A fifth group turns skin to neurons, creating a model for Alzheimer's disease

A few weeks ago, my colleague used this space to discuss the second and third papers showing teams had turned skin cells directly into neurons, noting that this replication of research results is essential to verifying the initial breakthrough while refining and improving it. She noted that only after much replication and refinement would she or anyone else want the resulting cells for therapy. Since then a fourth team reported another technique and now a fifth group is reporting the more likely short term benefit—a disease in a dish model for a neurodegenerative disease.

The first two papers came from work in the CIRM funded facility at Stanford University. The breakthrough paper in May from Marius Wernig reported a slow and inefficient process for using certain factors to directly reprogram skin cells into nerve cells without first taking them through an embryonic-like state. The follow-up paper in late July came from Stanford colleague Gerald Crabtree and showed marked improvement in efficiency and the nerve-like functioning of the cells. That same week at team from Milan reported another efficient system for creating nerve cells but this time directing them to become dopamine-producing cells like those lost in Parkinson's disease. And last week at team at the Gladstone Institutes in San Francisco, using another CIRM funded facility, reported yet another technic that also improved efficiency.

Now, a team at Columbia reported in today's issue of the journal Cell that they had developed a fifth way to accomplish this direct conversion of skin to nerve, and had done so with both skin from normal subjects and skin from patients with the inherited form of Alzheimer's disease. In both cases the cells matured and behaved like neurons, responding to neurotransmitters by letting ions like sodium and potassium cross the cell membrane. However, the cells derived form patients were also clearly abnormal. They had altered ability to process and transport the amyloid precursor protein (APP) and a resulting increase in production of amyloid beta, which has long been a suspect in the disease, but depending on what year you look at the literature, it is theorized to be a culprit or an artifact. This disease in a dish model may help to answer that question.

DG

Improved technique for directly converting skin to neurons

This is the way things often go in science: One group announces a breakthrough. Yah! Then for the next several years, scientists all over the world replicate and improve on that breakthrough until it's finally believable and widely useful.

To people outside science who read about the initial breakthrough, this may look a lot like scientists twiddling their thumbs, sitting on new therapies. But really, do you want a therapy based on a breakthrough that may or may not be real? Right, neither do I.

A paper from Marius Wernig's lab at Stanford University is a great example of this process. In January, 2010, Wernig's lab had a paper in Nature announcing their transformation of mouse skin cells directly into neurons. This was exciting work, bringing with it the possibility of directly converting skin from a person with a neuronal disease into neurons that can be studied in the lab. But that work was in mice, and one thing we know from past research is that mice are most certainly not humans.

About a year and a half later, Wernig replicated his work with human cells in another Nature paper, but the transformation was much less efficient than it was with mouse cells (here's our blog entry on that work). It took weeks for the transformation to take place, only 2 to 4 percent of the skin cells transformed into neurons and those neuronal cells were on the wimpy side. It's still exciting work — I mean how cool is it that human skin can be turned into neurons with the addition of just four molecules. But ready for therapeutic prime time? I think not.

Now we've entered the next stage where scientists all over the world incrementally improve upon the original work until it's good enough, fast enough and efficient enough to be broadly useful. One such improvement came from the Stanford University lab of Gerald Crabtree, who published his findings in a Nature paper last week.

Crabtree's lab employed two of the four factors that had been effective for Wernig, but supplemented those with a different kind of molecule — called microRNAs. This change dramatically improved how efficiently the skin cells converted to neurons, and produced neurons with much stronger electrical signaling. Another group from Milan published a paper in early July using three different factors to coerce the transformation from skin to neuron. In their case, the neurons were more like those that are lost in Parkinson's disease, known as dopaminergic neurons.

A Stanford press release quotes Crabtree:

“It’s been a long time in coming to this,” said Crabtree. “But science often progresses in leaps and starts, and then all of a sudden many scientists come to the same position at the same time. Now these studies have come out, and more will be coming, all of which are going to say that not only can you can make neurons different ways, but also you can make neurons of different types.”

At this point it's too soon to know which, if any, of these techniques is going to become most widely used. We can probably expect to see more improvements on these approaches coming out of some labs, while other labs start figuring out how this revolutionary transformation can be used to treat or understand disease. Crabtree's lab, for example, says they are already taking skin cells from people with Down's syndrome and transforming those into neurons in order to understand the disease and look for therapies.

A.A.

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.

A.A.

CIRM grantees convert skin to nerves, a step toward therapies for neurological disease

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.

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.