Autism-like syndrome modeled by in a lab dish

One of the biggest hurdles in understanding and treating neurological diseases is figuring out what has gone awry with those cells. People aren’t generally eager to donate a chunk of their brains for research. With the advent of reprogrammed iPS cells scientists have been able to recreate the diseases in a lab dish and begin to understand the origin of those diseases.

In the past few years, CIRM grantees have taken skin cells from people with Parkinson’s disease, schizophrenia and forms of autism, reprogrammed those into embryonic-like cells, and matured them into the cells that go awry in the disease. (We blogged about Parkinson’s here, schizophrenia here, and one form of autism here.)

The latest of these studies comes from CIRM grantee Ricardo Dolmetsch at Stanford University, who has created nerve cells out of people with the rare genetic disorder called Timothy Syndrome that includes autism as a symptom. Dolmetsch came to this research for personal reasons. In a conversation with Paul Costello in Stanford’s 1:2:1 podcost, he talked about his son, who was diagnosed with autism at age 4. In that interview he told Costello how that diagnosis altered the direction of his work:

“The thing that was disconcerting is that I’m an academic and I was horrified to discover that very little was known. And so I thought I’m a neurobiologist and I don’t work on this but at least in principle I could. And so I decided to turn my lab toward studying autism.”

As a part of that new research direction, Dolmetsch got a CIRM Tools & Technologies II award to use nerve cells created from the skin of people with Timothy syndrome to attempt to find drugs that reverse the symptoms, at least in the lab dish. A Stanford press release describes their findings:

In this study, the scientists suggest that the autism in Timothy syndrome patients is caused by a gene mutation that makes calcium channels in neuron membranes defective, interfering with how those neurons communicate and develop. The flow of calcium into neurons enables them to fire, and the way that the calcium flow is regulated is a pivotal factor in how our brains function.

The researchers also found brain cells grown from individuals with Timothy syndrome resulted in fewer of the kind of cells that connect both halves of the brain, as well as an overproduction of two of the brain’s chemical messengers, dopamine and norepinephrine. Furthermore, they found they could reverse these effects by chemically blocking the faulty channels.

In the release, Dolmetsch points out that although they did fund a chemical that reverses the effects, that chemical, called roscovitine, is not currently approved for use in humans and has never been tested in children. He said:

“The reported side effects are probably due to the fact that, in addition to targeting the channel that is mutated in autism, roscovitine also inhibits kinases that are required for cell proliferation. We think that roscovitine is a good starting point, but probably has to be optimized before it would be useful for autism.”

Nature Medicine, November 27, 2011
CIRM funding: Oleksandr Shcheglovitov (T1-00001)


San Diego area gets stem cell "Collaboratory"

Sanford Consortium for Regenerative Medicine

Today the ninth of twelve CIRM-supported stem cell facilities in California is opening its doors. The Sanford Consortium for Regenerative Medicine in La Jolla will be home to stem cell scientists from five San Diego area research centers — University of California San Diego, The Salk Institute, The Scripps Research Institute, The Sanford-Burnham Medical Research Institute and the La Jolla Institute for Allergy & Immunology.

As with all of the CIRM-supported facilities, the institute’s support leveraged public and private funds to build a facility that provided construction jobs and that will drive the local biotechnology industry, in addition to being a center for developing new therapies. CIRM provided $43 million to support the $127 million facility. Another $19 million came from philanthropist T. Denny Sanford, with the remainder coming from public and private sources.

According to a story in the North County Times:

That construction put money into the pockets of local builders, architects and other professionals. But the real economic benefit is to come from the research the building is expected to engender, and the products local companies hope to take to market. 

The story goes on to quote Louis Coffman, consortium vice-president, talking about the way the building was designed to promote collaboration:

“In terms of collaboration, we believe that you cannot force it,” Coffman said. “You can’t make it happen. It’s sort of an emergent property of people working together. They either work together or they don’t. All we can do is create the conditions to enable it to happen.” 

