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.

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.

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 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)

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