Arturo Alvarex-Buylla, PhD

CIRM grantee and UCSF professor Arturo Alvarez-Buylla, PhD, won the prestigious 2011 Prince of Asturias Award for Technical and Scientific Research for his work with neural stem cells. He is credited with first discovering the regenerative cells in the brains of mammals, work that laid the groundwork for a number of CIRM grants and clinical trials based on neural stem cells.

In their announcement about the award UCSF quotes Arnold Kriegstein, MD, PhD, director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF.

“Arturo’s contribution to the field of adult stem cell science has been tremendous. He has helped lay the foundation for our understanding of the role and behavior of neural stem cells in the adult brain, which could lead to new strategies for treating brain damage and diseases.”

In the announcement, Jennifer O’Brien describes the work that earned Alvarez-Buylla his recognition:

Alvarez-Buylla, specifically, was recognized for identifying neural stem cells in the brains of mammals, and for his ongoing research on their behavior – and potential therapeutic use – in treating diseases. He is exploring their possible role in the development of the most common type of brain tumor, the glioma, and their potential use in regenerating brain tissue damaged by injury or degenerative diseases. More generally, he is studying the way in which adult neural stem cells behave and function – their development into young neurons, the migration of these neurons from their site of birth to their final destinations, and their function in the adult brain.

Alvarez-Buylla has a CIRM Early Translational II Award to develop a cell-based therapy to inhibit the hyperactive neural circuits in people with epilepsy. In his public summary for the award he writes:

In 20-30% of these patients, seizures are unresponsive to drugs, requiring invasive surgical resection of brain regions with aberrant activity. The candidate cells we propose to develop can inhibit hyperactive neural circuits after implantation into the damaged brain. As such, these cells could provide an effective treatment not just for epilepsy, but also for a variety of other neurological conditions like Parkinson’s, traumatic brain injury, and spasticity after spinal cord injury.

It’s great to see CIRM grantees honored for the incredible advances they’ve in medicine and human health.

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Last year a group of CIRM grantees at Stanford University directly converted mouse skin cells into neurons, bypassing the need to first convert those cells into an embryonic-like state. Now they’ve gone a step farther, pulling off the same feat with human cells. They published the work in the May 26 Nature.

Krista Conger at Stanford University blogged about that work , quoting senior author Marius Wernig:

We are now much closer to being able to mimic brain or neurological diseases in the laboratory. We may perhaps even be able to one day use these cells for human therapies.

This past year has seen a number of scientists managing to convert adult cells directly into other adult cell types as we blogged about here. Recent reports about immune rejection of iPS cells makes this work even more interesting because the direct conversion bypasses the need to create iPS cells. As Conger writes:

Interestingly, this direct conversion technique may offer a way around the recently reported rejection of genetically identical iPS cells by laboratory mice. That unexpected finding, which I blogged about a couple of weeks ago, has researchers worried about the potential therapeutic value of the cells. But preliminary investigations suggested that the immune response was targeted at proteins used to make the original cells pluripotent, which shouldn’t be an issue with this approach.

That said, Wernig isn’t ready to give up on iPS cells. He’s part of a CIRM disease team that aims to use genetically modified iPS cells to treat the deadly skin condition epidermolysis bullosa. Here’s a link to a summary about that epidermolysis bullosa disease team award, and a link to a videos of the team describing their approach to the CIRM governing board last year.

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Each month CIRM President Alan Trounson gives his perspective on recently published papers he thinks will be valuable in moving the field of stem cell research forward. This month’s report, along with an archive of past reports, is available on the CIRM website.

The first paper I highlight in this month’s summary, purporting to have found master lung stem cells, is already generating controversy. (See our blog entry: Lung stem cell found, controversy ensues) Scientists have generally not been believed that one set of adult stem cells could generate all the types of tissues required to form complex mature lung. Regardless of whether others are able to reproduce this work, it is sure to generate interest because advances in the field of regenerating healthy lung tissue is something that could benefit millions of severely disabled patients.

This month’s literature continued to produce a yin and yang of good news and disappointment for reprogrammed cells. It saw one team directly reprogram skin tissue into functional liver cells and another produce a model of schizophrenia in a lab dish (See From stem cell to schizophrenia in a dish). That paper showed real differences between neurons grown from iPS cells made from normal individuals and those with the disease—and those differences could yield drug targets. But the literature also revealed that iPS cells could face immune rejection even when they are transplanted into an animal that is genetically matched. (See iPS cell smack down) We have to continuously tell ourselves that the iPS field is only five years old and these mixed results will get worked out and understood over time.

As we move closer to the clinic, we are increasingly concerned with efficiency of cell production and getting quantities of cells sufficient to run a clinical trial. This month saw papers greatly improving the efficiency of generating blood precursor cells from embryonic and induced stem cells and of generating neural precursor cells from embryonic stem cells.

Last, is a paper that offers some hope for my hair follicle challenged colleagues. Actively growing patches of hair appear to require some level of cross talk between hair stem cells. But this paper does have a more serous note. This same communication between stem cells may be critical in tissues like the intestine that have rapid cell turn over.

I hope you find the somewhat longer descriptions in my full report interesting.

A new Nature paper from CIRM grantees at Stanford University once again shows the value of reprogrammed iPS cells in understanding disease. Scientists can’t develop a therapy for a disease if they don’t know what it is going wrong. In many cases, iPS cells have provided the first ever way of peering into diseased cells and finding which proteins and genes need fixing.

