Stem cell stories that caught our eye: turning on T cells; fixing our brains; progress and trends in stem cells; and one young man’s journey to recover from a devastating injury

Healthy_Human_T_Cell

A healthy T cell

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.

Directing the creation of T cells. To paraphrase the GOP Presidential nominee, any sane person LOVES, LOVES LOVES their T cells, in a HUGE way, so HUGE. They scamper around the body getting rid of viruses and the tiny cancers we all have in us all the time. A CIRM-funded team at CalTech has worked out the steps our genetic machinery must take to make more of them, a first step in letting physicians turn up the action of our immune systems.

We have known for some time the identity of the genetic switch that is the last, critical step in turning blood stem cells into T cells, but nothing in our body is as simple as a single on-off event. The Caltech team isolated four genetic factors in the path leading to that main switch and, somewhat unsuspected, they found out those four steps had to be activated sequentially, not all at the same time. They discovered the path by engineering mouse cells so that the main T cell switch, Bcl11b, glows under a microscope when it is turned on.

“We identify the contributions of four regulators of Bcl11b, which are all needed for its activation but carry out surprisingly different functions in enabling the gene to be turned on,” said Ellen Rothenberg, the senior author in a university press release picked up by Innovations Report. “It’s interesting–the gene still needs the full quorum of transcription factors, but we now find that it also needs them to work in the right order.”

Video primer on stem cells in the brain.  In conjunction with an article in its August issue, Scientific American posted a video from the Brain Forum in Switzerland of Elena Cattaneo of the University of Milan explaining the basics of adult versus pluripotent stem cells, and in particular how we are thinking about using them to repair diseases in the brain.

The 20-minute talk gives a brief review of pioneers who “stood alone in unmarked territory.” She asks how can stem cells be so powerful; and answers by saying they have lots of secrets and those secrets are what stem cell scientist like her are working to unravel.  She notes stem cells have never seen a brain, but if you show them a few factors they can become specialized nerves. After discussing collaborations in Europe to grow replacement dopamine neurons for Parkinson’s disease, she went on to describe her own effort to do the same thing in Huntington’s disease, but in this case create the striatal nerves lost in that disease.

The video closes with a discussion of how basic stem cell research can answer evolutionary questions, in particular how genetic changes allowed higher organisms to develop more complex nervous systems.

kelley and kent

CIRM Science Officers Kelly Shepard and Kent Fitzgerald

A stem cell review that hits close to home.  IEEE Pulse, a publication for scientists who mix engineering and medicine and biology, had one of their reporters interview two of our colleagues on CIRM’s science team. They asked senior science officers Kelly Shepard and Kent Fitzgerald to reflect on how the stem cell field has progressed based on their experience working to attract top researchers to apply for our grants and watching our panel of outside reviewers select the top 20 to 30 percent of each set of applicants.

One of the biggest changes has been a move from animal stem cell models to work with human stem cells, and because of CIRM’s dedicated and sustained funding through the voter initiative Proposition 71, California scientists have led the way in this change. Kelly described examples of how mouse and human systems are different and having data on human cells has been critical to moving toward therapies.

Kelly and Kent address several technology trends. They note how quickly stem cell scientists have wrapped their arms around the new trendy gene editing technology CRISPR and discuss ways it is being used in the field. They also discuss the important role of our recently developed ability to perform single cell analysis and other technologies like using vessels called exosomes that carry some of the same factors as stem cells without having to go through all the issues around transplanting whole cells.

“We’re really looking to move things from discovery to the clinic. CIRM has laid the foundation by establishing a good understanding of mechanistic biology and how stem cells work and is now taking the knowledge and applying it for the benefit of patients,” Kent said toward the end of the interview.

jake and family

Jake Javier and his family

Jake’s story: one young man’s journey to and through a stem cell transplant; As a former TV writer and producer I tend to be quite critical about the way TV news typically covers medical stories. But a recent story on KTVU, the Fox News affiliate here in the San Francisco Bay Area, showed how these stories can be done in a way that balances hope, and accuracy.

Reporter Julie Haener followed the story of Jake Javier – we have blogged about Jake before – a young man who broke his spine and was then given a stem cell transplant as part of the Asterias Biotherapeutics clinical trial that CIRM is funding.

It’s a touching story that highlights the difficulty treating these injuries, but also the hope that stem cell therapies holds out for people like Jake, and of course for his family too.

If you want to see how a TV story can be done well, this is a great example.

Stem cell stories that caught our eye: herding stem cells, mini autistic brains, tendon repair and hair replacement

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.

Major advance in getting stem cells to behave.  The promise of embryonic stem cells comes from their ability to become any cell type in the body, but medical uses of the cells have been hampered by our poor ability to quickly get them to mature into pure populations of a desired adult tissue. Scientists at Stanford, partially funded by CIRM, and the Genome Institute of Singapore have teamed up to better understand the normal road map of how the various tissues develop in the embryo and in turn fine tune the recipes used to make specific tissues in the lab. They claim to have created pure colonies of 12 different specialized tissues in half the time or less of normal procedures, which usually result in an undesired mix of cells.

 “The problems of making or isolating pure samples of one specific cell type has been a substantial barrier to medical uses of embryonic stem cells. This research looks like a way around that problem,” said Hank Greely, a medical ethicist at Stanford not involved in the work in an article in the East Bay Times.

