Blood-forming stem cells for Japanese nuclear workers?

According to a story in The Guardian, Japanese officials are considering blood-forming stem cell transplants in workers exposed to high radiation levels. They write:

The proposal has been drawn up as a precautionary measure that could potentially save the lives of workers if they receive high doses of radiation while battling to bring the damaged nuclear reactors under control.

If those transplants take place and are effective, the brave men and women will be part of a story that began with the bombing of Hiroshima and Nagasaki during World War II. People exposed to radiation from those bombs frequently developed leukemias. Investigating those cancers led scientists in Canada to discover cells in the bone marrow that constantly form new blood and immune cells. The leukemias arose when bone marrow stem cells suffered mutations and turned some cells cancerous.

Eventually, scientists used these discoveries to develop bone marrow transplants, in which a person's bone marrow is eliminated by radiation then replaced with donor bone marrow. Blood-forming stem cells within that bone marrow then form a new blood and immune system — presumably one that's cancer-free. CIRM grantee Irv Weissman at Stanford University identified the blood-forming stem cells amidst the many cell types in the bone marrow.

Now, the technique that started with radiation-exposed people in Japan could help the brave men and women who have been exposed while trying to save the nuclear plants damaged during the country's earthquake and tsunami. The idea is that Japanese scientists would freeze blood-forming stem cells from workers, which could then be used to treat those workers if they are exposed.

Although the stored cells could treat blood cancers, some warn that workers might consider the cells a safety net and take unnecessary risks. Stored blood cells wouldn't be able to treat damage to other tissues. The Guardian quotes Robert Peter Gale, a US medical researcher advising the Japanese government:

"These cells can reconstitute bone marrow function; that is not the only target of high dose radiation, they would have damage elsewhere, to their lungs, gastrointenstinal tract and their skin."

He also warns about the logistics of extracting blood-forming stem cells from the roughly 800 workers.

- A.A.

Legislating science without scientists = confusion

It sounds like the Minnesota senate could use a little help from CIRM's Stem Cell Basics as they debate a proposed ban on… well, they aren't really sure what it's on. Reproductive cloning? Therapeutic cloning? Stem cell research? 

(Hint, reproductive cloning creates a new human — CIRM, the California constitution and all states actively supporting stem cell research oppose reproductive cloning. Therapeutic cloning, if it ever works in humans, would provide an additional way of creating embryonic stem cells. These cells, contrary to some science fiction scenarios mentioned in a Minnesota Independent story, can not form a new person.)

Perhaps including scientists in the discussion would have allowed lawmakers to clear up this confusion.

The Minnesota Independent wrote about a Senate Higher Education Committee debate over an amendment proposed by Sen. Michelle Fischbach banning taxpayer funding for a technique called somatic cell nuclear transfer. The confusion comes over the fact that SCNT is the first step in reproductive cloning, and is also the first step in creating embryonic stem cells identical to the donor's cells. So far, SCNT has been successful in a number of animals but has never worked in humans. (All human embryonic stem cells currently come from embryos left over after in vitro fertilization.)

The proposed ban would eliminate both uses of SCNT, and would prevent Minnesota scientists from using stem cells created via SCNT in other states. According to the Minnesota Independent, Sen. Kathy Sheran spoke up about confusing the two uses:

“I think we are really in danger of confusing the public about the difference between human cloning using stem cells for the creation of another human being and stem cells used for therapeutic purposes,” said Sheran. “They are very different and very separate, and this rolls them all in together and confuses the public into thinking this is all about human cloning when it isn’t.”

In a blog entry last week (Ban reproductive cloning not stem cell research), my colleague Geoff Lomax, who heads CIRM's Standards Working Group, made what I thought was a great comparison between the SCNT debate and genetics. Genetic engineering has resulted in untold new drugs and disease discoveries. It also underlies the fear of genetic discrimination made famous in the movie GATTACA. Did we ban genetic engineering in order to prevent GATTACA? No, we enacted the Genetic Non-Discrimination Act to prevent such a scenario.

Lomax said:

By the same logic, we shouldn't ban basic research due to unwarranted science fiction concerns over reproductive cloning.

Apparently the Minnesota lawmakers don't agree. An attempt to explicitly ban reproductive cloning failed in favor of more general language encompassing both uses of SCNT.

For more information about SCNT, see the report from CIRM's 2010 SCNT workshop.

- A.A.

