Coming Full Circle: Getting Research Results to Patients

Geoff Lomax is CIRM’s Senior Officer to the Standards Working Group 

Altruistic cell and tissue donors are my heroes. Without them there would be no “cell” in stem cell research. Individuals have voluntarily donated skin, blood, bone marrow and embryos remaining after infertility treatment to CIRM-funded researchers. Researchers have transformed these donations into stem cell lines. A stem cell line is a group of identical cells that can be grown and multiplied in a lab dish. Stem cell lines derived from patient donors are enabling scientists to better understand how their particular diseases develops and help identify potential drug and cell therapies.

To accelerate disease research and therapy development, CIRM is creating a clearinghouse designed to make high-quality patient stem cell lines available to scientists who need them (here’s more about that banking initiative). This stem cell repository will distribute the lines to researchers around the world. 
Before embarking on this initiative, CIRM’s Medical and Ethical Standards Working Group, which I oversee, put considerable thought into procedures for obtaining cells and tissue and how best to keep patient donors appraised of research developments. The crux of their recommendations is embodied in a model informed consent document, which is the topic of a recent paper I recently wrote with my colleague Kelly Sheppard.
This informed consent document is what we’re encouraging the people who collect cells from patients to use to inform donors about the nature and purpose of research and describe any risk or benefit to the participant. One consideration for donor informed consent is the potential for research to result in findings that are medically relevant to the donor. For example, the CIRM repository is designed to support the development of drug therapies for diseases affecting patient donors. If that research results in a possible medical benefit, we argue that those findings should be available to the donor and ideally the population with the disease.

Given the potential for iPS cells to support translational research, one should not preclude the ability to recontact donors. Based on this reasoning, the consent form does disclose that the identification of significant new findings may be the basis for recontact. CIRM intends to evaluate the efficacy of this approach to inform ongoing research efforts.

However, the Standards Working Group recognized that there is a delicate balance that must be struck between keeping lines of communication open without creating expectations that cannot be met. Suggesting to donors that beneficial results may emerge can contribute to a “therapeutic misconception” – the belief that research is designed to directly help the patient.
The working group endorsed an approach that very explicitly tells donors that the research is not designed to help them directly, but simultaneously acknowledges that cells will be used in research intended to develop potential commercial therapies.
Thus far, researchers have been receptive to this approach, but questions remain as to the most effective ways to compile and disseminate research findings. As with may challenges at CIRM, this is a work in progress, but one we are firmly committed to finding effective solutions for.
G.L.

Heart condition mimicked in a lab dish, hope for finding new therapies

Heart muscle cells generated from patient skin samples

Some grantees at Sanford-Burnham Medical Research Institute have made an interesting discovery about a sometimes deadly heart condition called ARVD/C.

The condition comes on when a person is in their 20s. Using stem cells created from a patient’s skin, the scientists created heart tissue. But those youthful cells showed no sign of the disease. The scientists had to in essence make the cells old – like in the heart of a 20 year old – before they started showing signs of the disease in a lab dish.

Prior to discovering how to make the cells age, the scientists were in a quandary. They had stem cells that carried the same genetics as the person with the disease, and yet those cells showed no sign of the disease. They were useless for studying the disease or looking for new drugs.

In their blog, Sanford-Burnham describes the technique like this:

Eventually, the team experienced the big “aha!” moment they’d been looking for. They discovered that metabolic maturity is the key to inducing signs of ARVD/C, an adult disease, in their embryonic-like cells. Human fetal heart muscle cells use glucose (sugar) as their primary source of energy. In contrast, adult heart muscle cells prefer using fat for energy production. So Chen’s team applied several cocktails to trigger this shift to adult metabolism in their model.

Once the team was able to mimic the disease in a lab dish, they found a molecule that might be at the heart of the disease (as it were). Chen recently received a CIRM Basic Biology IV award to find therapies for the disease using this model.

The work was published in the January 27 issue of Nature.
CIRM funding: Huei-sheng Chen (RS1-00171-1, RB2-01512 and RB4-06276)

A.A.

New video: Living with Multiple Sclerosis, Hoping for a Stem Cell Therapy | Nan Luke

Para los subtítulos en español, haga clic en el botón “CC” en la ventana de vídeo.
For English closed-captioning, click on the “cc” button in the video window.

