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.

The first section of my report this month focuses on trends spotted at this year’s annual meeting of the International Society for Stem Cell Research in Yokohama, Japan, June 13-16. The meeting showed a field that is clearly maturing both as a basic discipline helping us understand the underpinnings of life, but also as a field revealing ways to move stem cell science toward therapies.

At least three teams presented work in which they matured stem cells into complex tissues, not just various end stage cell types. One group showed they could grow gastric units they called organoids that could be transplanted into mice and integrated into the animal’s intestine. Another’s project resulted in what they called the first functional organ with networks of blood vessels, in this case a small piece of liver that was able to metabolize some drugs like a normal liver. The third team presented work that replicated in human tissue their work of a year ago in mouse cells. They coaxed stem cells into forming the multiple cells layers that make up the optic cup. Our full report here goes into each study in more detail, and our report from last April discussed the earlier optic cup work.

The remainder of this month’s report highlights four significant papers from research journals this month, but I want to discuss just one in some detail here. It could be a major advance in producing the types of cells needed for therapy in sufficient quantities and without fear of causing tumors. Traditionally researchers create a desired adult cell either by maturing pluripotent, embryonic or iPS, cells into that cell type, or by isolating adult stem cells from that lineage and maturing them into the desired cell. More recently, teams have been perfecting the art of direct reprogramming that turns one adult tissue directly into a different type of functional adult tissue. All three methods have obstacles in using them for clinical therapy. Starting with pluripotent cells results in lingering concern of a stray starter cell causing a tumor. With adult stem cells, most are difficult to isolate in usable quantities, and with direct reprogramming the end stage adult tissue produced generally is insufficient for therapy.

A UCSF team at the Gladstone Institutes seems to have gotten around all three issues by reprogramming skin cells to become neural stem cells instead of fully mature adult cells. This allows them to produce large quantities of their starting material, the neural stem cells, which can then be matured into various types of brain cells. They showed their neural stem cells could indeed produce multiple types of neurons as well as other types of brain cells and over time form neural networks in culture.

The other papers in this month’s report describe how a Swedish team used tissue engineering to give a young girl a new portal vein, and detail a potentially game changing theory on the origins of blood vessel disease, suggesting a newly found stem cell may be the culprit. My colleague blogged about this work earlier this month here.

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


First human cell model for Huntington’s shows value of consortium science

Image of striatal neuron (yellow) which is damaged in
Huntington’s disease (credit: Dr. Steven Finkbeiner)
We have written often, most recently last week, about the power of using stem cells reprogrammed from a patient’s skin to recreate the patient’s disease in a dish. You simply take a skin sample, or other tissue sample, and use one of many proven techniques to trick that adult tissue into thinking it is like embryonic stem cells. After that you use various chemicals and other tools to tell those stem cells to mature into the tissue impacted by the disease.
But the real trick is verifying that those nerve cells, or what ever you have in the dish, really are behaving like those same cells in the patient.
Now, a ten-institution international consortium says they have verified the validity of model cell lines made from several Huntington’s disease patients. A team led by Clive Svendsen at Cedars-Sinai, with the help of a CIRM-funded post doctoral fellow, made the cell lines. They then shared those cells with all the consortium members. They were able to mature them into the types of nerve cells that control movement and cognition—the ones impacted by Huntington’s. More important, they consistently found the same difference in those cells compared to normal nerve cells. In particular, the model cells were much more susceptible to the researchers creating “stressful” condition in the petri dish. The model cells were much more likely to die, as happens in the disease.
A press release from Cedars-Sinai quotes Svendsen, who is director of their Regenerative Medicine Institute.
This Huntington’s ‘disease in a dish’ will enable us for the first time to test therapies on human Huntington’s disease neurons. In addition to increasing our understanding of this disorder and offering a new pathway to identifying treatments, this study is remarkable because of the extensive interactions between a large group of scientists focused on developing this model. It’s a new way of doing trailblazing science.
The cell lines have been made available via a National Institutes of Health-funded repository at Coriell Institue in New Jersey.
CIRM funds $9.7 million in grants for projects in California trying to solve the Huntington’s dilemma, including one to Leslie Thompson at UC Irvine to participate in this consortium. The full list is here.