Blood-forming stem cells treat advanced stage of MS

A group in Greece has found that transplants of blood-forming stem cells in the bone marrow can treat some patients with multiple sclerosis. That work, published in the journal Neurology, could one day help the 400,000 Americans and 2.1 million people worldwide have MS (from the National MS Society).

The key here is "one day." Stem cell scientists have long listed MS, along with a variety of other autoimmune diseases such as lupus, as a likely candidate for treatment by blood-forming stem cells. The problem is that the transplants are extremely risky. Case in point, in the Greek study two of the 35 patients died from transplant-related complications.

The idea behind why the transplant could treat autoimmune diseases is simple. In diseases such as MS or lupus, the immune cells that are suppose to fight off infections instead begin attacking the body's own tissues. In the case of MS, they attack the lining of neurons in the spinal cord and brain. Without their protective insulation the neurons can't effectively transmit signals instructing the body to move.

Swap out the defective immune system with a fresh one and the person would be cured, right?

The problem so far has been in getting rid of the existing blood-forming system. In a bone marrow or blood-forming stem cell transplant, first the doctors must destroy a person's existing immune system with strong chemotherapy or radiation. This step is extremely risky. That's why a HealthDay story on this work quotes Aaron Miller, chief medical officer for the National Multiple Sclerosis Society and a professor of neurology at Mount Sinai School of Medicine in New York City as having doubts about this technique's widespread use:

This is a very heroic form of therapy for multiple sclerosis [MS], which is unlikely, in my view, ever to have a major impact on the field," added Miller. "It's a substantially risky therapy -- the mortality rates have been in the 2-3 percent range . . . and it's hugely expensive.

Many groups are working on less toxic ways of clearing the patient's problematic blood-forming system. You can read about some of those attempts in a WebMD story about the MS trial. If they are successful, this approach could become less risky and offer an effective way of treating not just MS but all autoimmune diseases. That would be something to celebrate.

Here's a list of CIRM awards targeting MS,  and our MS disease information page.

- A.A.

Finding stem cell clinical trials made easier

At CIRM we routinely get emails and phone calls from patients desperately seeking clinical trials for themselves or for family members. With all the talk about future stem cell cures, it only makes sense that people would be looking to stem cells for help.

CIRM doesn't maintain our own list of stem cell-based trials. Instead, we've always referred people to the national listing of all registered clinical trials maintained by the NIH: clinicaltrials.gov

Now we have a good resource for European patients, too. The European Medicines Agency yesterday revealed their new database of registered clinical trials in the EU: https://www.clinicaltrialsregister.eu/

Nature ran a story about the database on their blog:

Information on interventional trials run in all 27 EU member states, as well as Iceland, Liechtenstein and Norway, will now be searchable via the EU Clinical Trials Register website. The register effectively opens up the agency’s previously closed EudraCT database and brings Europe into line with the United States, which has long publicly listed all clinical trials online.

The old system attracted criticism from researchers concerned it would make it easier to bury bad results and hinder proper evidence-based medicine. (See, for example Europe's clinical trial database criticized in Nature Medicine or New EU trials database is criticised for lack of openness from the BMJ, both 2004.)

People turning specifically to stem cells for hope can search either database by the term "stem cell". A quick search of the U.S. database brought up 3459 results, most of them variations on bone marrow transplants for blood cancers and some immune diseases. A search of the new EU database pulled up 116 results, similarly focused on cancer and bone marrow transplantation. (It's the blood forming stem cells in the bone marrow that reform the blood system after a transplant.)

Bone marrow transplants have been taking place for about 50 years now, so it's no surprise trials to improve and expand on that technique dominate the databases. Over the past few years, some other types of adult stem cells have begun early phase clinical trials, including mesenchymal stem cells and neuronal stem cells, and now three trials based on embryonic stem cells are underway.

The NIH site has an especially good FAQ about clinical trials and how they are run, including a description of the different phases of the trials. Watching how people react to stem cell news it seems like an announcement of a new Phase I trial starting is often taken as proof that the cells are effective. (As in, there are more adult stem cells in phase I trials so obviously they are better than embryonic cells.) What that FAQ makes clear is that an initial Phase I trial is only intended to ensure that the potential therapy is safe in people. It's not until Phase II that scientists expect to find some indication that the technique is effective and in Phase III that they might find proof that it works.

In time we should see more diversity in the types of stem cells that come up in a search of either clinical trial database. Hopefully these early trials with various types of adult or embryonic stem cells will produce some winners in addition to the inevitable failures.

