Guest blogger Alan Trounson — June’s stem cell research highlights

Each month CIRM President Alan Trounson gives his perspective on recently published papers he thinks will be valuable in moving the field of stem cell research forward. This month’s report, along with an archive of past reports, is available on the CIRM website.

My report this month opens with a fascinating paper that finally provided definitive proof that adult human brains can generate new neurons, at least in the section of the brain dedicated to learning and memory. It also discusses a significant step toward creating universal donor cells that would not be rejected after transplantation, but this end goal will clearly require much more work.

The one paper in this month’s report that I want to highlight here is a tour-de-force showing the power of well-funded large international collaborations producing massive quantities of data. The paper in the May 23 Cell listed 42 authors who worked in 11 institutions in four countries. This would not be unusual for a paper in a physics journal, but is a phenomenon that has only recently started appearing in biology journals.

The members of the team, which included many of the leaders in stem cell science, were trying to understand how genes get turned on or turned off in early embryo development and how those gene switches change in later stages of embryo development. This study of the activation, enhancement, or suppression of specific genes is the relatively new field called epigenetics. It looks at all the molecular components on chromosomes that surround the actual genes, and influence the genes’ activity. Much of the current project was funded by the National Institutes of Health’s Epigenome Roadmap Project.

They looked at two types of cells that appear very early in the embryo and two types of cells that appear at later stages. They did indeed find significant differences in which genes were active and in the configuration of the epigenetic marks—those switches. But to do that they used elaborate high throughput technology to measure the expression of over 19,000 genes. They then looked at nearly 104,000 epigenetic marks. This provides valuable new understanding of normal embryonic development now, and could point to ways to enhance the creation of specific cell types from ESCs in the future.

This project clearly shows the power of collaboration within institutions, across institutions and across state and national borders. This is why CIRM has agreements with 15 international funding agencies and six state or foundation funding agencies in the U.S. You can see that list here.

My full report is available online, along with links to my reports from previous months.

A.T.

Stem cell interns show their experiences through their own lens

For the past two summers we’ve run a summer internship program to bring high school students from throughout California into stem cell labs. We call this our Creativity Awards because we also ask the students to carry out some research activity in addition to just their lab work with the idea that great ideas come from creative minds.

We shot a video with these students two years ago, which you can watch here to see why we love this program so much. The students are incredible. The future of stem cell research in the state looks strong if these are the people who will be working on the next generation therapies:

This summer we’ve decided to let our interns tell their stories in their own words (and images). They’ll be posting Instagram photos (follow #CIRMStemCellLab), videos to our YouTube channel, and blog entries (watch this space).

The first of the images and videos are already coming in, which you can see on our website on this page. We’ll be updating that page as the summer progresses. Here’s a preview of what’s come in so far:

A.A.

Young stem cells’ DNA has more genes switched to "on" position than geriatric ones

Skeletal muscle courtesy of Wikimedia Commons

Researchers at Stanford University have made a start in understanding why muscles in younger people heal so quickly compared to muscles in older people. Understanding these differences could help scientists find ways of helping muscles in older people heal more quickly after injuries.

In a study comparing muscle stem cells from young and old mice, the group found that histones, proteins that are intimately wound up with the DNA of animal and plant cells, display different chemical properties depending on how old the mice are. These changes seem to directly relate to why the older muscle stem cells don’t respond as promptly to injured muscle.

A few years ago, the team, led by Thomas Rando, realized that muscle cells of older mice exposed to a young mouse’s blood regained the capacity to heal themselves. They took a closer look at what caused this rejuvenation, suspecting histones were involved.

In cells that have a nucleus, the long strands of DNA wrap themselves around small bead-like histone proteins. This helps keep the DNA stored neatly. Histones also act like switches to turn genes on or off. Every cell in a human body has nearly identical genetic information, but histones are one reason brain cells only express brain cell genes, blood cells only express blood cell genes and muscle cells only express muscle cell genes.