 

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Weissman

This is a problem researchers around the world have been trying to crack since human embryonic stem cells were first isolated in 2008. The brief paragraph above on how they did it does not do justice to a very elegant and complex research project led by one of the leaders of the field, Irving Weissmann. Stanford’s press release provides more detail about how they achieved the milestone, which should significantly accelerate the field of regenerative medicine.

 

 

Mini brains to figure out oversize brains.  The many forms of autism have many different causes—though most are unknown—and a wide array of symptoms and physical manifestations. An international team has used a lab dish “mini-brain” model to discover the cause of one form of autism, one linked to over-sized brains, which occurs in about 20 percent of children with autism spectrum disorder (ASD).

Autistic neurons Muotri

Nerve precursor cells grown from iPS cells created from children with autism. Inhibitory nerves (in red) are not in sufficient numbers.

A team led by Alysson Muotri at the University of California, San Diego (UCSD), started with tissue samples from children with the disorder and reprogrammed them into iPS type stem cells. They matured those stem cells, first into nerve progenitors and then into the various nerves that in normal cells would result in mini-brains in the lab dish.  But instead of a healthy mix of cells that promote and inhibit nerve growth, they found a lack of inhibitory nerves allowing the overgrowth seen in the condition. They also showed the nerve cells did not send signals to each other properly; they lacked synchronization.

 “The bottom line is that we can now effectively model idiopathic ASD using a cohort of individuals selected by a clear endophenotype. In this case, brain volume,” said Muotri, in a university press release posted by Health Canal. “And early developmental brain enlargement can be explained by underlying molecular and cellular pathway dysregulation, leading to altered neuronal cortical networks.”

More important, they treated the nerves in the dish with a drug, IGF-1, that is currently being tested in the clinic for autism,  and found a reversal of the nerve miss-firing in some of the samples. Their model should make it easier to test more potential drugs, as well.

It has been a big week for improved understanding of ASD. Earlier in the week Fred Gage’s team across the street from UCSD at the Salk institute—where Muotri worked as a post-doctoral fellow—published a causal link for another form of autism, which my colleague Karen Ring wrote about earlier this week in The Stem Cellar.

 

shutterstock_425039020Help for weekend warriors. How many of your friends have ended up on crutches after a weekend of too much basketball or tennis, with a diagnosis of a torn ligament or tendon? And have they said they wished they had broken a bone instead because it would heal faster? Medicine has not been able to speed the healing of those delicate connecting straps in large part because we haven’t known much about how they are created during development. So a team at the Scripps Research Institute set out to find out how they develop and heal naturally.

 “If we understand the molecular mechanisms of tendon development, we can apply the findings to develop a new regenerative therapy for tendon diseases and injuries,” said team leader Hiroshi Asahara in an institution release posted by Sciencecodex.

 They found one gene in particular linked to tendon development and repair in an animal model. They used the new trendy gene editing tool CRISP to regulate the gene in rats. They found the gene results in the production of more tenocytes, which are needed to maintain healthy tendon. That pathway now becomes a target for developing new therapies to help those hobbling friends.

 

For the follicular challenged. On a lighter note, one of the least impactful but most common medical conditions, hair loss, has become a target of therapy development by many university and industry teams. Forbes posted a run down about the activities of some of the leaders of the hair pack.

Not all the author’s science is spot on, for example, when talking about the only organs that constantly regenerate the author ignored the fact that our gut lining turns over about every four days. But he provides a good review of how our hair follicles generally do a good job of replenishing hair and what goes wrong when they fail.

The author focuses most on the work of Japan’s RIKEN Institute, providing an easy to follow info-graphic on how the team there envisions harvesting a small skin sample, sorting the stem cells out of the hair follicles in the sample, growing those stem cells in the lab many fold and then injecting cells back to where they are needed. That team hopes to have a commercial product by 2020. In the meantime, the top of my head will remain intimately acquainted with sun screen.

Salk Scientists Unlock New Secrets of Autism Using Human Stem Cells

Autism is a complex neurodevelopmental disorder whose mental, physical, social and emotional symptoms are highly variable from person to person. Because individuals exhibit different combinations and severities of symptoms, the concept of autism spectrum disorder (ASD) is now used to define the range of conditions.

There are many hypotheses for why autism occurs in humans (which some estimates suggest now affects around 3.5 million people in the US). Some of the disorders are thought to be at the cellular level, where nerve cells do not develop normally and organize properly in the brain, and some are thought to be at the molecular level where the building blocks in cells don’t function properly. Scientists have found these clues by using tools such as studying human genetics and animal models, imaging the brains of ASD patients, and looking at the pathology of ASD brains to see what has gone wrong to cause the disease.

Unfortunately, these tools alone are not sufficient to recreate all aspects of ASD. This is where cellular models have stepped in to help. Scientists are now developing human stem cell derived models of ASD to create “autism in a dish” and are finding that the nerve cells in these models show characteristics of these disorders.

Stem cell models of autism and ASD

We’ve reported on some of these studies in previous blogs. A group from UCSD lead by CIRM grantee Alysson Muotri used induced pluripotent stem cells or iPS cells to model non-syndromic autism (where autism is the primary diagnosis). The work has been dubbed the “Tooth Fairy Project” – parents can send in their children’s recently lost baby teeth which contain cells that can be reprogrammed into iPS cells that can then be turned into brain cells that exhibit symptoms of autism. By studying iPS cells from individuals with non-syndromic autism, the team found a mutation in the TRPC6 gene that was linked to abnormal brain cell development and function and is also linked to Rett syndrome – a rare form of autism predominantly seen in females.

