Stem cells from rhino skin

Northern White Rhinoceros; Photo credit: San Diego Zoo

What are those rhinos doing in a stem cell blog? Researchers at Scripps Research Institute have converted skin cells from those rhinos (or their San Diego zoo-mates) into reprogrammed stem cells. The team also created stem cells out of skin samples from a primate called a drill.

Both projects came out of conversation between Oliver Ryder, the director of genetics at the San Diego Zoo Institute for Conservation Research, and Jeanne Loring, professor of developmental neurobiology at Scripps Research and CIRM grantee. Ryder’s team had already established the Frozen Zoo, a bank of skin cells and other materials from more than 800 species and wondered if the thousands of samples they had amassed might be used as starting points.

The group, which includes an intern from the CIRM Bridges to Stem Cell Research program, published their work in the September 4, 2011 advanced online edition of Nature Methods. According to a Scripps press release, the work has the potential of preserving and even strengthening populations of endangered animals.

One of the greatest concerns with small populations such as the northern white rhinos is that even if they did reproduce, which hasn’t happened in many years, their genetic diversity is inevitably and dangerously low, and such inbreeding leads to unhealthy animals.

But researchers are moving toward inducing stem cells to differentiate into sperm or egg cells. With that accomplished, one possibility is that scientists could take skin cells in the Frozen Zoo from long dead animals, induce pluripotency, trigger differentiation into sperm cells, and then combine these with a living animal’s eggs through in vitro fertilization. Otherwise-lost genetic diversity would then be reintroduced into the population, making it healthier, larger, and more robust.

Or, both eggs and sperm might be produced from the stem cells, with the resulting embryos implanted in live animals, a process that current research suggests could be much more reliable than existing cloning techniques.

Scientists are already exploring the possibility of producing sperm and eggs from stem cells as a potential solution to human infertility issues. Loring hopes that some of these groups might consider initial technique development using endangered species stem cells. “I think that work would be a lot easier ethically with endangered species than with humans,” she said, “so I suspect some people working in this area would love to have our cells for experiments.”

The press release goes on to quote Ryder:

“The best way to manage extinctions is to preserve species and their habitats, but that’s not working all the time.” The rhinos are a perfect example, he said, because there are so few. “Stem cell technology provides some level of hope that they won’t have to become extinct even though they’ve been completely eliminated from their habitats. I think that if humankind wants to save this species, we’re going to have to develop new methodologies.”

CIRM funding: Susanne Montague (TB1-01186)

- A. A.

Mountain climbing raises money for stem cell research, Parkinson's disease

A group of Parkinson's disease patients and family members have hit on a new twist to athletic fundraisers. Forget the local charity 10K race — they are hiking 19,000 foot Mt. Kilamanjaro in Tanzania to raise money for The Scripps Research Institute's Center for Regenerative Medicine, headed by CIRM grantee Jeanne Loring.

Loring has CIRM grants to understand what makes a stem cell a stem cell, to define ways of purifying stem cells and to help prevent the immune system from rejecting transplanted stem cells. She is also part of a project to develop stem cell-based therapies for Parkinson's disease, which this trek will help fund.

A North County Times story describes the project like this:

The stem cells will be produced from human skin cells of patients, transformed into IPS cells, then grown into the proper kind of cells. In the case of Parkinson's patients, these will be dopamine-making neurons. If all goes well, these replacement cells will be transplanted into the patients, making the missing dopamine, and relieving or curing their symptoms.Because the transplants will be autologous, immune reaction is not expected to be a problem.

On August 4, Loring and other members of the research team discussed their research with the group, organized as Summit4StemCell. Those talks are available on the North County Times website.

A.A.

German stem cell clinic shut down amidst safety concerns

On Sunday the UK Telegraph reported the closing of a stem cell clinic in Germany that has been the source of international concern. Last year, a clinic offering stem cell cures in Costa Rica was shut down by the country's health ministry.

In both cases, the concern came from claims that injected stem cells would cure a wide range of diseases, even though there is no proof that the cells will be effective. One child who received stem cell injections at the German clinic died last August, and a second child also had complications. His family is suing the clinic.


According to the Telegraph:

A Sunday Telegraph undercover reporter who suffers from multiple sclerosis and is confined to a wheelchair was told last week during a consultation at the XCell-Center that he could walk again.

According to XCell, about 25 British patients a month – including children with severe disabilities – are treated at its clinic in Düsseldorf and at another in nearby Cologne.