The study describes the team’s recent work with satellite cells, a rare kind of adult stem cell . They usually lay dormant, but pop into action when a muscle is injured to repair it by replacing muscle cells. When they looked at histones from dormant satellite cells of young mice and old mice side-by-side, the researchers were surprised to find that young-mouse satellite cells had histones with the “on” signal switched on not just for muscle cells, but also for several other cell types.

In a press release, about the findings, Rando said,

“When you look at these satellite cells the way we did, they seem ready to become all kinds of cells. It’s a mystery,” he said, suggesting that it could mean stem cells thought to be committed to a particular lineage may be capable of becoming other types of tissue entirely.

“Maybe their fates are not permanently sealed,” he said. “The door is not locked. Who knows what could happen if they’re given the right signals?”

The study was published today in the journal Cell Reports.

The team is now looking more closely at which histone changes are reversible in aging cells and testing other types of adult stem cells for this property. A former member of Rando’s lab, Irena Conboy at UC Berkeley, is also investigating the differences between old and young tissues to develop therapies for muscle injuries or diseases like muscular dystrophies. There’s more information about this CIRM-funded project on our web page.

R.S.L.

Funding cuts hurting research labs

Nature has a scary story about the impact of sequester on research labs. This paragraph sums up the situation:

The NIH for example, faces a US$1.5-billion budget cut over fiscal year (FY) 2012–13, which it says will result in the funding of some 700 fewer competitive research projects and the admission of 750 fewer new patients to the NIH Clinical Center in Bethesda. The US Department of Defense and the US National Science Foundation (NSF) each expects to offer 1,000 fewer grants, and the US Geological Survey has slashed its competitive-grants programme in water research to protect funding for key monitoring networks.

They go on to quote Joseph Haywood, vice-president for science policy with the Federation of American Societies for Experimental Biology in Washington DC saying that he could foresee 8% year-over-year decreases for the next nine years.

The NIH is the major source of funding for most biomedical research working toward new disease therapies–stem cell or otherwise. CIRM is funding important research in California (here’s the full list of awards), but these scientists can’t keep their full labs running on CIRM funding alone. A slowdown now could mean fewer trained people in the field ten years from now, and fewer therapies reaching patients.

A.A.

CIRM’s first Google Hangout to focus on ALS

We’d like to welcome our journalism fellow Rina Shaikh-Lesko, who will be helping us out this summer writing about progress in the stem cell field. This is her inaugural blog entry.

We’re about to kick off our first ever Google Hangout on July 3 at noon. Google’s foray into online video conferencing makes interacting with fellow participants easier than traditional webinar formats. CIRM grantees and patient advocates will be talking about progress in finding a stem cell-based therapy for Amyotrophic Lateral Sclerosis, or ALS, a devastating neurodegenerative disease.

On hand to provide an update on stem cell research into ALS and answer questions about the disease will be CIRM grantees Lawrence Goldstein of the University of California, San Diego, and Clive Svendsen of the Cedar Sinai Medical Center in Los Angeles, as well as ALS patient advocate and CIRM governing board member, Diane Winokur. Have a question for our panel? Send it to info@cirm.ca.gov or leave your question as a comment on this post. You can also post questions via Twitter to @cirmnews, or wait and ask during the Hangout.

ALS, sometimes called Lou Gehrig’s Disease, occurs when the nerve cells that control muscles, or motor neurons, die off for reasons scientists don’t entirely understand. The muscles they were connected to eventually wither away, leaving patients paralyzed. Most people who are diagnosed die within four years. According to the ALS Association, about 30,000 people in the U.S. have ALS. Stem cell researchers hope to develop an experimental treatment within a few years.

Goldstein leads a team working to mature stems cells into a kind of cell that normally lives near motor neurons, called astrocytes. They plan to transplant these astrocytes into people with the disease where the cells could protect neurons from further damage from ALS. This video explains his team’s research and how ALS has affected one family.

