Fly stem cells give insights into aging and longevity

Yesterday brought news about stem cells in older people. Today, there's news by CIRM grantees about how a single gene alteration in a stem cell can help keep an entire organ more youthful -- at least in flies.

The work was by a team of researchers at the University of California, Los Angeles, the Salk Institute for Biological Studies and the University of California, San Diego. It all started with a long-known observation: cutting calories in many laboratory animals can also dramatically extend the animal's life. This is true in common lab animals such as flies, worms, and mice, and also holds true in primates.

In addition to living longer, those hungry, long-lived animals have more of the energy-producing cellular structures called mitochondria. The researchers were curious if simply boosting the number of mitochondria without all that painful hunger would work the same trick. One known way of boosting mitochondria is to rev up a protein called PGC-1.

A press release from Salk describes the work of associate professor Leanne Jones' work like this:

"This chain of connections between the mitochondria and longevity inspired Jones and her colleague to investigate what happens when the PGC-1 gene is forced into overdrive. To do this, they used genetic engineering techniques to boost the activity of the fruit fly equivalent of the PGC-1 gene. The flies (known as Drosophila melanogaster) have a short lifespan, allowing the scientists to study aging and longevity in ways that aren't as feasible in longer-lived organisms such as mice or human."

The researchers specifically bumped up the PGC-1 gene in stem cells that line the fly intestine. They found two things: 1) those fly intestine stem cells had more mitochondria, and 2) the flies lived a lot longer than their unaltered lab-mates. All that, with no starvation.

Here, I should pause to say that if you think your intestine is so different from a fly's you'd be wrong. Their intestine is lined with stem cells not unlike our own, and those cells function in a very similar way using similar genes. That's not to say that all research in flies directly translates to humans, but it is a pretty good model for testing out ideas.

Jones, who has a New Faculty award from CIRM, had this to say in the press release about the findings:

"Slowing the aging of a single, important organ - in this case the intestine - could have a dramatic effect on overall health and longevity," Jones says. "In a disease that affects multiple tissues, for instance, you might focus on keeping one organ healthy, and to do that you might be able to utilize PGC-1."

This research is in the very preliminary stages and is far from being ready for an human use. However, it's this kind of basic discovery that continuously fuels new ideas for human therapies.

CIRM Funding: Leanne Jones (RN1-00544-1)
Cell Metabolism, November 1, 2011

- A.A.

Discoverer of brain stem cells becomes president of ISSCR

The North County Times had a good story yesterday about Fred Gage's new role as the president of the International Society for Stem Cell Research. Gage is a renowned stem cell scientists at The Salk Institute for Biological Studies, which also wrote about his new role.

Gage was the first to show that people do, in fact, produce new brain cells after birth. In work that is especially close to my heart, he also showed that mice that get (to quote the 1999 press release) "regular voluntary exercise on running wheels" also grow more brain cells than sedentary mice.

More recently, Gage has had CIRM funding to carry out studies modeling human neurological diseases in a lab dish as a way of understanding and treating those diseases. We've blogged about his work here and here.

As the new president of ISSCR, which represents about 4,000 stem cell scientists internationally, Gage said he hoped to advocate for stem cell science to the public and to politicians. He also hopes to advance ISSCR's mission of moving basic stem cell discoveries into clinical therapies. He told the North County Times:

"There's been a lot of fantastic basic research that has been done," Gage said. "We realize that part of our mission as a society is to translate these basic science into clinical applications. We call it bench to bedside. We're thinking about ways to do this most effectively."…

"You have to have the basic biologists helping in this, but we need the clinicians too, even though they don't have the (scientific) knowledge," Gage said. "We need to bring them up to speed. And underlying all this, we need to have a very effective fundraising effort for the society."

Gage talked to CIRM about how stem cells can be used to mimic disease in a lab dish:



A.A.

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)

A.A.

Gene replacement in stem cells made easier

A press release about CIRM grantees at the Salk Institute for Biological Studies contains what might be the truest words in stem cell science:

In principle, genetic engineering is simple, but in practice, replacing a faulty gene with a healthy copy is anything but.

Several CIRM grantees could sum up their work in that same way. We've funded a variety of projects that all intend to replace faulty genes in stem cells with healthy ones, and then use the tricked-up stem cells to treat disease. That's how both of our HIV/AIDS disease teams hope to conquer HIV infection and also underlies our sickle cell disease and epidermolysis bullosa teams. (A list of disease teams with links to their research summaries is available here.)

