Disease in a dish model provides insight on aging

Normal aging takes many decades to create major changes in our cells, so it is very difficult to study. As a result, very little is known about this fundamental inevitability of life. But that may change with the help of an unfortunate child, who by the bad luck of a single point mutation developed a rare disease that results in aging at eight to 10 times the normal pace.

A Salk Institute research team lead by Juan-Carlos Izpisua Belmonte has reprogrammed skin cells from the child, who has Hutchinson-Gifford progeria, into induced pluripotent (iPS) stem cells and then forced them to mature into smooth muscle cells in a dish that displayed all the characteristics of aging cells, a model for aging in a dish.

In a Salk press release Belmonte said:

Having a human model of accelerated aging may give us new insights into how we age. It may also help prevent or treat heart disease in the general aging population.

In a paper in Nature, the Salk team noted that this progeria is caused by a single point mutation in the gene encoding lamin A, and that there is evidence that defective lamin A also accumulates in the normal aging process via sporadic gene splicing.

The beauty of this model is the researchers were able to provide evidence for the impact of the defective protein. When the reprogrammed cells were in the embryonic-like state the lamin A was silenced, but when those cells were differentiated into smooth muscle the signs of premature aging appeared.

CIRM funding: Guang-Hui Liu  (TG2-01158)
Nature, February 23, 2011

D.G.

Reflecting on muscular dystrophy awareness week

This past week was muscular dystrophy awareness week, which seems like a short amount of time to focus on such a heartbreaking disease. One in every 3500 boys in the US develops that debilitating and fatal Duchenne muscular dystrophy (DMD) - the most common and serious form of muscular dystrophy - and there is no cure.

CIRM funds a few awards to researchers studying the muscle stem cells called satellite cells. These dot the muscle fibers, ready to spring to action when there’s damage. In kids with MD, those satellite cells can’t repair the damage and the muscles eventually waste away.

Here’s a list of CIRM-funded projects that could lead to new insights or therapies for MD. One Early Translational II project to Michele Calos at Stanford University is especially interesting. Starting in mice, she’s proposing to reprogram cells from animals with MD, fix the defective gene, then grow those cells into muscle stem cells that can be transplanted back into the mice. If the technique works, she and her team hope to start working with human cells.

As with all early research there are a lot of unknowns. Can they actually fix the gene? Can they grow up enough muscle stem cells for transplantation? Will those manipulated cells thrive and be able to repair the damaged muscle? And a big question: How on earth do you get those genetically altered cells to all the wasted muscles in the body?

Hopefully in future muscular dystrophy awareness weeks we’ll be able to answer some of those questions, and one day if all goes well we’ll be writing about a cure.

- A.A.

UC Davis scientist on a quest for cures in the cleanest of labs

Gerhard Bauer in the UC Davis GMP facility

One of the real thrills of working at CIRM is talking to the researchers who are so excited about finding new therapies. As part of our lunchtime talk series, today we heard from Gerhard Bauer of UC Davis. The only thing more exciting to Bauer than new therapies is the thought of having those therapies come out of his beautiful new GMP lab.

A GMP (Good Manufacturing Practice) lab is a clean facility that can be used to process the cells and other products that might one day go in people. When you see photos of scientists in white suits looking through microscopes, they’re likely in a GMP facility. If the lab sparkles so brightly you need sunglasses to look at the photos, it’s probably one of Bauer’s six GMP labs he’s built since moving from Austria to the U.S. in the 1980s to work on HIV/AIDS. He’s like the MacGyver of GMP labs. Nothing already manufactured was quite perfect enough for his facility, so in his spare time, you know, when he wasn’t running a lab and picking paint colors for the building, he also designed better GMP equipment.

Do I sound smitten? My apologies. I do aim for professional disinterest, but I am only human and I also really, really want to see therapies for some of the diseases they are tackling in that facility. It’s inspiring to see such enthusiasm in the people who are working toward those cures. Among the many diseases under investigation in the facility (Huntington’s disease, peripheral artery disease, bone fractures, liver disease) Bauer is part of the Stanford Disease Team working toward a therapy for the horrific childhood skin disorder epidermolysis bullosa. He and other members of that team recently spoke about the work at a governing board meeting. Videos of those talks are available here, but be warned that the disease is awful and the images are graphic. Personally, I can’t look.

