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.”

Roadmap to our epigenome reveals the genetic switches that make one adult cell type different from others

A decade ago scientists made a huge news splash when they announced the completion of the human genome project declaring it the first road map of our genes. But it did not take long to realize that the early road map was like some of the early days of GPS systems: it lacked knowledge of many on-ramps, off-ramps and one-way streets.

Today, the scientific world announced a massive fix to its genetic GPS. While all of our cells carry the same genes, their function varies wildly based one which genes are turned off, which are turned on, and even which are turned on in a hyper active way. Complex chemical and structural changes in the chromosomes that house our genes—collectively called the epigenome—determine that activity.

This video from Nature explaining the epigenome with music metaphors is linked in the last paragraph.

This video from Nature explains the epigenome with music metaphors.


A massive project, mostly funded by the National Institutes of Health through a consortium of research teams around the country, published a series of papers today in Nature. The Roadmap Epigenomic Consortium did extensive analysis of 111 epigenomes from different types of cells: normal heart tissue and immune cells, for example, as well as cells from patients with diseases such as neurons from patients with Alzheimer’s. The Scientist this morning quoted one member of the Consortium, MIT’s Manolis Kellis:

“The human epigenome is this collection of . . . chemical modifications on the DNA itself and on the packaging that holds DNA together. All our cells have a copy of the same book, but they’re all reading different chapters, bookmarking different pages, and highlighting different paragraphs and words.”

CIRM funding contributed to two of the papers authored by a team at the University of California, San Diego. One of the papers looked at how the genetic structure of stem cells changes as they mature and differentiate into specific types of adult tissue. The other looked at how structural differences determine which of the chromosomes we inherit—the one from mom or the one from dad—has a stronger influence on specific traits. The senior author on the studies, Bing Ren, noted in a university press release that these differences will be important as we think about individualizing therapies:

“Both of these studies provide important considerations for clinicians and researchers who are developing personalized medicines based on a patient’s genomic information”

The consortium’s publications today resulted from a massive data analysis. A press release from the Broad Institute in Cambridge, Massachusetts, describes the effort that required grouping two million predicted areas of change in the chromosomes into 200 sets or modules and then looking for how those modules impacted different cell types.

But if you are still having trouble understanding the concept of the epigenome, I highly recommend taking the five minutes it takes to watch this video produced by Nature. It equates the process to a symphony and what occurs when you change notes and intensity in the score.

Combination Cancer Therapy Gives Cells a Knockout Punch

For some forms of cancer, there really is no way to truly eradicate it. Even the most advanced chemotherapy treatments leave behind some straggler cells that can fuel a relapse.

By hitting breast cancer cells with a targeted therapeutic immediately after chemotherapy, researchers were able to target cancer cells during a transitional stage when they were most vulnerable. [Credit: Aaron Goldman]

By hitting breast cancer cells with a targeted therapeutic immediately after chemotherapy, researchers were able to target cancer cells during a transitional stage when they were most vulnerable.
[Credit: Aaron Goldman]

But now, scientists have devised a unique strategy, something they are calling a ‘one-two punch’ that can more effectively wipe out dangerous tumors, and lower the risk of them ever returning for a round two.

Reporting in the latest issue of the journal Nature Communications, bioengineers at Brigham and Women’s Hospital (BWH) in Boston describe how treating breast cancer cells with a targeted drug immediately after chemotherapy was effective at killing the cancer cells and preventing a recurrence. According to lead scientist Shiladitya Sengupta, these findings were wholly unexpected:

“We were studying the fundamentals of how [drug] resistance develops and looking to understand what drives [cancer] relapse. What we found is a new paradigm for thinking about chemotherapy.”

In recent years, many scientists have suggested cancer stem cells are one of the biggest hurdles to curing cancer. Cancer stem cells are proposed to be a subpopulation of cancer cells that are resistant to chemotherapy. As a result, they can propagate the cancer after treatment, leading to a relapse.

In this work, Sengupta and his colleagues treated breast cancer cells with chemotherapy. And here is where things started getting interesting.

