The best tools to be the best advocate

It’s hard to do a good job if you don’t have the right tools. And that doesn’t just apply to fixing things around the house, it applies to all aspects of life. So, in launching our new website this week we didn’t just want to provide visitors to the site with a more enjoyable and engaging experience – though we hope we have done that – we also wanted to provide a more informative and helpful experience. That’s why we have created a whole new section call the Patient Advocate Toolbox. shutterstock_150769385

The goal of the Toolbox is simple; to give patients and patient advocates help in learning the skills they need to be as effective as possible about raising awareness for their particular cause.

As an advocate for a disease or condition you may be asked to speak at public events, to be part of a panel discussion at a conference, or to do an interview with a reporter. Each of those requires a particular set of skills, in areas that many of us may have little, if any, experience in.

That’s where the Toolbox comes in. Each section deals with a different opportunity for you to share your story and raise awareness about your cause.

In the section on “Media Interviews”, for example, we walk you through the things you need to think about as you prepare to talk to a reporter; the questions to ask ahead of time, how to prepare a series of key messages, even how to dress if you are going to be on TV. The idea is to break down some of the mystique surrounding the interview, to let you know what to expect and to help you prepare as fully as possible.

If you are going to be asked questions about stem cell research there’s a section in the Toolbox called “Jargon-Free Glossary” that translates scientific terms into every-day English, so you can talk about this work in a way that anyone can understand.

There’s also a really wonderfully visual infographic on the things you need to know when thinking about taking part in a clinical trial. It lays out in simple, easy-to-follow steps the questions you should ask, the potential benefits and problems of being in a trial, including the risks of going overseas for unproven therapies.

The Toolbox is by no means an exhaustive list of all the things you will need to know to be an effective advocate, either for yourself or a friend or loved one, but it is a start.

We would love to hear from you on ways we can improve the content, on other elements that would be useful to include, on links to other sites that you think would be helpful to add. Our goal is to make this as comprehensive and useful as possible. Your support, your ideas and thoughts will help us do just that. If you have any comments please send them to info@cirm.ca.gov

Thomas Carlyle, the Scottish philosopher, once wrote: “Man is a tool-using animal. Without tools he is nothing, with tools he is all.” That’s why we want to give you the tools you need to be as effective as you can. Because the more powerful your voice, the more we all benefit.

CIRM Launches New and Improved Website

CIRM has experienced many exciting changes over the past year: we’ve welcomed a new president, revamped our blog and—perhaps most importantly—announced a radical overhaul in how we fund stem cell research with the launch of CIRM 2.0. That’s not even mentioning the 11 projects we are now funding in clinical trials.

And now, we’d like to announce our latest exciting change: we’ve given our website a facelift that reflects the new CIRM 2.0. Allow us to introduce you to the new digital home of California’s Stem Cell Agency:

CIRM Homepage

Our mission—accelerating stem cell treatments to patients with unmet medical needs—informs everything we do here at CIRM, and the redesign of our website is no different. In improving our site, we hope to better serve two important audiences who are critical in us achieving our mission:

  • Current and potential grantees from research institutions and industry; and
  • Patients, patient advocates and the public at large who are helping others understand how CIRM-funded scientists are turning stem cells into cures.

We are also using this opportunity to improve the way we are viewed on mobile devices. With up to 40 percent of our visitors coming to cirm.ca.gov via a smartphone or tablet, we wanted to create a superior mobile user experience—so that people can easily access the same content whether they are at home or on the go.

We began this project just a few short months ago, and are thankful for a stellar team of in-house staff and contractors who each dove in to lend a hand. We are especially grateful to Radiant, who worked with CIRM to develop an improved design and navigation.

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As part of the process of updating the website we also took the opportunity to update our logo. The old logo was ten years old, an eternity in the age of the Internet. We wanted something that reflected our new streamlined approach to funding, something that was visually appealing and contemporary and something that immediately connected the viewer to who we are and what we do. We hope you like it.

So please, take a look around at the new cirm.ca.gov—we hope you enjoy using it as much as we enjoyed creating it for you. And of course if you have any thoughts or suggestions on how we can improve this even more we’d love to hear from you in the comments below.