A story in the San Diego Union Tribune discusses the collaborative nature of the building and quotes CIRM President Alan Trounson discussing the value of encouraging scientists to work together:

The new building has been nickhamed the “Collaboratory” for its emphasis on teamwork. The center’s interior features almost 3,000 square feet of glass so that scientists from different disciplines will regularly see one another. Laboratories are linked by informal meeting areas. And seating in the auditorium was limited to 150 in the belief that crowds bigger than that discourage people from being social.

“The design means that you can’t walk from spot A to B to C without meeting other people,” said Alan Trounson, president of the California Institute for Regenerative Medicine (CIRM), a state agency that provided $43 million in public funds for the project. “This is not a conventional building. The idea is to integrate people from various places. Instead of taking a year and a half to meet, they’ll have done so in three months.” 

That Union Tribune story includes some highlights about the scientists who will be housed in the new facility and some of the technologies San Diego stem cell scientists will have access to.

The opening of the Sanford Consortium building also kicks off the annual Stem Cell Meeting on the Mesa, which includes a first-time partnering forum to bring together the investors, companies and academics who will need to work together to bring stem cell therapies to patients. We’ll have more on that forum in future blogs.

Last month the UC Berkeley stem cell facility opened, which you can read about here


Jonathan Thomas on CIRM’s progress toward stem cell therapies

Jonathan Thomas is Chair of the CIRM Governing Board

When I became Chair of CIRM this summer one of my first priorities was to reach out to the people of California and explain the progress we’ve made in developing new therapies. The agency only started funding research in 2007 and yet we already have 43 research projects that are in various stages of progress toward clinical trials.

At my first board meeting as chair, I and the rest of the board were excited about a presentation by Ellen Feigal, senior VP for R&D, and Pat Olson, executive director of scientific activities. They gave a detailed summary of all CIRM’s projects that have a goal of developing a therapy for one of 26 different diseases. Their summary, though exciting, was pretty technical. I thought if only the information were written in clear easy to understand language for the people of California, they couldn’t help but be as excited as I am about the agency and what it has accomplished. (We blogged about that presentation here.)

That summary is now available on our website, including a list of our awards that are in stages of developing therapies for 26 different diseases. We also explain the process our grantees go through to turn a basic science discovery into a new therapy, and we have information about what CIRM is doing to help smooth that pathway to get therapies to patients faster.

(You can also download this information in a PDF document.)

Given that it normally takes a decade or longer for a basic science discovery to reach clinical trials, 43 projects seemed to me like quite an achievement – an achievement that the people of California should take pride in supporting. Not only is CIRM driving stem cell science in our state, but through our national and international collaborations California has become a stem cell hub that accelerates stem cell progress worldwide.

I hope everyone who reads about our projects is as hopeful as I am about the future of stem cell therapies. As my friend Roman Reed says, CIRM is turning stem cells into cures.


Hope for treating heart disease with stem cells?

It’s a big day for announcing prizes to CIRM grantee, and a good week for stem cells in heart disease. CIRM scholar Li Qian from The Gladstone Institutes won the Louis N. and Arnold M. Katz Basic Science Research Prize for Young Investigators from the American Heart Association (AHA). Hers was one of several announcements this week regarding the potential treatments for heart damage after heart attack.

According to a press release from The Gladstone Institutes:

“Dr. Qian received the prize for her findings that non-muscle cells that normally form the architectural support for the heart can be reprogrammed into beating heart muscle cells. This reprogramming may allow scientists to transform non-beating scar tissue resulting from heart disease—and which was previously considered irreparable—into beating tissue again.”

Qian is carrying out her work in the lab of CIRM grantee Deepak Srivastava, who last year published work in which he and his colleagues converted mouse heart support cells called fibroblasts into beating heart cells in a laboratory dish (read our blog about that work here). For Qian’s work, which was presented at the AHA meeting in Orlando, she and Srivastava carried out the same feat in a living mouse. The team delivered factors directly into the hearts of mice with induced heart attacks (you can read the abstract for that work here). Those injections seemed to have induced support cells to convert into heart muscle cells, and three months later the mice had less heart dysfunction than their labmates who hadn’t received the injections.

Of course, mice aren’t humans and three months isn’t long enough to know if the benefits of the injections will last.

This award comes during what has been a big week for stem cells in heart disease. For many years now, research groups have been testing stem cells isolated from the bone marrow to see if they can effectively treat damage from heart attacks. Results had been ambiguous. Researchers saw some improvement, but it seemed to be short-lived in most studies.