Svendson’s team is working on a way to modify neuronal stem cells so they excrete a protein that can protect neurons. Those modified stem cells can be transplanted into a person’s brain or spinal cord to slow down the progression of ALS.

Winokur has been a fierce advocate for families coping with ALS and other neurodegenerative diseases since her own family was affected nearly two decades ago. Her youngest son, Douglas, was diagnosed with ALS in 1995 and died two years later in 1997. Her oldest son, Hugh, was diagnosed in 2005 and died in 2010.

You can register for our inaugural CIRM Google Hangout at this link. Future Google Hangouts will spotlight other diseases CIRM researchers are working on. Watch this blog and our Google+ page for updates. In the meantime, put our first one, July 3 at noon, on your calendar and come join the discussion.

R.S.L.

A Bridge to a new career; building the next generation of researchers

One of the many things we are proud of at the stem cell agency is our Bridges to Stem Cell Research program. It’s focused on helping aspiring scientists – students at the undergraduate and masters level – who are considering a career in research, giving them hands on experience in research labs. The ultimate goal is to help train the next generation of stem cell scientists and laboratory technicians. Meeting these young scientists is always inspiring. They have such infectious enthusiasm that you can’t help but be excited about the work they are doing.

Here are two emails we received from recent Bridges graduates at California State University, San Bernardino who took the time to say thanks.

Joshua Billings working in the lab

Here is what Joshua Billings wrote to us:  

Being a recipient for the CIRM Bridges to Stem Cell Research grant was an invaluably important feature of my education while attending college. The fellowship gave me a chance to train in and center my education around research aspects that interested me. After starting the grant term I was able to fully immerse myself in a research lifestyle that I otherwise would not have had access to.

My principal investigator, Dr. Lien, guided my project but gave me autonomy in my research which allowed me to really grasp the biological concepts and pathways while formulating my hypothesis. I was able to collaborate with my colleagues and also learn different protocols that allowed me to forward my analysis of the regenerative capacity of the zebrafish and neonatal mouse hearts. This gave me a chance to try my hand at survival surgeries and work with different organisms until I felt confident enough in my abilities that I was able to integrate them into my own experiments. I would have never had access to the equipment or research models had I not worked at the Saban Research Institute at CHLA.

The grant also allowed me to present my research in conference before my peers as well as my superiors. This gave me confidence in my presentation skills as well as in writing research papers and drafting presentations and posters.

The experience was also a pivotal point of interest in my medical school interviews and a central reason I believe I am matriculating to the David Geffen School of Medicine at UCLA in the Fall. I am extremely thankful for the grant because it gave a different facet to my education and allowed me a much more hands on learning experience while also guiding my way into a research position after the grant term ended, acceptance into medical school, and also a better understanding of my personal career goals.


Lindsay Lenaeus (right) when Stephen Hawking (center background) toured the lab

Here’s what Lindsay Lenaeus had to say:

The CIRM grant has been incredibly beneficial to my life. I received the scholarship and was trained on how to work with human embryonic and induced pluripotent stem cells. After my training, I fulfilled my internship at the City of Hope in Duarte, Ca. While at the City of Hope, I had hands on experience with a variety of laboratory techniques and procedures. At City of Hope, I was fortunate enough to work directly with human induced pluripotent stem cells and that opportunity opened up so many doors for me.

Following my internship and college graduation, I was offered a Research Associate I position at Cedars-Sinai Medical Center in Beverly Hills, Ca. I now work every day with human induced pluripotent stem cells and am incredibly blessed to work under Clive Svendsen, Ph.D. and with so many other talented scientists in such an emerging field.

I know for a fact, that without the CIRM grant, I would have never been able to achieve this level of experience this early in my career and for that I am so truly grateful for everything the CIRM Bridges to Stem Cell Research Program has awarded me.