- A.A.

CIRM grantees begin testing stem cells to prevent amputations

CIRM grantees at UC Davis have begun a trial that, if successful, could help prevent some amputations caused by blockages in the blood vessels.

Jan Nolta, who is director of the UC Davis Stem Cell Program and Institute for Regenerative Cures, came to CIRM offices last year and spoke about the animal studies that led up to this trial. The Davis team harvested a form of stem cells called mononuclear stem cells from the bone marrow — these are different than the blood-forming stem cells that recreate the blood system in a bone marrow transplant. Instead, these cells form blood vessels and other tissues.

In the data Nolta showed us, the mononuclear stem cells injected into the legs of animals with induced blood vessel blockages were able to restore circulation in those limbs. If the cells work as effectively in people as in the animals studies, they could unblock the arteries and save the people from possible amputation.

A story in the Daily Democrat quotes Jan Nolta:

"Our own research in mice has shown that adult human stem cells are very efficient at targeting areas of low oxygen and promoting the formation of new blood vessels. This next stage of our research will determine if the treatment truly offers hope for people without other options and who are at risk of losing a limb."

That same story has a good description of how the blockages form:

An estimated 85,000 leg amputations are performed each year in the U.S. due to advanced atherosclerosis -- also known as critical limb ischemia -- which occurs when the buildup of fatty deposits, calcium and plaque in arteries greatly reduces blood flow to lower extremities. Current treatments for the condition include opening blockages with balloon angioplasty, bolstering weakened arteries with metal stents or bypassing damaged arteries with vein grafts. When the disease progresses to the point of limb-threatening ischemia and when angioplasty, stents or surgery are not viable, amputation becomes the only option.

CIRM doesn't fund the research that led to this study, but we did help fund the sterile Good Manufacturing Practice lab where the team manufactures the cells that they'll use in the study. We did a video about that state-of-the-art facility right before it opened. With their own GMP lab, Davis scientists are able to manufacture cells that pass muster with the US. Food and Drug Administration, who has to approve all cells used in clinical trials.

As is always the case with preliminary human trials, it's too soon to know whether or not the technique will work. More initial trials fail than succeed. We'll be watching for news out of Davis over the next years to see how the technique fares in this and in subsequent trials.

- A.A.

Ban reproductive cloning not stem cell research

In Minnesota, legislation has been introduced that would essentially ban forms of basic stem cell research by defining nuclear transfer as "human cloning."

Just to get one thing perfectly clear: CIRM plays a leadership role in opposing human reproductive cloning. The California constitution, CIRM regulations and all other states that are actively supporting stem cell research expressly prohibit human reproductive cloning.

This seems like a good time to define some terms. First, human cloning. Here's a definition from  California Law:

"Human reproductive cloning" means the practice of creating or attempting to create a human being by transferring the nucleus from a human cell into an egg cell from which the nucleus has been removed for the purpose of implanting the resulting product in a uterus to initiate a pregnancy.

Now nuclear transfer, which is the basic stem cell research that would be banned under the Minnesota legislation. Keep in mind that this technique has been successful in a wide range of animals including primates, but has yet to be successful in humans. This is from CIRM's Stem Cell Basics:

Nuclear transfer is a technique to create embryonic stem cells that are genetically identical to a person’s own cells. This technique is also known as therapeutic cloning because it essentially clones a person’s cell to be used in a therapy.

The process of nuclear transfer involves removing the genetic material from an egg, then injecting the genetic material from an adult person’s cell into the egg. Researchers then stimulate the egg to begin maturing. About five days later the egg develops into a hollow ball of about 150 cells called a blastocyst. This is the same type of blastocyst that would be used to create cell lines from donated IVF embryos. Researchers remove the inner cell mass from the blastocyst and grow those cells in a lab dish to create a new embryonic stem cell line.

What the two have in common is that they both start by injecting a nucleus into an egg and allowing that egg to begin dividing. Where they differ is in intent. People attempting to carry out nuclear transfer intend to develop stem cell lines for therapies, which is why the technique has also been called therapeutic cloning. CIRM held a workshop on nuclear transfer and produced this report based on the finding.

