Techniques for tracking stem cells necessary for possible therapies

Last week The Scientist carried a story addressing a topic near and dear to the heart of anyone trying to develop a therapy based on transplanting stem cells, whether they are embryonic, adult, or iPS cells: Where do the cells go once they are transplanted?

The problem is this — if you, as a scientist, transplant stem cells near some damage that you are hoping they will repair, you've got to hope those cells actually make it to the damaged tissue. If they make a run for the liver when you are trying to treat the heart, or simply sit in a lump where you implanted them, those cells aren't going to fulfill their mission.

The story quotes CIRM grantee Joseph Wu of Stanford University who has SEED and Basic Biology III Awards to detect stem cells implanted into the heart and to develop stem cell transplantation therapies for hypertrophic cardiomyopathy.

“If you want to understand what happens to these stem cells, it’s important to track the fate of these cells without having to kill the animal,” says Joseph Wu, a cardiologist at Stanford University School of Medicine in Palo Alto, California. Stem cell transplants may settle down, proliferate, and differentiate as desired; they may form dangerous tumors; or they may simply falter and die.

The issue is also one CIRM grantee Paul Knoepfler of the University of California, Davis, touched on in his blog last week, saying:

Once these cells, which have spent weeks in a lab environment, are injected into a person, what happens next?

This is arguably the most important question in the regenerative medicine field, but there are few answers. We are literally mostly in the dark about what cells do after transplant, but there are some things that can be predicted pretty confidently.

He goes on to discuss some of what's known about the issue using Geron's clinical trial as an example.

In their article, the Scientist discusses a few techniques scientists are using (including some nice images) to address the question of where the cells go. The story includes a technique being used by CIRM grantee Eduardo Marban at Cedars-Sinai Medical Institute, who has a Disease Team Award to develop a therapy for heart disease.

This is the type of research that comes to mind when people who don't follow the science comment on the lack of cures. CIRM is funding a broad range of science, some of which is primarily dedicated developing new therapies, and some of which is working to understand these kinds of basic questions that need to be addressed before those therapies can become widespread.

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Heart, heal theyself

A group of researchers from University College London made a splash this week with their work prodding heart muscle to repair itself. This is big news, given both the number of people who have heart attacks (more than 1 million per year in the US) and the number of stem cell scientists working to regenerate the damage (23 awards worth $46 million from CIRM).

The big problem has been this: The heart appears to have some stem-like cells, but in adults they don't do much. They certainly aren't able to repair damage after a heart attack. When the heart is developing, however, those cells are the major source of new heart muscle. So, what gives? Why can't those cells perform in adults the way they do during development?

A story by Mitch Leslie in ScienceNOW has this to say about the UCL work:

To recapture the cells' youthful vigor, the researchers injected mice with thymosin β4, a compound already undergoing clinical trials as a heart attack treatment because it helps cardiomyocytes survive and spurs the growth of new blood vessels. The researchers then mimicked a heart attack in the animals by tying off one of the arteries that deliver blood to the heart, injuring part of the muscle.

Unlike control mice that didn't appear to fashion any new cardiomyocytes, animals dosed with thymosin β4 made some of the cells, the team reports online today in Nature. The cells infiltrated the damaged zone left by the simulated heart attack and meshed with other cardiomyocytes physically and electrically, allowing them to beat. They also seemed to prevent some of the damage that can result from a heart attack. Magnetic resonance imaging scans showed that the hearts of mice that had received thymosin β4 had smaller scars and were able to pump more blood with each contraction than were the hearts of untreated rodents.

The news is good, but thymosin β4 wasn't all that efficient. The group is hoping to find other compounds that can more effectively prod progenitors into action.

This work is interesting, too, because it shows the interplay between stem cell science and traditional drug-based medicine. Transplantation therapies are what grab the stem cell headlines. But studying how stem cells normally function can also lead to the development of new drugs, such as ones that could help the heart heal itself.

The ScienceNOW story quotes CIRM grantee Deepak Srivastava, who made headlines last year when he was able to directly transform support cells in the heart into heart muscle — a trick he'd like to replicated not in a lab dish but in an actual heart.

The study "provides strong evidence that there is a population of cells from the epicardium that can turn into new muscle," Srivastava says. "The real question is how robust is the process [of cell transformation] and how can it be improved." He recommends that researchers also investigate whether the cells can rebuild cardiac muscle during heart failure, a condition that afflicts some 5 million U.S residents and causes the organ to progressively weaken.