In this case, the disease in question is dyskeratosis congenita, in which the caps on the ends of chromosomes shorten abnormally and causes a wide variety of symptoms ranging from abnormal skin pigmentation and nail growth to lung scarring, bone marrow failure and cancer. The question has been why people with the same disease can have such dramatically different symptoms, and what to do about those symptoms.

The Stanford group reprogrammed the skin cells of people with the disease into embryonic-like iPS cells. They knew people with the disease made low levels of a protein conglomerate called telomerase, which is responsible for maintaining those chromosomal caps. What they found in those iPS cells is that the more severe a person’s disease, the less telomerase their iPS cells made.

A Stanford press release quotes senior author Steven Artandi:

“We were very surprised to find such a clear correlation between the quantity of functional telomerase, the severity of the cellular defect and the severity of the patient’s clinical symptoms,” said associate professor of medicine Steven Artandi, MD, PhD. “Our work suggests that, in patients with dyskeratosis congenita, tissue stem cells are losing their ability to self-renew throughout the body. This is a new, unifying way to think about this disease, and it has important implications for many other conditions.”

Reprogrammed iPS cells can normally divide indefinitely in the lab. The iPS cells made from people with dyskeratosis congenita eventually stopped being able to divide and instead matured into the body’s cell types. The researchers think this means the disease symptoms occur when stem cells in the tissues lose their ability to divide indefinitely. With no stem cells in the bone marrow, skin or other organs, the person’s body can’t repair damage or maintain tissues. That seems to be what causes symptoms of dyskeratosis congenita.

Nature, May 22, 2011
CIRM funding: Steven Artandi (RB2-01497)

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)

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California State University Long Beach has a nice story today about their students funded by our Bridges to Stem Cell Research program. Mostly, CIRM funds science. But in order for that science to move forward we also need to make sure the state has enough trained stem cell scientists. What’s the point of fostering new labs and biotech companies without people who know how to handle the notoriously tricky cells?

Thus the Bridges program. We first funded the undergraduate and masters programs back in January 2009 (here’s our press release about the funding). Each of the 16 funded schools supports a handful of students who take classes and participate in research with collaborating institutions. As the first round of students complete their programs we’re hearing back that the students are being hired in large numbers by the labs where they did their internships.

One of the students in the CSULB story, Colleen Worne, had this to say about her internship:

“The CIRM program will equip me with the skills and techniques necessary to succeed under such challenging conditions and achieve my career goals,” she continued. “From a young age I have pursued my passion for biology and research, knowing that helping society in a scientific capacity was, and is, my goal. CSULB has provided me with the scientific background for acceptance into the CIRM program. I am beyond excited to start my lifetime pursuit made possible by such an amazing program.”

We produced a video about Bridges students and California State University San Francisco last year. It’s fun to see how excited the students are about pursuing stem cell science.

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Michael J. Fox has an excellent — and somewhat pointed — Op-Ed in today’s San Francisco Chronicle in which he points out that if people want cures, they need to participate in research. He says:

Today, America is waiting expectantly for a new generation of scientific breakthroughs – in cancer, AIDS, Alzheimer’s disease and, of course, Parkinson’s disease. Yet we’ve lost sight of a critical element of any success – our own active engagement in the process.

He goes on to point out that 85 percent of clinical trials finish late because of trouble recruiting volunteers and nearly a third of all trials fail to recruit any patients at all. Case in point, Stem Cells Inc recently had to cancel their neural stem cell trial for the fatal childhood disorder Batten disease because they failed to recruit patients.

Fox goes on to say:

We’re doing everything we can to identify and dismantle roadblocks that stand in the way of research progress. So far we’ve invested more than $230 million in research to speed new and better treatments for the disease. But we’ve been aware for years that dollars alone won’t solve this problem. In particular, money cannot buy the critical contributions made by clinical trial volunteers.

At CIRM, that number is $1.2 billion, but the sentiment is the same. The only way research we fund can eventually become widely available therapies is through clinical trials that prove that the approach is safe and effective.

CIRM just started funding clinical trials, with a $25 million loan to Geron. We have 14 Disease Teams which are working toward clinical trials that they hope to start in 2013, and we have a new wave of Disease Teams coming down the pipeline. We look forward to working with patient advocacy groups to make sure those future trials are successful. In the mean time, if you or a loved one wants to participate in a clinical trial an excellent resource for finding those trials is the NIH clinical trials database: clincaltrials.gov.

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I’m thrilled to have a legitimate reason to blog about the lowly planeria. This little flat worm is renowned amongst high school and freshman biology students for it’s ability to regrow copies of itself when cut in half. In theory, slicing right between the planeria’s eyes can even produce a two-headed worm, though that’s one of the many experiments that never actually worked for me.

It turns out that what allows planeria to regenerate could also teach scientists about our own regenerative stem cells. Two papers in last week’s Science investigated the planeria’s regenerative stem cells, called neoblasts. They found that at least some of the neoblasts have the ability to form all tissues in the worm’s body, much like embryonic stem cells or reprogrammed iPS cells.

A press release from the Whitehead Institute quotes one of the co-first authors Dan Wagner:

“This is an animal that, through evolution, has already solved the regeneration problem,” says Wagner. “We’re studying planarians to see how their regeneration process works. And, one day, we’ll examine what are the key differences between what’s possible in this animal and what’s possible in a mouse or a person.”

The team also identified some of the signals that tell the neoblast whether it should form a head or a tail. This polarity issue is a big deal. A stem cell that can become anything needs clues to tell it what to and not to become. That’s as true in a human as it is in a worm.

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