New understanding of the inner workings of our genetic tool kit should help us make smarter repairs

For young biology students the steps from genes to their function becomes a mantra: DNA makes RNA and RNA makes protein. But it is really not quite that simple. A few different types of RNA act along the path and we are now learning that the structure, or shape, of the individual RNA molecules affects their function.

Which genes succeed in producing their designated protein determines what the cell actually does—what kind of tissue it is and how well it performs the role it is assigned. Switching gene function on and off turns out to be quite complex with players among the molecules that are part of the backbone of DNA as well as the various forms of RNA. We have made great strides in the past decade in understanding the role of those DNA structural components, the so-called epigenetics, but still have major gaps in our understanding of the many roles of RNA.

DNA dogmaWith CIRM-funding, a team headed by Howard Chang at Stanford has gotten around a major hurdle in unlocking this complex issue. Like DNA, RNA is made up of various repeats of four molecules called bases. Prior to Chang’s work researchers could only track the structure of RNA associated with two of those bases. His team modified a commonly used bio-chemical tool called SHAPE to reveal the workings of all four RNA bases in living cells.

The team verified something that is increasingly being shown, static cells frozen in time a lab dish do not necessarily reflect what goes on in living cells. In this study those differences manifest in the structure of the RNA that determines what molecules are next to each other, which impacts their activity. After more than 2 billion measurements of more than 13,000 RNAs in the lab and in living cells, the team quantified those differences and showed how this molecular “folding” changes the function of the various RNAs.

They published the work, for which they used mouse embryonic stem cells, on-line today in Nature. In the closing paragraph of the journal article they speculate on the impact of the new ability to better understand the roles of RNA:

“In the future, viewing the RNA structurome when cells are exposed to different stimuli or genetic perturbations should revolutionize our understanding of gene regulation in biology and medicine.”

Since so many of the research projects that seek to reverse the course of disease try to change the genetic functioning of cells, this new understanding should be able to reduce the number of blind alleys scientist have to go down to get a desired result. It should allow the design of studies based on more logic and less chance, speeding the development of therapies.

Conference provides critical connections between clinical projects and investors

Having a mission like CIRM’s, which calls on us to develop therapies for unmet medical needs, clearly means we cannot sit back and marvel at all the great projects we have in the pipeline. We have to deliver commercial products available to all patients in need. And that cannot be done without additional investors.

The Alliance for Regenerative Medicine (ARM) takes that maxim seriously as well. The international advocacy organization, of which CIRM was a founding member five years ago, will host its third annual RegenMed Investor Day in New York City next Wednesday March 25.
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During the full-day event 32 companies will present their progress to a wide array of investors. Traditional venture capital investors will be represented alongside investors from institutions and multinational pharmaceutical giants.

The day will be rounded out with three panel discussions and two fireside chats with market research analysts, company CEOs and leading clinicians. The fireside chat during lunch will feature CIRM President and CEO Dr. C. Randall Mills who will talk about public-private partnerships making joint investments to bring therapies to patients, and how the revised work plan we call CIRM 2.0 will make it easier for companies to work together with CIRM to advance promising therapies.

Getting just the eleven projects CIRM is funding in clinical trials today through to commercial products will require a broad mix of funding partnerships. With our portfolio and that of the industry as a whole growing rapidly, conferences like this one are critical.

Pathway discovered that could yield therapies to prevent hearts turning to “bone”

In the Rolling Stones’ lyrics having a “Heart of Stone” protected you from heartbreak. But over a million Americans are developing hearts of bone and it could kill them.

CIRM-funded researchers at the Gladstone Institutes think they have uncovered the path to this destructive hardening of the heart and that could lead to therapies to stop the damage. In particular, they looked at heart valves and why in some people the cells in those valves start acting like bone and produce calcium that causes them to get rigid and loose their proper function.

Valve cells come from a family of cells called endothelial cells that includes the lining of blood vessels, which are also prone to inappropriate production of calcium and hardening. So, the findings could have much broader implication for heart disease and therapy.