One fun thing we learned is that Bauer has been taking on CIRM Bridges interns and training them in GMP procedures (here's a video about the Bridges program if you aren't familiar with it). He’s hired one, and has another working in the lab now. That’s exactly what we were hoping for in the Bridges program. Undergrad or masters students are learning stem cell science and getting trained for jobs in California’s expanding stem cell biology sector.

The lunch talks are a great opportunity for CIRM staff to hear about how those disease teams are progressing and to understand the challenges. Getting to a cure isn’t easy. One thing we all learned from Bauer’s talk is that whatever therapy the team comes up with, it’s going to be absolutely, totally, completely GMP certified. And clean? It’s going to be clean. Because when Bauer wasn’t dreaming up better lab equipment he was also certifying the cleaning protocols.

Here’s a video we made last year about the GMP facility:



- A.A.

iPS cells lead to drug discovery for heart disease, autism up next

We’ve long claimed that one ideal role for iPS cells is modeling disease and screening drugs. In fact, we’re so committed to that idea we produced a video about it with CIRM grantee Bruce Conklin at the Gladstone Institutes. Scientific American also has a story on disease model their March issue, available online.

Well, a group at Stanford has proven us right. A team led by Ricardo Dolmetsch took skin cells from people with a heart condition called long QT syndrome, reprogrammed those to an embryonic-like state, then matured them into heart muscle cells. These heart cells contracted in the lab dish, but slower and with irregularities compared to similar cells created from people without the heart condition. The work was published online Feb. 9 in Nature.

Here’s the cool part. The team bathed those cells in a variety of different drugs that have been reported to affect heartbeat rhythms, and found one that restored a regular heartbeat in the diseased cells. The drug, called roscovitine, is currently in clinical trials for a different condition.

According to a Stanford University press release:

Dolmetsch cautioned that at this point roscovitine should not be considered an adequate treatment for LQTS — it hasn’t been tested for this purpose in living animals, let alone humans, and may have pronounced side effects. Still, he said, it’s a promising compound for further drug development. Stanford’s Office of Technology Licensing has applied for U.S. patents related to the discovery, and Dolmetsch is starting a new company that intends to license those patents once they’re granted.

The primary focus of Dolmetsch’s work is autism. The cells he created with irregular heartbeat came from people with a condition called Timothy syndrome, which causes long QT syndrome as well as a form of autism. He has a CIRM Tools and Technologies II award to create iPS cells from people with Timothy syndrome, mature those into neurons and test drugs to find one that improves signs of autism in those cells.

- A.A.

From Sputnik to Stem Cells

Guest blogger Geoff Lomax
Senior Officer to the Standards Working Group

I was chatting, over a nice bottle of wine, with some long-time friends of mine at the Breakthrough Institute. They advocate federal funding to advance clean energy technology in the U.S. They were curious about the ongoing litigation over NIH funding for human embryonic stem cell research. It was interesting to hear their view that the decision was a blow to human capital and strategic investment. They drew an analogy to the space race when they wrote:

The U.S. simply could not have won the space race without major federal investments in targeted education programs. Spurred on by the Soviet launch of Sputnik, Congress passed the National Defense Education Act in 1958, committing billions of dollars to equip a generation to confront the Soviet challenge. These investments developed the human capital necessary to put a man on the moon and invent the technologies that catapulted our world into the Information Age, from microchips and telecommunications to personal computing and the Internet.

The point was that almost all major advances in engineering, medicine and telecommunications track back to public investment. The policy question was not a narrow one of whether the Federal policy should fund human embryonic stem cell research, but, rather, does the U.S. want to maintain its leadership position in biomedicine. As is the case with clean energy technology, China and India are making massive public investments in human and physical capital to support innovation in biomedicine.