The treatment involves taking bone marrow from patients, harvesting stem cells from the bone marrow and then reinjecting those stem cells into other parts of the body, including the brain, the spine and the neck.

The U.S. and other countries regulate clinical trials and demand proof that the proposed treatment is going to be safe and effective before researchers are allowed to try the technique in human patients. That process is slow, but it's also what stands between people and possibly deadly and ineffective therapies. Countries without stringent regulatory controls are now playing host to clinics much like the one in Germany who offer the promise of cures without proof.

The international community has become so concerned about the risk of these clinics that the International Society for Stem Cell Research launched a website offering to investigate claims of stem cell clinics before people spend money to travel overseas (see A Closer Look at Stem Cell Treatments). CIRM also offers information about stem cell tourism on our website.

Last year, CIRM co-sponsored a public seminar in partnership with the ISSCR on the responsible path for delivering stem cell therapies to the clinic. The video of that stem cell tourism seminar is on our website.

Krista Conger at Stanford University School of Medicine recently wrote an excellent piece about stem cell tourism for their magazine, which begins:

On the surface it seems easy. Overseas stem cell “clinics” peddling unproven treatments to desperate and dying patients, charging tens of thousands of dollars for the privilege of being injected with mysterious concoctions of cells meant to cure almost every ailment: What’s not to hate?

She goes on to quote CIRM grantee Jeanne Loring of Scripps Research Institute who says desperate patients don't see it that way:

“When we report something good about stem cells, it gets picked up in the media, or in a blog that patients read,” says Jeanne Loring, PhD, director of the Center for Regenerative Medicine at the Scripps Research Institute in La Jolla, Calif. “It gives them more ammunition to say that the FDA is stupid for denying access to treatments that seem like they should work.”

Loring has been actively involved in educating people about the dangers of stem cell tourism, and participated in this video with CIRM:



A.A.

The right tool for the job: is it iPS, ES or adult? Answer: It depends

Two stem cell stories in the news today bring to mind yesterday's interview on NPR's Fresh Air, in which veteran journalist Matthew Wald of the New York Times said of the decision to store spent nuclear waste in Yucca Mountain, NV:

Yucca was chosen by the finest geologists in the United States Senate, which is to say they may not have made the best technical choice.

A similar statement could be made about stem cell research policies, which are to some degree being made by the best stem cell scientists in politics.

People who oppose embryonic stem cell research point to reprogrammed iPS cells and adult (or more accurately tissue-specific) stem cells as perfect replacements. These arguments are winning some political advocates around the world including France where they are debating a ban on human embryonic stem cell research and in Ireland (which we've blogged about recently), but aren't borne out by science.

Just to be clear, we here at CIRM are big fans of reprogrammed and tissue-specific stem cells, which is why we fund so much of that work (you can see all of our adult stem cell grants here and our reprogrammed iPS cell grants here). But we're also big fans of the right tool for the right job, and just because we love our hammer and screwdriver doesn't mean we don't still need a few wrenches to get the job done.

Today's news brings a story from Nature about a paper published in Cell Stem Cell in which scientists in France used embryonic stem cells to learn how a mutation leads to the muscle wasting disease myotonic dystrophy. The discovery could help scientists understand and treat the disease. They quote Marc Peschanski, director of the Institute for Stem Cell Therapy and an author of the latest paper.

Peschanski runs a large iPS-cell research programme in addition to his hES-cell work. "We make iPS cells to model particular diseases when we don't have access to the relevant hES cells — which remain our gold standard," he says.

Politicians who oppose hES-cell research often — wrongly — insist that iPS cells can always substitute for hES cells, says Peschanski. He is frustrated that the lower house of the French parliament invoked this argument when proposing a ban on hES-cell research in France. Peschanski has since been working with other French scientists to persuade the Senate to overturn the proposal next week.

A related story from Reuters cites several recent papers showing significant differences between iPS and embryonic stem cells. They write:

Stem cell scientists are not giving up on iPS cells, but instead of a replacement for embryonic stem cells, they see them filling a unique research role.

We've written quite a bit about the role of iPS cells (The confusing (and ongoing) story of iPS vs. embryonic stem cells) and their clear value in generating disease in a dish models for understanding diseases and testing drugs. The Reuters story goes on to quote George Daley of the Harvard Stem Cell Institute and Harvard Medical School:

"It has not ever been a scientifically driven argument that iPS cells are a worthy and complete substitute for embryonic stem cells," Daley said. "Those arguments were always made based on political and religious opposition to embryonic stem cells."