A mutation in the Notch1 gene makes cells react inappropriately to the sheer stress caused by blood flow. Team found BMP, SFB and MMP genes control this.

A mutation in the Notch1 gene makes cells react inappropriately to the sheer stress caused by blood flow. Team found BMP, SFB and MMP genes control this.

Led by senior author Deepak Srivastava, the team used stem cell technology to create endothelial cells from patients with genetic calcific aortic valve disease (CAVD) and from normal individuals. They then pushed those cells to mature into valve cells in the lab and monitored which genes were turned on or off during the process, comparing the disease carrying and normal cells.

They built on a previous discovery of Srivastava, who found that a defect in the gene NOTCH1 can cause valve birth defects and CAVD. Searching hundreds of genes and gene switches they came upon three genes that appear to be master regulators of the path that leads cells to overproduce calcium. In a press release from the Gladstone, he said:

“Identifying these master regulators is a big step in treating CAVD, not just in people with the NOTCH1 mutation, but also in other patients who experience calcification in their valves and arteries. Now that we know how calcification happens and what the key nodes are, we know what genes to look for that might be mutated in other related forms of cardiovascular disease.”

The release noted that the research team is now screening for drugs that can act on this gene network. Srivastava’s main focus has been on congenital pediatric heart disease. He discusses that research in three brief videos that include the story of one very special young patient.

Pioneer’s 25-year struggle to treat blindness

Being a pioneer is never easy. You are charting unknown territory, tackling problems that have defeated others before you. You have to overcome so many obstacles that at times the challenge can seem insurmountable. But for those who succeed in reaching their goal, the rewards can be extraordinary.

Graziella Pellegrini, Center for Regenerative Medicine, University of Modena, Italy

Graziella Pellegrini, Center for Regenerative Medicine, University of Modena, Italy

Last month Italian researcher Graziella Pellegrini saw 25 years of work pay off when a treatment she developed to cure a form of blindness was given approval for sale by the European Commission.

This is quite an achievement as this means her treatment, called Holoclar, is among the first commercial stem therapies in the world (the first was Prochymal, which has been approved in Canada and New Zealand for the treatment of pediatric GVHD. This drug was developed by Osiris, which was led by our current President & CEO, Dr. Randy Mills.)

Holoclar uses stem cells to help stimulate the regrowth of a cornea. It can only be used for certain rare conditions, but that in no way diminishes its importance for patients or significance for the regenerative medicine field as a whole.

Nature recently sat down with Dr. Pellegrini to talk about her work, her struggle, and the many obstacles she had to overcome to get market approval for her work.

The interview makes for fascinating reading, and is a timely reminder why this kind of groundbreaking research never goes quite as quickly, or smoothly, as one would hope.

CIRM currently has a number of projects focused treating different causes of blindness on limbal cells (the kind Dr. Pellegrini worked on) and other forms of blindness; including a project to treat macular degeneration that has been approved for a clinical trial, and a therapy for retinitis pigmentosa that we hope will be approved for a clinical trial later this year.

One-Time, Lasting Treatment for Sickle Cell Disease May be on Horizon, According to New CIRM-Funded Study

For the nearly 1,000 babies born each year in the United States with sickle cell disease, a painful and arduous road awaits them. The only cure is to find a bone marrow donor—an exceedingly rare proposition. Instead, the standard treatment for this inherited blood disorder is regular blood transfusions, with repeated hospitalizations to deal with complications of the disease. And even then, life expectancy is less than 40 years old.

In Sickle Cell Disease, the misshapen red blood cells cause painful blood clots and a host of other complications.

In Sickle Cell Disease, the misshapen red blood cells cause painful blood clots and a host of other complications.

But now, scientists at UCLA are offering up a potentially superior alternative: a new method of gene therapy that can correct the genetic mutation that causes sickle cell disease—and thus help the body on its way to generate normal, healthy blood cells for the rest of the patient’s life. The study, funded in part by CIRM and reported in the journal Blood, offers a great alternative to developing a functional cure for sickle cell disease. The UCLA team is about to begin a clinical trial with another gene therapy method, so they—and their patients—will now have two shots on goal in their effort to cure the disease.