The Salk researchers have published a paper in Cell Stem Cell describing a new way of replacing a gene with a therapeutic version. As a model, they used stem cells they had reprogrammed from a person with a genetic premature aging condition called Hutchinson-Gilford progeria. That condition is caused by a mutation in a gene called Lamin A. They used the technique to replace the defective Lamin A in the reprogrammed stem cells with a healthy copy of the gene. According to postdoctoral researcher and co-first author Guang-Hui Liu:

"The process was remarkably efficient and we couldn't detect any undesired off-target effects such genomic instability or epigenetic abnormalities," says Liu. "What's more, it allowed us to show that we can correct multiple mutations spanning large genomic regions."

The group also showed that their technique worked in mesenchymal stem cells, which are a form of tissue-specific stem cells many groups are also using to develop therapies.

The issue of being able to swap out defective genes is just one of many hurdles for scientists developing stem cell-based therapies. These behind-the-scenes issues rarely make the newspapers and remain largely invisible to the people who are waiting to see those future therapies, but are an active area of research for CIRM grantees. Hopefully work like this will help eliminate those hurdles and speed the path to the clinic.

Cell Stem Cell, May 19, 2011
CIRM Funding: Jeanne Loring (TR1-01250), Guang-Hui Liu (TG2-01158)

A.A.

From stem cells to schizophrenia in a dish

Kristen Brennand

CIRM grantee Fred Gage at The Salk Institute for Biological Studies and his lab are creating a veritable cellular hospital of disease conditions playing out in laboratory dishes. What they learn from these diseases-in-miniature could lead to new ways of creating and screening drugs to treat the disorder.

In 2008, he matured embryonic stem cells into the type of nerve cells damaged in ALS. This study led to insights in how the damage occurs and could provide a way of screening new drugs. Then in November of 2010, Gage and his colleagues published a paper in which they reprogrammed skin cells from people with a genetic form of autism spectrum disorders. They then matured those iPS cells into neurons that they could study in the lab.

Now, Gage and his team have published a paper in Nature in which they pulled off a similar feat, this time with schizophrenia. They took skin cells from people with a genetic form of the disease and reprogrammed those cells back to an embryonic-like state. They then matured those cells into neurons — neurons that produced significantly fewer connections than is normally seen. What's more, the drug Loxapine, used to treat schizophrenia, helped restore those connections. No other frequently prescribed antipsychotic medication was able to restore those connections.

A Salk press release quotes Fred Gage, who is professor in the Salk's Laboratory of Genetics and holder of the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Diseases:

"Schizophrenia exemplifies many of the research challenges posed by complex psychiatric disorders," says Gage. "Without a basic understanding of the causes and the pathophysiology of the disorder, we lack the tools to develop effective treatments or take preventive measures."

The group also found almost 600 genes whose activity was different between normal neurons and those from the schizophrenia cell. Roughly a quarter of those had been implicated in schizophrenia in the past.

The press release quoted Gage again:

"For many years, mental illness has been thought of as a social or environmental disease, and many thought that if affected people just worked through their problems, they could overcome them," says Gage. "What we are showing are real biological dysfunctions in neurons that are independent of the environment."

We produced a video of Gage discussing the role of stem cells in understanding diseases:


CIRM Funding: Kristen Brennand (T3-00007); Fred Gage (RL1-00649-1)
Nature, April 13, 2011

 - A.A.

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.

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.

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.

Stem cell model of autism allows testing of new drugs

Back in May 2009, CIRM held a workshop in which leading scientists discussed ways in which stem cell research could benefit people with autism (here is the autism workshop report from that meeting). I have two friends with children who are on the spectrum and have seen first-hand the toll the disease takes on the families.

This week, some CIRM grantees published an exciting paper that reflects the hopes of that workshop. The scientists took skin cells from people with a severe form of autism called Rhett syndrome, reverted those cells to an embryonic state, and matured them into neurons. The work was published in the in the November 11 issue of Cell. This is the first time scientists have been able to study what amount to autistic neurons in a lab dish.

It turns out they have some abnormalities, as you might expect. According to Technology Review:

They found that neurons derived from patients with Rett syndrome showed certain abnormalities, including markedly smaller cell bodies, dendrite connections, and decreased cell-to-cell communication.

The best part is that when the team from the Salk Institute and the University of California, San Diego exposed these neurons to a protein called insulin-like growth factor the neurons looked more normal.

This type of work is precisely what the workshop recommended as a starting point. Nerves grown from people with autism are an ideal environment for testing possible therapies and for understanding the disease. The group hopes to test therapeutic options suggested by these findings in mice, and to grow neurons from people with different forms of autism.