After chemotherapy, the breast cancer cells began to morph into cells that bore a close resemblance to cancer stem cells. For a brief period of time after treatment, these cells were neither fully cancer cells, nor fully stem cells. They were in transition.

The team then realized that because these cells were in transition, they may be more vulnerable to attack. Testing this hypothesis in mouse models of breast cancer, the team first zapped the tumors with chemotherapy. And, once the cells began to morph, they then blasted them with a different type of drug. The tumors never grew back, and the mice survived.

Interestingly, the team did not have similar success when they altered the timing of when they administered the therapy. Treating the mice with both types of drugs simultaneously didn’t have the same effect. Neither did increasing the time between treatments. In order to successfully treat the tumor they had a very slim window of opportunity.

“By treating with chemotherapy, we’re driving cells through a transition state and creating vulnerabilities,” said Aaron Goldman, the study’s first author. “This opens up the door: we can then try out different combinations and regimens to find the most effective way to kill the cells and inhibit tumor growth.”

In order to test these combinations, the researchers developed an ‘explant,’ a mini-tumor derived from a patient’s biopsy that can be grown in an environment that closely mimics its natural surroundings. The ultimate goal, says Goldman, is to map the precise order and timing of this treatment regimen in order to move toward clinical trials:

“Our goal is to build a regimen that will be [effective] for clinical trials. Once we’ve understood specific timing, sequence of drug delivery and dosage better, it will be easier to translate these findings clinically.”

All Things Being (Un)Equal: Scientists Discover Gene that Breaks Traditional Laws of Inheritance

One of the most fundamental laws of biology is about to be turned on its head, according to new research from scientists at the University of North Carolina (UNC) School of Medicine.

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As reported in the journal PLOS Genetics, UNC researchers identified a gene that does not obey traditional laws that determine how genes get passed down from parents to offspring. In experiments on laboratory mice, they found a gene called R2d2 causes female mice to pass on more genetic information than the males did—an observation that appears to contradict principles of genetic inheritance set forth more than a century ago.

As you may (or may not) remember from freshmen biology class, the laws of inheritance were laid down by the 19th century monk Gregor Mendel. Through meticulous observations of his garden’s pea plants, he found that each parent contributes their genetic information equally to their offspring.

But 150 years of scientific discovery later, scientists have discovered that this isn’t always the case.

Instead, in some cases one of the parents will contribute a greater percentage of genetic information than the other, a process called meiotic drive. Scientists had seen evidence of this process occurring in mammals for quite some time, but hadn’t narrowed down the driver of the process to a particular gene. According to UNC researchers, R2d2 is that gene. Senior author Fernando Pardo-Manuel de Villena explains:

“R2d2 is a good example of a poorly understood phenomenon known as female meiotic drive—when an egg is produced and a ‘selfish gene’ is segregated to the egg more than half the time.”

Pardo-Manuel de Villena notes that one example of this process occurs during trisomies—when three chromosomes (two from one parent and one from the other) are passed down to the embryo. The most common trisomy, trisomy 21, is more commonly known as Down Syndrome.

With these findings, Pardo-Manuel de Villena and the team are hoping to gain important insights into the underlying cause of trisomies, as well as the underlying causes for miscarriage—which are often not known.

“Understanding how meiotic drive works may shed light on the … abnormalities underlying these disorders,” said Pardo-Manuel de Villena.

This research was performed in large part by first author John Didion, who first discovered R2d2 when breeding two different types of mice for genetic analysis. Using whole-genome sequencing of thousands of laboratory mice, Didion and his colleagues saw that genes were passed down equally from each mouse’s parents. But a small section, smack dab in the middle of chromosome 2, was different.

Further analysis revealed that this section of chromosome 2 had a disproportionately larger number of genes from the mouse’s mother, compared to its father—showing a clear example of female meiotic drive. And at the heart of it all, Didion discovered, was the R2d2 gene.

The UNC team are already busy diving deeper into the relationship between R2d2 and meiotic drive with a focus on understanding, and one day perhaps correcting, genetic abnormalities in the developing embryo.