Though sickle cell disease causes dangerous changes to a patient’s entire blood supply, it is caused by one single genetic mutation in the beta-globin gene—altering the shape of the red blood cells from round and soft to pointed and hard, thus resembling a ‘sickle’ shape for which the disease is named. But the UCLA team, led by Donald Kohn, has now developed two methods that can correct the harmful mutation. As he explained in a UCLA news release about the newest technique:

“[These results] suggest the future direction for treating genetic diseases will be by correcting the specific mutation in a patient’s genetic code. Since sickle cell disease was the first human genetic disease where we understood the fundamental gene defect, and since everyone with sickle cell has the exact same mutation in the beta-globin gene, it is a great target for this gene correction method.”

The latest gene correction technique used by the team uses special enzymes, called zinc-finger nucleases, to literally cut out and remove the harmful mutation, replacing it with a corrected version. Here, Kohn and his team collected bone marrow stem cells from individuals with sickle cell disease. These bone marrow stem cells would normally give rise to sickle-shaped red blood cells. But in this study, the team zapped them with the zinc-finger nucleases in order to correct the mutation.

Then, the researchers implanted these corrected cells into laboratory mice. Much to their amazement, the implanted cells began to replicate—into normal, healthy red blood cells.

Kohn and his team worked with Sangamo BioSciences, Inc. to design the zinc-finger nucleases that specifically targeted and cut the sickle-cell mutation. The next steps will involve improving the efficiency and safest of this method in pre-clinical animal models, before moving into clinical trials.

“This is a promising first step in showing that gene correction has the potential to help patients with sickle cell disease,” said UCLA graduate student Megan Hoban, the study’s first author. “The study data provide the foundational evidence that the method is viable.”

This isn’t the first disease for which Kohn’s team has made significant strides in gene therapy to cure blood disorders. Just last year, the team announced a promising clinical trial to cure Severe Combined Immunodeficiency Syndrome, also known as SCID or “Bubble Baby Disease,” by correcting the genetic mutation that causes it.

While this current study still requires more research before moving into clinical trials, Kohn and his team announced last month that their other gene therapy method, also funded by CIRM, has been approved to start clinical trials. Kohn argues that it’s vital to explore all promising treatment options for this devastating condition:

“Finding varied ways to conduct stem cell gene therapies is important because not every treatment will work for every patient. Both methods could end up being viable approaches to providing one-time, lasting treatments for sickle cell disease and could also be applied to the treatment of a large number of other genetic diseases.”

Find Out More:
Read first-hand about Sickle Cell Disease in our Stories of Hope series.
Watch Donald Kohn speak to CIRM’s governing Board about his research.

Stay on Target: Scientists Create Chemical ‘Homing Devices’ that Guide Stem Cells to Final Destination

When injecting stem cells into a patient, how do the cells know where to go? How do they know to travel to a specific damage site, without getting distracted along the way?

Scientists are now discovering that, in some cases they do but in many cases, they don’t. So engineers have found a way to give stem cells a little help.

As reported in today’s Cell Reports, engineers at Brigham and Women’s Hospital (BWH) in Boston, along with scientists at the pharmaceutical company Sanofi, have identified a suite of chemical compounds that can help the stem cells find their way.

Researchers identified a small molecule that can be used to program stem cells (blue and green) to home in on sites of damage. [Credit: Oren Levy, Brigham and Women's Hospital]

Researchers identified a small molecule that can be used to program stem cells (blue and green) to home in on sites of damage. [Credit: Oren Levy, Brigham and Women’s Hospital]

“There are all kinds of techniques and tools that can be used to manipulate cells outside the body and get them into almost anything we want, but once we transplant cells we lose complete control over them,” said Jeff Karp, the paper’s co-senior author, in a news release, highlighting just how difficult it is to make sure the stem cells reach their destination.

So, Karp and his team—in collaboration with Sanofi—began to screen thousands of chemical compounds, known as small molecules, that they could physically attach to the stem cells prior to injection and that could guide the cells to the appropriate site of damage. Not unlike a molecular ‘GPS.’