Their concerns appear to be supported by recent research (account required for this link). Aaron Levine at Georgia Tech published survey results suggesting the legal challenge to the NIH hESC research policy has negative economic impacts and undermines the development of human capital for all aspects stem cell research. Specific impacts include:

• Delaying hESC research or new projects
• mpeding existing research projects
• Adopting suboptimal research designs

Levine concludes:

More surprisingly, these results also suggest that the ruling and ongoing policy uncertainty have negatively affected non-hESC stem cell research.

Levine’s findings are consistent with research conducted by CIRM. CIRM surveyed researchers with NIH grants to perform hESC research. 38% believed the funding freeze would have signification impacts. Loss of postdoctoral researchers was a major potential impact. Consistent with Levine’s findings, respondents to the CIRM survey indicated all forms of stem cell research would be hurt by the freeze.

Like my friends postulated, the loss of this critical human capital constitutes a blow to medical research broadly. As Levine suggests, to develop or maintain leadership in the field policies are needed that provide a clear legal and policy basis for ongoing research and innovation.

Where are the cures?

It seems like the stem cell news cycle alternates between stories of incremental hope (take the heart disease model for drug discovery out of Stanford today) and stories decrying the woeful lack of cures out of CIRM. I think the popular imagination went from the word “cure” when Proposition 71 passed in 2004 to an immediate need to see those cures by 2005. Or at least by 2011.

The very first stem cell-based “cure” came in 1968, when doctors at the University of Minnesota transplanted bone marrow from one person into a child with a genetic blood disease. Bone marrow contains the blood-forming stem cells that continuously rebuild the blood and immune system. Today, bone marrow or blood-forming stem cell transplants save lives daily, and are an active area of research by CIRM grantees working to develop new cures for HIV/AIDS, sickle cell anemia and other diseases.

Bone marrow and the related cord blood stem cells are the only stem cells that currently deserve the label “cure."

You can think of science like a giant hose with discoveries at the tap and cures coming out the nozzle. It’s a leaky hose, though, and ideas that look promising early on — and receive a great deal of press attention at the time — often leak out as they are disproven or shown to be ineffective. At CIRM, we fund the discovery end of the hose, constantly trying to generate good ideas that will one day make it out the other side. We fund the middle phases, where scientists figure out the best way of turning those early discoveries into cures (Here’s a video with Hans Keirstead explaining why that process takes so much time). And we fund the end everyone watches so closely — where the cures come out.

Bone marrow stem cells went in the discovery end of that hose decades ago, starting with research in the 1950s, and new therapies are still pouring out, including the recent Berlin patient who was effectively cured of HIV infection.

Various types of adult stem cell discoveries went into that hose starting in the 1990s as new tissue-specific stem cells such as those in the brain, fat, placenta and skin were discovered. Clinical trials involving those cells are still underway, which means that despite exciting news stories of mid-hose success the cells have yet to make it out the cures end of the nozzle. Many trials look promising, but until the cells are shown to be safe and effective in large controlled trials, they aren’t yet cures. CIRM funds a lot of adult stem cell research (here’s a list of those awards, many of which involve complex manipulations rather than the simple cell transplants of earlier work) and we’re excited about seeing some of the early discoveries start making it through clinical trials.

So, where are the embryonic stem cell cures? Well, they went into the discovery end of the hose in 1998 and we already have three clinical trials underway based on those cells. CIRM began funding stem cell research eight years later in 2006 and some of our grantees expect to be in clinical trials in the next few years. It’s true that they have yet to come gushing out the cures end of the nozzle, but it’s exciting to know that because of CIRM discoveries are at least in the the hose, making their way toward the end we're all watching so eagerly.

- A.A.

New UCSF stem cell building -- a beautiful setting for discovering new therapies

Today the University of California, San Francisco is unveiling their brand new CIRM-funded stem cell building. It’s not the largest of the 12 new buildings CIRM has funded throughout the state, but it sure is pretty with its labs perched along the Parnassus campus hillside. Like all of the new buildings, CIRM’s investment in this one required a substantial investment on the part of UCSF and inspired gifts from private donors. The Eli and Edythe Broad Foundation gave to the tune of $25 million, and two gifts from Ray and Dagmar Dolby were worth a total of $36 million.