Stem cell stories that caught our eye: repairing radiation damage, beta thalassemia clinical trial and disease models

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.

Stem cells repair brain damage from radiation therapy. Radiation for brain cancer can be a lifesaver but it can also be a dramatic life changer. If often leaves patients with considerably reduced brain function. Now a team at New York’s Memorial Sloan Kettering Cancer Center has found a way to instruct human stem cells to repair some of that damage—at least in rats.

The damage seems to be to the middle-man or so-called progenitor cells that maintain the myelin cells that insulate the nerves in the brain. When that myelin is damaged by the radiation those progenitor cells are no longer able to make repairs and that results in reduced nerve function. Rats given the stem cells regained both cognitive and motor skills lost after brain radiation.

The team leader, Viviane Taber, noted this work could make radiation therapy even more of a lifesaver. ScienceDaily quoted Tabar from materials provided by Cell Press that published the work:

“This will have to be proven further, but if we can repair the brain effectively, we could be bolder with our radiation dosing, within limits.”

This could be especially important in children, for whom physicians deliberately deliver lower radiation doses.


Stem cell trial for Beta-Thalassemia cleared to begin.
CIRM-grantee Sangamo BioSciences announced this week that the Food and Drug Administration (FDA) had accepted its application to begin a clinical trial using genetically edited stem cells to treat patients with beta-thalassemia. This trial, in patients who require regular blood transfusions to survive, is the ninth CIRM-funded clinical trail to gain clearance from the FDA.

Other clinical trials have used genetically modified stem cells, but they have used various techniques to add a correct gene or silence an unwanted gene. This will be the first clinical trial using one of the newer techniques that actually goes into a person’s genes and edits them to correct a disease. We wrote about this beta-thalassemia project here.

The Sacramento Business Times picked up the company’s press release that quoted Sangamo president Edward Lanphier on the company’s goal, “the aim of providing transfusion-dependent beta-thalassemia patients with a one-time treatment for this devastating disease.”

Disease modeling for science wonks. Vivien Marx wrote a feature article for Nature Methods that provides the most thorough review of the use of reprogramed iPS-type stem cells as disease models that I have read. In particular she discusses the power of using new gene editing tools to modify the cells so that when they mature into adult tissues they will display specific disease traits.

Svendsen hopes to use gene-edited iPS type stem cells to fully understand neurodegenerative diseases

Svendsen hopes to use gene-edited iPS type stem cells to fully understand neurodegenerative diseases

She starts with a narrative about CIRM-grantee Clive Svendsen’s work to understand spinal muscular atropohy (SMA) when he was in Wisconsin and to understand amyotrophic lateral sclerosis (ALS) now at Cedars Sinai in Los Angeles. She goes on to show just how powerful these gene-edited stem cells can be, but also how difficult it is to use the technology in a way that generates useful information. Marx is a strong science journalist, who for many years has shown a skill at explaining complex technologies.

She also discusses the various iPS cell banks developed around the world including CIRM’s cell bank and the value of having non-gene-edited cells from patients that naturally show the disease traits.

Thorough review of changes at CIRM.
Alex Lash at xconomy wrote an in-depth overview of our president Randy Mills’ plans for the next phase of our agency that Randy calls CIRM 2.0. Calling the plans an extensive “renovation” Lash described the portions of the new structure that were already in place and listed the ones set to come online in the next six months.

As a balanced journalist he runs through some of the highs and lows of our public perception during the initial phase of the agency and then discusses the new tone set by Mills:

“CIRM is less a grant-making government agency than a ‘discerning investor’ that’s going to be ‘as creative and innovative’ as possible in getting treatments approved, Mills says. ‘We have no mission above accelerating stem cell therapies to patients.’ ”

MIT Scientists Recreate Malaria in a Dish to Test Promising Drug Candidates

At the beginning, it feels like the flu: aches, pains and vomiting. But then you begin to experience severe cold and shivering, followed by fever and sweating—a cycle, known as tertian fever, that repeats itself every two days. And that’s when you know: you’ve contracted malaria.