Invisible pins and needles: we’ve all felt them from time to time when a hand or a leg falls asleep and we try to shake away the numbness. The prickly pain usually lasts a few seconds, at most a minute or two. But can you imagine enduring it for decades?

Just as Nan Luke was hitting her stride as a litigating attorney in her twenties, her left side went numb without warning from the bottom of her foot up to her chin. The diagnosis was multiple sclerosis (MS) and thirty years later the invisible pins and needles haven’t gone away. At the December Spotlight on Disease seminar, Nan spoke to the CIRM governing board about the challenges of living with MS and also about her excitement for the promise of stem cell treatments.

Multiple sclerosis is a disease in which the immune system attacks the central nervous system, causing short-circuiting of nerve signals in the brain, spinal cord, and optical nerves. The location and severity of symptoms varies for each person with MS and often the symptoms rear themselves in the form of flare-ups, or exacerbations. Nan spoke first-hand of her disease’s course:

I would suddenly with no warning go blind in one eye. And in order to treat that, I’d have to take high-dose steroids, and I still kept driving and working, ….and it would recede after a couple of months. Then I got, out of the blue, several years later, what they call the “MS Hug,” and that is your entire midsection–I woke up one morning, and all feeling, all muscle control was gone for a section of about eight inches, and it’s still gone, and the joy of that is you lose bowel and bladder control. Some of it has come back…The other thing that I found, after a few years of having MS, was I had excruciating fatigue. If I get hot, if I’m tired… The fatigue is something you’ve–it’s like from the core of your body, and that doesn’t change.

Although drugs can reduce symptoms, no cure exists. As Nan pointed out:

I’ve gotten progressive MRIs, I’m taking the medication, I’ve revamped my life. It has slowed down the progression. But the MRIs show that I have lesions and damage [in the brain], and they’ve gotten bigger, and there are more of them.

Nan looked healthy and full of energy as I watched her presentation. You’d never have guessed she had a debilitating chronic disease. Her symptoms were invisible to the audience and me. To help bring more visibility to the disease and to the need for effective treatments, Nan has been an active MS patient advocate and is on the board of trustees for the Pacific South Coast chapter of the National MS Society. Six years ago Nan’s advocacy led to patient advisory work with UC Irvine stem cell scientists, including Dr. Thomas Lane who also spoke at the seminar (Lane has received a SEED and an Early Translation award from CIRM). Dr. Lane described promising results that demonstrate sustained muscle control improvement in a mouse model of multiple sclerosis after spinal injection of stem cell-derived neural cells (note: we’ll post Lane’s video later this year after his data is published).

This work gives Nan profound hope and excitement for the MS community:

and let me tell you… the possibility of stem cell therapy is huge. What we have now– shots or pills daily–is nothing like the promise of stem cells, and what Dr. Lane is looking at is for people like me that have proven damage, and I’ve had it forever, is that there’s a possibility now with the stem cell therapy that there can be some repair. What helps with MS is also in many ways applicable to spinal cord trauma, arthritis, diabetes, Parkinson’s disease. There is so much … this basic science translates into hope for us and treatment for MS and other diseases, and I myself am grateful. Thank you for letting patient advocates get involved because we want to encourage you. Researchers rock!

T.D.

Governing board embraces change for a stronger future

Jonathan Thomas,
Chair of the CIRM governing board

When the IOM released its report on the stem cell agency last December, praising us for things they said we had done well but also identifying areas and making a series of major recommendations on how we could improve our performance (you can see those recommendations here), we said we took their recommendations seriously and would act on them promptly.

We have done that.
 Last week the Governing Board of the stem cell agency, the Independent Citizens Oversight Committee (ICOC), endorsed a framework of proposals that would dramatically change the way the Board works, and directly addresses the concerns and recommendations of the IOM, in particular their feeling that the way our Board works could create a perception of conflict of interest.

Key among the proposals the Board endorsed is that any member of the Board who is appointed from an institution that is eligible to receive money from the agency should not be able to vote, but should instead abstain from approving funding for any and all grants going forward. This puts the economic conflicts issue to bed once and for all.

