suggest that exquisite control of both processes occurs cross regulation of gene activity.

Dr. Robb Krumlauf one of authors on the paper talked about the significance of the result in a press release:

“Over the past 10 to 20 years, biologists have shown that cells are actively assessing their environment, and that they have many fates they can choose. The regulatory loops we’ve found show how the dynamic nature of cells is being maintained.”

Color me stem cells Looking to improve your life and the life of those around you? Then we highly recommend you pay a visit to today’s issue of Right Turn, a regular Friday feature of  Signals, the official blog of CCRM, Canada’s public-private consortium supporting the development of regenerative medicine technologies.

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Collage sample of CCRM’s new coloring sheets. Image: copyright CCRM 2017

As part of an public outreach effort they have created four new coloring sheets that depict stem cells among other sciency topics. They’ve set up a DropBox link to download the pictures so you can get started right away.

Adult coloring has swept the nation as the hippest new pastime. And it’s not just a frivolous activity, as coloring has been shown to have many healthy benefits like reducing stressed and increasing creativity. Just watch any kid who colors. In fact, share these sheet with them, it’s intended for children too.

Throwback Thursday: Progress to a Cure for Diseases of Blindness

Welcome back to our “Throwback Thursday” series on the Stem Cellar. Over the years, we’ve accumulated an arsenal of exciting stem cell stories about advances towards stem cell-based cures for serious diseases. This month we’re featuring stories about CIRM-funded clinical trials for blindness.

2017 has been an exciting year for two CIRM-funded clinical trials that are testing stem cell-based therapies for diseases of blindness. A company called Regenerative Patch Technologies (RPT) is transplanting a sheet of embryonic stem cell-derived retinal support cells into patients with the dry form of age-related macular degeneration, a disease that degrades the eye’s macula, the center of the retina that controls central vision. The other trial, sponsored by a company called jCyte, is using human retinal progenitor cells to treat retinitis pigmentosa, a rare genetic disease that destroys the light-sensing cells in the retina, causing tunnel vision and eventually blindness.

 

Both trials are in the early stages, testing the safety of their respective stem cell therapies. But the teams are hopeful that these treatments will stop the progression of or even restore some form of vision in patients. In the past few months, both RPT and jCyte have shared exciting news about the progress of these trials which are detailed below.

Macular Degeneration Trial Gets a New Investor

In April, RPT announced that they have a new funding partner to further develop their stem cell therapy for age-related macular degeneration (AMD). They are partnering with Japan’s Santen Pharmaceutical Company, which specializes in developing ophthalmology or eye therapies.

AMD is the leading cause of blindness in elderly people and is projected to affect almost 200 million people worldwide by 2020. There is no cure or treatment that can restore vision in AMD patients, but stem cell transplants offer a potential therapeutic option.

RPT believes that their newfound partnership with Santen will accelerate the development of their stem cell therapy and ultimately fulfill an unmet medical need. RPT’s co-founder, Dr. Dennis Clegg, commented in a CIRM news release, “the ability to partner with a global leader in ophthalmology like Santen is very exciting. Such a strong partnership will greatly accelerate RPT’s ability to develop our product safely and effectively.”

This promising relationship highlights CIRM’s efforts to partner our clinical programs with outside investors to boost their chance of success. It also shows confidence in the future success of RPT’s stem cell-based therapy for AMD.

Retinitis Pigmentosa Trial Advances to Phase 2 and Receives RMAT Status

In May, the US Food and Drug Administration (FDA) approved jCyte’s RP trial for Regenerative Medicine Advanced Therapy (RMAT) status, which could pave the way for accelerated approval of this stem cell therapy for patients with RP.

RMAT is a new status established under the 21st Century Cures Act – a law enacted by Congress in December of 2016 to address the need for a more efficient regulatory approval process for stem cell therapies that can treat serious or life-threatening diseases. Trial sponsors of RMAT designated therapies can meet with the FDA earlier in the trial process and are eligible for priority review and accelerated approval.

jCyte’s RMAT status is well deserved. Their Phase 1 trial was successful, proving the treatment was safe and well-tolerated in patients. More importantly, some of the patients revealed that their sight has improved following their stem cell transplant. We’ve shared the inspiring stories of two patients, Rosie Barrero and Kristin Macdonald, previously on the Stem Cellar.