CIRM grantee Jeanne Loring of The Scripps Research Institute in La Jolla has said that what's not known is what these differences between the cell types mean (here's our blog entry on that work). Are they deal breakers in terms of using the cells therapeutically, or are they just temporary set backs while scientists work to develop better iPS cells? For now that's not known.

Which is all to say that in order to get the job done of understanding and treating diseases, scientists need all the tools at their disposal. Sometimes tissue-specific stem cells are going to be ideal. Blood-forming stem cells in bone marrow have certainly proven their worth in treating a number of blood diseases. And iPS cells are becoming valuable tools for studying diseases in a dish. But I wouldn't want to build a house with just a hammer, and I'd hate to see stem cell scientists trying to generate new cures without a full toolbox of cells to work with.

- A.A.

More questions raised about iPS cells safety

Much has been written over the past few days about a spate of new papers by CIRM grantees showing significant differences between reprogrammed iPS cells and embryonic stem cells (see the San Diego Union Tribune,  Discover, Technology Review) and CIRM grantee Paul Knoepfler at UC Davis had an insightful blog entry on the topic.

What's causing the stir is the fact that when scientists first reprogrammed skin cells into embryonic-like iPS cells in 2006, those iPS cells seemed like the ultimate solution -- all the power of embryonic stem cells without the embryos. Everybody wins!

Since their introduction, many papers have been published announcing better ways of generating the cells and comparing the cells to their embryonic counterparts. What's emerging is a somewhat complicated story in which there are some clear wins, but also some questions. We reported yesterday and a few weeks ago on some of the wins: iPS cells have been proving themselves ideal for mimicking a disease in a dish.

However, the cells do appear to be significantly different than embryonic stem cells. My colleague Zachary Scheiner in our science office had this to say about the various papers that came out this week:

There are many similarities between embryonic and reprogrammed stem cells, but a number of recent papers have highlighted differences that could affect the utility of iPS cells for therapies. In one paper, Lister et al. examined a chemical alteration to DNA, called methylation, in a variety of cell types including embryonic stem cells, iPS cells, and adult skin and fat cells. DNA methylation is a normal biological process and helps determine which genes in the DNA get made into proteins in the cell. The DNA in your skin cells, for example, has different methylation than that in your liver cells because those two types of cells need to make different proteins.

Lister et al. found that reprogramming adult skin and fat cells to iPS cells caused hundreds of locations in the genome to have unusual methylation compared to embryonic stem cells. Importantly, these differences remain after the cells are matured into other cell types. This finding suggests that these aberrant DNA modifications could affect the function of cells derived from iPS cells for therapeutic purposes, such as transplantation into patients.

In a complementary paper, Gore et al. examined iPS cells for genetic changes, or mutations, in the DNA code itself, which can have profound effects on the safety of the cells. They found that the process of creating iPS cells introduced an average of six gene mutations per cell line, many more than would be predicted from normal cell culturing. Further, they found that 40% of the mutations discovered were in genes previously found to be mutated in cancers.

Let's review that last sentence: 40% of the mutations discovered in iPS cells were in genes associated with cancer.

In the San Diego Union Tribune, Keith Darce quotes CIRM grantee Jeanne Loring of Scripps Research Institute, who has published several papers showing genetic differences between the two cell types:

“The big question is, is there anything wrong with this stuff happening? We have no idea.”

My colleague Zachary Scheiner summed it up like this:

Taken together, these two papers raise cautionary flags for researchers seeking to develop cell therapies from iPS cells. However, they also empower these researchers by revealing the types of abnormalities that exist in these cells. Armed with this knowledge, researchers should be better able to assess and assure the safety of iPS cell-derived therapies prior to clinical translation.

The great thing about giving money to smart people (that would be our grantees) is that we can now hope to see papers investigating safety issues that result from these genetic changes, or developing ways of creating iPS cells with fewer anomalies.

CIRM funding:
Nature, March 3: Ronald Evans (RB2-01530)
Nature, March 3: Athurva Gora (TG2-01154) Lawrence Goldstein (RC1-00116)

- A.A.

Notes from Calgary: Stem cell hype and medical tourism

CIRM's Senior Officer to the Standards Working Group, Geoff Lomax, is blogging this week from Calgary where his attending the Canadian Stem Cell Network's meeting "Stem Cell Controversies".  

The Stem Cell Network meeting Understanding Stem Cell Controversies is refreshing for its focus on clinical trials and efforts to get basic stem cell research to patients. There is no controversy over the need to develop these treatments, but the process of getting there and how those treatments are understood by the public have raised troubling issues.

