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 directly create neuronal stem cells for research and therapies

CIRM grantees at the Scripps Research Institute, University of California, San Diego and Sanford-Burnham Research Institute have taken an intriguing step toward producing neural progenitor cells for research or therapies. The team, led by Sheng Ding who has recently moved to the Gladstone Institutes in San Francisco, started with mouse skin cells and converted them directly to an early stage of neural cell. The work was published in the April 26 online issue of Proceedings of the National Academy of Sciences.

This work falls somewhere between two other pieces of research starting with skin cells. Since 2006 it has been possible to convert mouse skin cells into reprogrammed iPS cells that are similar to embryonic stem cells in their ability to create all cell types. Scientists could then mature those cells into whatever cell type they are interested in studying.

Over the past year, other groups have started with skin and converted those cells directly to neurons or heart cells.

Ding and his colleagues fall somewhere in the middle, sidestepping some issues with both direct reprogramming and generating iPS cells.

• Converting skin directly into neurons has the major limitation that neurons can't divide. The number of neuronal cells available for research or therapies is limited by the number of starting skin cells.
• Going all the way back to iPS cells has limitations of its own. The cells multiply in a lab dish to create as many cells as a scientist might need for therapies or research uses, but maturing those cells into the appropriate cell type can be an arduous task any traces of the original iPS cells could lead to tumors.

Converting skin to these neural precursors avoids both problems. Those neural cells are already pushed down the pathway to become neurons, and they can multiply. The researchers also showed that the cells can integrate into a mouse brain without developing tumors.
In a press release from the Gladstone Institutes, Ding says:

“These cells are not ready yet for transplantation,” Dr. Ding said. “But this work removes some of the major technical hurdles to using embryonic stem cells and iPS cells to create transplant-ready cells for a host of diseases.”

That's all good, but the work is a long way from ending the need for iPS cells. First, it's in mice. There's no evidence yet that the protocol will work with human cells. Also, the resulting neural progenitors can only divide a few times, so they aren't an unlimited source of cells.

Those caveats aside, it's exciting to watch how quickly the field is evolving. Not long ago, the idea of converting one cell type into another was nothing but a dream. Now, scientists (many of them CIRM grantees) are finding ever more ingenious ways of converting skin, fat and other starting tissues into embryonic-like stem cells, adult cell types, and now in-between progenitors, each of which could be useful in their own way for understanding and treating disease.

PNAS, April 26, 2011
CIRM Funding: Sheng Ding (RN1-00536-1); Stuart Lipton (RC1-00125-1); Maria Talantova (T2-00004)

- 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.

Human skin cells converted to blood

Over the past two years we’ve watched a series of scientists shoot down the prevailing idea that one adult cell type cannot be converted into a different adult cell, with researchers directly converting skin cells into insulin-producing cells, nerve cells and heart tissue. (You can see our blog entry on this work here.)

A Canadian team has become the most recent to prove that idea false, directly converting human skin cells to blood cells. The work, by a group at McMaster University in Hamilton, Canada, is the first to show that human cells are capable of such transformations, and is the first to create progenitor cells, which can form all types of cells within a given tissue.

The work was published online November 7 in Nature, which also ran a news story about the work:

Mickie Bhatia, a stem-cell researcher at McMaster University in Hamilton, Canada, and his colleagues chose to make blood progenitors from skin cells because red blood cells created from stem cells do not make the adult form of haemoglobin. "Those cells, because they think they're embryonic, make embryonic and fetal blood," he says.

They also quote the scientist responsible for creating Dolly the sheep Ian Wilmut as saying:

"It takes us a step along the line to believing that you can produce anything from almost anything."

It could be many years before this discovery is being transfused into the first human patient. The group used a virus to introduce new genes into the skin cells, which is problematic for human transplantation. They also need to prove in the lab and in animals that the blood cells they’ve produced can actually replace the function of human blood.

When Yamanaka first created iPS cells in 2007, CIRM almost immediately saw a surge in grant applications proposing to incorporate or improve on the technique. Now more than 50 of our funded awards involve human iPS cells (you can see that list here). Over the next few rounds of grant applications it will be interesting to see how many new researchers incorporate direct reprogramming into their proposals.

A.A.