These leveraged funds at UCSF and other facilities around the state helped create 25,000 jobs and $200 million in tax revenue for the state — an achievement CIRM is especially proud of during these dark financial times.

Now that the building has created jobs, we’re looking forward to seeing the cures and the resulting biotech investment. A story about the new Ray and Dagmar Dolby Regeneration Medicine Building in the San Francisco Chronicle quotes CIRM president Alan Trounson:

"These buildings have galvanized an area (of medical research) that had an enormous amount of potential, but scientists were being careful about entering the field. Business is really taking off in California, whereas in other parts of the country, it's a struggle."

A hallmark of the stem cell buildings CIRM has funded is that they encourage collaboration and consolidate resources. I was talking to David Shaffer at UC Berkeley while filming this video about CIRM's major facilities and he highlighted the importance of having everything in one place. Scientists in his lab must sometimes walk samples across campus to access technologies. Those hours spent readying samples for transport and walking around campus can be better spent doing the research that leads to cures.

At UCSF, scientists who might once have needed shuttles to attend colleague’s seminars can now wander down the hall. Technologies are in one place, meetings are centralized and we hope ideas can flow as freely as the wide open workspaces.

To date, Davis, UC Irvine, UC Berkeley, UCLA, Stanford and USC have all opened their facilities. The remaining five are under construction and all but one is expected to open its doors this year.

- A.A.

The confusing (and ongoing) story of iPS vs. embryonic stem cells

It appears we weren't the only people to notice last week's convergence of reprogrammed iPS cell news -- first they are made better, then they are suggested to be worthless. USA Today ran a story summing up several years' worth of such news. (For those not up-to-speed on iPS cells, you can watch this video with UCLA's Jerome Zack talking about how the cells are made.)

The story goes something like this: One day, iPS cells reprogrammed from adult tissue are going to eliminate the need for embryonic stem cells. No destroying embryos!

Soon after, someone points out that the creation of iPS cells -- though cool -- requires inserting cancer-causing genes. Not good! They cause cancer! But then someone finds a better way, with no cancer genes. Good! But then iPS cells are shown to differ dramatically from embryonic stem cells. And they don't seem quite as willing to form all tissues. Confusing!

According to the USA Today story:

"Basically, we are looking at a lot of confusion," says Harvard stem cell scientist Alexander Meissner. "That's not to say one group is wrong and another is right. We have been making a lot of progress, but everyone is looking at the same problems from different sides."

The story mentioned last week's paper by Salk researchers showing a molecular memory in iPS cells and went on:

Combined with a September Nature paper showing similar memory signatures in mouse IPS cells and Scripps Research Institute researchers last month reporting more cancer genes in IPS cells compared to embryonic ones, things looked bad . "The finding suggests that (induced) cells may not be suitable substitutes for (embryonic) cells in modeling or treating disease," noted Nature science reporter Elie Dolgin.

Although iPS cells are clearly the source of some confusion in terms of their similarity to embryonic stem cells, they are still a great tool for mimicking disease. CIRM researchers at Salk have taken skin cells from people with ALS, matured those cells in a lab dish into the cells involved in the disease and learned details about the biology of that disease that would never have been possible without reprogrammed cells. (Here's a video about that work.)

Other grantees at the Parkinson's Research Institute are taking skin from people with Parkinson's disease, maturing those into the neurons involved in that disease, and using those cells that are genetically included to form Parkinson's disease to understand the disease and test drugs. (This video includes scientists at the Parkinson's Institute talking about that work.)

At Gladstone, CIRM grantees are generating heart tissue from the skin of people with genetic heart diseases and using those cells to screen drugs. (You can watch a video of Bruce Conklin talking about that work.)

In each case, it doesn't matter that iPS cells are not identical to embryonic stem cells. It matters that they are currently the only way to study mature disease-prone cells in a lab dish. Because those people with Parkinson's disease aren't giving up brain tissue and the heart disease patients aren't loaning out little chunks of their heart. But skin they can part with.