Malaria is caused by Plasmodium parasites and spread to people through the bites of infected mosquitoes

Malaria is caused by Plasmodium parasites and spread to people through the bites of infected mosquitoes

But you wouldn’t be alone. According to the World Health Organization, nearly 200 million people, mostly in Africa, contracted the disease in 2013. Of those, nearly half a million—mainly children—died. There is no cure for malaria, and the parasites that cause the disease are quickly developing resistance to treatments. This is a global public health crisis, and experts agree that in order to halt its spread, they must begin thinking outside the box.

Enter Sangeeta Bhatia, renowned biomedical engineer from the Massachusetts Institute of Technology (MIT)—who, along with her team, has devised a quick and easy way to test out life-saving drug candidates that could give doctors and aid workers on the front lines fresh ammunition.

One of the key hurdles facing scientists has been the nature of the disease’s progression itself. Caused by parasites transmitted via infected mosquitos, the disease first takes hold in the liver. It is only after a few weeks that it enters the blood stream, causing symptoms. By then, the disease is so entrenched within the patient that complete eradication is extremely difficult. Even if the patient recovers, he or she will likely suffer relapses weeks, months or even years later.

The trick, therefore, is to catch the disease before it enters the blood stream. To that effect, several promising drugs have been put forth, and scientists are eager to test them out on liver tissue infected with malaria. Except that they can’t: liver tissue donors are few and far between, and lack the genetic diversity needed for large-scale testing.

Liver-stage malarial infection in iPSC-derived liver cells, eight days after infection. [Credit Ng et al.]

Liver-stage malarial infection in iPSC-derived liver cells, eight days after infection. [Credit Ng et al.]

So Bhatia and her team developed a new solution: they’d make the cells themselves. Reporting in today’s issue of Stem Cell Reports, the team describes how they transformed human skin cells into liver cells, by way of induced pluripotent stem cell (iPS cell) technology. Then, by infecting these cells with the malaria parasite, they could test a variety of drug candidates to see which worked best. As Bhatia explained:

“Our platform can be used for testing candidate drugs that act against the parasite in the early liver stages, before it causes disease in the blood and spreads back to the mosquito vector. This is especially important given the increasing occurrence of drug-resistant strains of malaria in the field.”

Bhatia has long been known for finding innovative solutions to longstanding issues in science and medicine. Just last year, she was awarded the prestigious Lemelson-MIT Prize in part for her invention of a paper-based urine test for prostate cancer.

In this study, the researchers bombarded malaria-infected liver cells with two drugs, called atovaguone and primaquine, each developed to treat the disease specifically at the liver stage.

The results, though preliminary, are promising: the cells responded well to both drugs, underscoring the value of this approach to testing drugs—an approach that many call “disease in a dish.”

The potential utility of “disease in a dish” studies cannot be understated, as it gives researchers the ability to screen drugs on cells from individuals of varying genetic backgrounds, and discover which drug, or drugs, works best for each group.

Shengyong Ng, a postdoctoral researcher in Bhatia’s lab, spoke of what this study could mean for disease research:

“The use of iPSC-derived liver cells to model liver-stage malaria in a dish opens the door to study the influence of host genetics on antimalarial drug efficacy, and lays the foundation for their use in antimalarial drug discovery.”

Find out more about how scientists use stem cells to model disease in a dish in our video series, Stem Cells In Your Face.

Money matters: how investing in research advances stem cell science

Our goal at the stem cell agency is simple; to accelerate the development of successful therapies to patients with unmet medical needs. But on the way to doing that something interesting is happening; we’re helping advance the scientific understanding of stem cells and building a robust stem cell research community in California in the process.

You don’t have to take our word for it. A new paper in the journal Cell Stem Cell takes a look at the impact that state funding for stem cell research has had on scientific publications. The question the researchers posed was; have the states that fund stem cell research seen an increase in their share of scientific publications in the field? The answer, at least in California’s case, is absolutely yes.