In studies published earlier this week, a group from Louisville and a group of CIRM grantees from Cedars-Sinai both published results suggesting that stem cells isolated from the heart could produce improvements that last up to a year.

ABC News spoke to one of the patients who participated in the University of Louisville trial:

Mike Jones, the very first patient to receive the treatment in July 2009, said it not only gave him more years to live, but a better quality of life during those years.

“Now I can do more with my grandkids,” said Jones, 68, who lives in Louisville. “I pitched softballs with my granddaughter for probably 15 minutes today. I got a little bit winded at the end, but that’s something that before the stem cells would have been just impossible.”

These studies involved small numbers of people and the results need to be confirmed in much larger trials. Still, those of us with heart disease in the family will be watching to see how the cells fare in the larger trials. My own grandfather, unlike Jones, would not have been able to pitch softballs after his heart attack.


Presidential Award goes to UCSF high school internship program hosting CIRM-supported students

Last summer CIRM sponsored high school students to carry out stem cell research at five California universities in association with existing high school internship programs at those schools. Yesterday we learned that President Obama likes our choice of partner programs — the UCSF program that included six CIRM-supported students received the Presidential Award for Excellence in Science, Mathematics, and Engineering Mentoring. That award to the Science & Health Education Partnership (SEP) High School Internship Program comes with a $25,000 grant.

The SEP program is focused on drawing students from disadvantaged backgrounds and giving them experiences that will help them succeed in college. In a press release, UCSF described their students:

The program works closely with San Francisco high school science teachers to identify students from disadvantaged backgrounds with significant potential. For example, the majority of high school interns come from families where neither parent has completed college. The education outcomes of students who participate in the internship program far exceed that of their peers – 92 percent matriculate to college, 76 percent complete Bachelor’s degrees in the sciences, and 87 percent pursue post-baccalaureate degrees.

Congratulations to the UCSF team, and to the outstanding students who have gone through the program.

CIRM science officer Mani Vessal led the high school internship program for CIRM. The awards—called Creativity Awards—encourage participants to carry out research in an additional field unrelated to stem cell research. He said:

It really does foster creativity to have a mulitlinear approach to learning as opposed to just a single dimensional one. We’re hoping to get the next generation of stem cell scientists who can think outside the box.

This short video features Ben Koo, the Academic Coordinator for the SEP program, and Creativity Award students from the UCSF and other programs talking about their research projects.

After last summer’s success, CIRM is expanding our Creativity Awards program for next summer. The request for applications just got posted to our website.


The First International Vatican Adult Stem Cell Conference: A Gound-Breaking Achievement

John Wagner is Professor and Director of the Division of Pediatric Blood and Marrow Transplantation at the University of Minnesota Medical School. He performed the first umbilical cord blood transplant to treat a child with leukemia and pioneered the use of stem cells in the treatment of the skin disease epidermolysis bullosa. He is also a member of CIRM’s standards and grants working groups.

It was a fascinating week in Rome where I was one of several invited speakers attending the Vatican sponsored: “Adult Stem Cells: Science and the Future of Man and Culture.”

Overall, I was personally ‘moved’ by the uniqueness of this event that mixed science and history. Regardless of anyone’s personal religious beliefs, the Catholic Church does have an undeniable place in the history of western civilization with a legitimate obligation at least for Catholics and Catholic institutions around the world to try to understand the broader impact of science that no longer simply observes nature but now has the capacity to alter it.

My specific role was to highlight some of the ‘lessons learned’ from ‘our’ collective experiences with blood-forming stem cells, the only stem cell therapeutic with proven regenerative medicine potential. Those lessons learned include best practices in ethical conduct in high-risk clinical experimentation in vulnerable populations, the obstacle of the immune response and the need for earlier considerations on issues of access to new technologies and public education on reasonable expectations for phase I studies.