Another group from Yale generated “mini-brains” or organoids derived from the iPS cells of ASD patients. They specifically found that ASD mini-brains had an increased number of a type of nerve cell called inhibitory neurons and that blocking the production of a protein called FOXG1 returned these nerve cells back to their normal population count.

Last week, a group from the Salk Institute in collaboration with scientists at UC San Diego published findings about another stem cell model for ASD that offers new clues into the early neurodevelopmental defects seen in ASD patients.  This CIRM-funded study was led by senior author Rusty Gage and was published last week in the Nature journal Molecular Psychiatry.

Unlocking clues to autism using patient stem cells

Gage and his team were fascinated by the fact that as many as 30 percent of people with ASD experience excessive brain growth during early in development. The brains of these patients have more nerve cells than healthy individuals of the same age, and these extra nerve cells fail to organize properly and in some cases form too many nerve connections that impairs their overall function.

To understand what is going wrong in early stages of ASD, Gage generated iPS cells from ASD individuals who experienced abnormal brain growth at an early age (their brains had grown up to 23 percent faster when they were toddlers compared to normal toddlers). They closely studied how these ASD iPS cells developed into brain stem cells and then into nerve cells in a dish and compared their developmental progression to that of healthy iPS cells from normal individuals.

Neurons derived from people with ASD (bottom) form fewer inhibitory connections (red) compared to those derived from healthy individuals (top panel). (Salk Institute)

Neurons derived from people with ASD (bottom) form fewer inhibitory connections (red) compared to those derived from healthy individuals (top panel). (Salk Institute)

They quickly observed a problem with neurogenesis – a term used to describe how brain stem cells multiply and create new nerve cells in the brain. Brain stem cells derived from ASD iPS cells displayed more neurogenesis than normal brain stem cells, and thus were creating an excess amount of nerve cells. The scientists also found that the extra nerve cells failed to form as many synaptic connections with each other, an essential process that allows nerve cells to send signals and form a functional network of communication, and also behaved abnormally and overall had less activity compared to healthy neurons. Interestingly, they saw fewer inhibitory neuron connections in ASD neurons which is contrary to what the Yale study found.

The abnormal activity observed in ASD neurons was partially corrected when they treated the nerve cells with a drug called IGF-1, which is currently being tested in clinical trials as a possible treatment for autism. According to a Salk news release, “the group plans to use the patient cells to investigate the molecular mechanisms behind IGF-1’s effects, in particular probing for changes in gene expression with treatment.”

Will stem cells be the key to understanding autism?

It’s clear that human iPS cell models of ASD are valuable in helping tease apart some of the mechanisms behind this very complicated group of disorders. Gage’s opinion is that:

“This technology allows us to generate views of neuron development that have historically been intractable. We’re excited by the possibility of using stem cell methods to unravel the biology of autism and to possibly screen for new drug treatments for this debilitating disorder.”

However, to me it’s also clear that different autism stem cell models yield different results, but these differences are likely due to which populations the iPS cells are derived from. Creating more cell lines from different ASD subpopulations will surely answer more questions about the developmental differences and differences in brain function seen in adults.

Lastly, one of the co-authors on the study, Carolina Marchetto, made a great point in the Salk news release by acknowledging that their findings are based on studying cells in a dish, not actual patient’s brains. However, Marchetto believes that these cells are useful tools for studying autism:

“It never fails to amaze me when we can see similarities between the characteristics of the cells in the dish and the human disease.”

Rusty Gage and Carolina Marchetto. (Salk Institute)

Rusty Gage and Carolina Marchetto. (Salk Institute)


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The Spanish Inquisition and a tale of two stem cell agencies

Monty

Monty Python’s Spanish Inquisition sketch: Photo courtesy Daily Mail UK

It’s not often an article on stem cell research brings the old, but still much loved, British comedy series Monty Python into the discussion but a new study in the journal Cell Stem Cell does just that, comparing the impact of CIRM and the UK’s Regenerative Medicine Platform (UKRMP).

The article, written by Fiona Watt of King’s College London and Stanford’s Irv Weissman (a CIRM grantee – you can see his impressive research record here) looks at CIRM and UKRMP’s success in translating stem cell research into clinical applications in people.

It begins by saying that in research, as in real estate, location is key:

“One thing that is heavily influenced by location, however, is our source of funding. This in turn depends on the political climate of the country in which we work, as exemplified by research on stem cells.”

And, as Weissman and Watt note, political climate can have a big impact on that funding. CIRM was created by the voters of California in 2004, largely in response to President George W. Bush’s restrictions on the use of federal funds for embryonic stem cell research. UKRMP, in contrast was created by the UK government in 2013 and designed to help strengthen the UK’s translational research sector. CIRM was given $3 billion to do its work. UKRMP has approximately $38 million.

Inevitably the two agencies took very different approaches to funding, shaped in part by the circumstances of their birth – one as a largely independent state agency, the other created as a tool of national government.

CIRM, by virtue of its much larger funding was able to create world-class research facilities, attract top scientists to California and train a whole new generation of scientists. It has also been able to help some of the most promising projects get into clinical trials. UKRMP has used its more limited funding to create research hubs, focusing on areas such as cell behavior, differentiation and manufacturing, and safety and effectiveness. Those hubs are encouraged to work collaboratively, sharing their expertise and best practices.