Let’s back up a little. In the late 1990’s and early 2000’s the field of stem cell research was considered quite controversial, particularly when it came to human embryonic stem cells (hESCs). To help scientists get around some of the restrictions that were placed on the use of federal funds to do hESC research a number of states voted to provide their own funding for this work. This research focuses on four of the biggest supporters of this work: California, Connecticut, Maryland, and New York.

The researchers looked at the following factors:

  1. The percentage of scientific publications in the U.S.
  2. With at least one author from those four states.
  3. That focused on hESCs and induced pluripotent stem cells (iPSCs).
  4. Comparing the numbers from before the state funding kicked in to after.

Finally – stay with me here, we’re almost done – they compared those numbers to the number of publications for two other areas of non-controversial biomedical research, RNAi and cancer. For California the results were clear. The percentage of papers on RNAi and cancer from 1996 – 2013, that had at least one California author, stayed fairly consistent (between 15-18%). However, the percentage of papers on hESCs and iPSCS with a California author rose from zero in 1998 and 2006 (the year each was discovered) to a high of 45 percent in 2009. That has since dropped down a little but still remains consistently high.

Study graphic study code The article says the reason for this is really rather obvious: “that state funding programs appear to have contributed to over-performance in the field.”

“After the California Institute for Regenerative Medicine (CIRM) issued its first grants in April 2006, the share of articles acknowledging California funding increased rapidly. Between 2010 and 2013, approximately 55% of hESC-related articles published with at least one California author acknowledged state funding, suggesting that this funding program played an important role as California maintained and built upon its early leadership in the field.”

Connecticut also saw its share of publications rise, though not as dramatically as California. Maryland and New York, in contrast, saw their share of publications remain consistent. However, as the researchers point out, with California gobbling up so much more of the available space in these journals, the fact that both states kept their share consistent was an achievement in itself.

The researchers acknowledge that scientific publications are “only one measure of the impact of state science programs” and say it’s important we look at other measures as well – such as how many clinical trials arise from that research. Nonetheless they conclude by saying:

“This analysis illustrating the relative performance of states in the production of stem-cell-related research publications provides a useful starting point for policymakers and, potentially, voters considering the future of state stem cell funding efforts as well as others interested in state science and technology policy more generally.”

‘STARS’ Help Scientists Control Genetic On/Off Switch

All life on Earth relies, ultimately, on the delicate coordination of switches. During development, these switches turn genes on—or keep them off—at precise intervals, controlling the complex processes that guide the growth of the embryo, cell by cell, as it matures from a collection of stem cells into a living, breathing organism.

Scientists have found a new way to control genetic switches.

Scientists have found a new way to control genetic switches.

If you control the switch, you could theoretically control some of life’s most fundamental processes.

Which is precisely what scientists at Cornell University are attempting to do.

Reporting in today’s issue of Nature Chemical Biology, synthetic biologists have developed a new method of directing these switches—a feat that could revolutionize the field of genetic engineering.

At the heart of the team’s discovery is a tiny molecule called RNA. A more simplified version of its cousin, DNA, RNA normally serves as a liaison—translating the genetic information housed in DNA into the proteins that together make up each and every cell in the body.

In nature, RNA does not have the ability to ‘turn on’ a gene at will. So the Cornell team, led by Julius Lucks, made a new kind of RNA that did.

They engineered a new type of RNA that they are calling Small Transcription Activating RNAs, or STARS, that can serve as a kind of artificial switch. In laboratory experiments, Lucks and his team showed that they could control how and when a gene was switched on by physically placing the STARS system in front of it. As Lucks explained in a news release:

“RNA is like a molecular puzzle, a crazy Rubik’s cube that has to be unlocked in order to do different things. We’ve figured out how to design another RNA that unlocks part of that puzzle. The STAR is the key to that lock.”

RNA is an attractive molecule to manipulate because it is so simple, says Lucks, much simpler than proteins. Many efforts aimed at protein manipulation have failed, due to the sheer complexity of these molecules. But by downshifting into the simpler, more manageable RNA molecules, Lucks argues that greater strides can be made in the field of synthetic biology and genetic engineering.

“This is going to open up a whole set of possibilities for us, because RNA molecules make decisions and compute information really well, and they detect things really well,” said Lucks.