USA Today ends their story by instructing readers to hang on for a bumpy ride ahead as scientists resolve the meaning of the differences between iPS and embryonic stem cells. One day we'll know which cell type provides the best tool for treating and studying different diseases. In the mean time, USA Today is likely right that the ride won't be dull. 

- A.A.

Stem cells for a broken heart? Maybe one day

The LA Times has a timely story in the week leading up to Valentine’s day summarizing the role of stem cells in mending a broken heart. There’s been a lot of talk — and a lot of money invested -- over the past few years pushing bone marrow stem cells as a tool for repairing damage after heart attack.

I remember back in 2004 I wrote about Stanford’s Robert Robbins who had transplanted bone marrow stem cells into the hearts of mice with induced heart attacks. He found a temporary improvement in those mice, but that improvement didn’t last. In the end, their hearts were just as broken as their untreated lab-mates and the mice died at the same rate.

Years later, his result seems to have held up in people. From the LA Times:

From 2002 to 2006 alone, there were at least 18 randomized controlled studies involving nearly 1,000 patients.

"Everyone started putting bone marrow in the heart," says Christine Mummery, a researcher at Leiden University Medical Center in the Netherlands, who has studied how to turn stem cells into heart muscle cells called cardiomyocytes.

But the results, she says, were a mixed bag. The treatment appeared to be safe, but patients had only transient improvement.

"People went from being very sick to a little less sick," Mummery says.

These doubts about bone marrow stem cells for repairing heart damage haven’t discouraged CIRM grantees working with other stem cell types. CIRM grantee Eduardo Marban, who is director of the Cedars-Sinai Heart Institute in Los Angeles, has CIRM funding to use the heart’s own stem cells as a repair mechanism after heart attack. He is quoted in the LA Times story as saying:

The hope is that the cardiac stem cells will take root and reverse the scar. Results should be out later this year. "Let's just say we're extremely encouraged," Marbán says. "It looks like it's working, and cleanly."

Over at the Gladstone Institute of Cardiovascular Disease in San Francisco, CIRM grantee Deepak Srivastava has devised a way of directly converting heart connective tissue into heart muscle, at least in rodents. That work is still years from clinical trials — or even being proven to work in human cells — but has caused a stir in stem cell circles.

Still other CIRM grantees throughout the state are prodding human embryonic stem cells to mature into heart tissue that could be transplanted into the heart as a sort of cellular patch for the damaged region.

None of these approaches will arrive in time to repair a broken heart on this Valentine’s day, but one day down the road stem cells of some type — whether it’s heart stem cells, directly reprogrammed cells or embryonic stem cell derived — might be what patches up damaged hearts of the future.

Here’s a complete list of CIRM funding for heart disease.

A.A.

Exercising for the health of my stem cells

The New York Times health blog has a story today adding yet another reason for regular exercise: It’s good for stem cells in your bone marrow. When I run, I’m not generally thinking about my bone marrow, I admit. But there are times when I’m thinking about fat (or rather, how much of it I want to eat later in the day), and it turns out those thoughts apply to my bone marrow as well as to other places.

From the New York Times:

This idea is the focus of a series of intriguing recent experiments by Janet Rubin, a professor of medicine at the University of North Carolina and other researchers. For the work, scientists removed bone marrow cells from mice and cultured them. The cells in question, mesenchymal stem cells, are found in bone marrow in both animals and people, waiting for certain molecular signals to tell them to transform into either bone cells, fat cells or, less commonly, something else.

Just to be clear, these mesenchymal stem cells are different than the blood-forming stem cell cells also found in the bone marrow. In a series of experiments involving either mice or the mouse mesenchymal stem cells, exercise pushed the stem cells to form bone while high sugar levels and inactivity pushed those cells toward fat. Admittedly, simulating exercise for a plate of cells seems a bit abstract — they vibrated the cells and equated that mechanical force with jogging.