Weissman and Watt touch on the problems both agencies ran into, including the difficulty of moving even the best research out of the lab and into clinical trials:

“Although CIRM has moved over 20 projects into clinical trials most are a long way from becoming standard therapies. This is not unexpected, as the interval between discovery and FDA approved therapeutic via clinical trials is in excess of 10 years minimum.”

 

And here is where Monty Python enters the picture. The authors quote one of the most famous lines from the series: “Nobody expects the Spanish Inquisition – because our chief weapon is surprise.”

They use that to highlight the surprises and uncertainty that stem cell research has gone through in the more than ten years since CIRM was created. They point out that a whole category of cells, induced pluripotent stem (iPS) cells, didn’t exist until 2006; and that few would have predicted the use of gene/stem cell therapy combinations. The recent development of the CRISPR/Cas9 gene-editing technology shows the field is progressing at a rate and in directions that are hard to predict; a reminder that that researchers and funding agencies should continue to expect the unexpected.

With two such different agencies the authors wisely resist the temptation to make any direct comparisons as to their success but instead conclude:

“…both CIRM and UKRMP have similar goals but different routes (and funding) to achieving them. Connecting people to work together to move regenerative medicine into the clinic is an over-arching objective and one that, we hope, will benefit patients regardless of where they live.”

Spotlight on CIRM Grantee Joe Wu: Clinical Trials for Heart Disease in a Dish?

It’s always exciting to read a science article featuring a talented scientist who is breaking boundaries in the field of regenerative medicine. It’s especially exciting to us at CIRM when the scientist is a CIRM grantee.

Last week, OZY published a fun and inspiring piece on Stanford scientist Joe Wu. Dr. Wu is the Director of the Stanford Cardiovascular Institute and his lab studies how stem cells (both adult and pluripotent) function and how they can be used to model heart diseases and screen for new drug therapies. He also is a CIRM grantee and has a Disease Team Therapy Development grant that aims to clinically test human embryonic stem cell-derived cardiomyocytes (heart cells) in end stage heart failure patients.

Dr. Joe Wu. (Image Source: Sean Culligan/OZY)

Dr. Joe Wu. (Image Source: Sean Culligan/OZY)

The OZY piece does a great job of highlighting Dr. Wu’s recent efforts to use human induced pluripotent stem cells (iPS cells) to make heart tissue in a dish and model cardiovascular disease. And without getting too technical, the article explains Dr. Wu’s larger mission to combine precision medicine and stem cell research to identify drugs that would be best suited for specific patient populations.

The article commented,

“He envisions treatments based on an individual’s own iPS cells. For example, a popular breast cancer drug has an 8 percent chance of giving patients heart failure. In Wu’s world, we’d test the drug on stem cells first, and if a patient lands in that 8 percent, begin treatment for the side effects preemptively or avoiding the drug totally and avoiding heart failure, too.”

Basically, Dr. Wu sees the future of clinical trials in a dish using human stem cells. “His goal is to take these stem cells from thousands of patients to create a genetically diverse enough bank that will allow for “clinical trials in a dish” — Wu’s go-to phrase.”

Instead of following the traditional drug development paradigm that takes more than 10 years, billions of dollars, and unfortunately usually ends in failure, Dr. Wu wants to follow an accelerated path where stem cells are used for drug toxicity and efficacy testing.

This alternative path could improve overall drug development and approval by the FDA. The article explained,

“Testing drugs on stem cells will give big pharma and the FDA vastly improved heads up for toxic complications. Stem cells are “absolutely” the best avenue going forward, says Norman Stockbridge, director of the division of cardiovascular and renal products at the FDA’s Center for Drug Evaluation and Research.”

Not everyone is on the same page with Dr. Wu’s bold vision of the future of precision medicine, stem cells, and treatments for heart disease. Some believe he is overly ambitious, however top scientists in the stem cell field have praised Dr. Wu’s “systematic approach” to research and how he doesn’t stop at data discovery, he focuses on the big picture and how his work can ultimately help patients.

You can read more about Dr. Wu’s research on his lab website and I highly encourage you to check out the OZY article which is a great example of science communication for the general public.


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Stem cell stories that caught our eye: a surprising benefit of fasting, faster way to make iPSCs, unlocking the secret of leukemia cancer cells

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.

Fasting

Is fasting the fountain of youth?

Among the many insults our bodies endure in old age is a weakened immune system which leaves the elderly more susceptible to infection. Chemotherapy patients also face the same predicament due to the immune suppressing effects of their toxic anticancer treatments. While many researchers aim to develop drugs or cell therapies to protect the immune system, a University of Southern California research report this week suggests an effective alternative intervention that’s startlingly straightforward: fasting for 72 hours.

The study published in Cell Stem Cell showed that cycles of prolonged fasting in older mice led to a decrease in white blood cells which in turn set off a regenerative burst of blood stem cells. This restart of the blood stem cells replenished the immune system with new white blood cells. In a pilot Phase 1 clinical trial, cancer patients who fasted 72 hours before receiving chemotherapy maintained normal levels of white blood cells.

A look at the molecular level of the process pointed to a decrease in the levels of a protein called PKA in stem cells during the fasting period. In a university press release carried by Science Daily, the study leader, Valter Longo, explained the significance of this finding:

“PKA is the key gene that needs to shut down in order for these stem cells to switch into regenerative mode. It gives the ‘okay’ for stem cells to go ahead and begin proliferating and rebuild the entire system. And the good news is that the body got rid of the parts of the system that might be damaged or old, the inefficient parts, during the fasting. Now, if you start with a system heavily damaged by chemotherapy or aging, fasting cycles can generate, literally, a new immune system.”