In addition to my contribution, there were a host of other presentations focusing on public confusion on what stem cells are and the public’s understanding of the regenerative capacity of embryonic versus adult stem cells, the impact of politics particularly in the United States, sources and types of adult stem cells, technological advancements in organ and tissue regeneration, regulatory requirements for stem cell therapeutic manufacture from industry’s perspective, and clinical applications in neurological, cardiovascular, autoimmune diseases. These talks were intermixed with moving testimonials from patients who are looking to stem cells as a source of future therapies. Intriguingly, the Conference was also about ‘building bridges’ between the Church and scientists to enhance bioethical-humanistic-cultural considerations of stem cell research and develop strategies for educating the present and future generations of students in the life sciences.

As would be expected, the meeting had a strong focus on the promise of adult stem cells with relative silence on the impact of embryonic stem cells. Statements by others on the ethics of stem cell research were also predictable—“the destruction of the human embryo is never justifiable regardless of any claim to therapeutic benefit“(although it was often stated that any benefit from embryonic stem cells has yet to be demonstrated).

But, there were indeed surprises as well: 1) the Church voiced its desire to open a dialogue with scientists and educators in the life sciences, and 2) the Church announced its unprecedented financial investment into promoting adult stem cells and their role in regenerative medicine.

While we might have wished for more detail on how the Church planned to build such bridges and open dialogue with scientists, the intent was seemingly sincere. In fact the Church had already identified ‘partners’ whose work would itself promote adult stem cell research including neural stem cells derived from recently aborted fetuses, which are already in clinical trials for several conditions. The Church also clarified that its financial investments were principally focused on public education, such as through the Stem For Life Foundation, the philanthropic arm of NeoStem, Inc. which co-sponsored the Conference.

Despite the fact that my views might differ from those of some of the presenters, I was amazed by the uniqueness of this event that placed the science of today into an historical context. Consider the venue and the associated events that included a dinner reception at the Casina Pio IV (the Vatican Academy of Science), a concert at the Basilica of St John Lateran, and an audience with Pope Benedict XVI. At the end of the day, I had the feeling that perhaps this self-proclaimed ‘ground breaking’ achievement was more than self-aggrandizement. Perhaps, the Church indeed strived to promote dialogue and build bridges with those deeply involved in the science of stem cells and its clinical translation into meaningful therapeutics. For sure, the moral status of the embryo may be front and center in terms of the ethical issues, but there are other issues as well that need further discussion regardless of the stem cell source. The creation of such a dialogue on the broader philosophical and humanistic aspects of science in general and stem cell research in particular must be a good thing.

If we agree that the goal of science is the discovery of new knowledge and truth—and en-light-enment—we must also acknowledge that there are risks, such as those realized with the nuclear experiments of the last century. And, recall in Mary Shelley’s Frankenstein: A Modern Prometheus, that the not too distant cousin of light is fire. So, perhaps, it is not unreasonable to listen openly and dialogue with others who may have opposing but reasoned views, with the understanding that you need not completely accept all that others speak. From there new knowledge and a higher level of discourse may take place. If successful, that, in and of itself, would be a ‘ground breaking’ achievement.

John Wagner

Q&A about Geron’s decision and its implications for the stem cell field

Yesterday Geron announced that they would be discontinuing their embryonic stem cell program, including the groundbreaking spinal cord injury trial that CIRM had been supporting. You can read more about the decision in Geron’s announcement and in CIRM’s press release. Geron has returned the $6.4 million they had received from CIRM with accrued interest.

It’s not uncommon for companies to discontinue research programs for financial reasons. What makes this announcement different is the high-profile nature of the company and the trial. Geron was the first to pave a path through the Food and Drug Administration (FDA) to test a human embryonic stem cell-derived product in clinical trials. The trial was seen as a sign of hope for people waiting for therapies derived from embryonic stem cells, so its termination came as a shock to many patients and their families.

Today we wanted to take a step back and look at the announcement and what it means.

Q. What was Geron testing in their spinal cord injury trial?
A. Geron started with human embryonic stem cells and matured them into the precursor of type of cell that forms the coating on neurons. That coating is lost soon after a spinal cord injury, and without the coating electrical signals can’t travel up and down the spine. The idea was that after injecting some of these precursor cells they would mature and form a new coating on the spinal cord neurons, restoring the ability of signals to cross the injury site.