It was not an easy change to propose and certainly not an easy one for our Board members to approve. They all care deeply about our mission and devote a great deal of thought, time and energy to helping us do our work. So for 13 of them to agree to abstain from a key aspect of their work was difficult to say the least. And yet they did it because they felt it was important for the overall goal of the agency.

All our Board members will still be able to participate in debates and discussions on research, bringing their experience and expertise to help inform the final decision. They just won’t be able to vote on that decision, and they will continue to refrain from even participating in the discussion of applications submitted by their own institution. As Dr. Michael Friedman, CEO of City of Hope said, having to abstain on some votes is a small price to pay to demonstrate the integrity of the process: “This is necessary to ensure the public trust and I think these compromises are essential to enable us to reassure the public about the integrity of the work we do and to be able to continue with our mission.”



So why did we take this approach? It’s simple. We want people to focus on the great work we do, on the groundbreaking research we fund, and the impact we are having on the field of regenerative medicine not just in California but throughout the U.S. and around the world. As long as there are perceptions of conflict of interest hanging over the Board, this will continue to be difficult. By addressing the IOM’s recommendations and these perceptions of conflict of interest directly and taking them out of the equation we can focus on what really matters, finding therapies and cures for deadly diseases and disorders. 


The Board addressed the other recommendations made by the IOM in its report (you can see those here) and while most members supported most of the proposals no one began the meeting by supporting them all. What is important is that we all realized that we had to compromise for the greater good. We all had to stand back and understand that we had to put our own individual desires aside in the best interests of the agency. We knew that if we didn’t make these changes, then we could never shift the spotlight away from how we operate, and focus it instead on what we do. And ultimately that is what is truly important.

At the meeting on Wednesday a number of patient advocates spoke. As always their eloquence and passion reminded us of why we are here. It is not to defend institutional structures, or organizational procedures. It is to help find treatments, maybe one day even cures, for diseases that affect millions of people. Our Board understands that. That’s why they voted to make the changes they did, to put past criticisms behind us and to focus on the future.

J.T.

Do you speak stem cell? ¿Habla células madre?

CIRM video with subtitles for non-English speakers and the hearing impaired

Disease shows no mercy. It doesn’t care how old you are, where you’re from, or what language you speak. It can affect us all. That’s why we’re launching multilingual subtitling to our YouTube video channel, CIRMTV. We hope this new feature will invite non-English speakers as well as the hearing impaired to access our videos and learn about CIRM’s progress toward supporting the development of stem cell treatments for chronic disease and injury. The Modern Language Association estimates that 42% of the California population speaks languages other than English and about two-thirds of that population segment speaks Spanish. So we’re thrilled at the prospect that many more Californians and people worldwide will be able to watch and understand our stem cell videos.

Go ahead and try out this new feature with our latest video “Parkinson’s: Ask the Stem Cell Expert”: (1) Navigate to the video here. (2) Then click the “cc” button that appears in the video window as indicated by the yellow box in the picture below. (3) Then in the menu that appears, select Chinese, English, or Spanish. [note: avoid the English (automatic captions) selection].

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Enfermedades no muestran misericordia. No importa la edad que tengas, de dónde eres, o qué idioma habla. Puede afectar a todos. Es por eso que estamos añadiendo subtítulos en varios idiomas en nuestro canal de YouTube de vídeo, CIRMTV. Esperamos que esta nueva característica invitará a los que no hablan inglés, así como personas con discapacidad auditiva acceder a nuestros videos y conocer los avances de CIRM hacia el apoyo al desarrollo de tratamientos con células madre para enfermedades crónicas y lesiones. El Modern Language Association estima que el 42% de la población de California habla otros idiomas aparte del Inglés y cerca de dos tercios de ese segmento de la población habla español. Así que estamos encantados ante la perspectiva de que muchos californianos y más personas en todo el mundo será capaz de ver y entender nuestros videos.

Siga adelante y probar esta nueva función con nuestra última video “Parkinson: Pregunte al experto en células madre”: (1) Navegue hasta el vídeo aquí . (2) A continuación, haga clic en el botón “CC” que aparece en la ventana de vídeo como se indica en el cuadro amarillo en la imagen de arriba. (3) A continuación, en el menú que aparece, seleccione Chino, Inglés o español. [NOTA: Evite el "inglés (subtítulos automáticos)" selección].