In additional to necessary follow up studies, the team is looking into whether fasting could benefit other organ systems besides the immune system. If the data holds up, it could be that regular fasting or direct targeting of PKA could put us on the road to a much more graceful and healthier aging process.

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Faster, cheaper, safer way to use iPS cells

Science, like traffic in any major city, never moves quite as quickly as you would like, but now Japanese researchers are teaming up to develop a faster, and cheaper way of using iPSC’s , pluripotent stem cells that are reprogrammed from adult cells, for transplants.

Part of the beauty of iPSCs is that because those cells came from the patient themselves, there is less risk of rejection. But there are problems with this method. Taking adult cells and turning them into enough cells to treat someone can take a long time. It’s expensive too.

But now researchers at Kyoto University and three other institutions in Japan have announced they are teaming up to change that. They want to create a stockpile of iPSCs that are resistant to immunological rejection, and are ready to be shipped out to researchers.

Having a stockpile of ready-to-use iPSCs on hand means researchers won’t have to wait months to develop their own, so they can speed up their work.

Shinya Yamanaka, who developed the technique to create iPSCs and won the Nobel prize for his efforts, say there’s another advantage with this collaboration. In a news article on Nikkei’s Asian Review he said these cells will have been screened to make sure they don’t carry any potentially cancer-causing mutations.

“We will take all possible measures to look into the safety in each case, and we’ll give the green light once we’ve determined they are sound scientifically. If there is any concern at all, we will put a stop to it.”

CIRM is already working towards a similar goal with our iPSC Initiative.

Unlocking the secrets of leukemia stem cells

the-walking-dead-season-6-zombies

Zombies: courtesy “The Walking Dead”

Any article that has an opening sentence that says “Cancer stem cells are like zombies” has to be worth reading. And a report in ScienceMag  that explains how pre-leukemia white blood cell precursors become leukemia cancer stem cells is definitely worth reading.

The article is about a study in the journal Cell Stem Cell by researchers at UC San Diego. The senior author is Catriona Jamieson:

“In this study, we showed that cancer stem cells co-opt an RNA editing system to clone themselves. What’s more, we found a method to dial it down.”

An enzyme called ADAR1 is known to spur cancer growth by manipulating small pieces of genetic material known as microRNA. Jamieson and her team wanted to track how that was done. They discovered it is a cascade of events, and that once the first step is taken a series of others quickly followed on.

They found that when white blood cells have a genetic mutation that is linked to leukemia, they are prone to inflammation. That inflammation then activates ADAR1, which in turn slows down a segment of microRNA called let-7 resulting in increased cell growth. The end result is that the white blood cells that began this cascade become leukemia stem cells and spread an aggressive and frequently treatment-resistant form of the blood cancer.

Having uncovered how ADAR1 works Jamieson and her team then tried to find a way to stop it. They discovered that by blocking the white blood cells susceptibility to inflammation, they could prevent the cascade from even starting. They also found that by using a compound called 8-Aza they could impede ADAR1’s ability to stimulate cell growth by around 40 percent.

Jamieson

Catriona Jamieson – definitely not a zombie

Jamieson says the findings open up all sorts of possibilities:

“Based on this research, we believe that detecting ADAR1 activity will be important for predicting cancer progression. In addition, inhibiting this enzyme represents a unique therapeutic vulnerability in cancer stem cells with active inflammatory signaling that may respond to pharmacologic inhibitors of inflammation sensitivity or selective ADAR1 inhibitors that are currently being developed.”

This wasn’t a CIRM-funded study but we have supported other projects by Dr. Jamieson that have led to clinical trials.

 

 

 

 

What’s the big idea? Or in this case, what’s the 19 big ideas?

supermarket magazineHave you ever stood in line in a supermarket checkout line and browsed through the magazines stacked conveniently at eye level? (of course you have, we all have). They are always filled with attention-grabbing headlines like “5 Ways to a Slimmer You by Christmas” or “Ten Tips for Rock Hard Abs” (that one doesn’t work by the way).

So with those headlines in mind I was tempted to headline our latest Board meeting as: “19 Big Stem Cell Ideas That Could Change Your Life!”. And in truth, some of them might.

The Board voted to invest more than $4 million in funding for 19 big ideas as part of CIRM’s Discovery Inception program. The goal of Inception is to provide seed funding for great, early-stage ideas that may impact the field of human stem cell research but need a little support to test if they work. If they do work out, the money will also enable the researchers to gather the data they’ll need to apply for larger funding opportunities, from CIRM and other institutions, in the future

The applicants were told they didn’t have to have any data to support their belief that the idea would work, but they did have to have a strong scientific rational for why it might

As our President and CEO Randy Mills said in a news release, this is a program that encourages innovative ideas.

Randy Mills, Stem Cell Agency President & CEO

Randy Mills, CIRM President & CEO

“This is a program supporting early stage ideas that have the potential to be ground breaking. We asked scientists to pitch us their best new ideas, things they want to test but that are hard to get funding for. We know not all of these will pan out, but those that do succeed have the potential to advance our understanding of stem cells and hopefully lead to treatments in the future.”

So what are some of these “big” ideas? (Here’s where you can find the full list of those approved for funding and descriptions of what they involve). But here are some highlights.