This first trial was in its early stages and was testing a low dose of the cells to make sure they are safe. Remember that when this trial began the cells had only been tested in animals. Only after the company showed that the cells were safe would they be able to inject a dose that was expected to be high enough to show some signs of success.

Q. Why did Geron decide to discontinue the stem cell program?
A. The company decided to focus its resources on two oncology drugs that are in clinical trials. The decision was made based on financial considerations, not based on concerns about the science. Such a move is relatively common for biotechnology companies especially during the complex early-phase clinical trials such as this one.

Q. What does Geron’s decision mean for the field of stem cell research?
A. The field of stem cell research continues to be strong, with many promising therapies in the pipeline. Geron leaving the field does not alter the existing excellent programs that are working toward and carrying out clinical trials.

Q. What will happen to the patients who already received the cells?
A. Geron has been closely following the patients who have received the cells. So far, the patients have tolerated their injections and haven’t shown any serious adverse effects from the cells. The company says it will continue monitoring those patients and keeping the FDA appraised of the results.

Q. Will the trial continue?
A. For now, the trial is discontinued. Geron says they are looking for partners to further develop their stem cell programs. Whether or not the trial continues depends on whether partners come forward with the resources and the interest in continuing it.

Q. What happened to CIRM’s money?
A. CIRM had committed $24.8 million to support the trial, of which $6.4 had been dispersed. Geron has already returned the money in its entirety with accrued interest.

Q. Are there other trials testing products made from embryonic stem cells?
A. Yes. The company Advanced Cell Technology is testing an embryonic stem cell-derived product in two forms of blindness: macular degeneration and Stargardt’s disease. They have already begun enrolling patients in those trials.

Q. What other trials are in the pipeline to test embryonic stem cells?
A. World-wide, many groups are moving closer to clinical trials testing cells derived from embryonic stem cells. CIRM has funded four disease teams that have the goal of submitting a request to the FDA to move forward with clinical trials (that request is also known as an Investigational New Drug or IND filing). Those disease teams are working on diabetes, stroke, macular degeneration and ALS (also known as Lou Gehrig’s disease).


The Personhood Amendment: California here we come

Sen. Art Torres (Ret.) is vice-chair of the CIRM governing board. His biography is available here.

A ballot measure that defined a fertilized egg as a person failed to pass in Mississippi on Tuesday. The amendments passage would have restricted stem cell research, and the Washington Post reported on additional concerns caused by the measure:

Opponents say that measure could have criminalized birth control, affected in vitro fertilization practices and even forced doctors to decline to provide pregnant cancer patients with chemotherapy for fear of legal repercussions.

A substantially similar measure failed twice in Colorado by 2:1 margins.

The Mississippi and Colorado measures are a concern for the stem cell community because of their impact on patients, scientist and the public. By criminalizing the creation of embryonic stem cell lines, these laws restrict research in their home state and outside as well. For example, CIRM researchers have turned away donors residing in states with laws that criminalize the creation of stem cell lines from surplus IVF embryos. These restrictive laws frustrate prospective donors by limiting their options.

As Jonathan Moreno points out on Science Progress,

“the Mississippi movement will not be the last.”

In fact, a personho proposal has already been submitted in California. According the legislative analysis:

“this measure could restrict stem cell research and alter medical practices in both the public and private sector.”

CIRM plans to prepare an objective analysis of the effect on the proposed measure on stem cell research in the near future.

Art Torres

Lights…Camera…Stem Cells! Filming the 2011 CIRM Grantee Meeting

Todd Dubnicoff is CIRM’s videographer and video editor

No family reunion is complete until somebody brings out the video camera. Our CIRM family is no different. So my colleague Amy Adams and I went on-location to downtown San Francisco in mid-September to film the 2011 CIRM Grantee Meeting. This almost annual, three day event brings together the California stem cell scientists and trainees who receive CIRM funding (several international collaborators were also in attendance as well as out-of-state guest speakers).

Though the scientists produce research results back in their labs at their home institutions, getting the chance to discuss those results in person with fellow stem cell researchers can spark new discoveries. Eugene Brandon of ViaCyte, Inc. explained that:

One of the great things about the CIRM Grantee Meeting is that I can meet with other people that are working on related research that I wouldn’t necessarily come across otherwise. In talking to these people, sometimes our team gets ideas that we could add to our work that might make our work better; that might make the product we’re working on better.