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Athlete Behavior Most Deserving Scrutiny Is Not Making Headlines

Most news outlets the past week have been filled with scandal-suggesting headlines about a college football player with a fake girlfriend and a bicyclist who sort of admitted to behavior that might have inappropriately enhanced his performance. But neither of these actions really impacted many people in a meaningful way.

Contrast that with the long string of athletes who have very publicly announced they have gone to clinics, usually off shore, for unproven stem cell therapies. Those actions have probably led many families to decide to take on the expense and risk of following in their footsteps. So it was refreshing to see this long piece in the Scientific American blog by the well-respected science journalist Deborah Franklin.

Most of these athletes have received adult stem cells taken from one site in the body and injected into another site where it was hoped the cells would repair a performance limiting injury. Franklin notes that the athletes have stated that any health risk ought to be slight because the cells were their own. She quickly counters that assertion:

“That might not be such a safe bet. Numerous studies suggest that [athletes like] Colón, Nitkowski and others trying untested stem cell treatments may be risking more than they think. Even a syringe of one’s own stem cells taken from one part of the body and squirted into another ‘may multiply, form tumors, or may leave the site you put them in and migrate somewhere else’ the FDA warns on its Web site. More clinical research is needed to define safety procedures, as well as how many cells of which types and what other tissue factors produce the desired results.”

Most of these attempts to repair athletes involve a second, less well know, type of stem cell that resides in bone marrow, mesenchymal stem cells, which can multiply and produce all the connective tissues, including bone, cartilage, tendon and fat. The problem is, those connective tissues don’t generally have blood vessels and therefore don’t have all the different cell types that course through our blood, often carrying growth factors and other factors needed to get robust healthy growth of new tissue. Franklin used a quote from Rocky Tuan of the University of Pittsburgh to further explain:

“You can inject all the best cells, but if you don’t have the right combination of healing goodies around them, it’s useless.”

Franklin notes that animal studies looking at these types of injuries have raised as many questions as answers. She brings that point home with a quote from CIRM-grantee and active stem cell blogger Paul Knoepfler of UC Davis:

“The term ‘stem cell’ makes it sound cutting edge and exciting, but the role of these cells in sports medicine is essentially all hype.”

We have a web page that discusses issues about stem cell tourism. We also have a video in which CIRM-grantee Jeanne Loring discusses her concerns.

D.G.

CIRM governing board to discuss IOM recommendations

Jonathan Thomas is chair of the CIRM governing board

In early December the Institutes of Medicine (IOM) released its long-awaited report and recommendations on the stem cell agency, detailing what we do well and where we can do better. It was a report we commissioned ourselves because we want to make sure we are doing the best job we can to justify the trust the people of California placed in us when they voted to create CIRM.

The report had ten recommendations including changes to the grant applicant appeals process, to the way our Grants Working Group operates, to the responsibilities of the Chair and President, and changes to the structure of our Governing Board, the Independent Citizens Oversight Committee (ICOC) to reduce the possibility of the appearance of conflicts of interest.

In the month since the recommendations came out, we have been organizing a workshop to carefully consider them. While some of the IOM’s recommendations are administrative in nature and can be implemented, others are much more complex and would require changes in Board policy, or legislative changes.

We take the recommendations very seriously and have a procedure in place for our Board to consider them and decide on how best to respond to them.

On Wednesday, January 23rd we are holding a workshop for the Board to discuss the recommendations and to try and determine a course of action (here’s the agenda and audiocast details). Our goal is to come out with some clear ideas on what we intend to propose doing, and how we intend to begin that work.

If Board members decide during that meeting on a preferred way of addressing the IOM’s recommendations we will vote on that strategy either at the end of the workshop, if we’re ready, or at the Board meeting to be held the following day (agenda and audiocast details for that meeting are here). My goal is to strive to reach consensus on a course of action on the 23rd. However, if the Board isn’t able to choose a course of action at this time we will continue the conversation and bring it up at future Board meetings until we reach agreement. Throughout the process I’ll blog about important advances, and the agency will issue a press release once a final decision is reached.

It’s likely the debate will be passionate – everyone involved in this work cares deeply about it – and there will undoubtedly be disagreements, but ultimately we all share the same goal, a desire to make sure that whatever we decide helps make the stem cell agency even stronger and more effective, and is in the best interests of the people of California.