Starting with more than 9,000 compounds, the Sanofi team narrowed down the candidates to just six. They then used a microfluidic device—a microscope slide with tiny glass channels designed to mimic human blood vessels. Stem cells pretreated with the compound Ro-31-8425 (one of the most promising of the six) stuck to the sides. An indication, says the team, Ro-31-8425 might help stem cells home in on their target.

But how would these pre-treated cells fare in animal models? To find out, Karp enlisted the help of Charles Lin, an expert in optical imaging at Massachusetts General Hospital. First, the team injected the pre-treated cells into mouse models each containing an inflamed ear. Then, using Lin’s optical imaging techniques, they tracked the cells’ journey. Much to their excitement, the cells went immediately to the site of inflammation—and then they began to repair the damage.

According to Oren Levy, the study’s co-first author, these results are especially encouraging because they point to how doctors may someday soon deliver much-needed stem cell therapies to patients:

“There’s a great need to develop strategies that improve the clinical impact of cell-based therapies. If you can create an engineering strategy that is safe, cost effective and simple to apply, that’s exactly what we need to achieve the promise of cell-based therapy.”

Heroic three-year study reveals safe methods for growing clinical-grade stem cells

Imagine seeking out the ideal pancake recipe: should you include sugar or no sugar? How about bleached vs. unbleached flour? Baking power or baking soda? When to flip the pancake on the skillet? You really have to test out many parameters to get that perfectly delicious light and fluffy pancake.

Essentially that’s what a CIRM-funded research team from both The Scripps Research Institute (TSRI) and UC San Diego accomplished but instead of making pancakes they were growing stem cells in the lab. In a heroic effect, they spent nearly three years systematically testing out different recipes and found conditions that should be safest for stem cell-based therapies in people. Their findings were reported today in PLOS ONE.

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Pluripotent stem cells. Courtesy of Andres Bratt-Leal from Jeanne Loring’s laboratory.

Let’s step back a bit in this story. If you’re a frequent reader of The Stem Cellar you know that one of the reasons stem cells are such an exciting field of biology is their pluripotency. That is, these nondescript cells have the capacity to become any type of cell in the body (pluri= many; potency = potential). This is true for embryonic stem cells and induced pluripotent cells (iPS). Several clinical trials underway or in development aim to harness this shape-shifting property to return insulin producing cells to people living with diabetes or to restore damaged nerves in victims of spinal cord injury, to name just two examples.

The other defining feature of pluripotent stem cell is their ability to make copies of themselves and grow indefinitely on petri dishes in the laboratory. As they multiply, the cells eventually take up all the real estate on the petri dish. If left alone the cells exhaust their liquid nutrients and die. So the cells must regularly be “passaged”; that is, removed from the dish and split into more dishes to provide new space to grow. This is also necessary for growing up enough quantities of cells for transplantation in people.

Previous small scale studies have observed that particular recipes for growing pluripotent cells can lead to genetic instability, such as deletion or duplication of DNA, that is linked with cancerous growth and tumor formation. This is perhaps the biggest worry about stem cell-based transplantation treatments: that they may cure disease but also cause cancer.

To find the conditions that minimize this genetic instability, the research team embarked on the first large-scale systematic study of the effects of various combinations of cell growth methods. One of the senior authors Louise Laurent, assistant professor at UC San Diego, explained in a press release the importance of this meticulous, quality control study:

“The processes used to maintain and expand stem cell cultures for cell replacement therapies needs to be improved, and the resulting cells carefully tested before use.”

To seek the ideal recipe, the team tested several parameters. For example, they grew some cells on top of so-called “feeder cells”, which help the stem cells grow while other cells used feeder-free conditions. Two different passaging methods were examined: one uses an enzyme solution to strip the cells off the petri dish while in the other method the cells are manually removed. Different liquid nutrients for the cell were included in the study as well. The different combinations of cells were grown continuously through 100 passages and changes in their genetic stability were periodically analyzed along the way.

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Jeanne Loring (above) is professor of developmental neurobiology at TSRI and senior author of the study with Louise Laurent of the University of California, San Diego.