Alysson Muotri at UC San Diego has identified some anti-retroviral drugs – already approved by the Food and Drug Administration (FDA) – that could help stop inflammation in the brain. This kind of inflammation is an important component in several diseases such as Alzheimer’s, autism, Parkinson’s, Lupus and Multiple Sclerosis. Alysson wants to find out why and how these drugs helps reduce inflammation and how it works. If he is successful it is possible that patients suffering from brain inflammation could immediately benefit from some already available anti-retroviral drugs.

Stanley Carmichael at UC Los Angeles wants to use induced pluripotent stem (iPS) cells – these are adult cells that have been genetically re-programmed so they are capable of becoming any cell in the body – to see if they can help repair the damage caused by a stroke. With stroke the leading cause of adult disability in the US, there is clearly a big need for this kind of big idea.

Holger Willenbring at UC San Francisco wants to use stem cells to create a kind of mini liver, one that can help patients whose own liver is being destroyed by disease. The mini livers could, theoretically, help stabilize a person’s own liver function until a transplant donor becomes available or even help them avoid the need for liver transplantation in the first place. Considering that every year, one in five patients on the US transplant waiting list will die or become too sick for transplantation, this kind of research could have enormous life-saving implications.

We know not all of these ideas will work out. But all of them will help deepen our understanding of how stem cells work and what they can, and can’t, do. Even the best ideas start out small. Our funding gives them a chance to become something truly big.


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Adding new stem cell tools to the Parkinson’s disease toolbox

Understanding a complicated neurodegenerative disorder like Parkinson’s disease (PD) is no easy task. While there are known genetic risk factors that cause PD, only about 10 percent of cases are linked to a genetic cause. The majority of patients suffer from the sporadic form of PD, where the causes are unknown but thought to be a combination of environmental, lifestyle and genetic factors.

Unfortunately, there is no cure for PD, and current treatments only help PD patients manage the symptoms of their disease and inevitably lose their effectiveness over time. Another troubling issue is that doctors and scientists don’t have good ways to predict who is at risk for PD, which closes an important window of opportunity for delaying the onset of this devastating disease.

Scientists have long sought relevant disease models that mimic the complicated pathological processes that occur in PD. Current animal models have failed to truly represent what is going on in PD patients. But the field of Parkinson’s research is not giving up, and scientists continue to develop new and improved tools, many of them based on human stem cells, to study how and why this disease happens.

New Stem Cell Tools for Parkinson’s

Speaking of new tools, scientists from the Buck Institute for Research on Aging published a study that generated 10 induced pluripotent stem cell (iPS cell) lines derived from PD patients carrying well known genetic mutations linked to PD. These patient cell lines will be a useful resource for studying the underlying causes of PD and for potentially identifying therapeutics that prevent or treat this disorder. The study was partly funded by CIRM and was published today in the journal PLOS ONE.

Dr. Xianmin Zeng, the senior author on the study and Associate Professor at Buck Institute, developed these disease cell lines as tools for the larger research community to use. She explained in a news release:

Xianmin Zeng, Buck Institute

Xianmin Zeng, Buck Institute

“We think this is the largest collection of patient-derived lines generated at an academic institute. We believe the [iPS cell] lines and the datasets we have generated from them will be a valuable resource for use in modeling PD and for the development of new therapeutics.”

 

The datasets she mentions are part of a large genomic analysis that was conducted on the 10 patient stem cell lines carrying common PD mutations in the SNCA, PARK2, LRRK2, or GBA genes as well as control stem cell lines derived from healthy patients of the same age. Their goal was to identify changes in gene expression in the Parkinson’s stem cell lines as they matured into the disease-affected nerve cells of the brain that could yield clues into how PD develops at the molecular level.

Using previous methods developed in her lab, Dr. Zeng coaxed the iPS cell lines into neural stem cells (brain stem cells) and then further into dopaminergic neurons – the nerve cells that are specifically affected and die off in Parkinson’s patients. Eight of the ten patient lines were able to generate neural stem cells, and all of the neural stem cell lines could be coaxed into dopaminergic neurons – however, some lines were better at making dopaminergic neurons than others.

Dopaminergic neurons derived from induced pluripotent stem cells. (Xianmin Zeng, Buck Institute)

Dopaminergic neurons derived from induced pluripotent stem cells. (Xianmin Zeng, Buck Institute)

When they analyzed these lines, surprisingly they found that the overall gene expression patterns were similar between diseased and healthy cell lines no matter what cell stage they were at (iPS cells, neural stem cells, and neurons). They next stressed the cells by treating them with a drug called MPTP that is known to cause Parkinson’s like symptoms in humans. MPTP treatment of dopaminergic neurons derived from PD patient iPS cell lines did cause changes in gene expression specifically related to mitochondrial function and death, but these changes were also seen in the healthy dopaminergic neurons.

Parkinson’s, It’s complicated…

These interesting findings led the authors to conclude that while their new stem cell tools certainly display some features of PD, individually they are not sufficient to truly model all aspects of PD because they represent a monogenic (caused by a single mutation) form of the disease.

They explain in their conclusion that the power of their PD patient iPS cell lines will be achieved when combined with additional patient lines, better controls, and more focused data analysis:

“Our studies suggest that using single iPSC lines for drug screens in a monogenic disorder with a well-characterized phenotype may not be sufficient to determine causality and mechanism of action due to the inherent variability of biological systems. Developing a database to increase the number of [iPS cell] lines, stressing the system, using isogenic controls [meaning the lines have identical genes], and using more focused strategies for analyzing large scale data sets would reduce the impact of line-to-line variations and may provide important clues to the etiology of PD.”