Many questions remain, of course. It’s not clear, for one, whether fat cells generated in bone marrow remain in the marrow or move around to pad, say, the thighs. It’s also not known how exercise affects stem cells located outside the bone marrow. Can it prevent the birth of fat cells all over the body? In Clinton Rubin’s experiments with mice, the vibrated animals wound up with less overall body fat than the control mice, but the reasons are unknown.

Despite these questions, the general idea of producing more bone and less fat seems like a good one.

At CIRM, we’re focused on finding new ways of either treating or understanding disease through adult, embryonic, reprogrammed or cancer stem cells. But while we’re looking for those new cures it can’t hurt to keep the stem cells we have as happy and healthy and as focused on good—bone not fat—as possible. 

- A.A.

iPS developments - faster creation, but questions raised

Two pieces of news came out today about reprogrammed iPS cells — one showing a new way of making them and the other suggesting that they may not be all they’re cracked up to be.

First, the new technique. A team at Sanford-Burnham Medical Research Institute in La Jolla figured out a way of removing barriers to reprogramming, in which skin or other adult cells are reprogrammed back to an embryonic-like state. Most techniques for reprogramming involving adding DNA or other factors to push the cells back in developmental time. But the process isn’t very efficient. This team identified two barriers to reprogramming and removed them using small inhibitory molecules called miRNAs.

The Sanford-Burnham press release quotes CIRM grantee Evan Snyder, director of Sanford-Burnham’s Stem Cells and Regenerative Biology program:

“Up until now, cellular differentiation and de-differentiation has focused principally on the expression of genes; this work indicates that the strategic non-expression of genes may be equally important. The work has demonstrated that miRNAs do function in the reprogramming process and that the generation of iPSCs can be greatly enhanced by modulating miRNA action. In addition to helping us generate better tools for the stem cell field, such findings inevitably facilitate our understanding of normal and abnormal stem cell behavior during development and in disease states.”

Ironically, on the same day the authors published the fruits of many years of labor, the news cycle delivered a blow. Researchers down the road at The Salk Institute for Biological Studies published yet another report showing critical differences between iPS and embryonic stem cells. There’s been a steady drumbeat over the past year of studies pointing out that iPS cells might not exactly mimic embryonic stem cells, and for that reason might not be ideal replacements in therapies.

William Lowry, a CIRM grantee at UCLA, is quoted in a Nature news story about the finding:

"The problem is that we don't know if any of these differences are going to be consequential."

Whether these differences between iPS and embryonic stem cells will turn out to be insurmountable in terms of future therapies is unknown. What is clear is that scientists have many hours in the lab ahead of them before we understand which cells are the safest and most effective for eventual therapies.

- A.A.

Skin cells become beating heart cells in a lab dish

Scripps Research scientists have
created mature heart muscle cells
directly from skin cells.

Eventually, directly reprogramming one type of adult cell into another is going to be old news. For now, the entire field is new enough that each time scientists pluck one adult cell type and coerce it to become another, it’s exciting.

The most recent example comes from CIRM grantees at Scripps Research Institute, who converted mouse skin cells into beating heart cells in just 11 days. A press release quotes senior author Sheng Ding:

“It is like launching a rocket," he said. "Until now, people thought you needed to first land the rocket on the moon and then from there you could go to other planets. But here we show that just after the launch you can redirect the rocket to another planet without having to first go to the moon. This is a totally new paradigm.”

Since 2006, scientists have been able to convert skin cells into embryonic-like iPS cells, which they could then mature into different cell types including heart. Directly converting skin to heart saves time, and could result in more effective therapies. According to the Scripps press release:

When, for example, scientists induce iPS cells to become heart cells, the resulting cells are a mix of heart cells and some lingering iPS cells. Scientists are concerned that giving these new heart cells (along with the remaining pluripotent cells) to patients might be dangerous. When pluripotent cells are injected in mice, they cause cancer-like growths.

Other CIRM grantees who have succeed in direct reprogramming include Marius Wernig at Stanford, who converted skin to nerve, and Deepak Srivastava, who converted heart fibroblasts into heart muscle cells.


Nature Cell Biology, January 30, 2011
CIRM funding: Sheng Ding (RN1-00536-1)

- A.A.