Brain’s mysterious support cells underly some diseases

Neurons forming from embryonic stem cells | Courtesy of Guoping Fan at the University of California, Los Angeles

Scientific American ran a piece in their blog yesterday that’s both a great read about the brain’s support cells and also a good explanation for why therapies for diseases of the brain progress slowly.

The piece is about support cells called glia that make up the majority of cells in the brain. They don’t relay signals or hold memories, but they do support the cells that carry out those more well known tasks of the brain. The piece describes the role of glia in diseases:

Recent studies have found that a certain type of glial cell, known as an astrocyte, sends out some of the chemical signals that build up our sense of sleepiness throughout the day – and that inhibiting these signals can counteract some symptoms of depression. Other studies have found that glia can spark seizures, regulate blood flow in the brain, and gather protectively around damaged neurons. And in 2013, researchers who transplanted human astrocytes into mouse brains found that their modified mice learned more quickly and formed more memories than ordinary mice. Glia, it seems, may be starring players in their own right.

Although quite a bit is known about the cells, a lot of mysteries remain.  In diseases like ALS (Lou Gehrig’s disease) and multiple sclerosis, any potential therapy will need to target these glial cells. And to target them, scientists need to understand what makes those cells tick. (This need to understand the basic biology underlying diseases is what drives our Basic Biology funding program).

The piece has some great descriptions of how science unfolds and how scientists are still piecing together the role of different cell types in diseases of the brain.

A.A.

Stem cell stories that caught our eye: replacement organs, gene therapy for HIV and NIH budget cuts

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. 


Dr. Anthony Atala shows a kidney created using a 3D printer – Photo by Steve Jurveston  

Progress in creating replacement organs. Malcolm Ritter from the Associated Press wrote a good lay-level review of our progress toward one of the grand long-term goals of stem cell science—generating replacement organs. It got picked up the last few days all around the country. Here is one version. He duly notes that we have had considerable success, but only on very simple organs, sheets of skin and simple tubes like blood vessels and wind pipes. He interviews the leaders in the field who describe the hopes for building more complex organs, and the many hurdles that remain in achieving that goal.

Growing whole organs from scratch. While most work toward creating replacement organs involves seeding stem cells onto scaffolds like the work Malcolm discusses above, a Japanese researcher has proposed an entirely different approach. He wants to get pigs to grow new organs that contain human cells. For diabetes, for example, he starts by genetically altering pig embryos so that they can’t produce a pancreas, the organ needed to produce insulin. He proposes to then insert human stem cells, into those embryos. That should succeed in directing the pig embryo to make a human pancreas. After the piglet was born, the pancreas tissue could be isolated for transplant in patients. If the stem cells were made by reprogramming the patient’s skin into iPS type stem cells, they would be a genetic match and be less likely to be rejected by the patient’s immune system, making them better than current transplants. He has shown this works in other species, but Japanese law does not allow him to grow human tissue in a piglet that is born. This article in the journal Science discusses the research and potential changes in the regulations being proposed in Japan. The work would be legal in the U.S.

Gene therapy in stem cells for HIV. CIRM funds two multi-institution teams that are trying to recreate “the Berlin” patient, the HIV-positive person who needed a bone marrow transplant to treat his leukemia, and was given marrow stem cells from a person who was naturally immune to the virus. It worked for his leukemia and to give him an immune system that seems completely resistant to the virus. Our two teams are trying to use gene modifying techniques to alter a patients’ own stem cells so they have the same gene mutation as the Berlin patient’s donor. David Baltimore, one of the co-founders of Calimmune, the company leading one of our projects, discussed the effort at the recent World Science Festival in New York. This biotech web site offers a nice comparison of the two projects CIRM is funding and notes that the Calimmune project is taking the extra step of altering two different genes involved in infection by the virus. You can read more about both projects here.