Brian Kennedy, Buck Institute President and CEO, also pointed out the larger implications of this study by commenting on how these stem cell tools could be used to identify potential drugs that specifically target certain Parkinson’s mutations:

Brian Kennedy, Buck Institute

Brian Kennedy, Buck Institute

“This work combined with dozens of other control, isogenic and reporter iPSC lines developed by Dr. Zeng will enable researchers to model PD in a dish. Her work, which we are extremely proud of, will help researchers dissect how genes interact with each other to cause PD, and assist scientists to better understand what experimental drugs are doing at the molecular level to decide what drugs to use based on mutations.”

Overall, what inspires me about this study is the author’s mission to provide a substantial number of PD patient stem cell lines and genomic analysis data to the research community. Hopefully their efforts will inspire other scientists to add more stem cell tools to the Parkinson’s tool box. As the saying goes, “it takes an army to move a mountain”, in the case of curing PD, the mountain seems more like Everest, and we need all the tools we can get.


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Stem cell stories that caught our eye: Zika virus and brain stem cells, new guidelines, re-growing tails and better iPS cells

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.

Three more studies on Zika and brain stem cells. It’s heartening to see how quickly the scientific community has reacted to the recent Zika virus epidemic. They have already completed and published dozens of research projects. And science journals have responded by not only speeding up their often slow process to get results published, but also some are removing pay walls to ease disseminating the data.

After a pair of studies earlier this month showed how the virus could impact brain stem cells in mini human brain “organoids” in the lab, three studies this week showed how the virus does its damage in animal models. A colleague wrote two blog posts on the human mini-brain studies, one revealing the entry point the virus uses to enter brain stem cells and the other finding the virus negatively impacts the ability of brain stem cells to specialize into mature brain.

 

Zika in placenta Wash U

Zika virus (red) in a mouse placenta (Washington U.)

While those organoids can tell us a lot, they don’t show what happened when the fetus matures, so the new mouse models provided the first conclusive link between infection and microcephaly—the small brains seen in children born following their mother’s infection with the virus. But the three studies muddied the water a bit on the cause of the reduced brain size. One suggested that damage to the placenta could have reduced blood flow to the developing fetus. The other studies showed that the virus does indeed infect brain stem cells, but one suggested that the bulk of the damage from the virus occurs later in pregnancy acting directly on mature nerve cells, not the stem cells.

The papers in Cell from Washington University in St. Louis, in Nature, from the University of California, San Diego and in Cell Stem Cell from the Chinese Academy of Science got wide media coverage. Genetic Engineering News and Science Magazine did some of the most thorough reporting and Newsweek wrote a piece a bit easier to understand.

 

Stem cell research guidelines.  When an august scientific body issues guidelines for its work, the public generally either ignores it or never hears about it. That paradigm shifted a bit this week when the International Society for Stem Cell Research issued revised guidelines for numerous aspects of regenerative medicine research and practice. A large part of the difference probably resulted from the group self-cautioning its members to avoid hype and not oversell their results.

The Bloomberg business wire issued a story with the headline, “Stop Hyping Stem Cell Science, Say Stem Cell Scientists.” Four scientific journals simultaneously published various reviews of the guidelines including one in Science authored by five members of the 25-person committee that drafted them. That piece carried the title, “Confronting Stem Cell Hype.”

One of the authors, Tim Caulfield of the University of Alberta, acknowledged changing the discourse in the field will not be easy:

 “Because the forces that twist how science is communicated are complex, systemic, and interrelated, correcting for science hype will not be easy.”

Beyond the hype, the guidelines address several important issues in our field calling for:

  • a process to review all embryo research, not just when the embryo is destined to be a source of stem cells;
  • support for laboratory research on genetically modifying sperm, eggs and embryos, but banning such techniques for clinical use at this time;
  • defining proper research and clinical use of techniques to swap out healthy mitochondria, for defective ones in cells;
  • allowing compensation for women who donate eggs for research within certain defined parameters
  • creating robust standards for evaluating the outcome of stem cell clinical trials.

 

Just a few switches to regrow a tail.  Many lizards and amphibians regrow their tails with ease, but prior research has shown a great many genes get turned on to make it happen. Now, a team at Arizona State University has shown that just three genetic switches orchestrate much of that gene activity.

arizona_green anole lizard

Green Anole lizard (Arizona State U.)

The tiny genetic components called microRNAs turn out to be very powerful on-off switches for genes and can control many different genes at the same time.

 “Since microRNAs are able to control a large number of genes at the same time, like an orchestra conductor leading the musicians, we hypothesized that they had to play a role in regeneration,” said senior author Kenro Kusumi in a story in Bioscience Technology.

 The group hopes their research will lead to ways to get tissue regeneration in humans for repairing damage such as spinal cord injury or worn knee cartilage.

 

Making better iPS cells.  Although we have known for a decade the basics of how to turn an adult cell into an embryonic-like stem cell, iPS cells, virtually that entire time researchers have sought ways to make them even more like embryonic stem cells. Too often iPS cells retain memory of the adult cell they came from and stubbornly refuse to turn into certain other types of tissue.