I talked to my colleague Geoff Lomax, who heads CIRM's Standards Working Group, about the Minnesota legislation. He directed me to this New York Times opinion piece from 2006 written by Michael Gazzaniga who was a member of the President's Council on Bioethics under President Bush:

We voted unanimously to ban reproductive cloning — the kind of cloning that seeks to replicate a human being. We cited many reasons, from biomedical risk to religious concerns to the flat-out weirdness of the idea. But in fact human cloning has not been attempted, nor is it in the works; so it's a theoretical ban in the first place, like banning marriage between robots.

That pretty much sums up CIRM's ban, too. It's not even possible so the ban is purely theoretically, but if it were possible we'd still be against it. Geoff made the point that legitimate science such as genetic research is often the basis for science fiction:

I am still struck by how often the movie GATTACA comes up in discussion about DNA research. The lens of popular culture has a profound impact on our collective psyche.

We didn't ban genetic research, which has brought us a multitude of new drugs and therapies, just because Ethan Hawke met with genetic discrimination in a movie. We did, however, pass the Genetic Non-Discrimination Act to prevent such a scenario. By the same logic, we shouldn't ban basic research due to unwarranted science fiction concerns over reproductive cloning.

-A.A.

Stem cells reveal elusive developmental steps, origins of disease

Our colleagues at Sanford-Burnham Medical Research Institute have a post today on their excellent blog about work by CIRM grantee Alexey Turskikh, published in a recent issue of PLoS ONE. The teams work is another example of how embryonic stem cells can help scientists understand early events in development.

The team has been interested in a group of cells called the neural crest, which eventually form nerves, skin, bone and muscle in the developing embryo. If scientists could understand this important developmental step they could also understand diseases that result when those steps go awry. The problem is that they can't very well monitor the process in a developing human.

That's where embryonic stem cells come in. The team developed a method of maturing embryonic stem cells into neural crest cells. Sanford-Burhnam writes:

With this method, Dr. Terskikh’s group and others will now be able to better study what defines human neural crest stem cells, how they migrate during development, how they differentiate into other cell types, and the mechanisms that guide these processes. What’s more, producing workable quantities of neural crest stem cells in the laboratory might allow scientists to generate more of the tissues that they become – including clinically-relevant cell types like skin cells or neurons.

According to Dr. Maurer, one of the study’s co-authors, “This research allows for fast and easy access to an important developmental structure and one of the best examples of a particular stage in development – the epithelial-mesenchymal transition (EMT). Since EMT is now a hot topic in tumorigenesis and cancer progression, these cells might help us better understand the molecular mechanisms governing that process. ”

There's a long path from find the cells to developing cures, but you don't get to the end of a race without taking the first step.

CIRM Funding: Alexey Turskikh (RS1-00466-1)

- A.A.

Not-so-happy St. Patrick's day for Irish stem cell scientists

Irish stem cell scientists may be wearing a gloomy shade of green this year on St. Patrick's Day. February elections brought to power the Fine Gael party, which opposes human embryonic stem cell research.

The country's scientists had been working without clear stem cell guidance when the previous government — which had been supportive of biomedical research — failed to create regulations governing the work. According to a recent story in the Nature blog:

It had promised to do so in December 2009 as part of planned legislation governing assisted human reproduction. But that same month it disbanded the Irish Council for Bioethics (which might have provided independent advice on legislation) to save money, and the legislation never emerged.

Ireland’s public funding agencies, Science Foundation Ireland and the Health Research Board, both decided not to fund work involving hES cells until the legal situation is clarified. Two universities – Trinity College Dublin and University College Cork – have internal rules allowing such research on imported hES cell lines, if researchers are supported with foreign research grants. In the legislative uncertainty, no scientist has taken this up.

CIRM has long recognized that California scientists can't work in isolation from biomedical leaders around the world. Many of our rounds of funding include commitments from partner funding organizations in order to inspire collaborations between researchers. CIRM funds the California portion and other agencies fund the collaborator in their country. You can learn more about our collaborative stem cell funding program or see a list of awards with international collaborators. 

The Irish Stem Cell Foundation, established in 2009, has been working to promote stem cell science and international collaborations within the country's stem cell community. Anybody interested in promoting stem cell science and legislation in Ireland may want to weigh in on their website or follow them on Twitter (@IrishStemCell). If the group is successful perhaps next St. Patrick's Day will inspire a cheerier shade of green among the country's stem cells scientists. 