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Hit embryonic stem cell research, hurt iPS research too

Those of you who follow this space have read our opinions on embryonic vs. adult vs. reprogrammed iPS cells. For those of you who don't watch this space, here's our opinion in a nutshell: There is no "vs." All types of stem cells could be therapeutically valuable, and what we learn in one cell type often directly translates to discoveries in another cell type.

A paper coming out tomorrow in Cell supports that opinion. Christopher Scott at Stanford University and colleagues at the Mayo Clinic and the University of Michigan analyzed more than 2,000 papers published since 2007, when human iPS cells were first reported. According to a Stanford press release:

[The team] found that the iPS field is dominated by well-established, senior hES cell researchers. Many of these researchers are publishing studies that directly compare hES cells with iPS cells, rather than focusing exclusively on one cell type.

However, stem cell scientists are not abandoning hES cells in favor of iPS cells. In 2008, only three of the 15 iPS cell papers (5 percent) published also reported hES cell results; in 2010, 98 of the 158 iPS cell papers (about 26 percent) did so.

The work is especially important given an unresolved lawsuit that temporarily suspended federal funding for embryonic stem cell research last fall.

Stanford writes:

“If federal funding stops for human embryonic stem cell research, it would have a serious negative impact on iPS cell research,” said Stanford bioethicist Christopher Scott, citing a “false dichotomy” between the cell types. “We may never be able to choose between iPS and ES cell research because we don’t know which type of cell will be best for eventual therapies.”

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Blood from stem cells?

Blood has been among the most sought after and hardest to achieve tissue that CIRM grantees are attempting to derive from embryonic stem cells. It's an obvious target. The medical system needs a constant influx of blood, which comes entirely from volunteer donors. Creating that blood in an unlimited supply from human embryonic stem cells would significantly ease concerns about blood shortages at hospitals. We blogged about a Los Angeles Times story last January that discussed the value of this type of work.

The National Blood Data Resource Center has this to say about how much blood was used in 2001:

U.S. hospitals transfused nearly 14 million units of whole blood and red blood cells to 4.9 million patients in 2001 - that's an average of 38,000 units of blood needed on any given day.

Given those needs, the findings in a Nature paper by CIRM grantee David Traver at the University of California, San Diego could prove helpful. He and his team have discovered a gene called Wnt16 that, in the lab animal zebrafish, is key to the animal eventually developing a pool of hematopoietic stem cells, which are the source of all blood in the body.

In a press release from UCSD Traver said:

“What we need is the ability to generate self-renewing [human embryonic stem cells] from patients for treatments. But accomplishing this goal means first understanding the mechanisms involved in creating HSCs during embryonic development.”

Traver's work follow that of another CIRM grantee Inder Verma of the Salk Institute, who last month published a protocol for creating blood-forming progenitor cells from human embryonic stem cells and reprogrammed iPS cells. Discussing this work in his monthly stem cell research update, CIRM President Alan Trounson wrote:

Many more cancer and blood disorder patients could benefit from stem cell transplants if large numbers of blood forming stem cells could be grown in the laboratory. Because mature hematopoietic stem cells (HSCs) don’t expand well in culture, researchers have been trying to grow these cells from pluripotent stem cells, both embryonic stem cells and reprogrammed iPS cells. Most of these attempts have generated very low numbers of bone marrow colonizing blood precursors, and none have shown robust generation of transplantable HSCs. Now, Verma’s team has shown that with five iPS cells lines and two embryonic lines that they can efficiently generate precursors and progenitors of HSCs.

This work brings up another point often made by CIRM grantee Paul Knoepfler at the University of California, Davis. In his blog and in the Sacramento Bee Knoepfler has argued that supporting stem cell research is a matter of national security. Soldiers wounded on the battlefield need a source of blood for transfusions. Knoepfler wrote in his Sacramento Bee Op-Ed:

I hope that in the future stem cell research can perhaps slightly lessen the burden on our servicepeople and their families through technologies to save the lives of wounded soldiers.

Nature, June 9, 2011
CIRM funding: David Traver (RN1-00575-1)

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30th Anniversary of HIV/AIDS, CIRM teams making progress

Thirty years ago the first reports of a mysterious illness began appearing in the media. This illness would eventually become known as AIDS.