Texas makes the case for why science should take time

A few weeks ago, David Lesher wrote in the Sacramento Bee that science takes time if you want to make sure the new therapies being developed are safe. He was writing in particular about a CIRM-funded approach to treating HIV/AIDS.

None of the research under way will reach patients until long after the 10 years of funding by the ballot measure runs out. With the HIV project, researchers hope to be in human trials by 2014, but it is likely to be at least 10 years before they can show it might work in humans. And in the case of a stem cell cure for AIDS, it would be many years after that before a treatment is widely available.

That’s partly due to the caution of dealing with new and powerful techniques, and the reality that each scientific step takes time to assess. Even with rapid scientific advance, it also shows how much is still unknown.

 A great example of that concern is being reported in the Houston Chronicle, which gained access to a Food and Drug Administration review of the Texas stem cell company Celltex Therapeutics Corp. This is the company that treated Texas Gov. Rick Perry last year. The Chronicle reported:

The Sugar Land company involved in Gov. Rick Perry’s unlicensed adult stem-cell procedure is rife with basic manufacturing problems, according to the U.S. Food and Drug Administration.

In a report one expert called a blow to the entire adult stem-cell industry, the FDA found that Celltex Therapeutics Corp. cannot guarantee the sterility, uniformity and integrity of stem cells it takes from people and then stores and grows for eventual therapeutic reinjection.

A former FDA official who asked not to be identified, however, said the deficiencies – 79 in all, from incorrectly labeled products to failed sterility tests – are so serious that Celltex risks being shut down if it does not remedy the problems quickly.

Adult stem cells are cells in the body that multiply to replenish dying cells. Long used to treat leukemia and other cancers, they have shown promise for tissue repair in many other diseases in the last decade, although most scientists in the field consider them not ready for mainstream use.

 They also quote from the report itself:

“You have not performed a validation of your banking and thawing process to assure viability” of the stem cells, reads the April 27 report, meaning that the company cannot verify the cells are alive.

 This story makes clear why it’s so important for CIRM to work closely with grantees and with regulators like the FDA. It’s true that therapies take time to develop, in part because we want to be sure each step of the way that the therapy being developed will be safe as well as effective. Once therapies reach patients we want to be absolutely sure those patients will be helped instead of harmed.

Here’s more information about our efforts to work with regulatory agencies, from our 2011 annual report.


A ride with Matt — cycling for a cure for Huntington’s disease

Every once in a while you meet someone who fills you with admiration and just a hint of awe. Matt Austin is one of those people.

Matt just turned 22 this week and in a few days he is about to set out on a 1500 mile bicycle ride spanning the east and west coasts. The first leg takes him from New York to Massachusetts, the second from San Francisco to Boulder, Colorado.

That alone is pretty impressive. But there’s something else you should know about Matt to understand just how extraordinary he is. He has Huntington’s, a disease that claimed the life of his father and grand father.

Huntington’s is a particularly unpleasant genetic brain disorder that affects muscle coordination. Over time nerve cells in a particular part of the brain waste away or break down, leading to problems in moving and thinking. There are no treatments, no cures. It is a terminal illness that leaves Matt with no more than ten to fifteen years to live.

And Matt is determined to live those as completely as he can.

I recently met Matt when he visited the lab of Dr. Jan Nolta at the UC Davis Institute for Regenerative Cures. Dr. Nolta is trying to see if stem cell therapies can help ease or treat the symptoms of Huntington’s. The stem cell agency has been a big supporter of Dr. Nolta’s work, as are Matt and his family. They are doing what they can to help promote it, and to raise public awareness about Huntington’s disease.