A second stem cell trial for spinal cord injury

We've posted quite a bit about the Geron trial testing an embryonic stem cell-derived therapy for spinal cord injury. Now Palo Alto-based StemCells Inc has started a trial in Switzerland testing a tissue-specific stem cell therapy. The company announced that they'll be enrolling 12 people who have no feeling below their injury in this initial safety trial. Unlike the Geron trial, which is specifically enrolling people with recent injuries, StemCells Inc is testing their product in people whose injuries are three to twelve months old.

A significant difference between these two trials is the type of cell being tested. (You can read more about different types of stem cells in our Stem Cell Basics.) The Geron trial uses embryonic stem cells that have been grown in large quantities then matured into a type of neuronal precursor cells. In rodents, those cells are able to restore function after a recent spinal cord injury. The Geron trials will show whether those cells are also effective in people.

By contrast, the StemCells Inc trial uses cells that are already committed to becoming a type of neuronal cell. These neuronal stem cells can repair spinal cord injuries in rodents. Like the Geron trial, StemCells Inc is first testing these cells in a small number of people to ensure that they are safe.

It's exciting to see several different approaches being tested. When I think about these early stem cell trials I often reflect on the earliest cancer trials. I don't know very much about the first chemotherapy for lymphoma, but I'm grateful to the scientists who kept trying new approaches and improving on early successes because they're the reason my mother has been cancer-free for the past 10 years.

Whether or not these first trials are successful (and honestly, more early trials fail than succeed) we are witnessing the start of what I hope will one day be a cure for all those people living with spinal cord injuries. That cure might involve embryonic stem cells, neuronal stem cells, drugs tested on stem cells in the lab, or a combination of those approaches depending on the type of injury. CIRM is funding all of those stem cell approaches in the hopes finding the quickest path to a cure.

A.A.

Stem cell progress on brain awareness week

This week marks Brain Awareness Week, with events worldwide to bring people up to speed on brain research. I went to the cool search tool on the Dana Foundation web site and found that several CIRM grantees are hosting events this week. That makes sense, given that roughly a quarter of our funding goes to neuronal diseases. (You can see charts of CIRM stem cell research funding allocations here. The charts are slightly out of date — stay tuned for some updates in the next month.)

Brain diseases are seen as a big challenge for stem cell therapies, in part because the brain itself is such a complex web of neurons. Simply replacing a few lost neurons won't necessarily replicate the lost connections. We have a story discussing some of those issues and describint innovative approaches CIRM grantees are taking to developing new cures for brain diseases.

The good news is that some CIRM grantees are learning that stem cells can be coaxed to form the support cells in the brain that nourish neurons. These support cells could be what provide a therapy for diseases such as ALS, MS, stroke and spinal cord injury. Other grantees are using stem cells in the lab to test new drugs for Parkinson's disease.

A group at UC Davis is attempting to use the body's own mesenchymal stem cells to preserve unaffected neurons in people with Huntington's disease. This technique won't bring back lost cells, but saving additional cells from dying off could prevent some of the terrible side effects of the disease.

Another team of CIRM grantees at UC Irvine found that at least in rodents, stem cells were able to repair some memory loss due to Alzheimer's disease. This work is a long way from treating humans, but still provides hope for people who have lost loved ones to this devastating disease. Here's a video we produced about that work:



We've produced several other videos about CIRM's brain related research:

• Fred H. Gage talks about using embryonic stem cells to model neuronal disease
• Spinal Cord Injury: Progress and Promise in Stem Cell Research
• Huntington's Disease: Progress and Promise in Stem Cell Research
• Parkinson's Disease: Progress and Promise in Stem Cell Research
• Spotlight on ALS seminar
• Spotlight on Huntington's disease seminar
• Spotlight on Alzheimer's disease seminar
• Spotlight on Batten disease seminar
• Spotlight on Parkinson's disease seminar

 - A.A.

Stem cell research a national security issue

CIRM grantee Paul Knoepfler, who is assistant professor at UC Davis, had an editorial in the Saturday Sacramento Bee making the case for stem cell research as a national security priority. Knoepler has blogged about this issue in the past, as congress has looked to cut research funding as part of budget negotiations.

Knoepfler argues:

“As Congress debates the budget, Republicans are proposing a large cut to the National Institutes of Health, which funds stem cell research across America. At the same time, Republicans want increases for defense spending in the name of national security. Stem cells hold such promise for treating not only our civilians, but also our troops, that federal funding of stem cell research must be considered a national security issue as well.”