Face-to-face meetings also foster new collaborations. As Dennis Clegg of UC Santa Barbara pointed out:

“There are lots of opportunities to network and establish collaborations. A lot of the collaborations that we have going were established at this meeting”

To capture the palpable excitement of the event on film, we roamed the meeting hall to record quick “person-on-the-street” video interviews with several CIRM grantees. Most scientists aren’t particularly eager to jump in front of the camera lens, but once the videotape began rolling they delivered impressive impromptu responses. We interviewed graduate students, postdoctoral fellows, and senior scientists about their work developing therapies for a wide range of diseases.

To create the video I distilled 100 minutes of footage down to three-minutes that capture the mood and excitement of the meeting. I think it highlights well how our extended CIRM family is working together to accelerate the development of stem cell based treatments for chronic disease and injury. Pat Olson, CIRM’s Executive Director of Scientific Activities, summed it up best:

When scientists work together it helps move the science forward faster and ultimately that benefits patients and science”

And just like your typical family reunion, everyone was sad to say their goodbyes and yet they were excited to return home to try out that new “recipe” idea, and they looked forward to the next get together.

Note: In addition to the 3-minute piece, you can also view eight bonus videos from the meeting that give slightly more detailed explanations of various CIRM-funded projects. Also, last month we posted video recordings of Craig Venter’s keynote address and John Wagner’s closing scientific talk. Video of the Target Product Profile Workshop that was led by Ellen Feigal, CIRM’s Senior VP of R&D, will be posted soon.

Neurons made from embryonic stem cells treat Parkinson’s disease symptoms in animals

Last weekend Nature published a paper showing that nerve cells derived from embryonic stem cells can treat symptoms of Parkinson’s disease in mice, rats and monkeys.

The scientists, who were from Memorial Sloan-Kettering Cancer Centre in New York, started with embryonic stem cells. They matured those cells into precursors of the ones that disappear in people with Parkinson’s disease — so-called dopiminergic neurons. This step was hard-won. The Guardian quotes the lead author talking about the development:

“Previously we did not fully understand the particular signals needed to tell stem cells how to differentiate into the right type of cells,” said Dr Lorenz Studer at the Memorial Sloan-Kettering Cancer Centre in New York.

“The cells we produced in the past would produce some dopamine but in fact were not quite the right type of cell, so there were limited improvements in the animals. Now we know how to do it right, which is promising for future clinical use.”

Discover Magazine described how they tested the cells:

The researchers then injected over 100,000 of these newly grown neurons into the brains of mice that had a rodent equivalent of Parkinson’s disease: damaged dopamine-producing cells and the resulting difficulties controlling muscle movement. Over the course of three to five months, the transplanted neurons thrived, connecting with surrounding brain cells, and the mice’s motor function greatly improved. When the team repeated the experiment in rats, the result was the same: A few months later, the stem cell-derived neurons had integrated into the brain and the rats were moving around just fine.

This technique produced enough neurons that the researchers were able to inject two rhesus monkeys with Parkinson’s-like damage with 7 million new dopamine-producing brain cells each, far closer to the number a human patient would need. A month later, the transplanted neurons were alive and well in the monkeys’ brains—though it was too early to tell whether the new neurons would restore normal movement.

Maturing embryonic stem cells into a cell type that can be transplanted to treat Parkinson’s disease has been one of the great hopes for the field of stem cell research. There is currently no treatment for the 500,000 people living with Parkinson’s disease in the U.S. CIRM has invested almost $40 million into 20 projects aimed at developing stem cell-based therapies for the disease. (You can see a complete list of those awards here.)

Scientists still have the difficult task ahead of providing evidence to the Food and Drug Administration that these cells are safe to test in human trials. Even then, humans are quite different from mice, rats and even monkeys and there is no way of predicting whether a therapy that works in animals will be similarly successful in humans. The Guardian quoted Studer discussing the future of this research:

“We now have the right cells, but to put them into humans requires them to be produced in a specialised facility rather than a laboratory, for safety reasons. We have removed the main biological bottleneck and now it’s an engineering problem.”