Stem cells shed light on cancer. A new paper from the Harvard Stem Cell Institute (HSCI) used the understanding of how embryonic stem cells function to find a potential cancer therapy. They successfully tested it in liver cancer, but speculated that it might be effective in many cancers. Having worked with the founders of HSCI in the early years of the organization I know they were looking forward to both stem cell-based treatments, and medical advances made by understanding normal human function that could only be found using embryonic stem cells. In the current paper, published this week in the New England Journal of Medicine, and discussed in a university press release posted by Science Codex , they found that aggressive forms of cancer have a gene turned on that is normally only turned on in stem cells in the early stages of embryonic development. An inhibitor of that gene is the potential therapy they found.

Patient hopes versus federal cuts. CIRM works frequently with many patient advocates, many of whom are patients who struggle through major adversity to work toward the long-term goal of better therapies. The St Louis newspaper did a nice write-up on one of the more remarkable tails of patient determination. It details the struggles of Patrick Rummerfield who was a paralyzed in a car accident, and after intense physical therapy was able to participate in a triathlon. He finished last, but he did it. The article concludes with Rummerfield talking about the hope he has for stem cell research, and his fears that those hopes will take much longer to materialize now because of the federal budget cuts known as the “sequestration.”

Senate leader laments NIH budget cuts. I came across this video clip from the Senate floor yesterday thanks to a Tweet from the National Institutes of Health director Francis Collins. In it, Senate majority leader Harry Reid talks about the many lives saved through research funded at NIH, noting that there has been a 60 percent drop in deaths due to heart disease in the past 50 years and that AIDS is no longer a death sentence. However, he called the cuts from the sequester “short sighted cuts that will cost us cures tomorrow.” They slash $1.5 billion from NIH this year and $4 billion over the next two years. He lamented that while we are cutting our investment, our competitors are increasing theirs, siting a 25 percent increase in China, 20 Percent in India and 10 percent in Korea, Brazil and Germany. But one of the biggest losses he noted, may be the promising young scientists who will abandon the field of research completely. When we loose them, we loose a generation of scientific creativity

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DG

Stem cells in space; doing research in microgravity

Here at the stem cell agency we consider California to be a global leader in stem cell research. But in this guest blog Michael Roberts at CASIS explains how his organization is literally out of this world 
when it comes to research

                                              
International Space State: by NASA (Crew of STS-106) [Public domain], via Wikimedia Commons

In a field as critical to human health and drug development as stem cell biology, it is all the more important to explore and exploit new research pathways. One example of a new and uncharted pathway is the exposure of stem cells to reduced gravity conditions that induce changes in cell growth and differentiation. This pathway is now accessible to scientists and innovators for far less cost than ever before and is made available by the Center for the Advancement of Science in Space, or CASIS, via a formal Request for Proposals (RFP).

What is CASIS? About two years ago, we began to take over management of the U.S. National Laboratory on-board the International Space Station. The purpose of having CASIS (a nonprofit, non-government entity) take over management from NASA is to ultimately increase use of this National Lab by academics, industry and non-NASA government agencies for research that will improve life on Earth. CASIS supports research through both grant funding and facilitation of the NASA and service provider interactions necessary to get research into space—and our newest RFP is titled “The Impact of Microgravity on Fundamental Stem Cell Properties: A Call for Spaceflight and Ground-based Experiments.”

While biology in space might seem like a radical concept, CASIS works with investigators to transform their research questions into space-based experiments—and stem cell research in space may provide an experimental model system that enables improved ex vivo modeling of cell differentiation and tissue generation and yields new insights into biological processes for disease treatment. Microgravity-induced changes in cell cultures include global alterations in gene expression and the aggregation of cells into larger and more organized 3-D structures with tissue-like functions. Research in microgravity has already enabled breakthroughs in human health, medicine and fundamental biology (you can read more on our website —and when applied to stem cell science, microgravity research has the potential to advance stem cell therapies and to significantly reduce costs of drug development/screening by identifying accelerated models of cell proliferation and differentiation.