Knoepfler points to a few specific stem cell advances as being particularly relevant to battlefield injuries. The first is as a source of blood for transfusions. Today, all blood transfusions come from donations that must be stored until needed. In the past year, researchers have started being able to mature embryonic stem cells into different types of blood cells that could one day be stored in large quantities without the need for constant donations.

The value of embryonic stem cells is that they multiply in the lab, creating an unlimited supply of cells. By contrast, the adult blood forming stem cells don’t expand in the lab, limiting supply. (You can read our blog entry about the technology here.)

Knoepfler also points to skin stem cells as a way of healing life-threatening burns. This technology is already being tested. In the future, skin stem cells from an injured person could be multiplied outside the lab and used as a source for new skin. Alternatively, since the process of harvesting and multiplying a person’s own cells might take too long, skin cells matured from embryonic stem cells could serve as a source for therapies.

Similarly, stem cells are showing promise for repairing broken bones or cartilage injuries, which might otherwise not heal properly.

And finally, a major hope for stem cell research is the ability to heal spinal cord injuries that could otherwise leave a soldier in a wheelchair for life. A stem cell trial for spinal cord injury by Menlo Park-based Geron started in 2010.

Knoepfler concludes:

“The key fuel pushing these amazing biomedical advances is research funding, but that funding is jeopardized by budget politics and spurious federal court cases. We have a moral obligation to set aside politicking and do what is best for our troops: Fully legalize and stably fund stem cell research, including embryonic stem cell research. Embryonic stem cells are made from microscopic, frozen clumps of only a few dozen cells left over from fertility treatments that would otherwise be discarded. [Here’s more about how the cells are created.]The troops who could be saved by such stem cells are not only fully grown people, but also patriotic Americans.”

 -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.

Parkinson's disease modeled for the first time in a lab dish

CIRM grantees at Stanford University and The Parkinson's Institute have an exciting Cell Stem Cell paper out today showing that they can mimic Parkinson's disease in a lab dish using reprogrammed iPS cells.

The team, which includes Renee Reijo Pera and Theo Palmer and their lab members at Stanford and William Langston at the Parkinson's Institute, started with skin cells from a woman with a genetic form of Parkinson's disease. They reprogrammed those cells back to an embryonic-like state and matured them into the type of brain cells that are affected in a person with Parkinson's disease. These cells normally help control movement and other functions in the body. In people with Parkinson's disease those cells slowly diminish and leave the person unable to control movement and other vital functions. There is currently no cure for the disease.

Initially the cells behaved normally in the lab dish, but after 30-60 days the cells showed some of the same conditions that are found in people with Parkinson's disease. A Stanford press release quotes Theo Palmer:

“This is the first time that neurons from a Parkinson’s disease patient have exhibited disease qualities in a petri dish,” said Palmer. “And it provides hints of what to look for in patients who have different genetic mutations or where a cause has not been identified. By comparing neurons from patients with different forms of Parkinson’s disease, we may find commonalities or differences that will help to optimize future treatments for each patient.”

Today there is no cure for Parkinson's disease, and no good way to test possible drugs. With this paper, the researchers have for the first time created a way of mimicking the disease, and testing to see if drugs can reverse the symptoms in human cells.

Here's more information about stem cell therapy for Parkinson's disease and a list of all CIRM Parkinson's disease awards. This video features grantees at the Parkinson's Institute talking about their efforts to create iPS cell models of Parkinson's disease.



CIRM funding: Renee Reijo Pera (RL1-00670-1, CL-00518-1); Aleksandr Shcheglovitov (TG2-01159)
Cell Stem Cell, March 3, 2011

- 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

Understanding Stem Cell Controversies -- Texas Hold’em Anyone?

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

Today kicks off the Canadian Stem Cell Network’s intensive three-day course titled Understanding Stem Cell Controversies. The focus is on emerging ethical and policy issues as the science moves towards clinical application. The course will include a conversation about the process CIRM employs to develop policies to govern the institute. But, more on that later.

First, as we were leaving sunny San Francisco, the captain mentioned it was negative 24C in Calgary. Well at least it is not humid. After a full sprint from the terminal to the taxi, the driver and I engaged in the obligatory Canadian ritual of catching up on the latest developments in the hockey world. Fortunately the Calgary Flames “walloped em” – everything was right in the universe.