J.T.

Ask the Expert: Parkinson’s and Stem Cell Research with the Buck Institute’s Xianmin Zeng

I think they should call it “Hope on the Hill”. Or at least that’s how the Buck Institute for Research on Aging appeared to me as my colleagues and I drove up the winding Marin County hillside toward the institute’s campus. We visited the Buck to film the second installment of our Ask the Expert video series with associate professor Dr. Xianmin Zeng who is developing stem cell-based treatments for Parkinson’s disease. Dr. Zeng’s CIRM Early Translation II research grant is one of the furthest along the path toward clinical trials for Parkinson’s disease, giving hope to the many who suffer with the disease. (You can see all CIRM Parkinson’s disease awards here.)

Along with our video equipment, we brought the questions you submitted about Parkinson’s disease and stem cell research via this blog, Facebook, and Twitter. Amy Adams, CIRM’s communication’s manager, began the interview by asking for a quick description of Parkinson’s. Dr. Zeng summed it up this way:

Parkinson’s disease is a neurodegenerative disorder, which leads to progressive deterioration of motor function, and the cause is the loss of dopamine-producing nerve cells…The primary symptoms for Parkinson’s disease are tremor, slowness in movement, impaired balance, and stiffness. The secondary symptoms are anxiety, depression, and dementia.

There is no cure for Parkinson’s. And although drugs can help reduce symptoms, they eventually lose their effectiveness. Zeng also pointed out some startling statistics about the disease’s affect on the general population, in particular the workforce:

There are about one million Americans that suffer the disease, and with the aging population now, the number is expected to increase, and about 40% of the people affected by Parkinson’s disease are under the age of 60. So there is a clear impact on society in terms of losing productivity.

Ten years ago, Zeng was a researcher in one of the first labs in the world to work with embryonic stem cells. Through that early work she developed methods for transforming those stem cells into dopamine-producing nerve cells, the same cells that are lost in Parkinson’s disease. Now with her own lab at the Buck, Zeng described her latest progress:

At this moment, we have decided on an embryonic stem cell line which we know can be used for clinical purposes, and we have generated two lots of dopaminergic neurons suitable for direct transplantation into the brain to hope those cells will replace the lost cells and function in the brain. So we are now in a position to go to the FDA to file for a phase 1 clinical trial in the next two years, that’s my estimation, so, in hoping that we would be able to run a clinical trial in the next three to five years.

In addition to using embryonic stem cells as a cell source, Zeng has also generated dopamine-producing nerve cells by using reprogrammed adult cells, such as skin cells. These so-called induced pluripotent stem cells (iPSC) are cells that have been altered to have the properties of an embryonic stem cell so that under the right conditions, they can develop into any type of tissue. When asked why she works with iPSC as well embryonic stem cells, Zeng explained that:

Because iPS cells provide an additional cell source of producing the right type of dopaminergic neurons, also because you now have a cell source coming from both normal and patient subjects, and you can use the cells to test different drugs to be a better predictor of the potential clinical benefit.

Related to the question above, a person who wrote in asked, “What types of stem cells are best suited for treating Parkinson’s disease?” Zeng’s answer brings up an important point that applies to the stem cell research field as a whole:

I think this is a question nobody can now provide an answer, and that’s why people need to work with different types of the stem cells in order to find out exactly this question: What type of the stem cells is the best? So that’s why I’m working on both ES cells and iPS cells.

We really enjoyed our visit with Dr. Zeng and we hope you all learned something new from this Ask the Expert video. I know we did. And as we drove down the hill, I looked back up and marveled not only at the Buck Institute’s architecture but also at the hope contained inside it for people living with Parkinson’s and their caregivers.

You can watch the previous Ask the Expert interview with Dr. Lawrence Goldstein talking about therapies for Alzheimer’s disease here

(Note: With this video, we’re excited to launch closed-captioning for the hearing impaired as well as foreign subtitles. Click the “cc” button in the video player to change the language or general settings).

T.D.