Much of what we know about the effects of microgravity on stem cell properties comes from ground-based experiments using rotating bioreactors that create modeled or simulated microgravity on Earth. In both space-based and simulated-microgravity experiments, various types of stem cells and progenitor cells have shown distinct responses. Some types of cells (e.g., cord-blood and embryonic stem cells) show increased proliferation and viability. Others (e.g., hepatic, neuronal and adipocyte precursors) show enhanced differentiation. In fact, in some cases, simulated microgravity alone is sufficient to induce differentiation without addition of inducers.

In effect, depending on the cell type, microgravity may induce accelerated maturation and differentiation, maintenance of pluripotent marker expression and multi-lineage differentiation potential, or various lineage-restriction phenotypes. Affected properties include morphology, migratory potential, cytoskeletal structure, adhesion rates and cell-cycle kinetics. References for publications describing stem cell experiments in simulated microgravity on Earth and in space-based experiments can be found on the CASIS website (listed above).

CASIS believes that the ability of microgravity to alter the behavior of stem cells provides an exciting opportunity to augment traditional ground-based studies. Simulated microgravity experiments have demonstrated that further investigation is prudent—but the capability to perform long-term studies investigating stem cells in microgravity only recently became possible with the increased access to the space station’s National Lab for non-NASA research. Because of this, CASIS has allocated grant funding for this research area (for both ground-based and spaceflight experiments), hoping to encourage scientists from basic and applied fields of biology and medicine to explore the benefits of microgravity research and ultimately improve the quantity and quality of stem cell research on-board the National Lab.

Importantly, awarded projects from the CASIS stem cell RFP will receive support via not only grant funding but also facilitation of service-provider interactions and flight coordination to and from the space station. Proposers need not have any previous experience in space science; in fact, a major goal of the CASIS National Lab model is to make it easy for new-to-space investigators to transition their ground research into successful space experiments. Therefore, all U.S. individuals and entities are encouraged to submit proposals.

Finally, the powerful research platform of the National Lab supports not only cell biology research but also research across the physical and life sciences as well as technology demonstration and Earth/space observations. CASIS issues several funding opportunities each year in various areas, but we also accepted unsolicited proposals at any time through our website, and we are happy to talk with all interested parties about the benefits of space-based research and how it can be used to complement ground studies to accelerate innovation and discovery.

To learn more about the stem cell RFP and other research opportunities, visit http://www.iss-casis.org/solicitations.

Michael Roberts, CASIS Staff Scientist

Stem cell documentary starts out with flawed premise

Hype is a very common ingredient in promoting any media product. The world of medical discovery is no stranger to hype either. So it’s quite understandable why a project that marries the two worlds together would fall victim to this as well.

That was my first – and second – reaction when I read the news about a British team that is making a documentary about the promise of stem cells. It’s not the promise that struck me as hype but the claim in their news release that says:

“The documentary, which focuses on the controversy around stem cells in the United States, and how the US is falling behind within the medical field of stem cell treatments.”

It later goes on to say that:

“The UK is the hub of stem cell research in the world and by basing the project here we aim to portray the unbiased truth about the benefits of stem cell treatments.”

Now, working at California’s stem cell agency I might be considered a little biased in my judgment but I grew up in the UK, and I also worked in TV news and made some documentaries so I can see this from both perspectives. But theirs is just wrong.

Let’s take a look at the facts:
 • The US spends vastly more on stem cell research than the UK
 • California alone spends more on stem cell research than the UK
 • There are far more stem cell scientists in the US than in the UK

The UK is clearly an important player in the field, but it is certainly not on the field alone. There is a vast international community working on moving stem cell-based therapies to the clinic for patients.

CIRM has collaborative funding agreements with 13 international funding agencies to foster collaborations between the best scientists here and abroad. You can see the full list here. KM