The long-term experiment paid off: the team found that the stem cells grown on feeder free petri dishes and passaged using the enzyme solution accumulated more genetic abnormalities than cells grown on feeder cells and passaged manually. The team also observed genetic changes after many cells passages. In particular, a recurring deletion of a gene called TP53. This gene is responsible for making a protein that acts to suppress cancers. So without this suppressor, later cell passages have the danger of becoming cancerous.

Based on these results, the other senior author, Jeanne Loring, a professor of developmental neurobiology at TSRI, gave this succinct advice:

“If you want to preserve the integrity of the genome, then grow your cells under those conditions with feeder cells and manual passaging. Also, analyze your cells—it’s really easy.”

Stem cell stories that caught our eye; progress toward artificial brain, teeth may help the blind and obesity

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.

More progress toward artificial brain. A team at the RIKEN Institute in Japan has used stem cells in a 3-D culture to create brain tissue more complex than prior efforts and from an area of the brain not produced before, the cerebellum—that lobe at the lower back of the brain that controls motor function and attention. As far back as 2008, a RIKEN team had created simple tissue that mimicked the cortex, the large surface area that controls memory and language.

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The Inquisitr web portal wrote a feature on a wide variety of efforts to create an artificial brain teeing off of this week’s publication of the cerebellum work in Cell Reports. The piece is fairly comprehensive covering computerized efforts to give robots intelligence and Europe’s Human Brain Project that is trying to map all the activity of the brain as a starting point for recapitulating it in the lab.

The experts interviewed included Robert Caplan of Tufts University in Massachusetts who is using 3-D scaffolding to build functional brain tissues that can process electrical signals. He is not planning any Frankenstein moments; he hopes to create models to improve understanding of brain diseases.

“Ideally we would like to have a laboratory brain system that recapitulates the most devastating diseases. We want to be able to take our existing toolkit of drugs and understand how they work instead of using trial and error.”

Teeth eyed as source of help for the blind. Today the European Union announced the first approval of a stem cell therapy for blindness. And already yesterday a team at the University of Pittsburg announced they had developed a new method to use stem cells to restore vision that could expand the number of patients who could benefit from stem cell therapy.

Many people have lost part or all their vision due to damage to the cornea on the surface of their eye. Even when they can gain vision back through a corneal transplant, their immune system often rejects the new tissue. So the ideal would be making new corneal tissue from the patient’s own cells. The Italian company that garnered the EU approval does this in patients by harvesting some of their own cornea-specific stem cells, called limbal stem cells. But this is only an option if only one eye is impacted by the damage.

The Pittsburgh team thinks it may have found an unlikely alternative source of limbal cells: the dental pulp taken from teeth that have be extracted. It is not as far fetched at it sounds on the surface. Teeth and the cornea both develop in the same section of the embryo, the cranial neural crest. So, they have a common lineage.

The researchers first treated the pulp cells with a solution that makes them turn into the type of cells found in the cornea. Then they created a fiber scaffold shaped like a cornea and seeded the cells on it. Many steps remain before people give up a tooth to regain their sight, but this first milestone points the way and was described in a press release from the journal Stem Cells Translational Medicine, which was picked up by the web site ClinicaSpace.

CIRM funds a project that also proposes to use the patient’s own limbal stem cells but using methods more likely to gain approval of the Food and Drug Administration than those used by the Italian company.

Stem cells and the fight against obesity. Of the two types of stem cells found in your bone marrow, one can form bone and cartilage and, all too often, fat. Preventing these stem cells from maturing into fat may be a tool in the fight against obesity according to a team at Queen Mary University of London.

The conversion of stem cells to fat seems to involve the cilia, or hair-like projections found on cells. When the cilia lengthen the stem cells progress toward becoming fat. But if the researchers genetically prevented that lengthening, they stopped the conversion to fat cells. The findings opens several different ways to think about understanding and curbing obesity says Melis Dalbay one of the authors of the study in a university press release picked up by ScienceNewsline.

“This is the first time that it has been shown that subtle changes in primary cilia structure can influence the differentiation of stem cells into fat. Since primary cilia length can be influenced by various factors including pharmaceuticals, inflammation and even mechanical forces, this study provides new insight into the regulation of fat cell formation and obesity.”