Rosie Barrero

Kristin MacDonald

Both Rosie and Kristin were enrolled in the Phase 1 trial and received an injection of retinal progenitor cells in a single eye. Rosie said that she went from complete darkness to being able to see shapes, colors, and the faces of her family and friends. Kristin was the first patient treated in jCyte’s trial, and she said she is now more sensitive to light and can see shapes well enough to put on her own makeup.

Encouraged by these positive results, jCyte launched its Phase 2 trial in April with funding from CIRM. They will test the same stem cell therapy in a larger group of 70 patients and monitor their progress over the next year.

Progress to a Cure for Blindness

We know very well that scientific progress takes time, and unfortunately we don’t know when there will be a cure for blindness. However, with the advances that these two CIRM-funded trials have made in the past year, our confidence that these stem cell treatments will one day benefit patients with RP and AMD is growing.

I’ll leave you with an inspiring video of Rosie Barrero about her experience with RP and how participating in jCytes trial has changed her life. Her story is an important reminder of why CIRM exists and why supporting stem cell research in particular, and research in general, is vital for the future health of patients.


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Stem cell repair of birth defect during pregnancy possible, rodent study shows

As far-fetched as it may sound, performing prenatal surgery on a fetus still growing inside its mother’s womb is actually possible. This specialized procedure is done to repair birth defects like spina bifida, in which a baby’s back bones don’t form properly around the spinal cord. This opening in the spine that leads to excess spinal fluid and leaves spinal cord nerve cells unprotected from the surrounding tissue.  These abnormalities can lead to brain damage, paralysis and loss of bladder control.

Although prenatal surgery to close up the defect can reduce future neurological problems in the child’s life, there is an increased danger of significant complications including preterm birth, separation of the placenta from the uterus and premature breaking on the amniotic membrane (ie breaking the mother’s water).

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Microscopy image of iSkin, three-dimensional cultured skin derived from human iPSCs. Credit: Kazuhiro Kajiwara.

A research team at Japan’s National Research Institute for Child Health and Development is trying to overcome these problems by developing a less invasive prenatal therapy for spina bifida using stem cells. And this week, they published a Stem Cell Reports study that shows encouraging preclinical results in rodents.

The most severe and common form of spina bifida called myelomeningocele usually leads to the formation of a fluid-filled bulge protruding from a newborn’s back. The team’s therapeutic approach is to graft 3D layers of stem cell-derived skin early in the pregnancy to prevent the bulge from forming in the first place. This minimally invasive procedure would hopefully be less risky than the surgical approach.

To demonstrate a proof of concept for this approach, skin graft experiments were performed on fetal rats that had myelomeningocele-like symptoms induced by the hormone retinoic acid. Human amniotic fluid cells collected from two pregnancies with severe fetal defects were used to derived human iPSCs which were then specialized into skin cells. Over a 14-week period – a timeline short enough to allow the eventual human procedure to be performed within the 28th to 29th week of pregnancy – the cells were grown into 3D layers they call, “iSkin”.

The iSkin grafts were transplanted in 20 fetal rats through a small cut into the wall of the uterus. At birth, the myelomeningocele defect in four rats was completely covered and partially covered in another eight rats. It’s encouraging to note that no tumors formed from the skin transplants, a concern when dealing with iPSC-derived cell therapies. In press release, team lead Dr. Akihiro Umezawa spoke about the promise of this approach but also the work that still lies ahead:

“We are encouraged by our results and believe that our fetal stem cell therapy has great potential to become a novel treatment for myelomeningocele. However, additional studies in larger animals are needed to demonstrate that our fetal stem cell therapy safely promotes long-term skin regeneration and neurological improvement.”