CIRM board member Jeff Sheehy recently spoke as part of a KQED Forum radio show about the 30th anniversary of HIV/AIDS. As a long-time AIDS activist, Sheehy has been part of the fight for a cure. In his introduction, Sheehy talked about limitations of the current drug regimen for HIV/AIDS:

“We’re still losing people and I think that gets lost in a lot of this. People have a treatment optimism belief. HIV or medication side effects are shortening lifespans. Things are still tough for people with HIV and one of the things we need to talk about is a cure.”

That cure is looking more hopeful with the announcement of a man who has come to be known as the Berlin patient (we blogged about him here). He received a bone marrow transplant in Berlin from someone who was effectively resistant to HIV infection. That man, Timothy Brown, also became resistant to infection and now doctors are unable to detect HIV in his body.

In the Forum discussion, Steven Deeks, professor of medicine at UCSF and a leader in HIV/AIDS research, pointed out that although Brown’s HIV is now undetectable, his isn’t the treatment that will become a widespread cure. First, there aren’t enough bone marrow donors who are resistant to HIV. The bone marrow transplant itself is also an extremely risky procedure.

Deeks pointed to work being carried out by CIRM grantees who are attempting to engineer a person’s own bone marrow stem cells to carry the mutation that makes the cells resistant to HIV. Sheehy pointed out that CIRM has been alone in funding this type of work:

“It’s been lonely. Thank god for the voters in 2004 who voted for proposition 71[ the proposition that created CIRM]. What surprised me when I got appointed to this board I really didn’t think there was much in HIV that could be done.”

CIRM now funds more than $40 million in HIV/AIDS research (see a list of those awards here), including two disease teams that are both working toward beginning clinical trials in two to three years.

This video features Sheehy and John Zaia from the City of Hope who leads one of those disease teams.



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Marius Wernig on why we need many stem cell approaches to new therapies

Last week we blogged about work by Marius Wernig of Stanford University, who has successfully converted human skin into nerves, skipping the step of first converting the cells into embryonic-like iPS cells.

Wernig is quoted in a Nature news story talking about whether the work could replace induced pluripotent stem (iPS) cells or embryonic stem cells:

"I would say that both approaches should be actively pursued because you never know for which cases and specific applications one or the other may be more suitable."

I think the best example of why we need many approaches to treating disease came from patient advocate Rodney Paul, who spoke to an external review committee last year about CIRM. Here's what we wrote in our Best. Analogy. Ever. blog entry on October 13, 2010:

He pointed out that on this day the world saw awe-inspiring images of the first of 33 miners rising out of the Chilean mine where they’d been trapped — and that those miners were rescued through one of three shafts that had been dug as part of the rescue mission.

The shaft in question was dubbed “Plan B”. Drilling on plans A and C didn’t go as smoothly as hoped. That’s why on an important mission where time is limited and lives are at stake it’s important not to pin all hopes on one strategy.

With embryonic, adult, iPS and cancer stem cells plus the new direct conversion techniques CIRM is drilling a series of shafts all leading toward possible disease therapies.

We have a list of all our grants online. You can use the filters to see how many awards we're funding using different types of cells. Right now, the numbers are:

• Embryonic: 215
• iPS: 78
• Adult: 47
• Cancer: 10

Those numbers are updated whenever we fund new awards.

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Stem cell banking and the making of a patient "advocist"

In 2005 Chris Hempel gave birth to twin daughters Cassi and Addi. In 2007, she and her husband learned that their girls had a rare, fatal disease called Neiman Pick Type C.

Four years later, Hempel describes herself as a "advocist" for rare diseases. She's an advocate for scientific research but also an activist seeking to bridge the gap between patients and researchers. One of her primary messages is this: If patients donate tissue (skin, in her case) that contribute to science, then they should get to know the results and participate in the research.

That sounds easy, but has proven difficult. She spoke to CIRM's Standards Working Group in April to discuss her experiences and encourage CIRM to take a leadership role in creating policies that engage and inform the tissue donors.

During her talk, she said, "If the entire goal is really to use a patient's own cells to cure them, well, you really can't cure a patient if they are just a number."

CIRM funds several awards that have the intention of creating reprogrammed stem cell lines from skin samples to better understand genetic diseases, much like the research Hempel participated in. These scientists have creating disease-in-a-dish models of schizophrenia, Parkinson's disease and autism using this approach.

One of the issues the working group discussed is the types of standards that should be in place to protect the rights of the people who donate tissues for these and other CIRM studies. In addition there was discussion about ways of providing information to potential donors, research participants and the public.

The agenda from that meeting contains additional information about tissue donation and iPS banking: available here.

Here is Hempel's talk:



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