Researchers at the University of Pennsylvania have shed light on this stubborness using an emerging field called “3D epigenetics.”  Epigenetics looks at the various controls that turn genes on and off, but it traditionally cannot take into account the effect of DNA folding that puts genes next to each other adding a layer of regulation based on juxtaposition.  They found that in some iPS cells the DNA folding looked more like mature cells than embryonic stem cells, but that by manipulating the way the cells were grown they could modify that folding.

 “Our observations are important because they suggest that, if we can push the 3-D genome conformation of cells that we are turning into iPS cells to be closer to that of embryonic stem cells, then we can possibly generate iPS cells that match gold-standard pluripotent stem cells more rapidly and efficiently,” said graduate student Jonathan Beagan in a university press release.

Scientists Make Insulin-Secreting Cells from Stem Cells of Type 1 Diabetes Patients

Stem cell research for diabetes is in a Golden Age. In the past few years, scientists have developed methods to generate insulin-secreting pancreatic beta cell-like cells from embryonic stem cells, induced pluripotent stem cells (iPS cells), and even directly from human skin. We’ve covered a number of recent studies in this area on our blog, and you can read more about them here.

Patients with type 1 diabetes (T1D) suffer from an autoimmune response that attacks and kills the beta cells in their pancreas. Without these important cells, patients can no longer secrete insulin in response to increased glucose or sugar levels in the blood. Cell replacement is evolving into an attractive therapeutic option for patients with T1D. Replacing lost beta cells in the pancreas is a more permanent and less burdensome solution than the daily insulin shots that many T1D patients currently take.

Cell replacement therapy for type 1 diabetes

Stem cells are the latest strategy that scientists are pursuing for T1D cell replacement therapy. The strategy involves generating beta cells from pluripotent stem cells, either embryonic or iPS cells, that function similarly to beta cells found in a healthy human pancreas. Making beta cells from a patient’s own iPS cells is the ideal way to go because this autologous form (self to self) of transplantation would reduce the chances  of transplant rejection because a patient’s own cells would be put back into their body.

Scientists have generated beta cell-like cells from iPS cells derived from T1D patients previously, but the biological nature and function of these cells wasn’t up to snuff in a side by side comparison with beta cells from non-diabetic patients. They didn’t express the appropriate beta cell markers and failed to secrete the appropriate levels of insulin when challenged in a dish and when transplanted into animal models.

However, a new study published yesterday in Nature Communications has overcome this hurdle. Teams from the Washington University School of Medicine in St. Louis and the Harvard Stem Cell Institute have developed a method that makes beta cells from T1D patient iPS cells that behave very similarly to true beta cells. This discovery has the potential to offer personalized stem cell treatments for patients with T1D in the near future.

These beta cells could be the real deal

Their current work is based off of an earlier 2014 study – from the lab of Douglas Melton at Harvard – that generated functional human beta cells from both embryonic and iPS cells of non-diabetic patients. In the current study, the authors were interested in learning whether it was possible to generate functional beta cells from T1D patients and whether these cells would be useful for transplantation given that they could potentially be less functional than non-diabetic beta cells.

The study’s first author, Professor Jeffrey Millman from the Washington University School of Medicine, explained:

Jeffrey Millman

Jeffrey Millman

“There had been questions about whether we could make these cells from people with type 1 diabetes. Some scientists thought that because the tissue would be coming from diabetes patients, there might be defects to prevent us from helping the stem cells differentiate into beta cells. It turns out that’s not the case.”

After generating beta cells from T1D iPS cells, Millman and colleagues conducted a series of experiments to test the beta cells both in a dish and in mice. They found that the T1D-derived beta cells expressed the appropriate beta cell markers, secreted insulin in the presence of glucose, and responded well to anti-diabetic drugs that stimulated the beta cells to secrete even more insulin.

When T1D beta cells were transplanted into mice that lacked an immune system, they survived and functioned similarly to transplanted non-diabetic beta cells. When the mice were treated with a drug that killed off their mouse beta cells, the surviving human T1D beta cells were successful in regulating the blood glucose levels in the mice and kept them alive.

Beta cells derived from type 1 diabetes patient stem cells (top) express the same beta cell markers as beta cells derived from non-diabetic (ND) patients.

Beta cells derived from type 1 diabetes patient stem cells (top) express the same beta cell markers as beta cells derived from non-diabetic (ND) patients. (Nature Communications)

Big Picture

The authors concluded that the beta cells they generated from T1D iPS cells were indistinguishable from healthy beta cells derived from non-diabetic patients. In a news release, Millman commented on the big picture of their study:

“In theory, if we could replace the damaged cells in these individuals with new pancreatic beta cells — whose primary function is to store and release insulin to control blood glucose — patients with type 1 diabetes wouldn’t need insulin shots anymore. The cells we’ve manufactured sense the presence of glucose and secrete insulin in response. And beta cells do a much better job controlling blood sugar than diabetic patients can.”

He further commented that the T1D- derived beta cells “could be ready for human research in three to five years. At that time, Millman expects the cells would be implanted under the skin of diabetes patients in a minimally invasive surgical procedure that would allow the beta cells access to a patient’s blood supply.”

“What we’re envisioning is an outpatient procedure in which some sort of device filled with the cells would be placed just beneath the skin,” he said.

In fact, such devices already exist. CIRM is funding a type 1 diabetes clinical trial sponsored by the San Diego based company ViaCyte. They are currently testing a combination drug delivery system that implants a medical device capsule containing pancreatic progenitor cells derived from human embryonic stem cells. Once implanted, the progenitor cells are expected to specialize into mature pancreatic cells including beta cells that secrete insulin.


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