At this point the work is far too early to benefit my friends. The scientists still need to better understand the different forms of autism, study this proposed therapy in animals and understand the mechanism better before they can even begin thinking about a human trial. But for a disease that currently has so little clinical hope, even early stage work is a step in the right direction.

CIRM funding:
Fred Gage (RL1-00649-1 and RC1-00115-1)

Food begets stem cells?

Drosophila intestinal stem cells (ISCs)
respond to nutrient availabilityImage:
Courtesy of Dr. Lei Wang,
Salk Institute for Biological Studies

Researchers at the Salk Institute for Biological Studies have found an intriguing connection between stem cell behavior and food. The more food, the more stem cells, and those stem cells divide more vigorously.

The researchers did their work in flies, which provide a ready laboratory for studying tissue stem cells in their natural environment. Flies have a pool of stem cells in the testes and in the intestine that are easy to monitor under different conditions and that mimic similar cells in our bone marrow, liver or muscles in their capacity to rebuild tissue.

What they found is that in flies fed a poor diet, the stem cell pool in the testes and intestines dwindled and those remaining cells divided sluggishly. Improving the flies’ diets rebuilt the stem cell pool. It appears that the protein insulin, which is present in the blood after a meal, is what signals stem cells about the presence or absence of food. The findings are published in the Nov. 4, 2010, online edition of the journal Current Biology.

In a press release, Salk writes:

"Tissues that are maintained by stem cells respond to adverse environmental conditions by reducing the overall number of stem cells, as well as the activity of those stem cells, but maintain them in such a state that they can respond quickly and effectively once the nutritional conditions become more favorable," says Leanne Jones , Ph.D., assistant professor in the Laboratory of Genetics, who led the study.

Symmetric division of male germline
stem cells (GSCs) in a Drosophila testisImage:
Courtesy of Dr. Catherine McLeod,
Salk Institutefor Biological Studies

Jones has a New Faculty Award from CIRM, although this study is not part of her grant. Salk went on to write:

Jones and her team think it likely that the link between insulin signaling and stem cell response will turn out to be important not only for nutrient deprivation but also for other situations where a body's metabolism might be altered. "One may think of how tissue homeostasis is modified in a situation when the body cannot accurately monitor or utilize available nutrients-for instance, in case of a person who is diabetic," says Jones.

They also hint that if the presence or absence of food can alter stem cell behavior, perhaps dramatic changes in diet could be incorporated into therapies.

Following on the heals of Halloween, here’s hoping chocolate turns out to be a food that brings out the best in stem cells.

A.A.

Protein protects brain from damage, may prevent neurodegenerative diseases

Researchers at the University of California, San Diego and the Salk Institute for Biological Studies have found a protein that protects the brain from the kind of damage that can lead to Parkinson's disease. This protein, called Nurr1, has a long history in Parkinson's disease research. People who carry a mutation in the gene are prone to developing the disease. The new work explains how the protein prevents Parkinson's disease and could also help researchers find ways of treating of preventing the disease. The protein was especially important in two types of cells that protect and support the brain's neurons -- called microglia and astrocytes. In these cells, Nurr1 works with other proteins to limit inflammation after an immune response. Without it, these support cells produced toxic by-products that damaged the nerves in a way that could lead to Parkinson's disease or other neurodegenerative diseases.

Cell: April 3, 2009
CIRM funding: Beate Winner and Fred H. Gage (RC1-00115), Christian Carson (T3-00007), Leah Boyer (T1-00003)

Related Information: Press release, University of California, San Diego, Salk Institute for Biological Studies, Gage bio

Embryonic Stem Cells Generate Model for ALS

Researchers at the Salk Institute for Biological Sciences have grown embryonic stem cells into the motor neurons and support cells that underlie amyotrophic lateral sclerosis (ALS). Also known as Lou Gherig’s Disease, ALS has no cure and no effective treatment. In this disease, the motor neurons slowly degenerate leaving a person paralyzed. Why the neurons die is not known, however the support cells called astrocytes have long appeared to play a role. Now researchers have coaxed embryonic stem cells to form the motor neurons and astrocytes in a lab dish to better understand their relationship in ALS. What they learned is that astrocytes containing a mutation associated with ALS killed off the neighboring motor neurons. This mutation is in a gene that makes a protein whose normal role is to protect the body from damaging oxygen free radicals. When the group grew these same cells in the presence of a powerful anti-oxidant, the motor neurons survived. In addition to understanding the biology of ALS, the group thinks they could use this system to screen drugs that may be able to treat ALS.



Cell Stem Cell: December 4, 2008
CIRM funding: Fred H. Gage (RC1-00115)

Related Information:Press release, Salk Institute for Biological Sciences, Gage  bio