Brian Kwon from the University of British Columbia provided a very nice treatment of the issues that emerge in trying to move stem cell-based therapies to the clinic. Areas he emphasized were the types of evidence required before engaging in clinical trials and the challenge of evaluating how effective the therapies were over time. Although these issues are relevant in the development of any new therapy, stem cell therapies have some additional features that need to be taken into account before they can be tested in people. One example is the need to prove absolutely that the cells are safe before trials begin.

One recurring theme among the presenters has been concerns over “stem cell hype” and “medical tourism.” It was noted that patients will frequently inquire about stem cell treatments for a range of illness and injury. Speakers suggested this “hype” may be attributed, in part, to the many products incorporating stem cells (or at least suggesting on the label). Data indicate there is a growing promotion of direct-to-consumer stem cell treatments, and the claims in these promotions are not supported by scientific evidence. Tim Caulfield reported on his research indicating the average cost of an unverified, direct-to-consumer “stem cell treatment” is $24,350.

There was recognition among the speakers of the need to provide the public with more complete information about:

• The status of cell/stem cell treatments for specific diseases
• The risks of certain interventions
• Points to consider when evaluating treatments

Independent resources like CIRM's stem cell tourism page and the International Society for Stem Cell Research website A Closer Look At Stem Cell Treatments were viewed as important counter weights to the numerous web sites promoting miracle cures to our ailments.

Here's a video CIRM produced about stem cell tourism, featuring Jeanne Loring of the Scripps Research Institute:



- Geoff Lomax

Costa Rica strikes against false hope

Many people in the stem cell community and at CIRM have been concerned about the growing trend of stem cell tourism -- people going overseas to receive unproven "stem cell" therapies. The term Stem Cells is in quotes here because in general these clinics are less than open about what, exactly, the therapy entails. One tourism destination in Costa Rica owned by an Arizona entrepreneur was just shut down by the country's Health Ministry. According to a story in Reuters the treatments cost between $5,000 and $30,000.

We'd love nothing more than to see people truly healed by stem cell therapies, but the only way to get there is through good research and clinical trials that prove a therapy's safety and effectiveness. Clinics such as the one in Costa Rica profit off of people's hopes without offering a verifiably effective therapy.

The International Society for Stem Cell Research provides some helpful information on stem cell therapies, and how to avoid clinics that misrepresent what their therapies can do. You can download it here: http://www.isscr.org/public/

We also have a video with CIRM grantee and Scripps faculty member Jeanne Loring discussing her concerns about the practice of stem cell tourism.



If you want to learn more about stem cell tourism you can attend the public seminar in San Francisco on June 15, in which a panel of stem cell scientists will discuss with the audience the safe path to the clinic. Information about that panel is available here. A video of that discussion will also be posted on the CIRM web site.

A.A.

Small DNA changes, life or death consequences

Two recent papers by CIRM grantees highlight the importance of understanding basic stem cell biology while developing new cures. Both have to do with chemical modifications to the DNA – called epigenetics.

One of the two papers shows that an epigenetic change in DNA, called methylation, changes dramatically as human embryonic stem cells mature into specific cell types; the other shows that even subtle DNA methylation differences alter the way a cell behaves.

The first paper, by Jeanne Loring at The Scripps Research Institute, working with scientists in Singapore and New York, provides detailed maps of DNA methylation over the entire 3 billion “letters” that make up our DNA. By comparing methylation patterns of human embryonic stem cells and more mature cells, the scientists tracked the large number of epigenetic changes, many of them surprises, that occur when cells differentiate.

A press release quotes first author Louise Laurent as saying:

"The data are publicly available, and we are looking forward to learning what other scientists discover from using this information for their own studies on individual genes, embryonic development, and stem cells."

The second paper, from UCLA, focuses on epigenetic differences in pancreatic cancers, showing that differences in these modifications translate to different responses to chemotherapy. This means that a few DNA modifications here or there could mean life or death.

In a press release the authors say the next step is to develop a test doctors can use to figure out which patients will respond well to standard chemotherapy and which need an alternative treatment.

Taken together, the papers make a compelling case for how basic biology research such as understand DNA modifications can inform scientists who are actively pursuing cures.

Genome Research, February 4, 2010
CIRM funding: Jeanne Loring (RT1-1108 and TR1-01250)

Journal of Clinical Oncology, February 8, 2010
CIRM funding: Siavash Kurdistani (RN1-005505)

A.A.