One of those ways is through a documentary film that is being made of Matt and his ride. A film crew is going to accompany Matt and his uncle Adam, recording their journey together. Ultimately they hope to show the documentary at a major film festival and any money they make will be used to help pay for care for people with the disease, and to fund research for a cure.

We wish Matt and his uncle all the best as they set out on their journey. If you want to find out more about their journey, and follow them along the way you can do so at .

You can read more about CIRM support of Huntington’s disease research here


Ask the stem cell expert — Alzheimer’s disease

Lawrence Goldstein

We’re excited to announce a new video series in which we’ll take questions from you, our readers, and pose them to one of CIRM’s stem cell experts. We’ll then post the video of those answers to our YouTube channel (and here, of course).

For our first video we’re focusing on Alzheimer’s disease, with questions being answered by Lawrence Goldstein of UC San Diego. He has several CIRM awards to study stem cell approaches for treating both Alzheimer’s disease and ALS and is director of the UCSD stem cell program.

Go ahead and post your questions in the comments section below by July 6. People can also post questions for Dr. Goldstein on our Facebook page or by tweeting with the hashtag #askCIRM_alz. We’ll go through the questions and pick several for Dr. Goldstein to answer. Also let us know which diseases you’d like us to take questions on for future Ask the Expert videos.

If you want to brush up on stem cell approaches to treating Alzheimer’s disease, see a list of Alzheimer’s awards, or watch our Alzheimer’s disease videos go to our Alzheimer’s disease fact page.


New stem cell findings point to future therapies for spinal musclar atrophy

Clive Svendsen

In the past few years, stem cell researchers have been taking advantage of the ability to create embryonic-like stem cells from skin to develop laboratory models of disease. The idea is simple: first, take skin from someone with a genetic disease (the skin cells will have the same genetic mutation as the cells effected in the disease). Next, turn those skin cells into embryonic-like stem cells called iPS cells. Then mature those stem cells into the type of cell that goes awry in the disease.

So far, researchers have followed this procedure to create cells in the lab dish with symptoms of Parkinson’s disease, autism, schizophrenia, Alzheimer’s disease, ALS and others. Researchers at Cedars-Sinai used the technique to create a laboratory model of the fatal childhood disorder spinal muscular atrophy, or SMA, back in 2009. Now, in work published in the June 19 online issue of PLoS ONE they have created more lab models of SMA but with newer techniques that are less likely to cause unwanted changes in the cells.

The point of all this work is to figure out what goes wrong in the disease, and to find drugs to fix the problem. Since all of these diseases occur in living neurons, which in general people are loath to part with, scientists have never had a way of studying how the disease forms in the lab. And if you don’t know what goes wrong in the first place, how can you fix it?

The latest in these disease-in-a-dish models comes from CIRM grantees led by Clive Svendsen who created motor neurons from the skin of two people with SMA. In the roughly 100,000 newborns born with the disease each year, the motor neurons that control muscle movement don’t form properly and the children are generally paralyzed by age three.

Svendsen and his group found that in the lab dish, the SMA stem cells didn’t form as many motor neurons as iPS cells from people without the disease. What they noticed is that the cells seemed to be dying off through a regulated process of cell death known as apoptosis. When they exposed the neurons to molecules that block apoptosis, the neurons lived.

A press release from Cedars-Sinai quotes Svendsen, who is director of their Regenerative Medicine Institute.

“With this new understanding of how motor neurons die in spinal muscular atrophy patients, we are an important step closer to identifying drugs that may reverse or prevent that process.”

The goal now is to start testing drugs on these SMA neurons to find ones that seem to reverse the disease. Those drugs could then become possible therapies for people with SMA.

CIRM funds $15 million in awards that could one day benefit people with SMA. You can see the complete list of those awards here.


Improved way of treating sickle cell disease with stem cells

June 19th has been designated as World Sickle Cell Awareness Day to try and raise public awareness about this disease. So it’s rather appropriate that the Science Daily is carrying a story about a Chicago woman who has been cured of her sickle cell disease using a bone marrow stem cell transplant.