In the future, Lucks envisions a system based solely on RNA that has the capability to manipulate genetic switches to better understand fundamental processes that guide the healthy development of a cell—and provide clues to what happens when those processes go awry.

Stem cell stories that caught our eye: new ways to reprogram, shifting attitudes on tissue donation, and hockey legend’s miracle questioned

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.

Insulin-producing cells produced from skin. Starting with human skin cells a team at the University of Iowa has created iPS-type stem cells through genetic reprogramming and matured those stem cells into insulin-producing cells that successfully brought blood-sugar levels closer to normal when transplanted in mice.

University of Iowa researchers reprogrammed human skin cells to create iPS cells, which were then differentiated in a stepwise fashion to create insulin-producing cells. When these cells were transplanted into diabetic mice, the cells secreted insulin and reduced the blood sugar levels of the mice to normal or near-normal levels. The image shows the insulin-producing cells (right) and precursor cells (left). [Credit: University of Iowa]

University of Iowa researchers reprogrammed human skin cells to create iPS cells, which were then differentiated in a stepwise fashion to create insulin-producing cells. When these cells were transplanted into diabetic mice, the cells secreted insulin and reduced the blood sugar levels of the mice to normal or near-normal levels. The image shows the insulin-producing cells (right) and precursor cells (left).
[Credit: University of Iowa]

The cells did not completely restore blood-sugar levels to normal, but did point to the possibility of achieving that goal in the future, something the team leader Nicholas Zavazava noted in an article in the Des Moines Register, calling the work an “encouraging first step” toward a potential cure for diabetes.

The Register discussed the possibility of making personalized cells that match the genetics of the patient and avoiding the need for immune suppression. This has long been a goal with iPS cells, but increasingly the research community has turned to looking for options that would avoid immune rejection with donor cells that could be off-the-shelf and less expensive than making new cells for each patient.

Heart cells from reprogramming work in mice. Like several other teams, a group in Japan created beating heart cells from iPS-type stem cells. But they went the additional step of growing them into sheets of heart muscle that when transplanted into mice integrated into the animals own heart and beat to the same rhythm.

The team published the work in Cell Transplantation and the news agency AlianzaNews ran a story noting that it has previously been unclear if these cells would get in sync with the host heart muscle. The result provides hope this could be a route to repair hearts damaged by heart attack.

Patient attitudes on donating tissue. A University of Michigan study suggests most folks don’t care how you use body tissue they donate for research if you ask them about research generically. But their attitudes change when you ask about specific research, with positive responses increasing for only one type of research: stem cell research.

On the generic question, 69 percent said go for it, but when you mentioned the possibility of abortion research more than half said no and if told the cells might lead to commercial products 45 percent said nix. The team published their work in the Journal of the American Medical Association and HealthCanal picked up the university’s press release that quoted the lead researcher, Tom Tomlinson, on why paying attention to donor preference is so critical:

“Biobanks are becoming more and more important to health research, so it’s important to understand these concerns and how transparent these facilities need to be in the research they support.”

CIRM has begun building a bank of iPS-type stem cells made from tissue donated by people with one of 11 diseases. We went through a very detailed process to develop uniform informed consent forms to make sure the donors for our cell bank knew exactly how their cells could be used. Read more about the consent process here.

Mainstream media start to question hockey legend’s miracle. Finally some healthy skepticism has arrived. Hockey legend Gordie Howe’s recovery from a pair of strokes just before the holidays was treated by the general media as a true Christmas miracle. The scientific press tried to layer the coverage with some questions of what we don’t know about his case but not the mainstream media. The one exception I saw was Brad Fikes in the San Diego Union Tribune who had to rely on a couple of scientists who were openly speaking out at the time. We wrote about their concerns then as well.

Now two major outlets have raised questions in long pieces back-to-back yesterday and this morning. The Star in hockey-crazed Canada wrote the first piece and New York Magazine wrote today’s. Both raise serious questions about whether stem cells could have been the cause of Howe’s recovery and are valuable additions to the coverage.