Mixed emotions for newest CIRM governing board member

Diane Winokur being sworn in by Lieutenant Governor Gavin Newsom

Diane Winokur said being sworn in as the newest member of our Governing Board, the Independent Citizens Oversight Committee (ICOC) was a day of very mixed emotions. Diane is the patient advocate representative for the ALS (Lou Gehrig’s disease) and Multiple Sclerosis communities. She says while she is proud and honored to be part of the stem cell agency’s mission, she knows she only became involved in the search for cures because she lost two sons to ALS. She says the memory of her sons is with her in everything she does.

Diane was sworn in on Wednesday, January 16th by Lt. Governor Gavin Newsom, who appointed her to the ICOC late last year. The Lt. Governor praised her for her compassion, dedication and determination and said she would make an incredible contribution to the work of the agency.

Diane says she is very mindful of the fact that while she is the patient advocate for ALS and MS, she has a responsibility to represent all patients and patient advocates in California, and intends to give a voice to those who are too often overlooked.

We are honored and delighted to have Diane join us.

We have more information about the other members of our governing board on our website, along with information about our funding for ALS and MS.

K.M.

CIRM Supporting a Remarkable Experiment in Research Ethics

Geoff Lomax is CIRM’s Senior Officer to the Standards Working Group 

The American Journal of Bioethics dedicated its 100th issue, published this month, to the topic of stem cell research. Editor David Magnus noted, “the explosion of research in this area created an experiment in research ethics oversight—the Embryonic Stem Cell Research Oversight (ESCRO) committee.”

ESCROs are committees of scientists, ethicists, patients and public members that oversee stem cell research. CIRM requires ESCRO committees to oversee the research we fund.

In this issue, Stanford Professor Hank Greely authored a major target article looking at the history of what he calls “the great ESCRO experiment.” He describes the ESCRO experiment as “a truly remarkable experiment in applied research ethics.” Greely describes the history of ESCROs and then focuses on two questions (1) have they been successful and (2) what it their future. Greely points out that research centers across the country have invested considerable resources to establish and operate ESCRO committees. He suspects that committees have been successful in preventing abuses and making sure research is conducted in accordance with existing guidelines and regulations.

Perhaps the most provocative aspect of the article is Greely’s question about the future of ESCROs. He suggests that the day-to-day responsibility for research oversight might be moved to existing review boards and committees.

“It may be time to thank ESCROs for their valuable past services and to begin moving toward a world without ESCROs, at least as we have know them.”

The journal invited CIRM and others to author commentaries on Professor Greely’s article – eight were published. I found his article to be a cogent historical analysis that provided a robust framework for continued assessment of the great ESCRO experiment. I do, however, argue that ESCROs still play a valuable role in supporting research and provided a number of examples from CIRM experience where ESCRO committees have taken actions to ensure research was performed according to our regulations.

In the more distant future, when stem cell research becomes commonplace, there may no longer be the need for the specialized expertise offered by ESCRO committees. Ideally, this future includes the routine treatment of patients with effective cell-based therapies. We are not quite there yet, but along the way we should heed Greely’s counsel and explore, rigorously, the results of the great ESCRO experiment.

A number of other commentaries were also supportive of keeping ESCRO committees or ensuring that their expertise is maintained. Audrey Chapman of the University of Connecticut argues that trying to transfer the responsibilities to existing review boards “is likely to be met with agreement of those bodies.” She concludes, “it seems preferable to continue the great ESCRO experiment.” Julie Aultman from Northeast Ohio Medical University offers the following perspective:

“The downside to not having an ESCRO, or future IRB that would absorb some of the responsibilities of the ESCRO at a small university, is the inability to support the development of promising new programs with appropriate ethical guidance and oversight.”

Mary Devereaux and Michael Kalichman of the University of California, San Diego suggest there is still a need for ESCRO oversght:

“The fact that past problems have been solved does not mean that we have already anticipated, or are prepared to address, future challenges in this rapidly evolving field. Our choices about how to move forward should thus not be based on the assumption that we have settled or can avoid future ethical and/or policy issues.”

For now CIRM continues to see value in ESCRO committees, and we applaud our grantees’ efforts to establish effective oversight programs. As Sherry Lansing (ICOC and Standards Working Group members) reminds us, CIRM is a “work in progress.” As we move forward, we continually discuss and evaluate the best approaches to research and oversight. As evidenced by the American Journal of Bioethics series we are in good company.

G.L.