Bone marrow transplant is currently the only way of curing sickle cell disease, but the procedure itself can be deadly so it is only used as a last resort. Traditionally, before a person receives the new bone marrow stem cells their own bone marrow is eliminated through high doses of chemotherapy. That procedure itself is risky, and leaves the person without an immune system until the new bone marrow takes over and begins producing immune cells. So, it’s no wonder the technique is only used in critical cases.

The doctors treating the Chicago woman took a different approach. They didn’t completely eliminate her own bone marrow, lessening the risk of infection. If this type of less risky bone marrow transplant becomes widely available, it could open up the possibility of bone marrow transplants to treat multiple sclerosis and other diseases of the immune system.

CIRM-funded researchers are also working on a similar approach to treating sickle cell disease. However, instead of taking bone marrow from a donor Dr. Donald Kohn and his team at UCLA are using the patient’s own bone marrow that has been genetically modified to replace the defective gene that causes the disease. They then give the patient a full dose of chemotherapy to destroy the defective bone marrow and replace it with the corrected version.

Dr. Kohn is now working with other CIRM-funded researchers at USC, and Children’s Hospitals in Los Angeles and Oakland to move this this therapy into clinical trials. You can read about their work here. We also have a video of researchers talking about their approach to treating sickle cell disease.

It’s an example of how researchers around the US are taking different approaches to reach the same goal, curing a disease that affects 80,000 Americans. 


Embryonic stem cell funding at a critical moment in EU

Legal and policy issues relating to stem cell research continue to make headlines in Europe. On June 15 a coalition of leading funders of biomedical research and patients groups issued a joint statement calling on the European Parliament to continue funding research using embryonic stem cells. Members of this collaboration include CIRM funding partner the UK Medical Research Council.

In the statement, Sir Mark Walport, Director of the Wellcome Trust, said Europe “must send a clear sign that it recognizes the importance of embryonic stem cell research.”

Indeed, it is a critical moment for research in Europe because funding there occurs in seven-year cycles. Decisions made this year will determine the EU’s program for research and innovation running from 2014 to 2020. The funding renewal comes on the heal of last October’s ruling by the European Court of Justice that products and procedures involving human embryonic stem (ES) cells cannot be patented.

A recent article by Professor Aurora Plomer of the University of Sheffield School of Law argues that the EU court’s ruling shows complete disregard for settled policy among member states in Europe. She illustrates how the Court’s decision trumped a variety of national and EU wide policies.

The article situates the ruling of the Brustle ruling in the wider legal context of the interaction of European Union law with national laws and European Convention law on fundamental human rights in Europe. Professor Plomer argues that the EU court’s ruling shows “complete disregard for the diversity of moral and legal cultures on the human embryo in Europe as recognized by the European Court of human rights.”

She goes on to suggest:

The EU court’s ruling in Brustle represents a complete break with the settled policy of the European court on human rights to respect the diversity of national moral cultures in Europe on this very sensitive question. The views adopted by the EU Court amount to judicial imposition of a uniform (most likely religiously inspired view) on the whole of Europe where the moral and legal reality is that there is no such consensus.

We asked Professor Plomer whether a decision to extend EU-wide funding would influence policy. She indicated any decision taken on the funding of hESC research will not affect the court.

She made the following observation:

One of the things I find striking is that the critics are trying ‘to have their cake and eat it’ as we say over this side of the pond. They are trying to have it both ways. On the one hand they are acknowledging that there is a division of opinion in Europe amongst states, which support hESC research and those which don’t. But on the other hand, they are also seeking to impose the view of states which are opposed to stem cell research on the whole of Europe, much as the EU Court’s ruling has done. The European Union is founded on respect for the diversity of moral and cultural values in Europe, democracy and the rule of law. Cutting funding for stem cell research would be contrary to the fundamental values on which the EU is founded.