The NHL was followed by the “what brings you to Calgary line.” I was immediately thrust into my “stem cell basics rap” (always good to practice before a big training). My driver was particularly interested in knowing what was so unique about stem cells. He could easily learn from CIRM's Stem Cell Basics online, but since driving a web browsing is frowned on I gave him the verbal run down. Fortunately, he showed his hand by expressing his fascination about cell division, so we quickly covered progenitor and differentiated cell types. He was also curious about genes and how they relate to the splitting process. We discussed how the splitting process relates to disease.

Then came the utterly brilliant moment. My driver is a BIG poker player (loves to go the Vegas) and believes in cosmic connections. He then spent the remainder of the journey relating cell division to the odds of where the aces would fall in a game of Texas hold em. It was actually a brilliant metaphor for stochastic events in biology. It was an extraordinarily coherent explanation of how the probability of “aces showing” changes over time as players drop out. In his view, there could be some connection to stem cell division. Yes, the probability of a disease-causing mutation may change in relation to cellular changes or environmental events.

It was a wonderful example of how probabilistic events in cell biology can be related to everyday activities. For myself, it is a useful metaphor to use the next time I find myself needing to explain stem cells to non-biologists.

The moral of the story: Try your stem cell rap on your next taxi driver, it’s good practice and you may learn something. And you may dispel a few popular stem cell myths while you are at it.

- Geoff Lomax

Guest blogger Jeff Sheehy - CIRM Grantees Show Progress Towards a “Cure for HIV” in Boston

At the 18th Conference on Retroviruses and Opportunistic Infections (CROI) in Boston, two members of CIRM’s HIV/AIDS Disease Team led by John Zaia at City of Hope presented new research showing the team’s progress toward the clinic.

The team’s overall goal is to use technology developed by Sangamo Biosciences to modify the blood-forming stem cells of people infected with HIV. The modifications would effectively remove the doorway protein—called CCR5—the HIV virus uses to enter immune cells. The less than one percent of the population who lack CCR5 are naturally resistant to HIV infection and one HIV patient in Berlin who received a complete bone marrow transplant from someone born lacking the CCR5 receptor has been functionally “cured” of HIV.

In a presentation on Monday, Sangamo Biosciences released preliminary data from 6 HIV patients in its gene therapy clinical trial targeting T-cells, which are the primary immune cells invaded by the HIV virus. The study uses Sangamo’s zinc finger gene modification technique to remove the CCR5 receptor from T-cells taken from the patients with HIV. Those modified T cells were then returned to the patients’ blood system. The patients saw both survival and expansion of the modified T-cells—a critical finding since this implies some competitive advantage for cells protected by CCR5 deletion over cells that are not protected.

This finding is not itself a cure, since T-cells are just one type of immune cell that HIV attacks. However, it is encouraging for the CIRM funded Disease Team project, which seeks to use the same gene modification technique on a HIV patient’s blood-forming stem cells in the bone marrow. These tissue-specific stem cells give rise to all of the blood cells in the body and modifying them successfully could lead to protection for all of the immune cells that HIV attacks – not just the T cells. A full bone marrow transplant replacing the entire blood-forming stem cell compartment with modified cells carries significant risk, with mortality close to twenty percent. However, partial replacement of the stem cell compartment with CCR5 deleted cells and successful survival and expansion might be a safer and more accessible avenue for replicating the functional cure achieved in the single Berlin patient.

In a presentation Wednesday at CROI supporting this approach, Paula Cannon from USC and a member of the same Disease Team, will expand on her research on the use of hematopoietic stem cells genetically modified with the Sangamo zinc finer technology to remove CCR5 in mice with humanized immune systems. In her previously published study (here's a link to the Nature paper), the partial replacement of the bone marrow stem cell compartment with a minority of gene-modified cells led to competition between modified and unmodified cells with the CCR5 deleted modified cells (here's our blog entry on the work). In the humanized mice, the modified cells were eventually selected to the point where the humanized immune systems of the mice were able to control HIV successfully to a level where HIV is undetectable and without the use of antiretroviral therapies.

Together these two studies suggest that the Sangamo technology is able to effectively remove the CCR5 protein from modified cells, and that those cells are able to resist HIV infection.

Here are a few news reports about the work:
http://www.aidsmeds.com/articles/HIV_Sangamo_CCR5_1667_19952.shtml


http://m.apnews.com/ap/db_8559/contentdetail.htm?contentguid=YVSgAu1f

This video discusses the City of Hope HIV/AIDS disease team:



- Jeff Sheehy is is director for communications at the AIDS Research Institute at UCSF, and a member of the CIRM governing board.