Policy and funding decisions in the EU could be important for those scientists hoping to leverage existing CIRM’s collaborative funding agreements. While these agreements are not directly impacted by the EU decision, a reduction in funding or an increase in prohibitive policies in the broader research environment in the UK, Germany, Spain, and France, where we have do agreements, may be detrimental.


Stem cell meeting of the minds in Yokohama, Japan

This past week several people from CIRM have been in Japan at the yearly meeting of the International Society for Stem Cell Research. These meetings are a great chance to stay current with stem cell science and see where the field is moving. If we’re going to accelerate new therapies, our science officers need to be out there meeting the people who are carrying out those groundbreaking discoveries.

The meeting is also a chance to sit down with our international collaborative funding partners (here’s a list of those partners). It’s not every day collaborators from Spain, Germany, Australia, the UK, Japan and others can gather around a table to discuss the best ways of moving the field forward.

A developmental biology blog called The Node summarized of the first day of the meeting, including a quote from NBC journalist Charles Sabine, who was recently diagnosed with Huntington’s disease and who spoke about his hopes for stem cell research at the opening plenary session.

“In a world of total darkness, a glimmer of light emboldens human spirit”

You can read the blog to learn more about some of the individual topics of discussion. The writer summed the day up like this:

While the topic of the day’s talks varied widely, the singular mood was one of forward-facing hope for the future of stem cells and their use in regenerative medicine. Looking up into the neon-tinged night sky, I felt the potential for our research was as high as the towering skyscrapers of Yokohama Bay.


Irv Weissman on the many barriers to stem cell therapies and why they matter

Stem cell pioneer Irv Weissman has a rather feisty correspondence in the June 14 issue of Cell Stem Cell in which he takes issue with the many barriers standing in the way of stem cell therapies. His targets include fraudulent stem cell clinics, lack of Food and Drug Administration oversight, private cord blood banks, lack of biological models of how diseases progress, bad science, and problematic business development practices. To name a few.

So comprehensive is his list of guilty parties that he writes, “So, whom have I failed to annoy here?” Pretty much nobody, Irv.

Weissman, who directs Stanford’s Institute for Stem Cell Biology and Regenerative Medicine and has several CIRM awards, became the first person to isolate a stem cell when, in 1988, he identified the stem cell in the bone marrow of mice that can reform the entire blood system. (There’s a great profile of this discovery here.) The reason for his frustration regarding the future of the field he helped found stems, surprisingly, from optimism. He writes:

I fear that therapies using purified tissue and organ-specific stem cells—the only self-renewing cells in a tissue or that can regenerate that tissue or organ for life—will remain elusive. Before I go further, just think about that statement: regenerate that tissue or organ for life. No pharmaceutical, no biotech-developed protein, and no other transplanted cells can do that. If we can deliver purified stem cells safely and effectively as a one-time therapy, we can change medicine, especially for diseases that drugs and proteins can’t touch. Moreover, if we manage the costs and charges carefully, this form of therapy could lower overall health care costs dramatically. This vision is based on solid scientific evidence that stem cells regularly maintain, and, if necessary, regenerate tissues in a homeostatically controlled process. So it’s worth the extra effort to find a way to make it happen.

The one group that failed to draw Weissman’s wrath was CIRM, thank you very much. He wrote:

The largest and best funding experiment I have seen so far comes from the California Institute for Regenerative Medicine. CIRM’s charter allows it to fund promising stem-cell-based discoveries to and through phase I trials, taking out the risk that leaves our field bereft of suitable funds and in the “valley of death.”

Weissman has one of the awards he praises—the so-called Disease Team Awards. His is aimed at developing a therapy for leukemia. The next round of these awards are due to be voted on in July.

He ends with a reminder of why he is so eager to see the barriers to stem cell therapies overcome, and to see the promise of the field be fulfilled:

Remember, right now our patients, friends, and families are contracting diseases that have a very short window of opportunity in which regenerative therapies can save them, and each delay removes a cohort of them from possible cures. We should not fail them.